Early detection of epidemic influenza

57

In British female doctors, followed up for 22 years by Doll et al, smokers in the category 1-14 cigarettes per day had slightly lower mortality from CHD and from all causes.’ In a 12-year prospective study in Swedish women aged 38-60 smoking was not a current

significant risk factor for myocardial infarction, angina pectoris, or overall mortality.’ In another prospective study, in which over 100 000 nurses aged 30-55 were followed up for 6 years, only 5 deaths from CHD were recorded in women who smoked fewer than 15 cigarettes a day.6 This study was based on mailed questionnaires and no information was provided on overall mortality. The trends of heart disease mortality in twenty-six countries, between 1950 and 1978, in women

aged 45-64, were uniformly downwards, even though during

the same period the proportion of women smoking increased.6 No one has explained why. Risk-factor epidemiology, as exemplified by numerous case-control studies on which the bulk of evidence for smoking and CHD in women rests, fails to meet scientific criteria for inference.’ CHD is a vague term and its clinical diagnosis is notoriously imprecise.8 Smokers, ex-smokers, and non-smokers are self-selected categories. Their misclassification causes further difficulties in the evaluation of epidemiological evidence. We need reliable information on the dose, age, race, and associated conditions, since what you say now about diet ("the enormous complexity of diet and CHD") may well apply for smoking too. The final proof will depend on randomised controlled studies of smoking cessation in women, and its effect on mortality from CHD and from all causes. Similar studies in men have so far been inconclusive,9 but such equipoise should serve as ethical justification for further randomised trials. Department of Community Health, Trinity College,

PETR SKRABANEK

Dublin 2 Ireland

information that demonstrates a relationship between the reported inhibition of PAF by triazolam (Halcion) and any of the reported effects of Halcion on patients". Dr Roberts and Professor Barnes (Dec 7, p 1459) note that sedative doses of triazolam do not inhibit PAF-induced responses in human skin.’ In reviewing van der Kroefreport Adam and Oswald are mistaken; blistering was not mentioned, nor were urticaria or oedema. Urticaria and oedema may be related to PAF function, but not blistering.4 We also question figures they cite for reactions suggesting inflammation in the US Food and Drug Administration spontaneous reporting system. Cumulative reports issued in October, 1991, contain 25 for temazepam and 175 for triazolam (pharyngitis, glossitis, vasculitis, all other "-itis", asthma, oedema). Limitations of the FDA spontaneous reporting system are well known; it can only provide signals for generating hypotheses about a particular medication since several factors can account for differences in numbers of reports.’7 In summary, there is no evidence that clinical doses of triazolobenzodiazepines or their cessation affect PAF. PAF does not have any reported CNS behaviour effects, so it is unlikely that the inhibitory effect of some of these drugs on PAF is a mechanism for reported adverse medical events. Upjohn Company, Kalamazoo, Michigan 49001, USA

JEFFREY M. JONAS

E, Erhch YH, Lenox RH. Platelet-activating factor induced aggregation of human platelets specifically inhibited by triazolobenzodiazepines. Science 1985; 226: 1454-56. 2. Nohara R, Bergmann SR. Reduction of stenosis-induced cyclic flow variations by inhibition of platelet-activating factor in dogs Coronary Artery Dis 1990; 1: 347-54. 3. Torr SR. Abolition of cyclic flow variations (CFV) and diminution of reocclusion by inhibition of platelet activating factor (PAF). American Heart Association meeting 1. Kornecki

(Dallas, 1990): (abstr). M, Hosford D, Guinot P, et al. Platelet activating factor (PAF): a review of its effects, antagonists and possible future clinical implications, part I. Drugs 1991; 41:

4. Koltai 1 Seltzer CC The

in the

between cigarette smoking and Framingham heart study data. J Clin

negative uncomplicated angina pectoris in Epidemiol 1991; 44: 871-80 2 Friedman LA, Kimball AW Coronary heart disease mortality and alcohol consumption in Framingham. Am J Epidemiol 1986; 124: 481-89 3 Doll R, Gray R, Hafner B, Peto R. Mortality in relation to smoking. 22 years’ observations on female British doctors. Br Med J 1980; 280: 967-71. 4. Lapidus L. Ischemic heart disease, stroke and total mortality in women-results from a prospective population study in Gothenberg, Sweden. Acta Med Scand 1985; suppl 705· 1-42. 5 Willett WC, Green A, Stampfer MJ, et al. Relative and absolute excess risks of coronary heart disease among women who smoke cigarettes. N Engl J Med 1987; association

women

317: 1303-09. 6. Thom TJ, Epstein FH, Feldman JJ, Leaverton PE. Trends in total mortality and mortality from heart disease in 26 countries from 1950 to 1978. Int J Epidemiol

1985; 14: 510-20. Fraud, distortion, delusion and consensus the problems of human and natural deception in epidemiological studies Am J Med 1988; 84: 475-78. 8 Stehbens WE. Imprecision of the clinical diagnosis of CHD in epidemiological studies and atherogenesis. J Clin Epidemiol 1991; 44: 999-1006. 9. McCormick J, Skrabanek P. Coronary heart disease is not preventable by population interventions. Lancet 1988; ii: 839-41 7 Feinstein A.

Triazolam and PAF inhibition SIR,—Dr Adam and Professor Oswald (Nov 2, p 1157) speculate that the triazolo moiety in triazolobenzodiazepines such as triazolam is responsible for a unique inhibitory effect on platelet-activating factor (PAF) and is a mechanism for medical events reported in patients who use these drugs. However, neither the preclinical and clinical research on PAF that they cite nor the reports of van der Kroef support their theory. In-vitro studies showed that only very high concentrations of triazolobenzodiazepines affect PAF.1 In the dog, doses above 10 mg/kg are necessary to decrease PAF-induced platelet aggregation and produce modest, short-lived reductions in impairment of blood flOW.2,3 Such doses are several orders of magnitude greater than those recommended for sleep induction (1 8-3-6 ag/kg). There is no evidence that triazolam inhibits PAF in clinical doses, and it is highly improbable that cessation of these medications would have any effect on PAF. Nor is there evidence in clinical research that PAF has any behavioural effects, though PAF does have a role in neuronal development and in neuronal degeneration resulting from trauma and stroke.’ Braquet et al5 note that there is no relation between the CNS effects and PAF activities of triazolobenzodiazepines. Dr E. Komecki is quoted as saying "there is no

9-29. 5.

Braquet P, Touqui L, Shen TY, Vargaftig

BB. Perspectives in platelet-activating factor research. Pharmacol Rev 1987; 39: 97-145. 6 Talan J. Rude awakenings. New York Newsday Oct 29, 1991: 61-65 7. Sachs RM, Bortnichak EA. An evaluation of spontaneous adverse drug reactions monitoring systems. Am J Med 1986; 81 (suppl 5B): 49-55.

SIR,—Dr Adam and Professor Oswald suggest that some of the events associated with triazolam may be explained by its PAF-antagonistic activity. Several pharmaceutical companies are developing potent and specific PAF-antagonists and in our laboratories we compared the potency of apafant (WEB 2086) and triazolam in a model of PAF-induced platelet and neutrophil aggregation. Apafant was at least 15 times more potent than triazolam.1 In volunteers the availability of the oral formulation of apafant is 68 %, and single doses up to 400 mg and multiple doses up to 100 mg three times daily for 7 days were well tolerated with no withdrawal symptoms.2 Also, in more than one hundred patients treated with at least 100 mg apafant per day for 6 weeks we have not adverse

events reported for triazolam. The strong PAF-antagonistic activity of apafant and the fact that the doses were much higher than those of triazolam mean that these data do not support the mechanism suggested by Adam and Oswald.

observed the adverse

Boehringer Ingelheim, D-6507 Ingelheim, Germany

ERNST-RUDOLF KEMPE BURKHARD BLANK

1. Casals-Stenzel J, Muacevic G, Weber KH. Pharmacological actions of WEB 2086, a new specific antagonist of platelet activating factor. J Pharmacol Exp Ther 1987; 241: 974-81. 2. Brecht HM, Adamus WS, Heuer HO, Birke FW, Kempe ER. Pharmacodynamic, pharmacokinetic, and safety profile of the new platelet-activating factor antagonist apafant in man. Drug Res 1991; 41: 51-59

Early detection of epidemic influenza SIR,—Since November, 1984, we have developed a computerised system of surveillance of communicable diseases (Reseau National Teleinformatique de Surveillance et d’lnformation sur les Maladies Transmissibles, RNTMT), under the auspices of the French Department of Health and National Institute of Health and Medical Research (INSERM). RNTMT collects in real time data on seven frequent communicable diseases,’1

58

Fig 1-Application for epidemic detection tool Box shows the 8 years surveillance in

same

region.

to

Pays de la Loire region.

WNCP=weekly

number of

new cases

per practitioner.

including influenza-like illness. The information is supplied on-line by about 500 general practitioners throughout France who do the work voluntarily and without pay. These sentinel general practitioners hook into the central computer at least once a week (via a personal computer or a specialised terminal [MINITEL]) and

Electronic bulletins provide the users of RNTMT with an immediate return of the epidemiological information. Lately software has been introduced to permit detection of epidemics2 in real time, and as geographical spread. Using these techniques, we picked up the 1991-92 epidemic of influenza in week 49

communicate cases encountered that meet the criteria. For influenza-like illness the criteria are sudden fever of over 39°C, myalgia, and respiratory symptoms.

(Dec 2-8). Fig 1 shows results in one of the twenty-two French regions. The decision rule for announcing an epidemic is that the epidemic threshold line is crossed for two consecutive weeks. Validation for this criteria was obtained in previous epidemics.2 Regional analysis demonstrated that an epidemic has started in Pays de la Loire (fig 1) and in four other regions (Rhône-Alpes, Bourgogne, Aquitaine,

Midi-Pyrenees). Fig 2 shows the application of software to describe the spread of the epidemic over the past two weeks. The two virus reference centres in France reported an increase in isolations of influenza A(H3N2) virus during the week Nov 25 to Dec 1. INSERM Unit Biomathematical and Biostatistical Research (INSERM CHU Saint-Antoine, Pierre and Marie Curie University, 75012 Paris, France

U263),

A.-J. VALLERON F. CARRAT PH. GARNERIN

1 Valleron AJ, Bouvet E, Garnerin Ph, et al. A computer network for the surveillance of communicable diseases the French experiment. Am J Public Health 1986; 76: 1289-92. 2. Costagliola D, Flahault A, Galinec D, Garnerin Ph, Menares J, Valleron AJ. A routine tool for detection and assessment of epidemics of influenza-like syndrome in France Am J Public Health 1991; 81: 97-99.

Cholesterol embolisation

syndrome after thrombolytic therapy myocardial for

infarction

Fig 2-Recent spread of epidemic of influenza-like illness in France.

Upper week 48 (Nov 25 to Dec 1) Lower.week 49(Dec2toDec8) m weekly numbers of new cases per

Lines indicate isolevels expressed practitioner

SIR,—The cholesterol embolisation syndrome (CES) after intravenous thrombolytic therapy for myocardial infarction is rare, and has been described only four times.1-3 We report CES that developed 7 h after the start of intravenous thrombolytic therapy for myocardial infarction, without any invasive causal procedure. A 57-year-old man was admitted to intensive care 4 h after a postero-basal myocardial infarction, and received 1 5million units of intravenous streptokinase. 7 h later bilateral thigh myalgias, livedo reticularis of the lower abdomen and legs, and painful purple toes developed. Peripheral arterial pulses were preserved and he had acute renal failure (with severe hypoperfusion of both kidneys on renal perfusion scintigraphy). We noted sensory and sphincter troubles which regressed and were attributed to transient medullar conus terminalus ischaemia on the basis of T2-weighted magnetic resonance imaging. Abdominal computed tomography showed severe aortic atherosclerosis with plaques protruding into the lumen. He had three episodes of rectal bleeding but colonoscopy