Volume 173 Issue 6

Olympic Games Drug testing at the Sydney Olympics With pre-Olympic and out-of-competition testing, as well as a new, validated test for erythropoietin, athletes will be exposed to more comprehensive drug testing at the Sydney Olympics Brian Corrigan and Ray Kazlauskas MJA 2000; 173: 312-313 See also, Kennedy Drug screening - Sample collection - Analysis - Conclusion - References - Authors' Details - - More articles on Sports medicine Testing for drugs used to enhance performance has been carried out at the Olympic Games since they were held in Mexico in 1968, when Australia's Ron Clarke became the first athlete to be tested. Doping at the Olympic Games is banned for two very good reasons: the use of drugs is cheating, and drugs have adverse effects on the health of athletes.1 The International Olympic Committee (IOC) has maintained a list of proscribed substances and methods for their detection since 1967, and this list is updated each year to form the basis for determining banned substances in all sport.2In much the same way as random breath testing is used to deter drink driving, drug testing is intended as a deterrent rather than a method of catching all offenders. Thus, in Olympic final events, the competitors who gain the first four places, plus one other usually chosen at random, are subjected to a drug test. During Olympic heats, any athlete may be selected at random for testing. In past Olympic Games, athletes were not tested for drugs until after they had competed in their events. At the Sydney Olympics, for the first time, many athletes will be subject to pre-Olympic, out-of-competition testing, as it is during this period that some drugs, such as anabolic steroids, may be best detected. This represents a huge change in the IOC position and has occurred after much lobbying by, among others, the Drug Committee of the Sydney Organising Committee for the Olympic Games (SOCOG). Drug screening Although blood testing has been performed in a limited fashion at Winter Olympics since 1994, screening for drugs at the Summer Games has, until these Sydney Games, been restricted to urine testing. Urine samples are generally preferable to blood samples for testing for most substances banned by the IOC, as it is easier to collect adequate volumes of urine, and collection of urine is not so invasive. Also, drug and metabolite levels are much higher in urine than in blood, so their detection has greater retrospectivity.3 However, there is a subset of drugs -- the peptide hormones such as erythropoietin (EPO) and human growth hormone (hGH) -- for which establishing a reliable urine test has proved a major obstacle. However, a validated test for EPO has just been accepted by the IOC and will be available for use at the Sydney Games. It involves both a blood test perfected by Australian scientists, and a urine test perfected by the French. Sample collection The procedures of urine collection for doping control are rigorously controlled.1 First, a chaperon meets the chosen athlete at the conclusion of the event, provides documentation of his or her selection, and obtains the athlete's signature for verification. The chaperoned athlete attends the doping control station, where forms are filled in to document all prescribed, complementary and other medicines he or she may be taking. The athlete selects his or her own container and provides a urine sample under the observation of the chaperon, and possibly a team representative. Athletes are required to provide a specimen of approximately 75 mL. This can take some time if the athlete is dehydrated, and athletes are permitted to attend press conferences or receive medals in the interim, provided they are always accompanied by their chaperons. Fluids (not containing caffeine) are provided in the waiting room. The urine sample is checked for volume, pH, and specific gravity (SG). A low SG (< 1.010) could indicate an attempt to dilute the urine by taking a diuretic or drinking litres of water. Athletes may have taken sodium bicarbonate to prevent the build-up of lactic acid and so delay the onset of fatigue. While it is difficult to detect sodium bicarbonate, its use markedly elevates the pH (normally about p H 5-6 post-exercise).4 Also, at high pH, basic drugs such as the amphetamines are very poorly excreted,5 so, if a urine sample is dilute or has a high pH, the athlete will be asked to remain in the collection area and to produce further samples. Athletes divide their own 75 mL urine specimens into two aliquots in bottles labelled A and B, which have the same unique identifying number. These are secured for shipment to the laboratory. There are at least three copies of the associated paperwork -- one for the athlete, one for the testing authority (the IOC) and a third, abbreviated version (that does not identify the athlete) for the laboratory. The athlete verifies that the process was satisfactory. The information recorded at the doping control station initiates a chain of custody, which identifies the custodian of the sample at every stage. This extends from urine collection through storage, transport, delivery to the drug-testing laboratory, testing and then the final report sent to the appropriate authority. Correct storage of the urine sample is important and refrigeration is essential to inhibit bacterial growth and endogenous steroids, which can be modified under some conditions to produce, or, more usually, break down, testosterone.6 Analysis State-of-the-art technology and quality control are integral to the whole analytical procedure. The 27 laboratories around the world currently accredited by the IOC are subjected to rigorous reaccreditation testing each year.7 The IOC-accredited laboratory in Sydney has been accredited since 1990 and performs about 4000 tests within Olympic sports each year as part of the Australian program to eliminate doping in sport (Australian Sports Drug Agency, annual report, 1998). Medical practitioners cannot request testing for competing athletes outside this system unless the athletes have bona fide medical conditions and proper documentation is supplied. During the two weeks of the Sydney Olympic Games, up to 2000 samples will be analysed (some 10 000 individual drug tests). Samples are screened for banned substances by means of sophisticated instruments such as gas chromatography mass spectrometers. Such instruments can provide unambiguous identification of drugs or metabolites to confirm a positive result. To obtain higher sensitivity for anabolic steroids, and hence longer detection periods of banned substances that may have been used during training but not at event time, the IOC has introduced the use of high-resolution mass spectrometry. This technique can detect smaller quantities and was made compulsory by the IOC for the Atlanta Olympics. The techniques have been refined and extended and will play an integral part of the testing protocol at the Sydney Olympics. The most common method of detecting exogenous testosterone, rather than natural testosterone, is the testosterone/epitestosterone (T/E) ratio.8 Epitestosterone is normally secreted as an epimer of testosterone, and testosterone is not converted to epitestosterone, so the population mean for the T/E ratio is approximately one.9 An elevated T/E ratio remains an excellent indicator of exogenous testosterone abuse,10 and the IOC has determined that values above six indicate doping. However, a very small group of individuals have a naturally elevated T/E ratio. An endocrinological investigation must be performed to detect individuals with an elevated T/E ratio due to either a medical condition or low normal epitestosterone production.9 More recently carbon isotope ratio mass spectrometry has been used11 and this technique may also assist in deciding these cases. All testing is carried out on one of the duplicate samples from each athlete (the A sample). The presence of a banned substance or its metabolites is sufficient to constitute a positive test -- it is not the responsibility of the testing authorities to determine how that substance got into the body. However, positive results are further investigated by the IOC Medical Commission. This may require analysis of the second (B) sample, during which the athlete or his or her representative may be present.1 If this analysis supports the initial result, a hearing is held to determine if a doping offence has occurred. The IOC Code clearly specifies the penalties that apply for doping offences. Conclusion Use of performance-enhancing drugs demeans both sport and the athletes who use them. Now that sport is a multi-billion dollar business, antidoping programs must be correctly undertaken so as not to allow evasion by the use of legal arguments and loopholes. This requires constant research into doping practices and programs. It goes without saying that the whole drug-testing process has to be, like Caesar's wife, beyond suspicion. References Olympic Movement Anti-Doping Code. Lausanne, Switzerland: International Olympic Committee, 1999. Kicman AT, Cowan DA. Peptide hormones and sport: misuse and detection. Br Med Bull 1992; 48: 496-517. Donike M, Geyer H, Gotzmann A, et al. Blood analysis in doping control. Advantages and disadvantages. In: Hemmersbach P, Birkeland K, editors. Proceedings of the Second International Symposium on Drugs in Sports. Towards the use of blood samples in doping control? Lillehammer, Norway, 1993. Oslo, Norway: On Demand Publishing, 1994: 75-92. Tiryaki GR, Atterbom HA. The effects of sodium bicarbonate and sodium citrate on 600m running time of trained females. J Sports Med Physical Fitness 1995; 35: 194-198. Mottram DR. Drugs in sport. 2nd ed. London: Spon, 1996: 8-9. Ayotte C. Evaluation of elevated testosterone epitestosterone values in athlete's urine samples. IAAF Quarterly 1997; 2: 87-94. Doping. An IOC white paper. Lausanne, Switzerland: International Olympic Committee, 1999. Anguilera R, Becchi M, Casabianca H, et al. Improved method of detection of testosterone abuse by gas chromatography combustion isotope ratio mass spectrometry analysis of urinary steroids. J Mass Spectrom 1996; 31: 169-176. Dehennin L, Matsumoto AM. Long-term administration of testosterone enanthate to normal men: alteration of the urinary profile of androgen metabolites potentially useful for detection of testosterone misuse in sport. J Steroid Biochem Biol 1993; 44: 179-189. Catlin DH, Hatton CK, Starcevic SH. Issues in detecting abuse of xenobiotic anabolic steroids and testosterone by analysis of athletes' urine. Clin Chem 1997; 43: 1280-1288. Becchi M, Anguilera R, Farizon Y, et al. Gas chromatography/combustion/isotope-ratio mass spectrometry analysis of urinary steroids to detect misuse of testosterone in sport. Rapid Commun Mass Spectrom 1994; 8: 304-308. Authors' Details Institute of sport, Concord Hospital, Sydney, NSW. Brian Corrigan, AM, FRACP, FRCP, Director. Australian Sports Drug Testing Laboratory, Pymble, NSW. Ray Kazlauskas, PhD, Director. Reprints will not be available from the authors. Correspondence: Dr B Corrigan, 1 Lookout Avenue, Dee Why, NSW 2009. abcATsouthernx.com.au Make a comment

Brian Corrigan · Ray Kazlauskas

Olympic Games Newer drugs used to enhance sporting performance Michael C Kennedy MJA 2000; 173: 314-317 Controversy surrounding drug use in sport makes this a difficult area for rigorous research. However, it is striking that what data there are on drugs currently used for performance enhancement rarely indicate any clear benefit. Testosterone precursors - 5 Alpha-dihydrotestosterone - Clenbuterol - Erythropoietin - Insulin - Growth hormone - Insulin-like growth factors - β-Hydroxy-β-methylbutyrate - Conclusions - Disclaimer - Acknowledgements - References - Authors' details - - More articles on Sports medicine Historically, many different drugs have been used in attempts to enhance sporting performance. Strychnine, cocaine, heroin and ethyl alcohol were in common use at the turn of the century, but they were later supplanted by amphetamines, pseudoephedrines and anabolic steroids. Caffeine has remained popular for over a hundred years and anabolic steroids have been in steady use since the early 1960s.1Nevertheless, the magic elixir of sporting performance remains elusive. The search continues in the face of unsatisfactory results, adverse reactions and drug control efforts within sport and through legislation. With advances in drug development there is also the further hope that new drugs will be difficult for laboratories to detect. My aim in this article is to provide a brief review of some of the newer drugs that have become popular over about the past 10 years, providing, where possible, doses used, their International Olympic Committee (IOC) status, their adverse reaction profiles, and methods used to detect them. The best known of these newer drugs are the testosterone precursors, dihydrotestosterone, clenbuterol, growth hormone, insulin-like growth factor, insulin, erythropoietin and β-hydroxy-β-methylbutyrate. Unfortunately, there are few published data quantifying the present use of these drugs in Australia. The doses of drug taken are difficult to ascertain -- those in this article have been obtained largely from Internet searches. There are many difficulties in deciding whether a drug actually enhances sporting performance. While a laboratory study may find a small change in strength or some other physiological parameter such as maximal oxygen uptake, this may not translate to increased performance in actual competition. When considering adverse reaction profiles it must be remembered that most of the drugs mentioned here are not subjected to the postmarketing surveillance procedures used for newly released therapeutic drugs. It is necessary to rely almost entirely on reports by interested professionals or projections made from the known pharmacological properties of the drug. There are no data on the effects of these agents on developing fetuses, children or adolescents. Testosterone precursors The pathway of testosterone synthesis is shown in the Box. Testosterone precursors are taken with the aim of increasing testosterone levels without the need for testosterone injections, and also in the hope of foiling current drug detection methods. The most popular agents in this group of drugs are dehydroepiandrosterone and androstenedione. Dehydroepiandrosterone (DHEA) has been the subject of a recent comprehensive review in the Journal.2 This drug is a weak androgen that circulates in two interconvertible forms -- unconjugated DHEA and DHEA sulfate, the latter in higher concentration. The physiological role of DHEA remains unclear. Concentrations fall with age and it has been trialled as therapy in a wide variety of conditions with little evidence of a positive effect, apart from increasing well-being and sexuality (term derived from a psychometric questionnaire) in women with adrenal insufficiency.3 While one study showed an increase in lean body mass, this was not confirmed in another. There is one study of the effects of DHEA on strength and aerobic performance; a comparison of DHEA, androstenedione and placebo in 40 healthy middle-aged men did not show any advantage of the steroid precursors over placebo.4 The effects of long-term, high-dose administration are unknown.2 In Australia, there has been one high-profile case involving a footballer receiving DHEA for chronic fatigue syndrome. After legal argument, the player was allowed to continue playing if he ceased taking the drug.2 Androstenedione and related compounds, such as 5-androstenedione, 4-androstenediol, 5-androstenediol, 19-norandrost-4-enedione, 19-norandrost-5-enediol and 19-norandrost-4-enediol, have become extremely popular in the United States since baseball home run record holder Mark McGwire admitted using androstenedione.5 As with DHEA, androstenedione is used in an attempt to increase testosterone concentrations. There is a well-conducted, double-blind controlled trial evaluating the effects of androstenediones on endocrine function, body composition and strength. In the first part of this study, 10 people received 100 mg of androstenedione orally for two days, and then received the same regimen of placebo one week later; the effects on serum testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH) were measured. In the second part of the study, 300 mg of androstenedione or placebo was given in a cyclical dosing regimen over eight weeks to 20 men, only one of whom had any previous experience in resistance training. Strength was assessed by a number of resistance exercises and training was standardised over eight weeks. Compared with placebo, androstenedione did not increase concentrations of free or total testosterone and did not increase strength or alter lean body mass, but it did increase serum concentrations of oestradiol. Levels of high-density lipoprotein (HDL) became depressed in the treatment group compared with pretreatment levels. While this study used lower doses than are often used by athletes, these results suggest it is unlikely that androstenedione increases sporting performance.6 While it did not evaluate sporting performance, one study found that 300 mg of oral androstenedione given to 14 volunteers caused a significant rise in testosterone levels.7 There was also considerable individual variation in the levels, which suggests variations in metabolism of the drug. Dose: Up to 1100 mg/day of DHEA; athletes take doses of androstenedione which exceed the dose used in these studies. IOC status: Banned (but androstenedione is not banned in major league American baseball). Adverse reactions: There do not appear to be any immediate clinically detectable adverse effects. Long term administration of testosterone precursors will reduce HDL, and so predispose some athletes to coronary disease. Elevated levels of oestrone and oestradiol could have effects on malignant processes and also cause gynaecomastia. Detection: The testosterone/epitestosterone (T/E) ratio in urine is used to detect exogenous testosterone. A ratio greater than 6:1 is usually taken as an indication of misuse. DHEA has been reported to increase the T/E ratio in some, but not all, studies. Doses as low as 50 mg for three days can alter the ratio to more than 6:1 in some, but not all, individuals, suggesting there may be individual differences in the metabolism of this drug.8 In addition to the T/E ratio there has been considerable progress in detecting exogenous testosterone by measuring the ratio of the carbon isotopes 12C and 13C. This method may become one of the major means of detecting steroid misuse in the near future. 5 Alpha-dihydrotestosterone 5 Alpha-dihydrotestosterone (DHT) is the principal active metabolite of testosterone and has a greater binding affinity to the androgen receptor than testosterone. It transforms more readily to the steroid receptor complex and dissociates from this complex more slowly than does testosterone. It is used to enhance performance in a variety of sports. DHT has been a licensed pharmaceutical in some countries and gained considerable prominence when 11 Chinese swimmers were found to have taken the drug in the 1994 Asian Games in Tokyo. There are no published data showing there is any effect on sporting performance. Dose: Probably greater than 25 mg twice daily, percutaneously. IOC status: Banned. Adverse reactions: While there are few data, it is reasonable to expect that typical androgenic adverse effects such as baldness in males, hirsutism in females and acne will occur. Detection: DHT does not alter the T/E ratio, but it can be detected by determining the ratios of other steroids to epitestosterone and LH.9 Clenbuterol Clenbuterol is a β2-agonist with a half-life of 35 hours which came to prominence during the Barcelona Olympics.10,11 It is marketed in some countries as a bronchodilator and is not approved for human use in Australia. There are excellent data showing that other β2-agonists allow asthmatic athletes to compete at international level, but few showing that these drugs improve strength or aerobic performance in people who do not have asthma. In animals large doses of clenbuterol have been shown to increase lean body mass.12 Athletes usually take clenbuterol to increase muscle mass, and it is taken orally in conjunction with anabolic steroids. There are no data showing clenbuterol alters athletic performance or strength in healthy people. Dose: Up to 60-120 mg/day may be taken in cycles of 6-12 weeks' duration. IOC status: Banned. Adverse reactions: Clenbuterol will produce a predictable tremor and tachycardia. There are anecdotal reports of sudden death in two bodybuilders.13 Detection: Clenbuterol can be easily detected in urine by mass spectroscopy. Erythropoietin Autologous and homologous transfusions, commonly known as blood doping, have been used to enhance performance since the 1970s. This practice received considerable prominence when some members of the 1984 United States Olympic cycling team confessed to receiving transfusions. Endurance athletes experience very complex physiological adaptations such as an increase in red cell mass and a decrease in haemoglobin concentration resulting from a considerable increase in plasma volume. It appears that aerobic performance is improved by blood transfusion in some circumstances.14The ready availability of synthetic erythropoietin (r-HuEPO) scandalised the 1998 Tour de France.15 This substance has been commercially available since that time and has essentially replaced transfusion as a means of blood doping. There is no doubt that rHuEPO can enhance physical performance in patients with anaemia secondary to renal failure. Both haemoglobin levels and physical performance were shown to have increased in 24 young healthy males who received r-HuEPO for seven weeks.16 As it seems to be widely accepted that r-HuEPO will increase aerobic performance, it is not surprising that it is widely misused in endurance sport. As the haematocrit may be measured to detect misuse, plasma expanders are sometimes used to avoid detection. Dose: Often three injections per week for six weeks. Vials contain varying concentrations, so doses are likely to vary considerably. IOC status: Blood transfusions and r-HuEPO are both banned. Adverse reactions: As dehydration will increase blood viscosity during any endurance event, the most serious adverse reactions to r-HuEPO seem likely to result from vascular events caused by thromboses when blood viscosity is markedly increased. However, there are no reported cases of this in the refereed literature. Sporting magazines and the lay press have reported deaths allegedly caused by r-HuEPO. These deaths have not occurred during exercise, but during periods of physical inactivity or sleep.17 Detection: Difficult because of its short half-life of 5-6 hours and the long duration of action on erythropoiesis. r-HuEPO differs from the endogenous hormone in its carbohydrate moiety, and this confers different physicochemical properties, thus allowing the potential for it to be detected in both blood and urine.18 Alternative methods of detection rely on measurement of various haematological and ferruginous parameters in capillary samples of blood.19,20 At present there are a number of studies under way to ascertain which of these methods would be fair to athletes and also stand up to the rigours of legal argument in the setting of a tribunal. On 1 August 2000, the Scientific Committee of the IOC approved a test based on urine and blood analysis (N Vance, Programme Manager, Doping Control, Sydney 2000 Olympics, personal communication). Insulin Insulin is an anabolic hormone, so it is not surprising that it has become popular in power sports. There are no studies showing an enhancement of sporting performance and, not surprisingly, there are reports of hypoglycaemia in users.21Insulin is often used in association with anabolic steroids. Clearly, medical practitioners need to be mindful of this area of misuse should unknown patients request renewal of a prescription for insulin. Insulin is also available in Australia without a prescription if the patient is prepared to pay the over-the-counter price, so this caution also applies to dispensing pharmacists. Dose: 2-15 U 20-40 minutes after exercise with a carbohydrate load, or as 10 U twice daily.22 IOC status: Allowed for athletes with insulin-dependent diabetes. Adverse reactions: Hypoglycaemia. Detection: There are numerous analytical methods of detecting insulin. No criteria have been set for insulin misuse in sport. Growth hormone Growth hormone (GH) has become popular since the advent of DNA-derived production removed concerns about human pituitary sources and Creutzfeldt-Jakob disease. Athletes usually take it in association with anabolic steroids. There is no doubt about the anabolic effects of the hormone -- the increase in muscle strength in hypopituitary patients receiving treatment and observations that the hormone is released in response to exercise. There is also no doubt that legitimate sources are being diverted into the sporting area.23 In spite of its widespread use there are no data showing an enhancement of sporting performance. One well conducted investigation in experienced training weightlifters showed that 14 days of growth hormone use did not alter protein synthesis or breakdown.24 Another study of exercising elderly men did not show any increase in strength.25 While muscle protein is probably not altered, a placebo-controlled trial showed that lean body weight increased as a result of decreasing body fat. In that study supraphysiological doses of GH were given thrice weekly for six weeks to eight progressive-resistance weight-trained athletes.26Dose: 2.1 U 2-4 times per week. Cycle length varies depending on availability, but is usually about six weeks. IOC status: Banned. Adverse reactions: Clinical acromegaly would be expected, yet a case has yet to be reported in the refereed literature. Detection: Difficult to detect in urine. The synthetic form can be detected by measurement of isoform ratios in serum,27 as recombinant GH manufacture produces only one isoform, while the pituitary releases principally the single 191 amino acid polypeptide chain with a molecular mass of 22 kDa, a smaller 20 kDa form and some smaller and larger forms. Insulin-like growth factors Insulin-like growth factor (IGF) production is principally regulated by GH. IGF is an important factor for some of the actions of GH, such as its anabolic and growth-promoting effects, but not its effects on carbohydrate and lipid levels, which are a direct action of GH on a GH receptor.28,29 At present there are few established clinical applications for IGF and, in sport, it is probably used less than growth hormone. There are no studies of IGF in sporting performance. Dose: Unknown. IOC status: Banned. Adverse reactions: No data from athletes. High-dose intravenous use causes hypoglycaemia; hypophosphataemia causing hypotension and asystole has been reported. Longer-term effects are parotidomegaly, facial pain, hand oedema, sinus tachycardia, gynaecomastia, Bell's palsy and avascular necrosis of the femoral head.28 Detection: Detecting IGF in urine is difficult and, as for GH, determining compound ratios in serum may be a means of detecting misuse. β-Hydroxy-β-methylbutyrate Infusions of some branched-chain amino acids will decrease protein breakdown in postoperative patients. This is probably the result of an inhibitory action on protein metabolism by metabolites of leucine such as a-ketoisocaproate.30 More recently, its further metabolite, β-hydroxy-β-methylbutyrate (HMB), has been considered to be more active in inhibiting protein breakdown. HMB is available as a food supplement in the US, which means that it avoids many of the regulatory hurdles that are required of a drug. A state of clinical deficiency of HMB is yet to be described. This substance has no approved use in Australia. It is currently widely used by athletes in a variety of sports and has no clinical applications in medicine at present. A randomised trial of doses of 0 g, 1.5 g and 3 g per day and three levels of protein supplementation in 41 subjects showed increases in strength during resistance training.31 A further study in eight cyclists has shown a small increase in maximal oxygen consumption.32 At present there are too few data to ascertain whether the compound has a positive effect on sporting performance and whether high doses have significant toxicity. Dose: Up to 15 grams/day are sometimes consumed. IOC status: Not banned. Adverse reactions: None have been described to date. Detection: Can be quantified in urine. Conclusions Despite the paucity of data showing that any of these drugs, except probably erythropoietin, have positive effects on sporting performance, they are used increasingly for performance enhancement. As toxicity and adverse reactions do not seem to deter such use, detection and its consequences appear to be the main deterrent in top-level sport. Detection methods therefore need to be constantly updated and enhanced, and possibilities in this area include the introduction of blood sampling, the use of carbon isotope ratios to detect anabolic steroid misuse, and widening the scope of out-of-competition testing. Doctors need to bear in mind that drug misuse is not restricted to elite athletes -- indeed, most drug use in sport occurs at a non-elite level. The possibility that a patient has used unusual drugs to enhance performance, and that this may be either causing or confounding the clinical state, should always be considered in athletes presenting with an unusual illness. Disclaimer While all efforts have been made to ensure the correct information about the IOC status of the drugs mentioned, this may vary between sports. The IOC status of any drug is subject to frequent revision. Athletes and coaches should check the latest status of any drug mentioned in this article with the relevant sporting body or with the Australian Sports Drug Agency. Acknowledgements I thank Ms Dianne James, Librarian, Manly Hospital. References Laura R, White S, editors. Drug controversy in sport. Sydney: Allen and Unwin, 1991: 1-4. Corrigan AB. Dehydroepiandrosterone and sport. Med J Aust 1999; 171: 206-208. Arlt W, Callies F, van Vlijmen JC, et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 1999; 341: 1013-1020. Wallace MB, Lim LA, Cutler A, Bucci L. Effects of dehydroepiandrosterone vs androstenedione supplementation in men. Med Sci Exercise Sports 1999; 31: 1788-1792. Yesalis CE. Medical, legal, and social implications of androstenedione use. JAMA 1999; 281: 2043-2044. King DS, Sharp RL, Vukovich MD, et al. Effect of oral androstenedione on serum testosterone and adaptations to resistance training in young men. JAMA 1999; 281: 2020-2028. Leder BZ, Longcope C, Catlin DH, et al. Oral androstenedione administration and serum testosterone concentrations in young men. JAMA 2000; 283: 779-782. Bowers LD. Oral dehydroepiandrosterone supplementation can increase the testosterone/epitestosterone ratio. Clin Chem 1999; 45: 295-297. Kicman AT, Coutts SB, Walker CJ, Cowan DA. Proposed confirmatory procedure for detecting 5 alpha-dihydrotestosterone doping in male athletes. Clin Chem 1995; 41: 1617-1627. Muscling in on clenbuterol [editorial]. Lancet 1992; 340: 403. Kamburoff PL, Prime FJ, Schmidt OP. The bronchodilator effects of NAB 365. Br J Clin Pharm 1977; 4: 67-71. Harahan JP, editor. Beta-agonists and their effects on animal growth and carcass quality. London: Elsevier Applied Science, 1987. Prather ID, Brown DE, North P, Wilson JR. Clenbuterol: a substitute for anabolic steroids? Med Sci Sports Exercise 1995; 27: 1118-1121. American College of Sports Medicine. The use of blood doping as an ergogenic aid. Med Sci Sports Exercise 1996; 28: 1-8. Peddling drugs to the pedal pushers [editorial]. Lancet 1998; 352: 415. Ekblom B. Blood doping and erythropoietin, the effects of variation in haemoglobin concentration and other related factors on physical performance. Am J Sports Med 1996; 24 (6 Suppl): S40-42. Leith W. EPO and cycling. Athletics Magazine (Willowdale, Ontario, Canada) June 1992: 24-26. Choi D, Kim M, Park J. Erythropoietin: physico- and biochemical analysis. J Chromatog 1996; 687: 189-199. Saris WHM, Sneden JMG, Brouns F. What is a normal red-blood cell mass for professional cyclists? [letter]. Lancet 1998; 352: 1758. Gareau R, Audran M, Baynes RD, et al. Erythropoietin abuse in athletes. Nature 1996; 380: 113. Willey WJ. Insulin as an anabolic aid? A danger for strength athletes. Physician Sports Med 1997; 25: 103-104. Dawson RT, Harrison MW. Use of insulin as an anabolic agent. Br J Sports Med 1997; 31: 259. Council on Scientific Affairs. Drug abuse in athletes. Anabolic steroids and human growth hormone. JAMA 1988; 259: 1703-1705. Yarasheski KE, Zachwieja JJ, Angleopoulos TJ, Bier DM. Short-term growth hormone does not increase muscle protein synthesis in experienced weight lifters. J Appl Physiol 1993; 74: 3073- 3076. Taaffe DR, Pruitt L, Reim J, et al. Effect of recombinant human growth hormone on the muscle strength response to resistance exercise in elderly men. J Clin Endocrinol Metab 1994; 79: 1361-1366. Crist DM, Peake GT, Egan PA, Waters DA. Body composition response to exogenous GH during training in highly conditioned adults. J Appl Physiol 1988; 65: 579-584. Wu Z, Bidlingmaier M, Dall R, Strasburger CJ. Detection of doping with growth hormone. Lancet 1999; 353: 895. Bach LA. The insulin-like growth factor system: Basic and clinical aspects. Aust N Z J Med 1999; 29: 355-361. Ascoli M, Segaloff DL. Adenohypophyseal hormones and their hypothalamic releasing factors. In: Goodman & Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996: 1363-1382. Sapir DG, Mackenzie W, Moyer ED, et al. Effects of alpha-ketoisocaproate and of leucine on nitrogen metabolism in postoperative patients. Lancet 1983; 1: 1010-1014. Nissen S, Sharp R, Ray JA, et al. Effect of leucine metabolite β-hydroxy-β-methylbutyrate on muscle metabolism during resistance-exercise training. J Appl Physiol 1996; 81: 2095-2104. Vukovich MD, Adams GD. HMB may improve Vo2peak [abstract]. Med Sci Sports Exerc 1997; 29: S252. Authors' details Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Sydney, NSW. Michael C Kennedy, MD, FRACP, Physician. Reprints will not be available from the author. Correspondence: Dr M C Kennedy, Manly Non Invasive Cardiac Laboratory, 22 Darley Road, Manly, NSW 2095. drmkennATozemail.com.au Make a comment Back to text

Michael C Kennedy

Olympic Games Monitoring acute diseases during the Sydney 2000 Olympic and Paralympic Games Sarah V Thackway, Valerie C Delpech, Louisa R Jorm, Jeremy M McAnulty and Maria Visotina MJA 2000; 173: 318-321 Abstract - Morbidity and mass gatherings - Public health services in Sydney during the XXVII Olympiad - The NSW Health Olympic Surveillance System - The role of general practitioners during the Games - Surveillance system constraints - Public health response - Acknowledgements - References - Authors' details - - More articles on Public and environmental health Abstract The Sydney 2000 Olympic Games (the XXVII Olympiad) will be the biggest peacetime event ever held in Australia. During the Games, all public health decisions will be centralised, with daily briefing sessions held to review emerging public health issues and facilitate responses. Infectious diseases will be monitored and reported through the Olympic Surveillance System, with particular attention to foodborne diseases and conditions spread via the respiratory route. This system relies heavily on the cooperation of key notifiers such as emergency departments, laboratories and general practitioners. The lessons learned during the Games, and the new and enhanced systems and linkages that have been developed to support it, will strengthen future disease surveillance in NSW. The Sydney 2000 Olympic Games (the XXVII Olympiad) will be the biggest peacetime event ever held in Australia, attracting over 10 000 athletes and about 5100 officials from 200 countries, around 15 000 media people and 300 000 domestic and international visitors. The Games period will extend for 60 days; it commenced with the opening of the Olympic Athletes' Village on 2 September and ends with the closure of the Paralympic Athletes' Village on 1 November. During this period, there will be a succession of mass gatherings, including the opening and closing ceremonies and many Olympic-related activities in the city. An estimated 150 000 extra people a day will be in central Sydney between noon and 10 pm. On the night of the closing ceremony, 750 000 people will gravitate to the city centre to attend festivities, and up to 500 000 are expected on Sydney Harbour's foreshores for a fireworks spectacular. Mass gatherings, such as sporting events and outdoor celebrations, require public health and medical services to be provided for the large numbers of people who attend.1-4 Protecting the health of the Olympic "family" (athletes and officials), visitors and residents during the Sydney Olympic Games presents unique challenges. Public health planning commenced shortly after the 1993 announcement that Sydney was to host the 2000 Games. It covers counterdisaster planning,5 environmental hazard monitoring, and food safety strategies. Here, we describe selected public health issues associated with large mass gatherings and outline enhancements made to disease surveillance in Sydney prior to the Games. Morbidity and mass gatherings Injuries and death Although relatively rare, mass gatherings have been associated with significant morbidity and death. Examples include crowd crushes at Hillsborough Stadium in the United Kingdom,6 and more recently at a rock concert in Copenhagen; the collapse of a pedestrian bridge at the 1997 Maccabiah Games in Israel, which led to the deaths of four Australians and injuries to almost 60 other athletes; and terrorist activities resulted in 11 deaths at the Munich (1972) and one death at the Atlanta (1996) Olympic Games.7 Infectious agents Infectious disease outbreaks at mass gatherings are also uncommon. Between 1966 and 1993, a review article identified 38 reports of disease outbreaks or "other instances of transmission" of disease associated with competitive sports.8 In 24 of these outbreaks the disease was transmitted by person-to-person spread associated with contact sports (such as wrestling and rugby); the most common infectious agent identified was herpes simplex virus (12 reports). Other agents implicated in person-to-person spread have included enteroviruses (cocksackieviruses and echoviruses), with many reports indicating that infection was spread through shared water sources and drinking containers.8Infections transmitted through the air or by droplets (or both) have also been reported. This year, the largest recorded outbreak of serogroup W-935 meningococcal disease was reported to the World Health Organization.9 It involved 384 reported cases of meningococcal disease diagnosed in pilgrims from 12 countries who contracted the disease while attending the hajj in Mecca; 71 died.10 In 1991, there was an outbreak of measles in the United States at the International Special Olympic Games,10 a competition launched in 1968 to increase quality of life for people with intellectual disabilities.11 Sixteen US athletes, spectators and volunteers from seven different States were initially affected, followed by another nine (there was no follow-up among international delegations).12 The primary case was identified as a track and field athlete from Argentina, and transmission occurred during the opening ceremony (held in a domed stadium), during track and field events and at first aid stations. This outbreak is an example of the way an international sporting event can provide the means of transmission of measles even in a country where the disease is relatively uncommon. There are a number of particular considerations for the Sydney Olympic and Paralympic Games. The first is that nine cruise ships will be berthed in Sydney Harbour, acting as floating hotels for up to 32 000 guests. Outbreaks of disease, including gastroenteritis, Legionnaires' disease, influenza, and tuberculosis are well documented aboard cruise ships,13-18 and a number of gastroenteritis and influenza outbreaks have occurred on ships visiting Sydney.19-20 The closed environment and controlled ventilation systems aboard ships create the potential for disease outbreaks to affect large numbers of individuals. Secondly, with increased international travel, a range of communicable diseases could be imported. For example, in 1996 tourists travelling in countries where yellow fever is endemic unknowingly imported the disease into the US and Switzerland.21 The same year saw approximately 10 000 reported cases of malaria imported into the European Community.21 Measles is now rare in New South Wales, and people with recent infections have acquired the disease overseas; if measles is encountered during the Games period, it is likely to be an imported strain. Thirdly, the Sydney Olympic and Paralympic Games will be held during spring, which, in our temperate climate, is a time generally associated with increased incidence of diseases like meningococcal infection and pertussis. Finally, an estimated 1.8 million meals will be served to athletes and officials and another one million to staff (John Shields, Food Safety Adviser, Olympic Planning Unit, personal communication), amplifying the potential for foodborne disease outbreaks. Public health services in Sydney during the XXVII Olympiad Public health issues associated with Olympic Games have been recognised and reported since the XIX Olympiad in Mexico City in 1968.22 Public health preparations and surveillance during the Sydney 2000 Olympic Games are based on the experience of previous Olympic Games (Box 1), particularly Atlanta. Routine surveillance of public health conditions in NSW is conducted through 17 Public Health Units in Area Health Services and a centralised Public Health Division within the NSW Health Department (NSW Health). Under the NSW Public Health Act (1991), medical practitioners, hospital chief executives (or general managers), pathology laboratories, directors of childcare centres and school principals are required to notify certain medical conditions to the local public health unit. These data are entered into the NSW Notifiable Diseases Database (NDD) and used to track the incidence of communicable diseases across the State and monitor risks and trends to enable direct intervention to control transmission. The NDD has been effectively used to detect, confirm and monitor outbreaks in NSW. Recent examples include hepatitis A associated with the consumption of oysters,27 hepatitis A among drug users in Kings Cross28 and a cluster of cases of haemolytic-uraemic syndrome.29 The NSW Health Olympic Surveillance System Existing NSW Health structures will be enhanced during the Games and strategic public health decisions facilitated through a centralised NSW Health Olympic Coordination Centre, which will review emerging public health issues daily. The NSW Health Olympic Surveillance System (OSS) will be used to monitor acute disease outbreaks and potentially preventable injuries. This system integrates multiple data sources described in Box 2. It enhances existing mechanisms and includes new surveillance systems, giving particular attention to injury, food-borne diseases, conditions spread via the respiratory route and the need for rapid detection of clusters. Detecting unusual patterns of disease presents a particular challenge. At the Health Olympic Coordination Centre, a team of public health experts will examine the Emergency Department Olympic Surveillance System (EDOSS), food safety, environmental inspection and cruise ship trend data. Three-day moving averages will be used to assist in detecting unusual patterns of disease incidence. Detection of aberrations in the NDD data will be enhanced by using a statistical method to compute a normal confidence theory interval.30 This method can detect significant differences in incidence by comparing the current situation with historical data while adjusting for reporting delays and seasonality. The role of general practitioners during the Games Currently, in NSW, general practitioners should routinely report clusters of disease and notify scheduled medical conditions to the local public health unit (Box 3). During the Games, this role remains vital in the early detection of unusual patterns of disease. Many conditions are notifiable on clinical suspicion rather than waiting for confirmation of the diagnosis to allow early detection of disease and timely public health intervention. GPs should be particularly aware of reporting two or more related cases of gastroenteritis or foodborne illness. Infectious diseases uncommonly encountered in Sydney (such as malaria, dengue, cholera and typhoid) should be considered among travellers with unusual presentations. Surveillance system constraints All surveillance systems have limitations.31 The ability of the Olympic Surveillance System to detect unusual patterns of disease depends on: timely reporting of notifiable conditions by all concerned; presentation of "target cases" at emergency departments; and maintenance of electronic systems for data collection and transfer, and back-up options. To ensure the valididty of newly established data collections, a range of measures were undertaken. For example, EDOSS has been trialled at mass gatherings in Sydney over the past year (eg, Olympic Test Events [September 1999], New Year's Eve 1999-2000] and the Sydney Gay and Lesbian Mardi Gras [March 2000]). In May 2000, a full trial of the system was successfully undertaken in all participating hospitals. A validation of EDOSS test data assessed how many true target cases were missed (sensitivity) and how many of those cases identified failed to fulfil the target case criteria (specificity). EDOSS performed well on both measures, with sensitivity and specificity rates around 85%. Problems with identifying target cases were addressed in subsequent training sessions. Although the surveillance system is designed to detect disease clusters, small localised clusters of some diseases and injuries may not be identified because they are obscured by "background" levels. Measures such as enhanced reporting by laboratories and general practitioners may help overcome this. The notification of suspected clusters on clinical grounds by general practitioners is very important. Public health response In the event of a small disease cluster, public health units, in close collaboration with the Health Olympic Coordination Centre, will implement existing outbreak management plans.32 If unusual patterns of injury are detected, the geographical location will be provided by NSW Health to the relevant authorities, such as police or the Olympic Road and Traffic Authority. In the event of a major public health incident, investigations will be elevated to the State level. To assist any large-scale investigations, the telephone call-room used by the NSW Health Survey Program will be on stand-by to conduct interviews or provide information to the public. Also, public health investigation teams located in public health units on the periphery of metropolitan Sydney are on stand-by, to be deployed in the event of major public health incident. In the event that an emergency is declared, the coordination and control arrangements for any investigations will come under the provisions of the NSW Healthplan,33 which provides detailed procedures to coordinate all health services and resources within the State. Acknowledgements We acknowledge the contribution of Ross O'Donoghue, Tim Churches, John Kaldor, Sue Campbell-Lloyd, Rob Menzies, Mark Bartlett, Kerry Chant, Michael Hills, Peter Waples, Pam Albany, Michael Flynn, Karen Banwell, the staff at public health units and the sentinel hospitals: Auburn, Blacktown, Concord, Liverpool, Nepean, Prince of Wales, Royal Prince Alfred, St Vincent's, Sydney, Royal North Shore, Ryde, Sydney Children's, St George, The New Children's, and Westmead. References Stiel D, Trethowan P, Vance N. Medical planning for the Sydney 2000 Olympic and Paralympic Games. Med J Aust 1997; 167: 593-594. Green GB, Burnham G. Health care at mass gatherings. JAMA 1998; 279: 1485-1486. Leonard RB. Medical support for mass gatherings. Emerg Med Clin North Am 1996; 14: 383-397. Thompson JM, Savoia G, Powell G, et al. Level of medical care required for mass gatherings: the XV Winter Olympic Games in Calgary, Canada. Ann Emerg Med 1991; 20: 385-390. Evangeli A. Disaster planning: bioterrorism and the Olympics. Medicine Today July 2000: 148-153. Wardrope J, Ryan F, Clark G, et al. The Hillsborough tragedy. BMJ 1991; 303: 1381-1385. Meehan P, Toomey KE, Drinnon J, et al. Public Health Response for the 1996 Olympic Games. JAMA 1998; 279: 1469-1473. Goodman RA, Thacker SB, Solomon SL, et al. Infectious diseases in competitive sports. JAMA 1994; 271: 862-867. Centers for Disease Control. Serogroup W-135 meningococcal disease among travellers returning from Saudi Arabia-United States, 2000. MMWR Morb Mortal Wkly Rep 2000; 46: 345-346. World Health Organization. Disease outbreaks reported. 12 May 2000. Meningococcal disease, serogroup W135 -- update. 12 May 2000 <http://www.who.int/disease-outbreak-news/n2000/may/12may2000.html> (accessed August 2000). Feldman CA, Giniger M, Sanders M, et al. Special Olympics, special smiles: assessing the feasibility of epidemiologic data collection. J Am Dent Assoc 1997; 128: 1687-1696. Ehresmann KR, Hedberg CW, Grimm MB, et al. An outbreak of measles at an international sporting event with airborne transmission in a domed stadium. J Infect Dis 1995; 171: 679-683. Jernigan DB, Hofmann J, Cetron MS, Genese CA. Outbreak of Legionnaires' disease among cruise ship passengers exposed to a contaminated whirlpool spa. Lancet 1996; 347: 494-499. Distasio AJ II, Trump DH. The investigation of a tuberculosis outbreak in the closed environment of a US Navy ship, 1987. Military Med 1990; 155: 347-351. Christenson B, Lidin-Janson G, Kallings I. Outbreak of respiratory illness on board a ship cruising to ports in southern Europe and northern Africa. J Infection 1987; 14: 247-254. O'Mahony M, Noah ND, Evans B, Harper D. An outbreak of gastroenteritis on a passenger cruise ship. J Hyg (Lond) 1986; 97: 229-236. Waterman SH, Demarcus TA, Wells JG, Blake PA. Staphylococcal food poisoning on a cruise ship. Epidemiol Infect 1987; 99: 349-353. Rowbotham TJ. Legionellosis associated with ships: 1977 to 1997. Commun Dis Public Health 1998; 1: 146-151. Gupta L, Towler B, Frommer M. Investigation of an outbreak of gastroenteritis on a container ship returning from Asia. NSW Public Health Bull 1994; 5: 61-62 . Ferson MJ, Paraskevopoulos P, Hatzi S, et al. Presumptive summer influenza A: an outbreak on a trans-Tasman cruise. Commun Dis Intell 2000; 24: 45-47. World Health Organization. Global infectious disease surveillance. Fact sheet No. 200. June 1998. <http://www.who.int/inf-fs/en/fact200.html> (accessed August 2000). Thomas CL. Public health problems in the Olympic Games setting. JAMA 1968; 205: 130-132. Panella H, Plascenia A, Sanz M, et al. Evaluation of epidemiologic surveillance system for infectious diseases in the Barcelona Olympic Games 1992. Gaceta Sanitaria 1995; 47: 84-90. Wetterhall SF, Coulombier DM, Herndon JM, et al. Medical care delivery at 1996 Olympic Games. JAMA 1998; 279: 1463-1468. Weiss BP, Mascola L, Fannin SL. Public health at the 1984 Summer Olympics: the Los Angeles County experience. Am J Public Health 1988; 78: 686-688. Keim ME, Williams D. Hospital use by Olympic athletes during the 1996 Atlanta Olympic Games. Med J Aust 1997; 167: 603-605. Conaty S, Bird P, Bell G, et al. Hepatitis A in New South Wales, Australia from consumption of oysters: the first reported outbreak. Epidemiol Infect 2000; 124: 121-130. Delpech V, Thackway S, Young L, et al. Outbreak of Hepatitis A among illicit drug users in South Eastern Sydney [letter]. Med J Aust 1999; 175: 633. Bartlett M, McAnulty J, Rutherford A, et al. Haemolytic uraemic syndrome: a cluster of cases in early 1999. NSW Public Health Bull 1999; 10: 109-112. Stroup DF, Williamson D, Herndon J. Detection of aberrations in the occurrence of notifiable diseases surveillance data. Stat Med 1989; 8: 323-329. Teutsch SM, Churchill RE. Principles and practice in public health surveillance. Oxford: Oxford University Press, 1994. NSW Health Department. Notifiable diseases manual. 5th ed. Sydney: NSW Health, 2000. NSW Health Department. NSW Healthplan. Sydney: NSW Health, 1997. Authors' details NSW Health Department, Sydney, NSW. Sarah V Thackway, MPH, Manager, Olympic Surveillance, Olympic Planning Unit; Valerie C Delpech, FAFPHM, Medical Epidemiologist, Communicable Disease Surveillance and Control Unit; Louisa R Jorm, PhD, Director, Epidemiology and Surveillance Branch; Jeremy M McAnulty, FAFPHM, Manager, Communicable Disease Surveillance and Control Unit; Maria Visotina, MAdmin, Manager, Olympic Planning Unit. Reprints will not be available from the authors. Correspondence: Ms S Thackway, Olympic Planning Unit, NSW Health, Locked Mail Bag 961, North Sydney, NSW 2059. SATHAATdoh.health.nsw.gov.au Make a comment 1: Lessons from previous Olympic Games In most instances, existing surveillance systems were enhanced to monitor infectious disease outbreaks.7,23-26 During the 1992 Barcelona Games enhanced reporting for hepatitis, meningococcal disease, Legionnaires' disease and foodborne disease23 identified no increases in disease compared with the same period in previous years. However, there was an increase in reports of foodborne illness - particularly domestic foodborne illness - by emergency departments. At the 1996 Atlanta Games, enhanced surveillance of infectious diseases in eight sentinel hospitals and public health laboratories detected: No increase in emergency department presentations; No outbreaks of disease at Olympic venues despite increased reporting of gastrointestinal symptoms during the first week; and Management of 106 people at 11 emergency departments for injuries associated with the Olympic Park bombing (including 21 admissions and one death).7 Back to text 2: The NSW Health Olympic survellance System The Notifiable Diseases Database (NDD) reporting of all notifiable conditions has been enhanced in two ways. Firstly, laboratories will be contacted daily by metropolitan public health units to ensure timely reporting of notifiable diseases. Secondly, notification data from public health units will be transferred to a centralised location at NSW Health three times a day. The Emergency Department Olympic Surveillance System (EDOSS) has been implemented in 15 Sydney metropolitan hospital emergency departments to monitor cases of food-related illness, Legionnaires' disease, meningococcal disease, influenza, hepatitis A, pertussis and measles. Approximately 40 hospital staff will collect specific patient data on target cases upon arrival. Data will be entered into a database locally and sent electronically to the Health Olympic Coordination Centre at 8am daily for collation and analysis, thus making EDOSS an early warning system. EDOSS will operate from three weeks before the Games until after the closure of the Olympic Village. National and global epidemic surveillance: National trends in infectious diseases will be regularly reviewed through the Communicable Disease Network of Australia and New Zealand. Data from the World Health Organization and ProMed (a resource of the International Society for Infectious Diseases for Monitoring Emerging Diseases) will be reviewed to provide information on global trends. The Vessel Inspection Program has been modelled on the American Vessel Sanitation Program operated by the United States Centers for Disease Control and Prevention. Cruise ship medical staff are required to report notifiable conditions and complete daily reports outlining the number of passengers on board, the number of medical consultations, hospitalisations, deaths and cases of influenza-like illness, suspected pneumonia and gastroenteritis. Influenza surveillance: Trends in influenza will continue to be monitored by combining reports from major laboratories and clinical data from general practitioners in the Australian Sentinel Practice Research Network. Food safety monitoring: Since early 1999, metropolitan public health units and local councils have enhanced food hygiene surveillance for food premises. This program will play an important role in minimising the occurrence of foodborne illness outside Olympic venues. In addition, NSW Health and local government officers will inspect food premises inside Olympic venues and delivery and distribution outlets to ensure compliance with food hygiene standards. Summary inspection reports will be relayed daily to NSW Health. Environmental inspection program: Priority has been given to minimising risk associated with Cryptosporidium in pools and Legionnaires' disease in water cooling towers. All water-cooling systems, clinical waste management services, toilet hygiene and general public health safety matters at Olympic and Paralympic venues will be inspected before sporting events commence. Waste and toilet services will be routinely inspected and summary inspection reports relayed daily to NSW Health. Back to text 3: Conditions notifiable by doctors under the NSW Public Health Act (1991) Acute viral hepatitis Adverse event following vaccination AIDS Foodborne illness in two or more related cases Gastroenteritis in two or more related cases Leprosy Measles Pertussis (whooping cough) Syphilis Tuberculosis Back to text

Sarah V Thackway · Valerie C Delpech · Louisa R Jorm · Jeremy M McAnulty · Maria Visotina