Bhs Inggris Who Cds Cpc Tb 99.264 Eng

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CONSENSUS STATEMENT

Global Burden of TuberculosisEstimated Incidence, Prevalence, and Mortality by CountryChristopher Dye, DPhil

Suzanne Scheele, MS

Paul Dolin, DPhil

Vikram Pathania, MBA

Mario C. Raviglione, MD

for the WHO Global Surveillanceand Monitoring Project

THE MOST RECENT PUBLISHED

estimates of the global bur-den of tuberculosis (TB)1- 5

are based on data availableup to 1990 and, with 1 exception,5

give figures for regions of the worldrather than individual countries. Themagnitude of the tuberculosis prob-lem has changed since 1990, due tochanging control practices, spread ofhuman immunodeficiency virus(HIV), and population growth. As aninterim measure, the World Health

Organization (WHO)6

published arevised set of estimates for 1996,obtained by scaling earlier WorldBank5 estimates to 1996 populationsizes. A more thorough review isneeded to take account of nearly adecade of change in TB epidemiologyand to accommodate new data.

Our main aim was to estimate riskand prevalence of Mycobacteriumtuberculosis (MTB) infection and TBincidence, prevalence, and mortalityfor 1997. The results are the fullestand most up-to-date assessment wecan currently make of TB burden bycountry, by region, and globally.They define the magnitude of theglobal TB control problem for use inassessing present control efforts and

provide a baseline from which toforecast and measure impact of con-trol efforts.

METHODS

Data and Methods of Estimation

For all countries, participants re-viewed available data on:

case notifications (all forms, pul-monary, smear-positive, extrapulmo-nary) and case detection rate, includ-ing evidence for overreporting andunderreporting;

prevalence of infection (via tuber-culin surveys), giving estimates of theannual risk of infection (ARI), and an-nual rate of decline in ARI;

Author Affiliations: Communicable Diseases Preven-tionand Control,World Health Organization, Geneva,Switzerland.A complete list of the panel members of the WHOGlobal Surveillanceand Monitoring Project appears atthe end of this article.Corresponding Author and Reprints: ChristopherDye,DPhil, Communicable Diseases Prevention and Con-trol, World Health Organization, CH-1211Geneva 27,Switzerland (e-mail: [email protected]).

Objective To estimate the risk and prevalence ofMycobacterium tuberculosis (MTB)infection and tuberculosis (TB) incidence, prevalence, and mortality, including diseaseattributable to human immunodeficiency virus (HIV), for 212 countries in 1997.

Participants A panel of 86 TB experts and epidemiologists from more than 40 coun-tries was chosen by the World Health Organization (WHO), with final agreement be-ing reached between country experts and WHO staff.

Evidence Incidence of TB and mortality in each country was determined by (1) casenotification to the WHO, (2) annual risk of infection data from tuberculin surveys, and(3) data on prevalence of smear-positive pulmonary disease from prevalence surveys.

Estimates derived from relatively poor data were strongly influenced by panel mem-ber opinion. Objective estimates were derived from high-quality data collected re-cently by approved procedures.

Consensus Process Agreement was reached by (1) participants reviewing meth-ods and data and making provisional estimates in closed workshops held at WHOs 6regional offices, (2) principal authors refining estimates using standard methods andall available data, and (3) country experts reviewing and adjusting these estimates andreaching final agreement with WHO staff.

Conclusions In 1997, new cases of TB totaled an estimated 7.96 million (range, 6.3million11.1 million), including 3.52 million (2.8 million4.9 million) cases (44%) ofinfectious pulmonary disease (smear-positive), and there were 16.2 million (12.1 million22.5 million) existing cases of disease. An estimated 1.87 million (1.4 million2.8 mil-lion) people died of TB and the global case fatality rate was 23% but exceeded 50%in some African countries with high HIV rates. Global prevalence of MTB infection was

32% (1.86 billion people). Eighty percent of all incident TB cases were found in 22countries, with more than half the cases occurring in 5 Southeast Asian countries. Nineof 10 countries with the highest incidence rates per capita were in Africa. Prevalenceof MTB/HIV coinfection worldwide was 0.18% and 640 000 incident TB cases (8%)had HIV infection. The global burden of tuberculosis remains enormous, mainly be-cause of poor control in Southeast Asia, sub-Saharan Africa, and eastern Europe, andbecause of high rates ofM tuberculosis and HIV coinfection in some African countries.

JAMA. 1999;282:677-686 www.jama.com

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prevalence of disease (surveys ofsmear microscopy and sputum cul-ture studies; x-ray surveys);

incidence and prevalence of HIVand acquired immunodeficiency syn-drome (AIDS)(general population sur-

veys, surveys among special groupssuch as pregnant women and TB pa-tients);

numbers of cases untreated; num-bers treated under the WHO controlstrategy (directlyobservedtherapy, short-course [DOTS]) and other programs;

TB mortality (case fatality rates[CFRs] from vital registration and pa-tient cohort data, DOTS/non-DOTSprograms, HIV infected/uninfected);

duration of illness (DOTS/non-DOTS programs, untreated cases, HIVinfected/uninfected);

proportion of smear-positive casesand ratio of smear-positiveincidence toARI; and

demography (population size,population fractionage 15 years, lifeexpectancy from birth).

These data were used to estimate TBincidence(new infections or cases of dis-ease), prevalence (existing cases), andmortality in each country by 3 differ-ent methods, based on (1) cases noti-fied to WHO,6,7 (2) ARI data derivedfromtuberculin surveys, and(3)data on

prevalence of smear-positive pulmo-nary disease from prevalence surveys.We made estimates for eachcountry us-ing the most reliable of the 3 kinds of

data, identified in Appendix 1 (all4 appendixes are available at http://www.jama.com). We ranked thedata byquality, using 3 grades, from low (*) tohigh (***). Low means there were no re-cent data or the data were not collected

using standard epidemiological meth-ods. Estimates derived from relativelypoor data were strongly influenced bypanel member opinions. More objec-tive estimates were derived from high-quality data collected recently and byapproved procedures. For case notifi-cations, reliability was judged by con-sistencyof reports from year to year andfromsurveillance methodsusedandcov-erage within countries. Prevalence sur-veys of infection and disease, includingsurveys of HIV, were judged by their de-sign (sample size, choiceof study popu-

lations, and analytical methods), bywhether they appeared to be represen-tative of an entire country, and by sur-vey date. Although the decision regard-ing best data from a countrysometimesrequired comparison of different kindsof information (eg, case notifications vsprevalence survey), rankings were gen-erally obvious. The following formulasformed the basis of the analysis:

(1) Incidence/105 Persons/Year =(Case Notifications/105 Persons/Year)/Estimated Proportion ofCases Detected

(2 ) Pr ev al ence/ 1 05 Per so ns =Incidence/105 Persons/Year AverageDuration of Illness, Year

(3) Deaths/105 Persons/Year =Incidence/105 Persons/Year CFR

(4) IncidenceSputumSmear-PositiveCases/105 Persons/Year = Annual Riskof Infection, % S

S in equation 4 is the empirically de-rived ratio of smear-positive inci-dence to percentage ARI. Equations 1through 4 can be rearranged to esti-mate incidence, prevalence, and mor-tality via the 3 methods mentionedherein (notifications [method 1], riskof infection [method 2], or diseaseprevalence [method 3]).

Case Notifications, Case Detection,

and Incidence

To calculate incidence from case noti-fications, an independent estimate of the

case detection rate is required (equa-tion 1), ie, the proportion of incidentcases that is notified to WHO,1,7 whichis often smaller than the proportion ofincident cases treated. Tuberculosiscases are mostly underreported, so thecase detectionrate is generallyless than100%. However, the fraction underre-ported is sometimes offset by overdi-agnosis (especially by x-ray) and bydoublereporting of individualcases (eg,where patient visits rather than pa-tients are recorded and where refer-

rals are made between notifying treat-ment centers).

Information is most reliable forsmear-positive cases recorded and re-ported as recommended for DOTS pro-grams.8 Thus, in this analysis, we firstestimated, where possible, the smear-positive incidence rate in DOTS areas.In countries that do not have signifi-cant DOTS coverage (10% of thepopulation6,7), we estimated the pro-portion of treated cases from data onhealth services coverage, drug avail-

ability, and patient condition (eg, ad-vanced disease suggests long delays toseeking treatment and low case detec-tion). The incidence rate for all formsof disease was obtained by dividing by0.45 (for HIV-uninfected cases; range,0.4-0.5 for uncertainty analysis;TABLE1). For HIV-infected cases, weused the divisor 0.35 (range, 0.3-0.4;

Table 1.Global Values of Parameters Used in Calculating TB Incidence, Prevalence, andMortality Rates, With Ranges Used for Uncertainty Analysis*

Variable Value (Range)Reference

Sources

Proportion of HIV-negative incident cases that aresmear-positive

0.45 (0.4-0.5) 2

Proportion of HIV-positive incident cases that aresmear-positive

0.35 (0.3-0.4) 15, 26, 35-37

Duration of illness in untreated HIV-negative cases, y 2.0 (1.5-2.5) 9, 17

Duration of illness in untreated HIV-positive cases, y 0.5 (0.25-1.0) 10-13

CFR in unt reat ed smear-positive cases 0.7 (0.55-0.75) 2, 16, 17

CFR in untreated smear-negative cases 0.2 (0.1-0.3) 17, 18

CFR in untreated HIV-positive cases 0.9 (0.85-1.0) Assumed: no data

Ratio of smear-positive incidence/105/year toannual risk of infection, %

50 (30-70) 9, 14; Thi s study

*Parameters shown in this table are those having the same values for all countries. Parameters with country-specificvalues are given in the Appendixes. TB indicates tuberculosis; HIV, human immunodeficiency virus; and CFR, casefatality rate.

GLOBAL BURDEN OF TUBERCULOSIS

678 JAMA, August 18, 1999Vol 282, No. 7 1999 American Medical Association. All rights reserved.



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Table 1). These are averages across allage groups and accommodate the factthat children with TB rarely producebacteriologically positive sputumsamples. Given the uncertainty associ-ated with crude estimates of inci-

dence, we have not attempted to breakdown incidence by age or sex, nor havewe adjusted the values of the fractionsherein for the difference in age distri-butions of cases between countries.

Prevalence and Duration of Illness

If the incidence is stable through time(with change of10% per year, as inmost high-burden countries), preva-lence can be calculated by multiplyingincidence by duration of illness (equa-tion 2). Alternatively, crude incidencecan be calculated from prevalence/

duration, having adjusted the resultsof adult prevalence surveys for agestructure.

Few direct measurements have beenmade of duration of illness, so judg-ments were made on the basis of healthservices quality, including patterns ofdrug useand availability, andfraction ofcases treated in the private sector. Theduration of infectious pulmonary dis-ease is easiest to define because it can beequated with thetime duringwhich a pa-tient receiving treatment produces vis-

ible bacilli in sputumsmears, thoughthedelay between the onset of symptomsand diagnosis is often uncertain.

We made separate assessments of thelength of illness for patients treated us-ing DOTS, those treated in other pro-grams (non-DOTS), HIV-infected per-sons, and those receiving no treatment(Table 1 and Appendixes 2 and 3). Anuntreated individual wasassumed to beill for 2 years (range, 1.5-2.5 years) onaverage13 or 0.5 years (range, 0.25-1.0years) for TB cases with HIV infec-

tion.

14-17

Good control programswill re-duce average length of illness by mini-mizing diagnostic delays and ensuringthat patients adhere to short-coursetreatment. Poor programs, in which di-agnostic delays are longer and treat-ment failure is common, can result inan increase in average duration of ill-ness to beyond 2 years. The duration

was thus varied from 0.5 to 3.5 yearsin 6-month steps, according to data foreach country. The agreed-on durationof illness was 0.8years in countries withgood DOTSprograms (eg,United Statesand western Europe), and 1.5 years in

countries with less effective programs(eg, Laos andPapua New Guinea). Theduration of illness in non-DOTS pro-grams is typically more variable andlonger on average; the agreed-on rangewas 1 year (eg, industrialized coun-tries) to 3.5 years (eg, Cambodia andIndonesia, where surveys show rela-tively high disease prevalence). Theweighted average duration was calcu-lated for each country by assessing theproportion of cases in each category,and this weighted average was used inequation 2.

Mortality and CFRs

The annual TB mortality rate was cal-culatedas the product of the annual in-cidence rate and the CFR (equation 3).The CFR is the proportion of personswith incident cases dying of TB. It in-cludes TB deaths during the 6 to 8months of short-course treatment andafterward in a proportion of treatmentfailures, treatment defaulters, and re-lapses. Like duration of illness, case fa-tality differsby whethercases aretreated

in DOTS or non-DOTS programs or nottreated, are HIV-infected, and/or haveother infectious or noninfectious dis-ease. The CFRs for untreated cases areshown in Table 1.2,18-22 The CFRs un-der treatment varied between coun-tries and are shown in Appendix 2.23-26

The DOTS programs provide rela-tively accurate data on death in pa-tients evaluated in cohorts7; these rateshave been adjusted upward to esti-mate number of deaths in all patientstreated via DOTS. Death rates in non-

DOTS areas are generallymeasuredlessaccurately; they are more variable andhigher on average than in DOTS ar-eas.7 The weighted CFR was calcu-lated from the proportions of cases ineach category and used in equation 3.Published mortality rates27 generally un-derestimate deaths and have been usedto put lower bounds on the CFR.

Annual Risk of Infection

The incidence of infectious TB can becalculated from the ARI (equation 4).An increase of 1 percentage point in ARIhas been associated with an increase of49 (95% confidence interval, 39-59)

smear-positive cases per 100000 popu-lation.4,18 The approximate 1:50 ratiohas become a rule of thumb in TB epi-demiology. However, difficulties us-ing this method arise because the rulewas established from only 6 studies ofincidence, prevalence, and mortal-ity,14 the ratio is expected to increaseas TB incidence declines due to che-motherapy,28 it is likely to be affectedby rates of HIV, and there are numer-ous problems in interpreting tubercu-lin survey results.29 Since the validityof the 1:50 rule is in question, we

checked its usefulness with a math-ematical model developed to forecastthe impact of TB control.28 Based oncomputer simulation results, we choseto use the 1:50 ratio (range, 35-65)where nomore than5% ofTB cases hadHIV infection.

Prevalence of Infection

Having estimated ARI directly (tuber-culin surveys) or indirectly (back-calculated from incidence using equa-tion 4), we calculated the proportion,

p, of the population infected with MTB.In the simplest case, where ARI hasbeen constant through time and hu-man survivorship is roughly constantwith age,p (L[1 eARI.L])/(ARI.L),where L is life expectancy.30 This is eas-ily modified for the case where risk ofinfection has been declining throughtime. These are approximate calcula-tions ofpbecause (1) estimates of ARIfor 1997 aregenerally imprecise;(2) therate of ARI decline has rarely been mea-sured accurately andmay not have been

constant through time; and (3) mortal-ity rate varies with age, more soin developed countries. More sophisti-cated calculation methods will onlybe justified by availability of betterdata.

The best data are for industrializedcountries, such as the Netherlands,United States, and Japan, where TB in-





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cidence has been in decline (6% peryear) for several decades. For these 3countries, more refined age-struc-tured models have been used to esti-mate infection rate.31-33 We interpo-lated between the results of these

analyses to estimate infection rate inother industrialized countries or re-gions (western Europe, NorthAmerica,Australia and New Zealand) and in Ca-ribbean islands, in preference to themethod mentioned earlier.

TB AND HIV

The prevalence of MTB infection,p,hasbecome especially important in coun-tries with high HIV infection rates be-cause those who are coinfected are athigh risk of developing TB.34 The HIVprevalence in adults and children in

1997 by country has been estimated bythe Joint United Nations Programme onHIV/AIDS (UNAIDS) and WHO,35 andwe have used their estimates through-out. A crude estimateof MTB/HIV coin-fection prevalence can be obtainedfromthe product of MTB and HIV preva-lencesin thewhole population. TheHIVprevalence in all TBcases has been takenfrom various sources, particularlytheUSCensus Bureaus HIV/AIDS Surveil-lance Database, January 1997.36

Parameters having the same values

for all countries are given in Table 1.Country-specific values of all other pa-rameters arelisted in Appendix 2. Theseare, for smear-positive and smear-negative patients in DOTS and non-DOTS programs, fractions of patientsuntreated and treated in different pro-grams, andCFRs. They also include du-ration of illness, proportion of smear-positive cases notified, ARI, percentagechange in ARI per year, and preva-lence of smear-positive disease.

With these input data, and using

equations1 through 4, we estimated thevaluesof11TB indicators for each coun-try, including incidence (all forms),incidence of smear-positive disease,prevalence (all forms), prevalence ofsmear-positivedisease, prevalence of in-fection, deaths, CFR, fraction ofTB casesinfected with HIV, fraction of personswith MTB/HIV coinfection, case detec-

tion rate (all forms), and case detectionrate (smear-positive disease).

Uncertainty Analysis

Multivariate uncertainty and sensitiv-ity analyses were used to evaluate mag-

nitude and causes of error surround-ing estimates of incidence, prevalence,and mortality. For the 22 highest-incidence countries (estimated to have80% of all new cases), we assignedlower and upper bounds, as well aspoint estimates, to all parameters (Ap-pendix 4a). To fix these bounds, weused the literature on TB natural his-tory (eg, to assess variation in the frac-tion of new cases that is smear-positive), confidence limits on pointestimates calculated fromdiseasepreva-lence surveys, and alternative esti-

mates from secondary sources of data(eg, incidence estimated from ARI andnotificationdata). For each country, weassumedtriangular distributions for pa-rameter values, with the apex at themost likely value and lower and upperbounds fixing the width of the base.One thousand Monte Carlo simula-tions were done using Palisade@Risksoftware (Palisade Corp, Newfield,NY).The 5th and 95th percentiles were usedas lower and upper bounds for inci-dence, prevalence, and deaths.

Software for Estimation

Calculations underpinning the 3 meth-ods of estimation (based on notifica-tions, risk of infection, and prevalenceof disease) were arrayed on 3 templatesusing Microsoft Excel (Microsoft Inc,Redmond, Wash). One template waschosen for each country and calcula-tions carried out with country-specificdata.Copiesof spreadsheets forall coun-tries are available from the authors.

Consensus

Agreement was reached in 3 steps. First,most of the 86 participants (from morethan 40 countries) attended regionalworkshops. At the workshops, meth-ods were presented, discussed, andagreed on, and preliminary calcula-tions carried out for the major en-demic countries withineach region. The

second round of analyses was done bythe principal authors on spreadsheetsin standard format using all availabledata as appropriate. Third, each par-ticipant was sent copies of data, as-sumptions, analyses, and results from

round 2 for the relevant countries.These were reviewed and adjusted ifnew information had become avail-able, and final agreement was reachedwith WHO staff.

RESULTS

As expected, data were highly variablein type, quality, and availability. In Ap-pendix 1 (parts a, b, c, d, e, and f), foreach country, the types of data ob-tained and sources are given. In Ap-pendix 2, the input data used for esti-mates for each country are provided.

The estimates were based on case no-tifications for 141 countries, particu-larly in Africa, the Americas, and Eu-rope (Appendix 2a); on tuberculinsurveys for 24 countries, notably inNorth Africa and the Middle East (Ap-pendix 2b); and on prevalence sur-veys for 14 countries, mainly in South-east Asia andtheWestern Pacific region(Appendix 2c).

Incidence, prevalence, and deaths for1997 were calculated as numbers andrates (percentages or per 100 000 per-

sons). TABLE2 summarizes the resultsfor various parts of the world by WHOregion.TABLE3presents results for the22 highest-incidence countries. The re-sults for all countries are shown in Ap-pendixes 3a, 3b, 3c, 3d, 3e, and 3f, andFIGURE 1 and FIGURE 2, including inci-dence and prevalence of smear-positivedisease, prevalenceof infection,percent-ageof cases that were HIV-positive, andrates of MTB/HIV coinfection.

A total of 7.96 million new cases ofTB in 1997 were estimated, including

3.52 million (44%) cases of infectiouspulmonary disease (smear-positive)(Table 2). In that year, 1.87 millionpeopledied of TB. Theaverage CFR was23% but it exceeded 50% in some Af-rican countries with high HIV rates.Point prevalence was16.2 million cases,of which 7.1 million were smear-positive (the majority of infectious





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cases). A total of 1.86 billion peoplewere infected with TB, or 32% of theworld population, while 10.7 millionpeople had MTB/HIV coinfection(0.18% of the world population), and640 000 incident TB cases (8%) were

associated withHIVinfection. Lessthanhalf (42%) of all estimated TB cases andabout one third (37%) of smear-positive cases, were reported to WHO.

Uncertainty analysis showed that thetop 22 TB countries had 6.36 millionnew cases, ranging from 5.0 million to8.9 million (Appendix 4b), ie, thesecountries might have 21%fewer, or 40%more cases, though we are more confi-dent about results for Brazil (7% to21%) and Peru (6% to 9%). By assum-ing that errors for estimates for the top22 countries apply globally (thereby

overestimating error), we calculate thatthe total number of new cases in 1997was in the range of 6.3 million to 11.1million cases andglobalprevalence wasbetween 12.1 million and 22.5 millioncases. Mortality could be 23% lower or

47% higher, which places total deathsin the range of 1.4 million to 2.8 mil-lion. Thus, highest and lowest esti-matesare separatedby a factorof roughly2 for incidence, prevalence, anddeaths.

Incidence estimated via case notifi-

cations (method 1, 12 of 22 high-burden countries) is most sensitive tovariation in the case detectionrate. Sen-sitivity analysis showed that death es-timates were most influenced by thecase detection rate when using method1 (5 countries, eg, India, Brazil), ex-cept where HIV rates were high. ThentheHIV infectionrate in TBpatientswasthe dominant source of uncertainty (5countries, eg, South Africa, Ethiopia).Estimates of all indicators (incidence,prevalence, deaths) derived from ARIdata (method 2, Afghanistan, Myan-

mar, Vietnam) depended primarily onS and ARI, in that order. Indicators de-rived from prevalence data (method 3)were most sensitive to the duration ofillness under non-DOTS treatment(China, Pakistan,the Philippines, Thai-

land), or to prevalence itself (Indone-sia, Bangladesh).

The 1997 incidence rate per capitawas highest in sub-Saharan Africa (259per 100 000 persons). The SoutheastAsian region accounted for the largest

number of cases (2.95 million) fol-lowed by the Western Pacific region(1.96 million). The European andAmerican regions had the fewest cases,both total and per capita. Africa had byfar the highest fraction of persons withMTB/HIV coinfection (1.2%) and thehighest fraction of TB cases that wereHIV-positive(32%, Table 2).These highrates of HIV partlyexplain thehigh CFRin Africa of 34%. Case detection rateswere highest in the Americas and Eu-rope, and low in North Africa and theMiddle East (WHOs eastern Mediter-

ranean region) and in Southeast Asia.Both of the latter 2 regions reportedonly 1 out of 4 or 5 estimated smear-positive cases.

The relatively high average inci-dence rate in Africa south of the Sahara

Table 2.Estimates of TB Burden by WHO Region*

WHO RegionPopulation,Thousands

Rates

IncidenceSS+

Incidence PrevalenceSS+

Prevalence

InfectionPrevalence,

%

TBDeathRate

CFR,%

HIV-PositiveCases,

% TB/HIV

CDRAll,

%

CDRSS+,

%

Africa 611 604 259 108 384 168 35 88 34 32 1194 31 36

The Americas 792330 52 23 72 32 18 8 16 6 64 60 75

Eastern Mediterranean 475 415 129 58 258 115 29 30 23 3 23 21 19

Europe 870 386 51 23 73 33 15 7 14 2 10 80 57

Southeast Asia 1 458 274 202 91 524 234 44 48 24 2 162 44 28

Western Pacific 1 641 179 120 54 230 96 36 22 18 0 19 43 43

Total 5 849 188 136 60 277 121 32 32 23 8 183 42 37

Numbers, Thousands

Incidence

NotifiedCases,

AllSS+

Incidence

NotifiedCases,

SS+ PrevalenceSS+

PrevalenceInfection

PrevalenceTB

Death

HIV-Positive

Cases TB/HIV

Africa 611 604 1586 499 662 241 2351 1027 211 318 540 515 7302

The Americas 792 330 411 247 182 137 567 253 142 263 66 25 510

Eastern Mediterranean 475 415 615 127 276 53 1226 547 138 010 141 16 107Europe 870 386 440 354 197 113 632 284 130 235 64 10 84

Southeast Asia 1 458 274 2948 1311 1321 368 7634 3410 646 385 705 64 2364

Western Pacific 1 641 179 1962 835 882 376 3774 1581 587 670 355 9 307

Total 5 849 188 7962 3372 3521 1287 16 184 7102 1 855 880 1871 640 10 675

*TB indicates tuberculosis; WHO, World Health Organization; incidence, new cases; SS+, sputum smear-positive; prevalence, all forms (new and existing) of cases; infection preva-lence, percentage of population infected with Mycobacterium tuberculosis(MTB); CFR, case fatality rate among TB cases; TB/HIV, MTB/HIV coinfection; CDR all, all-forms TBcase detection rate (all-forms TB case notifications/estimated all-forms incident TB); and CDR SS+, smear-positive case detection rate (SS+ case notifications/estimated SS+incident TB).

Data are given as rate per 100 000 persons unless otherwise indicated.





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Table 3.Estimates of TB Burden in the 22 Highest-Incidence Countries*

Rank CountryWHO

RegionPopulation,Thousands

Rates

IncidenceSS+

Incidence PrevalenceSS+

Prevalence

InfectionPrevalence,

%

TBDeathRate

CFR,%

HIV-PositiveCases,

%TB/HIV

CDRAll,

%

CDRSS+,

%

1 India SEAR 960 178 187 84 505 227 44 46 24 3 188 63 34

2 China WPR 1 243 738 113 51 219 91 36 21 18 0 12 30 30

3 Indonesia SEAR 204 323 285 128 786 350 49 68 24 1 12 4 7

4 Bangladesh SEAR 122 013 246 111 508 221 46 55 23 0 8 21 25

5 Pakistan EMR 143 831 181 81 405 180 40 44 25 1 18 0 0

6 Nigeria AFR 118 369 214 93 383 166 36 58 27 14 702 7 10

7 Philippines WPR 70 724 314 141 693 310 47 68 22 0 16 94 83

8 South Africa AFR 43 336 392 159 604 263 38 166 42 45 2540 62 80

9 Russian Federation EUR 147 708 106 48 163 73 18 17 16 1 5 78 60

10 Ethiopia AFR 60 148 260 109 367 161 36 82 31 30 1543 37 24

11 Vietnam WPR 76 548 189 85 289 102 44 26 14 1 50 59 82

12 DemocraticRepublicof Congo

AFR 48 040 269 114 397 175 36 81 30 25 706 0 0

13 Brazil AMR 163 132 75 33 115 51 25 11 15 5 91 68 80

14 Tanzania AFR 31 507 308 127 396 173 23 99 32 37 1026 48 55

15 Kenya AFR 28 414 297 122 371 161 36 99 33 40 2013 47 55

16 Thailand SEAR 59 159 142 63 305 135 43 29 21 10 561 36 3617 Myanmar SEAR 46 765 171 77 348 146 41 40 24 5 384 21 27

18 Afghanistan EMR 22 132 333 150 753 342 34 104 31 5 0 2 2

19 Uganda AFR 20 791 320 128 451 195 34 146 46 50 1532 42 65

20 Peru AMR 24 367 265 119 288 129 44 30 11 2 131 65 95

21 Zimbabwe AFR 11 682 538 207 626 264 36 283 53 65 4603 70 60

22 Cambodia WPR 10 516 539 241 963 426 64 90 17 3 792 28 50

Total 3 657 421 174 77 375 164 39 41 24 7 213 41 34

Numbers, Thousands

Incidence

NotifiedCases,

AllSS+

Incidence

NotifiedCases,

SS+ PrevalenceSS+

PrevalenceInfection

PrevalenceTB

Death

HIV-PositiveCases

TB/HIV

1 India SEAR 960 178 1799 1136 805 274 4854 2182 422 569 437 45 1804

2 China WPR 1243 738 1402 419 630 189 2721 1132 445 343 258 5 143

3 Indonesia SEAR 204 323 583 22 262 19 1606 715 99 920 140 6 25

4 Bangladesh SEAR 122 013 300 63 135 33 620 270 56 260 68 1 10

5 Pakistan EMR 143 831 261 0 117 0 583 259 57 110 64 3 25

6 Nigeria AFR 118 369 253 17 110 11 454 197 42 773 69 35 831

7 Philippines WPR 70 724 222 208 100 83 490 219 33 523 48 1 11

8 South Africa AFR 43 336 170 105 69 55 262 114 16 449 72 76 1101

9 Russian Federation EUR 147 708 156 121 70 42 241 108 26 587 26 1 7

10 Ethiopia AFR 60 148 156 59 66 16 221 97 21 471 49 47 928

11 Vietnam WPR 76 548 145 85 65 54 221 78 33 592 20 1 39

12 DemocraticRepublicof Congo

AFR 48 040 129 0 55 0 191 84 17 140 39 32 339

13 Brazil AMR 163 132 122 83 54 43 188 83 41 382 19 6 149

14 Tanzania AFR 31 507 97 46 40 22 125 54 7277 31 36 323

15 Kenya AFR 28 414 84 40 35 19 106 46 10 156 28 34 572

16 Thailand SEAR 59 159 84 30 37 13 180 80 25 175 17 8 332

17 Myanmar SEAR 46 765 80 17 36 10 163 68 19 074 19 4 179

18 Afghanistan EMR 22 132 74 1 33 1 167 76 7431 23 4 0

19 Uganda AFR 20 791 66 28 27 17 94 41 7120 30 33 31820 Peru AMR 24 367 65 42 29 27 70 32 10 795 7 1 32

21 Zimbabwe AFR 11 682 63 44 24 15 73 31 4188 33 41 538

22 Cambodia WPR 10 516 57 16 25 13 101 45 6738 9 2 83

Total 3 657421 6367 2583 2824 956 13 728 6011 1 412074 1506 421 7791

*These countries are ranked by number of cases and are positioned in a list of the 22 highest-incidence countries on the basis of numbers of new cases. TB indicates tuberculosis;WHO, World Health Organization; incidence, new cases; SS+, sputum smear-positive; prevalence, all forms (new and existing) of cases; infection prevalence, percentage ofpopulation infected with Mycobacterium tuberculosis (MTB); CFR, case fatality rate among TB cases; TB/HIV, MTB/HIV coinfection; CDR all, all-forms TB case detection rate(all-forms TB case notifications/estimated all-forms incident TB); CDR SS+, smear-positive case detection rate (SS+ case notifications/estimated ss+ incident TB); SEAR, South-east Asian region; WPR, Western Pacific region; EMR, Eastern Mediterranean region; AFR, African region; EUR, European region; and AMR, American region.

Data are given as rate per 100 000 persons unless otherwise indicated.





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(Table2) is influenced by very high ratesin some southern African countries. Ofthe 10 countries with the highest inci-dence rates per capita, 9 were in Africa(Cambodia is the exception). They in-clude Botswana, Namibia, South Af-

rica, Zambia, and Zimbabwe, and allhave incidence rates of about 400 per100 000 persons or more. These highrates were associated with high MTB/HIV coinfection rates (more than 2.5%in the general population). East Afri-can and coastal West African countrieshad intermediate incidence rates in therange of 250 to 300 per 100 000 per-sons, whilelower rates (upto about250per 100 000 persons) are found inlandin West and Central Africa (BurkinaFaso, Cameroon, Central African Re-public, Chad, Niger).

Not surprisingly, the Americas werethemostepidemiologicallydiverseof the6 regions (Appendix 3). Incidence rates

in major countries varied from less than10 (Canada, the United States) to morethan 250 per 100 000 persons (Bolivia,Haiti,Peru), andtheprevalence of MTB/HIV coinfection varied from almost 0%to more than 1% in Haiti. The greatest

numbersofcaseswere inBrazilandPeru,the2 South Americancountries that arerepresented in the top 22 (Table 3).

More than 60% of the new cases inNorth Africa and the Middle East werein 3 countries: Pakistan(42%),Afghani-stan (12%), and Sudan (9%). Afghani-stan reported only 2% of the esti-mated total number of cases, andPakistan did not report any cases in1997. The high incidence rate inDjibouti (668 per 100 000 persons) isdue to many TB cases coming fromneighboring countries solely for TB

treatment. We have includedthese non-nationals in our estimate because theyare also included in the case notifica-

tions reportedto WHO. Compared withthe rest of the region, a relatively highproportion of cases (15%) had HIV in-fection in Djibouti and Sudan.

Europe remains divided betweenwest and east in terms of TB rates. In-

cidence rates in western Europe werebelow 25 per 100 000 persons in 1997,except for Spain (61 per 100 000) andPortugal (55 per 100 000). In easternEurope, rates were more than 30 per100 000, except in the Czech Repub-lic (20 per 100 000), and more than 70per 100 000 in Romania, the RussianFederation, and the 5 republics of cen-tral Asia. Independently estimated in-cidence and CFRs were only weaklycorrelated across Europe. The expla-nation is that, in low incidence coun-tries of western Europe, a high propor-

tion of cases occur in elderly peoplewho die of other causes while under-going TB treatment. Eastern Euro-

Figure 1.Estimated Per Capita Incidence Rates of Tuberculosis (All Forms) by Country in 1997

Range of Rates(per 100000)


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pean countries have a higher inci-dence, but mortality is markedlyreduced by drug therapy, though pa-tients receiving inadequate regimensmay remain chronically ill.

Southeast Asia contained 3 of the 4

highest-burden countries: India (1.8million new cases in 1997), Indonesia(583 000 cases), and Bangladesh(300 000 cases). Thailand and Myan-mar also ranked among the top 22(Table 3). The smear-positive case de-tection rate was low in all these coun-tries, especially Indonesia (7%). WhileMTB/HIV coinfection rates were high-est in Africa, more people were coin-fected in India (1.8 million in 1997)than in other countries.

The Western Pacific region is domi-nated by China, which in 1997 sup-

ported three quarters (76%) of the re-gions population and a similar fractionof TB cases (1.40 million [72%]). Next

in importance were the Philippines(219 000 cases) and Vietnam (145 000cases) followed by Cambodia, Korea,Japan, and Malaysia. Less than 1% ofall TB cases and deaths in the regionwere associated with HIV. Cambodia,

where 3% of cases are linked to HIV,departed most markedly from the re-gional average.

COMMENT

This country-by-country analysis hasyielded a relatively high number of in-cident TB cases globally (7.96 mil-lion) compared with previous esti-mates for 1990.1-5 In carrying out thisstudy, we have had to work with theconsiderable uncertainties that sur-round estimates for many countries.These uncertainties explain some of the

differencesbetween present results andprevious ones. However, our new es-timate of worldwide incidence prob-

ably reflects real and marked in-creases in human population size andHIV infection rates,and changes in con-trol practices occurring since 1990.

The highest incidence of HIV infec-tion is in Africa; Kenya and Zimbabwe

now rank among the top 22 TB-endemic countries, and South Africa,Ethiopia, andTanzaniahavemoved fur-ther up thelist.6 Tuberculosiscontrolhasimproved substantially in some coun-tries but deteriorated in others. Break-down of control in some countries hasledto obvious increasesin reportedcases(eg, the Russian Federation), but im-provements elsewhere have not yetcaused convincing declines in inci-dence (eg, Peru, Morocco).6,7 If globalTB incidence is increasing, the rise ap-pears roughly consistent with the fore-

cast of 8.4 million new cases in the year200028; thehigherprediction of10.2 mil-lion cases1 now seems less likely.

Figure 2.Estimated Numbers of Tuberculosis Cases (All Forms) by Country in 1997

Ranges

0-999

1000-9999

10000-99999

100000-999999

>1000000

No Estimate

No estimates are available for disputed territories Taiwan, Kashmir, and Western Sahara. Estimates for French Guyana and Guadeloupe are included with France, fol-lowing their system of case notification. Circled arrows represent islands off the map. Left, top to bottom: Cook Islands, French Polynesia, Pitcairn Island, Niue. Right,Tokelau, Samoa, American Samoa, Wallis and Futuna, Tonga. Printed with permission from the World Health Organization.





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While incidence is high, our esti-mate of the TB death rate in 1997 (32per 100 000) is lower than some pre-vious estimates. This reflects the grow-ing conviction among TB experts thatCFRs have previously been overesti-

mated. Inferior drug treatment may notdefinitively cure patients or signifi-cantly reduce transmission, but it willoften prevent death. We have also as-sumed lower CFRs for smear-negativedisease (average, 20%) than some pre-viousauthors.2 If there has been anyrealreduction in case fatality globally or inthe major endemic countries since1990, this analysis is not sensitiveenough to detect it.

The proportion of TB cases with HIVinfection has certainly been rising dur-ing the 1990s. Our global 1997 esti-

mate of 8% is2 to 10timesgreater thanthe 1990 estimates.1,3 However, it ap-pears not to have increased as fast asin previous forecasts of 8.4% for 1995and 13.8% for 2000.1 The burden ofHIV per capita is outstandingly highin sub-Saharan Africa (32% of TBcases infected), though there is greatvariation among African countries(0%-75%). However, the largest num-ber of coinfected individuals residesin India.

We would like to be able to call the

results presented here best estimatesin a formal statistical sense. However,given the poor quality of much of theunderlying data,they are better thoughtof as plausible estimates. They repre-senta consensus among manyTB expertsaround the world but will certainly besubject to improvementwhenbetter dataareavailable. Theuncertainty surround-ing incidenceandmortalityestimates islarge: uncertainty analysis for the 22highest-burden countries suggests thatglobal incidence and prevalence could

be21%loweror40%higher.Therecouldbe 23% fewer or 47% more deaths. Thedifferencebetweenlower andupper esti-mates is a factor of about 2. Percentageerrors on estimates from low-burdencountrieswill belower,but these smallererrors attached to lower incidence esti-mates will have little impact on uncer-tainty on a global scale.

There are various ways to improvedata quality, andeach hasits merits. Spe-cial surveys of the prevalence of diseaseor infection can provide accurate esti-matesof theTB burden inselected coun-tries.Forexample,a recent diseasepreva-

lence survey in the Philippines

37

hasgreatly improved understanding of thescale of theTB problem there. But goodprevalencesurveysofbothinfectionanddisease arescarce, andresources arenotavailableto survey the entire world. Ontop of this, surveys of MTB infectionprevalence havebecome harder to inter-pret in the presence of HIV. The rule ofthumb that smear-positive incidenceincreasesby 50 per 100000 persons peryear for every 1% increase in ARI18 doesnot hold in areas where HIV infectionrates are high and where TB incidence

is in rapid decline.28

The only way to improve data qual-ity globally is to increase case notifica-tion reliability, ie, by improving TB sur-veillance. In this analysis, incidenceestimates for most countries (141 of 179countries and island groups) were ob-tained by dividing case notification rateby estimated case detection rate (equa-tion 1). In general, this method is lessaccurate where the case detection rateis low, andthe case detectionis thoughtto be less than 50% (all forms or smear-

positive cases) for about half of the top22 countries (Table 3). The case detec-tion rates for many countries are prob-ably lower than estimated here be-cause notifications include casesreported more than once. Moreover,certain forms of TB are difficult to di-agnose, especially smear-negative dis-ease, even when facilities are ideal. Butthe error for the case detection ratecould be reduced for many countries,perhaps to within 10%. Reaching thisgoal would bring significantbenefits be-

cause good TB surveillance often en-courages good TB control, and rou-tinely collected data would give a moreaccurate picture of the global impact ofcontrol efforts.

Web Site Posting: The appendixes referred to in thisarticle are available at http://www.jama.com.Disclaimer: The designations used and the presen-tationof material onFigures1 and 2 donotimply theexpression of any opinion whatsoever on the part of

the World Health Organization concerning the legalstatus of any country, territory, city, or area or of itsauthorities, or concerning thedelimitationof itsfron-tiers or boundaries. Linesrepresent approximatebor-ders on which there may not yet be full agreement.Contributors: The work described in this article wascarried outby theauthorsin conjunction with thefol-lowing external advisor panel (identified by countryof origin) and WHO staff:

African Region: Francis Adatu-Engwau, MD, MPH,Giuliano Gargioni, MD (Uganda); Pierre Chaulet, MD(Algeria); Pieter Feenstra, MD, Takele Geressu, MD,MPH (Ethiopia); Anthony David Harries, MA, MD,FRCP (Malawi); Bah Keita, MD (Cote dIvoire);DanielK. Kibuga, MD (Kenya); Edward T. Maganu, MD(South Africa); Nyagosya S. Range, BS, MSc (Tanza-nia); Olayemi Sofola, MBBS (Nigeria) (WHO staff:Oumou Bah-Sow, MD, Christy L. Hanson, MPH,Eugene A. Nyarko, MD).American Region: Olga Balestrino (Argentina); JoseE. Becerra, MD,MPH,NancyJeanneBinkin,MD, MPH,GeorgeCauthen,PhD, Christopher J. L. Murray, MD,PhD, Joshua A. Salomon (United States); C. Ruiz-Matus (Mexico); J. UeleresBraga(Brazil); Alvaro Yanez(Chile) (WHO staff: Jose Ramon Cruz, MD, RodolfoRodriguez Cruz, Fabio Luelmo,MD, Diana Weil, MSc).Eastern Mediterranean Region: SalahThabit Al-Awaldi,MD (Oman); Elsadig Mahgoub El Tayeb, MD(Sudan); Talaat Helmy Girgis, MD, Pieter J. M.van Maaren, MD, MBA (Egypt); Imtiaz Jehan, MD(Pakistan); (WHO staff: MohammadAkhtar, MD, MSc,MPH, Flavia Bustreo, MD, MPH, Zuhair Hallaj, MD,DrPh, Akihiro Seita, MD).EuropeanRegion: AlexanderG. Khomenko,MD, PhD(Russia); Hans L. Rieder, MD, MPH (Switzerland);Kazimierz R oszkowski, MD (Poland); Vale rieSchwoebel, MD, MPH (France); and Jaap Veen,MD, PhD (the Netherlands) (WHO staff: SieghartDittmann,MD, EvaMarie Englund,MPH, MalgorzataGrzemska, MD, Tunde-Agnes Madaras, MD,Richard Zalesky, MD).SoutheastAsian Region: Marijke Becx-Bleumink, MD,PhD(the Netherlands); Pierpaolode Colombani, MD(Bangladesh); Asit KumarChakraborthy, MBBS,DTCD,MNAMS, Sankaran Nair, MSc, MPH, Ganham NagaVenkata Ramana, MD (India) (WHO staff: ThomasR. Frieden, MD,MPH, M. Gunaratne, JacobKumare-s a n , M D , P h D , L i i s a P a r k k a l i , M D , P h D , S .

Radhakrishna, Holger Sawert, MD, MSc, Ian Smith,MB, ChB, MPH).Western Pacific Region: ThuridurArnadottir, MD, MPH(Iceland); Jane C. Baltazar, MD, DrPH, Vivian S. Lo-franco, MD (the Philippines); Maarten C. J. Bosman,MD (theNetherlands); ZhaoFeng-Zeng,MD (China);P. Gondrie, Eun-Gyu Lee (Republic of Korea); Woo-Jin Lew (Democratic Peoples Republicof Korea); ToruMori, Takashi Yoshiyama (Japan); Mohd Salleh MatJais(Malaysia); NouSovann,MD (Cambodia); N. ThienHuong (Vietnam) (WHO staff: Dongil Ahn, MD,Leopold Blanc,MD, MPH, Michael Levy, MD,Pierre-Yves Norval, MD, MPH, Gilles Poumerol, MD, MSc).Acknowledgment: Eduardo Martins Netto, MD, MMS,MPH, Paul Nunn, MD, Bernhard Schwartlander, MD,PhD, Philippe Sudre, MD, PhD, and Brian Williams,PhD, gave valuable adviceon analyticalmethods andpresentation.

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It is not the answer that enlightens, but the question.Eugene Ionesco (1912-1994)




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