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sensitizing antibodies in sera from patients with immediate systemic allergic reactions to penicillin. J ALLERGY 1964; 35:488. 15. Gorevic PD, Levine BB. Desensitization of anaphylactic hypersensitivity specific for the penicilloate minor determinant of penicillin and carbenicillin. J ALLERGY CLIN IMMUNOL 1981;68:267. 16. Van Dellen RG, WalshWE, PetersGA, Gleich GJ. Differing patterns of wheal and flare skin reactivity in patients allergic to the penicillins. J ALLERGY 1971;47:230. 17. Levine BB. Antigenicity and cross-reactivityof penicillins and cephalosporins.J Infect Dis 1973;128(suppl):364. 18. Delafuente JC, Parrish RS, Caldwell JR. Penicillin and cephalosporin immunogenicity in man. Ann Allergy 1979;43:337. 19. Green CR, Rosenblum A. A report of the penicillin study group. J ALLERGY CLIN IMMUNOL 1971;48:331. 20. Parker CW. Allergic drug responses-mechanisms and unsolved problems. CRC Crit Rev Toxic01 1972;1:261. 21. Dixon FJ, Feldman JD, Weigle WO, Cochrane CG. Pathogenesisof serum sickness.Arch Path011958;65:18. 22. Kniker WT. CochraneCG. The localization of circulating immune complexes in experimental serum sickness.J Exp Med 1968;127:119. 23. CochraneCG, Koffler D. Immune complex diseasein experimental animals and man. Adv Immunol 1973;16:185.

to beta-lactam

antibodies

24. Hensen PM, CochraneCG. Immune complex diseasein rabbits: the role of complement and of a leukocyte-dependent release of vasoactive amines from platelets. J Exp Med 1971;133:554. 25. HensenPM. Interaction of cells with immune complexes: adherence release of constituentsand tissue injury. J Exp Med 1971;134(suppl):554s. 26. Benveniste J, Hensen PM, Cochrane CG. Leukocytedependenthistamine release from rabbit platelets: the role of IgE, basophils, and a platelet activating factor. J Exp Med 1972;136:1356. 27. Lawley TJ, Yancey KB, Bielory L, Young N, GasconP, Frank MM. Semm sickness.N Engl J Med 1985;312:1328. 28. Peck SM, Siegal S, Glick AW, Kurtin A, Bergamini R. Clinical problems in penicillin sensitivity. JAMA 1948;138:631. 29. Roberts AE. Occupational allergic reactions among workers in a penicillin-manufacturing plant: simple and inexpensive method of diagnosis and treatment. Arch Indust Hyg 1953; 8:340. 30. Grieco MH, Durbin MR, Robinson JL, Schwartz MJ. Penicillin hypersensitivity in patients with bacterial endocarditis. Ann Intern Med 1964;60:203. 31. Stark BJ, Gross GN, Lumry WR, Sullivan TJ. Oral desensitization of penicillin-allergic patients [Abstract]. J ALLERGY CLIN I~~MUN~L 1984;73:112.

Asthma mortality: A review of recent experience in New Zealand M. R. Sears, MB., F.R.A.C.P.,+ H. H. Rea, M.D., F.R.A.C.P., and R. Beaglehole, M.D., F.R.A.C.P. Dunedin and Auckland, New Zealand

Until recently, mortality causedby asthmahasbeen apparently stable or declining slowly in most countries, with the notable exceptions of the “epidemic” of asthmadeathsin the mid- 1960sin the United KingFrom the University of Otago Medical School, Dunedin, New Zealand, and Green Lane Hospital and Department of Community Health and General Practice, University of Auckland School of Medicine, Auckland, New Zealand. Supportedby Medical ResearchCouncil of New Zealand,the Maurice and Phyllis Paykel Trust, New Zealand Asthma Society, and regional asthmasocieties. Received for publication Oct. 9, 1986. Accepted for publication March 24, 1987. Reprint requests: M. R. Sears, M.B., Department of Medicine, University of Otago Medical School, P.O. Box 913, Dunedin, New Zealand. *Dr. M. Sears was on sabbatical leave at the Firestone Regional Chest and Allergy Unit, St. Joseph’s Hospital, and McMaster University. Hamilton, Ontario, Canada, when this article was prepared.

I

I

Abbreviation used ICD: International Classification of Diseases

dom, Australia, and New Zealand, and the recent “second epidemic” in New Zealand. During the last 5 years, however, it has become apparent that mortality causedby asthmamay be increasingin a number of Western countries, including the United States, Canada,and England and Wales.The purposeof this article is to review the recent New Zealand epidemic andto draw attention to factorsthat could be important in other countries that may be now experiencing a similar problem. Background

In 1981, Wilson et al.’ reported an apparent increasein mortality causedby asthmain young people 319

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1960 1965 1970 1915 10 YEAR FIG. 1. Mortality rates for asthma in New Zealanders of all ages, and in those aged 5to 34 years, 1960-l&5. The dashed lines indicate the estimated variation in reported mortality b-n ?#99 and 1969 and between 1978 and 1979 had the ICD remained unchanwd; the remainderof the decrease (1969) or increase (1979) is attributable to the effect of introduction of a revised ICD (see text). This effect was negligible in persons aged 5 to 34 years.

Zealand. Review of national statistics confirmed a substantialrise in asthma mortality in young people, most evident in the late 1970swhen mortality in people aged 5 to 34 years rose from 2.0/100,000 in 1976, a rate already considerably higher than that reported in any other country, to 3.6/100,000 in 1977 (Fig. 1). Between 1978 and 1982, asthma mortality in this age group was sustained between 3.0 and 4.1/ 100,000, rates at least four times ratesin England and Wales. Such a rise was not apparent at that time in national mortality statistics for other comparable countries.* However, during the last 5 years, mortality rates as determined from death certificates have been rising gradually in young people in the United State~,~ Canada,4 and England and Wales,’ whereas in New IiZkxdand,mortality in this agegroup hasdeclined since 1982, reaching 1.9/100,000 in 1985.6 Wilson et al.’ speculatedthat the rise in New Zealand aathmamortahty may have beendue to increasing use of the eMon of inhaled fj-agonists and oral _ An impxived formulation of the latter avWk in New Zealand in 1976. This s, l2astxlon a small number easeseriesfrom as widely debated in the medical literat~re.~-~In 1982, Dr. Ian Grant*ovisited New Zealand and later suggestedthat the high asthmamortality rate with the widespread use of highmay-be i-ss& in New

dose $ktgonists inhaled via neb&zers powered by air compressorpumps debatein the medic mid-1960s increase m by England &Wales, Austtxtha, and and commonly ascribed to toxicity from or over&iante on high-dose isoproterenol,‘l~ I2 apponred obvious to many. Meanwhile, the asthma Research Council of New in which the wo report were investigated, and detailedinfo all 342 patients less @hair 70 yearsof agewas

as dying of asthma had in fact had died of as&ma. The rate

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conducted in Auckland, the largest city in New Zealand.17,‘* FACTORS AFFECTING ASTHMA MORTALITY

REPORTED

Data from three epidemiologic studies, the New Zealand national asthma mortality study, the Auckland’case-control study, and a study of asthma mortality conducted in 1979 in two regions of England,“, ‘O allow examination of some factors that might influence reported mortality from asthma in these and other countries. Accuracy

of certification

Neither the abrupt rise in mortality in New Zealand nor the differencesbetweenNew ZealandandEngland canbe explained by inaccuraciesin deathcertification. The net overestimateof asthmamortality in Caucasian patients aged 15 to 64 years was in fact slightly lower in New Zealand than in England.I5 When nonCaucasianpatients are included, the net overestimates were virtually identical at 13%.14The false positive certification rate in young people in New Zealand was negligible.14 The false negative certification rate in young people in New Zealand was previously demonstratedto be very low.’ It doesremain possible that other countries have higher rates of false negative reporting of asthmadeaths, accounting for part of the international differences in reported mortality rates. The definition of asthmamay have widened gradually with time, leading to an apparent increase in asthma mortality, if casesthat formerly would have been attributed to other lung diseasewere now certified as causedby asthma. However, in personsaged 5 to 34 years in New Zealand, there was very little change in reported rates of death caused by other respiratory diseasesbetween 1975 and 1980.’ The increasein asthma mortality in this age group cannot be explained by a change in diagnostic fashion. Revision of International of Diseases

Classification

An apparentincreasein asthmamortality could be related to the 1979 transition from the eighth to the ninth revision of the ICD. The major change in the ninth revision affecting classification of asthmadeaths was the “uncoupling” of asthmaand bronchitis; thus, death certificates containing both terms that formerly would be coded to bronchitis were now coded to asthma.*I The extent of the increasein reportedasthma mortality attributable to the introduction of the ninth revision of the ICD was determined acrossall age groups as 28% in Englandz2and 35% in the

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United States.23Similarly, we could expect a rise in reported mortality in 1979 across all age groups in New Zealand of about 30%; the actual increase was 42%. More than two thirds of this increasecan therefore be attributed to the introduction of the ninth revision, as indicated in Fig. 1. In younger age groups, the effect of this ICD revision was much smaller. In England, a 6% increasein reported mortality in subjects aged 15 to 44 years was calculated,‘* whereas in the New Zealand study, all but two of 86 casesin patientsaged5 to 34 yearswould havebeenidentically coded according to the eighth and ninth revisions, a difference of only 2.5%. Furthermore, the major increasein mortality in young people in New Zealand occurred in 1977, 2 years before the ninth revision was introduced; therefore, it cannot be attributed in any part to changesin classification. Neither can the sustained higher mortality rates in young people in New Zealand between 1977 and 1982be attributed to this cause. We concluded that the incidence in mortality in young people was real, substantial, and not significantly affected by revisions of ICD classification, whereasin older age groups, the introduction of the ninth revision of the ICD had a significant upward effect on already rising reported mortality rates. Ethnic differences

The high New Zealand asthmamortality rate was partly explained by the very high ratesfound in Maoris (indigenous Polynesians)and Pacific island (migrant) Polynesians, whose mortality rates were respectively 18.9 and 9.4/100,000, whereasfor Caucasian New Zealanders, the verified asthma mortality rate was 3.4/100,000.‘3 The higher non-Caucasianrates accountedfor 36% of the “excess” New Zealand mortality in persons aged 15 to 64 years comparedwith the rate of similarly verified asthma deaths reported in England.” However, there was no major increase in the nonwhite population of New Zealand in the latter part of the 1970sto explain the abrupt increase in asthmamortality. Gender

The sex distribution of the 271 verified deaths causedby asthmastudied in New Zealand in 1981 to 1983was not significantly different to that of the total population, except for a slight excessof female subjects (60.5%) in the age group 5 to 34 years. This was largely due to a predominanceof female subjects in the relatively small group of Pacific island Polynesians(nine female and five male subjects).During the previous decade, asthma mortality as reported in New Zealand national statistics had risen proportion-

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ately in male and female subjects, in contrast to England, where deaths rose more in male subjects.’

A change in either incidence of asthmaor in casefatality rate is required to explain the increasedmortality rate. As incidence rates for asthmaare not generally known, we have to rely on measuredprevalence rates. Taking into accountcurrent knowledge, we can examine the potential contribution of prevalenceand severityof asthmato the recentNew Zealandmortality epidemic. Increased

prewalence

It appears unlikely that the prevalence of asthma should increase substantially within New Zealand in a short period of time or that there should be major international differences in prevalence. The prevalence of current symptoms of asthma coupled with airway hyperresponsivenessto histamine in Auckland childrer? was only marginally higher than in Australia where studies were conducted earlier with the same methods.25’26Australia and New Zealand may have prevalencerates that are somewhathigher than those determined in the United Kingdom or the United States, although none of these studies were standardized.27-30 Interestingly, no major difference in prevalence rates of airway hyperresponsivenessand symptoms of asthma between Caucasian and nonCaucasianchildren were detectedin Auckland despite the much higher mortality rate in non-Caucasian children.3’ Many countries have noted increased hospital admission rates for asthma, especially in children.32”4 There is at present little epidemiologically sound evidence to support the hypothesis that this reflects increasedprevalenceor severity of asthma. Studiesthat have examined prevalencerates for asthmaover time have been flawed either by use of different questions to elicit the diagnosis3’or by a change in ethnic mix in the study population and questionnaire response rate.36Coupled with changing public attitudes to the diagnosisof asthma,theseproblems cast doubt on the validity of the findings. Other plausible reasons for increased admission rates include an increase in severity of asthma,changesin therapeuticapproach,and admission policies, i.e., a shift from community to hospital care in severeasthma,perhapsrelated to fear of mortality, and changesin diagnostic fashion. Cncreased swerity

Could asthma have become more severe in New Zealand, and could it be more severe than in Australia, England, or the United States?Although

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most deaths caused by asthma in New Zealand and England were consideredpreventable,relatively fewer of the New Zealanddeathswere associatedwith avoidable factors or could have been as readily prevented asreportedin England.” Joint review of representative New Zealand patients suggestedthat in somepatients the disease was innately more severe than that observed in patients dying of asthma in England, whereasin other patients, attacksprogressedvery rapidly despite apparently optimal care. Apart from mortality rates,the only longitudinal datathat might reflect severity areper capita salesof antiasthmadrugs, which are higher in New Zealand than in England and Australia.37A rapid rise in drug sales occurred in 1980, after the rise in asthmamortality in young people had occurred but before this becamewidely known either to the medical profession or to the public. Possible explanations include an increasein either diseaseprevalence or severity or changesin therapeutie fashion. The rise in saleswas observed with four drug groups (B-agonists,theophylline, corticosteroid aerosols,and cromolyn) and therefore cannot be attributed solely to aggressive marketing of one or two products. However, the relatively abrupt rise in I year (i980) is difficult to attribute to a sudden change in severity. The increasedprevalenceof asthmaamongTokelauan Islanders who migrated to New Zealand compared with those remaining in the islands suggested that someenvironmental factor in New Zealand cau&d an increasein prevalenceof asthma among this popdation group,38but severity was not compareddirectly. Most difficult to quantitate is the anecdotalexperience of physicians coming to New Zealand after practicing in the United Kingdom, Canada,or the United States, who state that asthmain New Zealand is more Severe and more difficult to managethan that which they had experienced in those countries.“9 Taking all these piecesof “evidence” together,a casecan be madethat severity of asthma may have increased in New Zealand, but at best the evidence is only suggestive. By contrast, studies of symptoms and airway hyperresponsiveness in children in New Zealand and Australiaw~26have found very similar degreesof responsiveness, suggesting, at least in children, that there is no major difference in severity of asthma. Drug toxicity There is little evidence to supportthe hypothesisof Wilson et al. ’ that increased asthma mortality in New Zealand was related to toxicity from the corn-bination of oral theophylline and inhaled B-agonists.” New Zealand does use more of these drugs per capita tban Australia or the United Kingdom,~but the.temporal relationship between increasedaalesa&deaths doesnot suggesta direct causalrelationship. The ma-

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Asthma mortalitv

jor rise in drug salesoccurred 3 years after the abrupt rise in mortality in young people. Deaths are now falling despite a continued high rate of drug sales. Substantial increases in asthma drug sales were recorded in both Australia and the United Kingdom in the late 1970swithout an appreciableincreasein mortality at that time. Although direct drug toxicity appeared unlikely in the 271 case histories examined in the 2-year New Zealand national mortality study, inappropriate drug therapy was frequently encountered. Many of the patients studied who suffered fatal asthma were taking multiple drugs, but these were often used in inappropriate combinations and doses. The most notable deficiency observed in both the New Zealand and the English studies of asthma mortality was insufficient use of corticosteroidsin long-term management and in the acute attack, often in the context of increased (perhaps “excessive”) use of bronchodilator therapy. Although neither the English nor the New Zealand study provided evidence for mortality caused by direct toxicity from P-sympathomimetic drugs, both studies yielded vivid illustrations of over reliance on these agents by patients and doctors and consequentdelays in seekingand instituting more appropriate therapy, including corticosteroids. Grant’s” hypothesis that abuseof domiciliary nebulizers may have been a major factor in the New Zealand “epidemic” was not supportedby the data. At most, only 8% of all subjectswith asthmadying of their disease delayed seeking help because of over reliance on P-agonistsdelivered by a home nebulizer,16whereas over reliance on pressurized aerosols of bronchodilator drugs was much more common. Management

deficiencies

The deficiencies in management of New Zealand patients suffering fatal asthma were similar to those identified in earlier studies in the United Kingdom.19,Q 4’ These deficiencies included inadequate long-term treatment, frequently compoundedby discontinuity of medical care and poor patient compliance, inadequate arrangementsby general practitioners and hospital staff for follow-up of patients suffering an acute exacerbation,reluctanceby doctors to use or increase corticosteroid therapy for exacerbations, failure to use corticosteroids in the long term to control symptomsand establishmaximal lung function, and inadequatemonitoring of lung function, especially in the interval between acute exacerbations. In short, the problems were those of inadequateongoing supervision, underassessmentof severity, and inappropriatenessof therapy, and the problemschiefly manifest as inadequatecorticosteroid therapy for patients with severeasthma.

323

Although 23 patients (8.5%) who died of asthma were prescribed antianxiety and antidepressanttherapy for concomitant psychologic illness, in only one casewas a sedativeprescribedspecifically for asthma. Avoidance of sedativesin acute asthmais one lesson that appearsto have been well learned. Use of medical

services

The New Zealand health system is structured around general (family) practice, with specialist support available both privately and through public hospitals. Only the latter service is free to the patient. Paymentof $10 to $12 fees for eachvisit to a general practitioner may have deterred some patients from attending for regular care and encourageduse of free hospital emergency services for acute care, leaving the patient to drift from one attack to another without adequatefollow-up and assessment. Most New Zealanders (80%) live in urban areas and are within easy reach of medical services. Only 7% of all deaths of asthma during the 2-year study period occurred in areas remote from medical care, and evenin thosecases,improved long-term caremay have preventedsome of the fatalities. Despite concernsabout the possible adverseeffects of a fee-for-servicemedical system,it should be noted that there was no clustering of mortality from asthma in the lower socioeconomicgroups. The distribution of socioeconomic status of patients dying of asthma did not differ significantly from that of the whole population.42 IDENTlFlCATlON OF THE “HIGH-RISK” SUBJECT WlTH ASTHMA

The New Zealand studies allowed identification of certain groups of subjectswith asthmaat higher risk of having fatal attacks. Patient risk factors include: 1. Age: The late teenage years and early twenties were overrepresentedin mortality statistics.I3Case histories frequently suggestedthat removal of parental care coupled with rebelliousnessagainstthe “authority” of the doctor results in less reliable self-care and compliance with therapy in this group. Similar psychologic factors were noted in a case-control study of children dying of asthma in the United States.43 2. Ethnicity: Non-Caucasian subjects had mortality ratesup to five times higher than age-matchedCaucasian subjects.l3 Differing attitudes to medical care and cultural and economic barriers to good quality medical care appearedlikely reasons for this finding. 3. Previous life-threatening attacks of asthma (episodesresulting in alteration of level of consciousness or documented hypercapnia) were recorded

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more frequently for subjectswith fatal asthmathan for control subjects.‘* 4. Hospital admission for asthmawithin the last year was associatedwith a 16-fold increasedrisk of fatal asthmaI when subjects who died were compared with subjects with asthma in the community. 5. Psychosocial problems: Documented depression, alcohol abuse, recent family bereavement,or recent unemployment were significant risk factors.18 Certain aspects of medical management (or lack thereof) were also found to be significant risk factors: 1. Failure of the general practitioner to measure peak expiratory flow rate (or any other simple objective test of pulmonary function) in the last year of life carried a threefold increasedrisk of mortality. 2. Low scores for adequacy of prescribed drug therapy, as evaluated by a panel of experienced respiratory physicians, were associated with an increasedrisk of death.” WHAT CAN BE zEALM#OEX-E?

fYKMTHE#EW

As asthmamortality rates increaseslowly in several countries with highly developedhealth care systems, we need to review measuresto reduce the risks of dying of what is, at least initially, a reversibledisorder. Although studies of patients who die of asthma are the logical starting place for such review, even the national New Zealand study covering all deathscaused by asthma throughout the whole country during a 2-year period could not provide answersto many questions. Case-control studies in larger populations, for instance England or the United States, could provide more powerful epidemiologic data. Because of the confounding effects of diagnostic fashion and the change in ICD, we remain uncertain as to the magnitude of the real increase in asthma mortality in older subjects but are certain that there has been a significant and substantial rise in younger people. Although the masonsfor the temporal change in mortality within New Zealand and for the international differencesremain uncertain, data now available do allow elimination of some of the original hypothesesand lend increasedsupport for others. There are no data that allow for a valid assessmentof possible increases in prevalence or severity; therefore, both of these remain possibilities. Drug toxicity per se is an unlikely explanation of rising mortality, but the multiplicity of therapiesnow available for the control of asthma may be a source of confusion to both patient and doctor. Failure of patients and doctors to appreciate the clinical severity of asthma (compoundedby failure to make objective measurements), over reliance on bronchodilator therapy and the in-

CLiN. :b’MUNC,~.. SEPTEMBER I%‘;7

sufficient use of corticosteroid therapy wcn: iudji)r factors contributing to many “preventable” ::ithma deaths. In the light of current knowledge. we :;ugge>tthat for optimum managementof asthma and prevention of mortality, the following measuresare appropriate: 1. Determination of an effective therapeuttc re&men with which a patient can comply 2. Provision of easyaccessto continuing and emergency medical care 3. Monitoring of the efficacy of therapy with objective lung function tests at regular intervals both when the patient is asymptomatic (or well controlled) as well as symptomatic 4. Identification of the “high-risk” patient for more frequent follow-up 5. provision of a “crisis plan,” at least for highrisk subjectswith asthma, by which the patient can recognizeworsening asthmabefore the stage of severity that requires hospitalization and initiate self-medication with corticosteroid therapy aspreviously arrangedbetweenpatient and physician 6. provision of effective education programs not only for the patient but also for the family, and aboveall for physicians and other health professionals without whose knowledge and cooperation all other education will be ineffective In short, we cannot be complacentaboutthe current state of managementof asthma. Despite some evidencefor a possible increasein the severity of asthma; which, if it is real, may accountfor part of the increase in mortality experienced in New Zealand, the inescapable fact remains that most deaths caused by asthma, wherever they were studied, were potentially preventableby optimum management.Meticulous attention to detail is required in. treating patients with this potentially life-threatening disorder. We acknowledgethe majorcontributionsto the national asthmamortality study of our colleaguesDrs. R. P. G. Rothwell, P. E. Holst, T. V. O’Donnell, A. J. D. Gillies, andD. C. Sutherland.Theco&ming coop?mtionof memhersof the British ThoracicAssociationAsthmaMortality subcommittee is alsogratefullyacknowledged. 1. Wilson JD, Sutherland DC, Thomas AC. Has the chat~geto beta-agonistscombined with orai tbeophylline increasedcases of fatal asthma?Lancet 1981$:1235. 2. JacksonRT, BeagIeholeR, Rea HH, SutherlandDC. EveortGty from asthma: a new epidemic in New Z.&a&. Br Med I 1982;285:771. 3. Annual summary of births,. deaths, mamia@a, a@ dive&c&s, United States-1% at& earl& yeam. Hyt&svi&; Mfk; Ng

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tional Center for Health Statistics, DHEW publication (PHS) (Vital and health Statistics). 4. Causesof death. Health Division, Vital Statistics and Disease registries section, Statistics, Canada, 1970-1984. 5. Bumey PGJ. Asthma mortality in England andWales:evidence for a further increase, 197484. Lancet 1986;2:323. 6. National Health Statistics Center. Mortality and demographic data. Wellington: Department of Health, 1985 and earlier years. 7. Beaglehole R, Harris EA. Rea HH. Has the change to betaagonists combined with oral theophylline increasedcasesof fatal asthma?Lancet 1981;2:38. 8. Barclay J, Smith WGJ, Addis GJ. Asthma deathsand theophylline/beta,-agonist therapy. Lancet 1981;2:369. 9. Weinberger M. Asthma deathsand theophylline/beta,-agonist therapy. Lancet 1981;2:370. 10. Grant IWB. Asthma in New Zealand. Br Med J 1983;286:364. 11. Speizer FE, Doll R, Heaf P. Observationson recent increase in mortality from asthma. Br Med J 1968;1:335. 12. Stolley PD, SchinnarR. Associationbetweenasthmamortality and isoproterenol aerosols:a review. Prev Med 1978;7:519. 13. SearsMR, Rea HH, Beaglehole R, et al. Asthma mortality in New Zealand: a two-year national study. NZ Med J 1985; 98:271. 14. SearsMR, Rea HH, de Boer G, et al. Accuracy of certification of death due to asthma: a national study. Am J Epidemiol 1986;124:1004. 15. SearsMR. Rea HH, Rothwell RPG, et al. Asthma mortality: comparison between New Zealand and England. Br Med J 1986;293:1342. 16. SearsMR, Rea HH, Fenwick J, et al. 75 deathsin asthmaticsprescribed home nebulisers. Br Med J 1987;294:477-80. 17. SutherlandDC, Beaglehole R, Fenwick J, JacksonRT, Mullins P, ReaHH. Death from asthmain Auckland: circumstances and validation of causes.NZ Med J 1984;97:845. 18. Rea HH, Scragg R, Jackson R, Beaglehole R, Fenwick J, SutherlandDC. A case control study of deaths from asthma. Thorax 1986;41:833. 19. British Thoracic Association. Deaths from asthma in two regions of England. Br Med J 1982;285:1251. 20. British Thoracic Association. Accuracy of deathcertificatesin bronchial asthma. Thorax 1984;39:505. 21. World Health Organization. Manual of the international statistical classification of disease,injuries, and causesof death: basedon the recommendationsof the ninth revision conference, 1975, vol 1. Geneva: WHO, 1977. 22. Stewart CJ, Nunn AJ. Are asthma mortality rates changing? Br J Dis Chest 1985;79:229. 23. Sly RM. Increases in deaths from asthma. Ann Allergy 1984;53:20. 24. Asher MI, PattemorePK, Harrison AC, Mitchell EA, ReaHH, StewartA. Internationalcomparisonof prevalenceand severity of asthmain children. Am Rev Respir Dis 1986;133:A58.

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25. Woolcock AJ, Dowse GK, Temple K, Stanley H, Alpers MP, Turner KJ. The prevalenceof asthmain the South-Forepeople of PapuaNew Guinea: a method for field studiesof bronchial reactivity. Eur J Respir Dis 1983;64:571. 26. Britton WJ, WoolcockAJ, Peat JK, Sedgwick CJ, Lloyd DM, Leeder SR. Pmvalenceof bronchial responsivenessin children: the relationship betweenasthmaand skin reactivity to allergens in two communities. Int J Epidemiol 1986;15:202. 27. Jones DT, Sears MR, Holdaway MD, Hewitt CJ, Flannery EM, HerbisonGP, Silva PA. Childhood asthmain New Zealand [in press]. Br J Dis Chest 28. Williams H, McNicol KN. Prevalence, natural history, and relationship of wheezy bronchitis and asthma in children: an epidemiologic study. Br Med J 1%9;4:321. 29. Lee DA, Winslow NR, Speight ANP, Hey EN. Prevalenceand spectrumof asthmain childhood. Br Med J 1983;286:1256. 30. Dodge RR, Burrows B. The prevalence and incidence of asthmaand asthma-likesymptomsin a generalpopulation sample. Am Rev Respir Dis 1980;122:567. 31, Harrison AC, Asher MI, PattemorePK, Mitchell EA, Rea HH, Stewart A. Do racial differences in asthma prevalence and severity accountfor racial differencesin asthmaadmissionand mortality rates?Am Rev Respir Dis 1986;133:A176. 32. Mitchell EA, Cutler DP. Paediatric admission to Auckland hospital from asthmafor 1970-1980.NZ Med J 1984;97:67. 33. Mitchell EA. International trends in hospital admission rates for asthma. Arch Dis Child 1985;60:376. 34. Hospital morbidity. Health Division, Institutional Care Statistics, Statistics Canada, 1981 and previous years. 35. Smith JM, Harding LK, CummingG. The changingprevalence of asthmain school children. Clin Allergy 1971;1:57. 36. Mitchell EA. Increasingprevalenceof asthmain children. NZ Med J 1983;96:463. 37. Keating G, Mitchell EA, JacksonR, Beaglehole R, Rea HH. Trendsin salesof drugs for asthmain New Zealand, Australia, and the United Kingdom. Br Med J 1984;289:348. 38. Waite DA, Eyles EF, Tonkin SL, O’Donnell TV Asthma prevalencein Tokelauanchildren in two environments.Clin Allergy 1980;10:71. 39. Thomley PE, Dawson KP. Asthma in New Zealand. Br Med J 1983;286:890. 40. CochraneGM, Clark TJH. A survey of asthma mortality in patientsbetweenages35 and64 in the greaterLondonhospitals in 1971. Thorax 1975;30:300. 41. MacDonald JB, Seaton A, Williams DA. Asthma deaths in Cardiff 1963-74: 90 deaths outside hospital. Br Med J 1976;1:1493. 42. Sears MR, O’Donnell TV, Rea HH. Asthma mortality and socioeconomicstatus. NZ Med J 1985;98:765. 43. StrunkRC, Mrazek DA, FuhrmannGSW, LaBrecqueJF. Physiologic andpsychologicalcharacteristicsassociatedwith deaths due to asthma in childhood: a case-controlledstudy. JAMA 1985;254:1193.