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Prevalence trends of latent tuberculosis infection at the global, regional, and country levels from 1990–2019

  • Cheng Ding
    Affiliations
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China
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  • Ming Hu
    Affiliations
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China
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  • Wanru Guo
    Affiliations
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China
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  • Wenjuan Hu
    Affiliations
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China
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  • Xiaomeng Li
    Affiliations
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China
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  • Shuting Wang
    Affiliations
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China
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  • Yanwan Shangguan
    Affiliations
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China
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  • Ying Zhang
    Correspondence
    Corresponding author State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China
    Affiliations
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China
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  • Shigui Yang
    Correspondence
    Corresponding author State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China
    Affiliations
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China
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  • Kaijin Xu
    Correspondence
    Corresponding author State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China
    Affiliations
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China
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Open AccessPublished:May 13, 2022DOI:https://doi.org/10.1016/j.ijid.2022.05.029

      Highlights

      • Prevalence of latent tuberculosis infection decreased slowly worldwide.
      • Disease burden in the prevalence of latent tuberculosis infection varied geographically.
      • Much more effort on latent tuberculosis infection should be made worldwide.

      Abstract

      Objectives

      To track the prevalence trends of latent tuberculosis infection (LTBI) at the global, regional, and national levels.

      Methods

      Data on the prevalence of LTBI were extracted from the Global Burden of Disease database. The average annual percent change (AAPC) was estimated by joinpoint regression and was used to evaluate the epidemic of the disease.

      Results

      Globally, the prevalence rate of LTBI decreased from 30.66% in 1990 to 23.67% in 2019, with an AAPC of -0.9%. The prevalence rate of LTBI varied from 5.02% (Jordan) to 48.35% (Uganda) in 1990 and from 2.51% (Jordan) to 43.75% (Vietnam) in 2019 at the country level. The prevalence decreased in all the six World Health Organization (WHO) regions and in most countries, with the AAPC ranging from -0.5% in the Western Pacific Region to -2.1% in the European Region and from -4.3% (Bhutan) to -0.1% (Malaysia, Myanmar, South Africa, Tokelau, and Vietnam), respectively. Disparities were also observed among different sex and age groups.

      Conclusion

      The prevalence of LTBI decreased slightly worldwide in the last three decades, but the decrease is slow and not sufficient to meet the targets of WHO tuberculosis elimination. Much more effort and progress should be made in order to decrease the prevalence of LTBI.

      Keywords

      Introduction

      Tuberculosis (TB), which is caused by the acid-fast bacillus, Mycobacterium tuberculosis (MTB), is present in all countries and age groups (

      World Health Organization, Tuberculosis, 2021c. https://www.who.int/news-room/fact-sheets/detail/tuberculosis; Accessed October 15, 2021.

      ). TB was the leading cause of death in 2019 (

      World Health Organization. Global tuberculosis report 2020, Available at https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2020; Accessed March 9, 2021.

      ) and second only to COVID-19 in 2020 from a single infectious agent (), despite the fact that it is a curable and preventable disease. In 2020, an estimated 10 million people fell ill (127 cases per 100,000 population) and 1.5 million died due to TB worldwide (

      World Health Organization, Tuberculosis, 2021c. https://www.who.int/news-room/fact-sheets/detail/tuberculosis; Accessed October 15, 2021.

      ).
      Latent TB infection (LTBI) is defined as a state of persistent immune response to stimulation by MTB antigens with no evidence of clinically manifest active TB (

      Programme GT. WHO consolidated guidelines on tuberculosis: module 1: prevention: tuberculosis preventive treatment, 2020, https://apps.who.int/iris/bitstream/handle/10665/331525/9789240002906-eng.pdf; (accessed December 6, 2021).

      ). Individuals with LTBI have a 5–10% lifetime risk of progressing to active TB (
      • Bloom BR
      • Atun R
      • Cohen T
      • Dye C
      • Fraser H
      • Gomez GB
      • et al.
      Tuberculosis.
      ;
      • Vynnycky E
      • Fine PE.
      Lifetime risks, incubation period, and serial interval of tuberculosis.
      ;

      World Health Organization, Tuberculosis, 2021c. https://www.who.int/news-room/fact-sheets/detail/tuberculosis; Accessed October 15, 2021.

      ), and half of that risk is progression during the first two years after infection and remains for the lifetime(
      • Jacobson KR.
      Tuberculosis.
      ;
      • Lillebaek T
      • Dirksen A
      • Baess I
      • Strunge B
      • Thomsen VØ
      • Andersen AB.
      Molecular evidence of endogenous reactivation of Mycobacterium tuberculosis after 33 years of latent infection.
      ). An estimated 32% of the world population were infected with MTB in 1997 (
      • Dye C
      • Scheele S
      • Dolin P
      • Pathania V
      • Raviglione MC.
      Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country.
      ;
      • Getahun H
      • Matteelli A
      • Chaisson RE
      • Raviglione M.
      Latent Mycobacterium tuberculosis infection.
      ), and it was 23.0% in 2014 (
      • Houben RM
      • Dodd PJ.
      The global burden of latent tuberculosis infection: A re-estimation using mathematical modelling.
      ). Currently, the World Health Organization (WHO) reports that about one-quarter of the population is latently infected (

      World Health Organization, Tuberculosis, 2021c. https://www.who.int/news-room/fact-sheets/detail/tuberculosis; Accessed October 15, 2021.

      ).
      Individuals with LTBI represent a reservoir of infection and there remains to be significant uncertainty regarding the progression to active disease. LTBI is increasingly recognized as central to the programmatic TB control effort (
      • Denholm JT
      • Millan-Marcelo JC
      • Fiekert K.
      Latent tuberculosis infection and the EndTB Strategy: ethical tensions and imperatives.
      ;
      • Mancuso JD
      • Diffenderfer JM
      • Ghassemieh BJ
      • Horne DJ
      • Kao TC.
      The prevalence of latent tuberculosis infection in the United States.
      ). Both epidemiologic data and models underline the necessity of addressing LTBI in eliminating TB (
      • Knight GM
      • McQuaid CF
      • Dodd PJ
      • Houben RMGJ.
      Global burden of latent multidrug-resistant tuberculosis: trends and estimates based on mathematical modelling.
      ;
      • LoBue PA
      • Mermin JH.
      Latent tuberculosis infection: the final frontier of tuberculosis elimination in the USA.
      ;
      • Xu K
      • Ding C
      • Mangan CJ
      • Li Y
      • Ren J
      • Yang S
      • et al.
      Tuberculosis in China: A longitudinal predictive model of the general population and recommendations for achieving WHO goals.
      ). The pool of latently infected individuals will generate 16.3 and 8.3 active TB cases per 100,000 population by 2030 and 2050, respectively (
      • Houben RM
      • Dodd PJ.
      The global burden of latent tuberculosis infection: A re-estimation using mathematical modelling.
      ). The detection, treatment, and prevention before LTBI becomes infectious is a crucial component of TB elimination (
      • Barry M.
      Prevalence of latent tuberculosis infection in the Middle East and North Africa: A systematic review.
      ;
      • Chee CBE
      • Reves R
      • Zhang Y
      • Belknap R.
      Latent tuberculosis infection: opportunities and challenges.
      ).
      Notably, the global TB control efforts are not on track even before the advent of the COVID-19 pandemic, and actions are needed to reach global milestones and targets (
      • Floyd K
      • Glaziou P
      • Zumla A
      • Raviglione M.
      The global tuberculosis epidemic and progress in care, prevention, and research: an overview in year 3 of the End TB era.
      ). Although the treatment of TB has expanded in the past decades, the long-term trend in the prevalence of LTBI is uncertain and needs to be assessed (
      • Getahun H
      • Matteelli A
      • Chaisson RE
      • Raviglione M.
      Latent Mycobacterium tuberculosis infection.
      ). This study aimed to assess the global long-term trends in the prevalence of LTBI and help disease control and policy making at the global, regional, and country levels.

      Methods

      Data resources

      Data on annual prevalence of LTBI, incidence and mortality of TB, and sociodemographic index (SDI, an index used to evaluate social development) for each country were extracted by the Global Health Data Exchange (GHDx) query tool (

      Global Burden of Disease Collaborative Network. Global burden of disease Study 2019 (GBD 2019) results, 2020, Available at http://ghdx.healthdata.org/gbd-results-tool; Accessed June 1, 2021.

      ). A total of 204 countries or territories were included from 1990–2019. To match the countries listed in the WHO regions (

      World Health Organization, Countries 2021. 2021a. https://www.who.int/countries; Accessed July 21, 2021.

      ), data in Greenland, Taiwan, and the United States Virgin Islands were aggregated into Denmark, China, and the United States, respectively. Countries or territories were classified into the six WHO regions, namely, the African Region (AFR), the Region of the Americas (AMR), the Eastern Mediterranean Region (EMR), the European Region (EUR), the South East Asian Region (SEA), and the Western Pacific Region (WPR).
      The GHDx is a data catalog created and supported by the Institute for Health Metrics and Evaluation, which captures health-related data to populate the information for more than 350 diseases and injuries in 195 countries worldwide from 1990 to the present. The GBD study integrated a large number of available multisource data (annual case notifications, prevalence surveys, population-based tuberculin surveys, and estimated cause-specific rates) with the specific epidemiology of disease, and the Bayesian meta-regression tool DisMod-MR 2.1 was used as the main method of the estimation (
      GBD Tuberculosis Collaborators
      Global, regional, and national burden of tuberculosis, 1990–2016: results from the Global Burden of Diseases, Injuries, and Risk Factors 2016 Study.
      ). The purposes, history, protocols, data resources and definitions, efforts to improve the quality, and modeling were previously detailed ((
      • GBD 2017 Disease and injury incidence and prevalence collaborators
      Disease and injury incidence and prevalence collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.
      ), Institute for Health Metrics and Evaluation (

      Institute for Health Metrics and Evaluation (IHME). Protocol for the Global Burden of Disease, Injuries, and Risk Factors study (GBD), 2020, http://www.healthdata.org/gbd/about/protocol; (accessed November 18, 2021).

      ,

      Institute for Health Metrics and Evaluation (IHME). The Global Burden of Disease: a critical resource for informed policymaking, 2021b, http://www.healthdata.org/gbd/about; (accessed November 18, 2021).

      ,
      • Murray CJ
      • Ezzati M
      • Flaxman AD
      • Lim S
      • Lozano R
      • Michaud C
      • et al.
      GBD 2010: design, definitions, and metrics.
      ;
      • Murray CJ
      • Lopez AD.
      Measuring the global burden of disease.
      ). No ethical approval was obtained because the data included in this study were deidentified and publicly available.

      Statistical analysis

      The prevalence was used as the main indicator to evaluate the epidemics of LTBI by sex and age groups (0–14, 15–59, and 60+). Prevalence rate (%) was defined as the number of LTBI cases divided by the population size. The age-standardized rates (ASRs) were adjusted by the world standard population (

      Surveillance Epidemiology and End Results (SEER) Program. World (WHO 2000–2025) Standard, 2013,Available at https://seer.cancer.gov/stdpopulations/world.who.html; Accessed April 19, 2021.

      ). The average annual percentage change (AAPC, %) and its 95% confidence interval (95% CI) were used to estimate the prevalence trends. The natural logarithm of rate was assumed to be linear along with time; that is Y = α + βX + ε, where Y refers to ln (rate), X represents year, and ε is the error, β represents the trend of the period segment. AAPC was calculated as [(Exp (β)-1)] × 100, and its 95% CI was estimated by the linear model. Whether an AAPC value was different from zero was assessed by the Z test. The associations between the LTBI prevalence and SDI, incidence, and mortality rate of TB were further evaluated by linear regression. The SDI is a composite indicator and is the geometric mean of 0–1 indexes of total fertility rate under the age of 25, mean education for those ages 15 and older, and lag distributed income per capita (
      • GBD 2017 Disease and injury incidence and prevalence collaborators
      Disease and injury incidence and prevalence collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.
      ,

      Institute for Health Metrics and Evaluation (IHME). Global burden of disease Study 2019 (GBD 2019) socio-demographic index (SDI) 1950-2019, 2021a, http://ghdx.healthdata.org/record/ihme-data/gbd-2019-socio-demographic-index-sdi-1950-2019; Accessed June 1, 2021.

      ). Data collation and analysis were conducted by SAS 9.4 (SAS Institute Inc., Cary, NC, USA). The values of AAPC and pairwise comparisons of trends among different WHO regions were estimated by the Joinpoint Regression Program (Version 4.9.0.0. March 2021). SAS 9.4 and Origin 2021 (Microcal Software Inc., Northampton, MA, USA) were used to draw the figures. The statistical significance level was set at 0.05 (two-sided).

      Results

      Prevalence trends of LTBI at the global, regional, and country levels

      LTBI cases worldwide increased from 1,599,070,892 in 1990 to 1,799,195,771 in 2019, whereas the prevalence rate of LTBI decreased from 30.66% (ASR: 31.57%) in 1990 to 23.67% (ASR: 20.67%) in 2019 with the AAPC of -0.9% (95% CI: -0.9, -0.8, P <0.001) (Table 1). The prevalence at country level varied from 5.02% (Jordan, ASR: 6.58%) to 48.35% (Uganda, ASR: 51.27%) in 1990 and from 2.51% (Jordan, ASR: 2.71%) to 43.75% (Vietnam, ASR: 41.92%) in 2019. China accounted for the most LTBI cases in 2019, followed by India and Indonesia. From 1990–2019, the prevalence decreased in most countries with negative values of AAPC (all P<0.05), which ranged from -4.3% (Bhutan) to -0.1% (Malaysia, Myanmar, South Africa, Tokelau, and Vietnam). LTBI increased in countries of American Samoa, Cook Islands, Democratic People's Republic of Korea, Fiji, Guam, Iran, Kenya, Kiribati, Marshall Islands, Mauritius, Micronesia, Nauru, Northern Mariana Islands, Palau, Papua New Guinea, Philippines, Samoa, Seychelles, Solomon Islands, Sri Lanka, Tonga, Tuvalu, and Vanuatu, with negative AAPCs (all P <0.05), which ranged from 0.1–1.0%. The prevalence trend was stable in Indonesia and Niue (AAPCs: 0.0%) (Figure 1, Table 1, and Supplementary Figure 1).
      Table 1Prevalence trends of LTBI at the global, regional, and national levels, 1990-2019
      19902019AAPC (95% CI), P-value
      WHO Regions/

      Country
      AbbreviationCasesCrude/Age-standardized RateCasesCrude/Age-standardized RateTotalFemaleMaleAge 1-14Age 15-59Age 60+
      Global159907089230.66/31.57179919577123.67/20.67-0.9(-0.9, -0.8), <0.001-0.9(-1, -0.8), <0.001-0.8(-0.9, -0.7), <0.001-1.4(-1.6, -1.2), <0.001-0.9(-1, -0.8), <0.001-0.9(-0.9, -0.8), <0.001
      WHO African RegionAFR16997494634.79/38.4225028139223.51/24.86-1.4(-1.4, -1.3), <0.001-1.4(-1.5, -1.4), <0.001-1.3(-1.3, -1.2), <0.001-1.8(-1.9, -1.7), <0.001-1.3(-1.4, -1.2), <0.001-0.7(-0.8, -0.6), <0.001
      AlgeriaDZ437085517.81/22.1738612249.42/9.43-2(-2.1, -1.9), <0.001-2(-2, -1.9), <0.001-2(-2.1, -2), <0.001-3.4(-3.5, -3.4), <0.001-2.5(-2.6, -2.4), <0.001-2.5(-2.6, -2.5), <0.001
      AngolaAO364822737.02/40.73823180628.31/33.4-1(-1.1, -0.8), <0.001-1.1(-1.3, -1), <0.001-0.9(-1, -0.7), <0.001-1.7(-1.9, -1.5), <0.001-0.7(-0.8, -0.5), <0.001-0.2(-0.3, -0.1), <0.001
      BeninBJ158205434.15/39.41226474318.58/22.53-2(-2.1, -1.9), <0.001-2.2(-2.3, -2), <0.001-1.8(-1.9, -1.7), <0.001-2.4(-2.4, -2.3), <0.001-2.1(-2.2, -1.9), <0.001-1.1(-1.2, -1), <0.001
      BotswanaBW31765925.16/27.9233095714.44/15.3-1.7(-1.9, -1.5), <0.001-1.9(-2.1, -1.8), <0.001-1.6(-1.8, -1.4), <0.001-2(-2.1, -1.9), <0.001-2.1(-2.3, -1.9), <0.001-1(-1.1, -0.9), <0.001
      Burkina FasoBF339268237.14/41.63428779619.66/23.75-2.1(-2.2, -2.1), <0.001-2.3(-2.3, -2.2), <0.001-2(-2.1, -2), <0.001-3(-3.1, -2.9), <0.001-2(-2.1, -1.9), <0.001-1.1(-1.1, -1), <0.001
      BurundiBI193895036.42/41.24254513922.15/25.98-1.8(-1.9, -1.8), <0.001-2(-2.1, -2), <0.001-1.6(-1.7, -1.6), <0.001-2.1(-2.2, -2), <0.001-1.9(-2, -1.8), <0.001-0.8(-0.9, -0.8), <0.001
      Cabo VerdeCV10227630.06/33.487719513.96/14.31-2.6(-2.8, -2.4), <0.001-2.8(-3, -2.6), <0.001-2.4(-2.6, -2.3), <0.001-3.6(-3.8, -3.5), <0.001-2.9(-3.2, -2.7), <0.001-2.3(-2.5, -2.1), <0.001
      CameroonCM362965036.46/40.5521916318.48/21.64-2.3(-2.5, -2.1), <0.001-2.5(-2.6, -2.3), <0.001-2.2(-2.3, -2), <0.001-3.1(-3.3, -3), <0.001-2.2(-2.4, -2), <0.001-1.2(-1.4, -1.1), <0.001
      Central African RepublicCF98578737.51/40.93184502936.07/40.59-0.2(-0.3, -0.2), <0.001-0.4(-0.5, -0.3), <0.001-0.1(-0.2, 0), 0.046-1(-1.2, -0.9), <0.0010(0, 0.1), 0.6070.2(0.2, 0.3), <0.001
      ChadTD221587938.67/42.88337929621.58/27.19-2(-2.1, -1.8), <0.001-2.1(-2.3, -1.9), <0.001-1.8(-2, -1.7), <0.001-2.6(-2.8, -2.5), <0.001-1.6(-1.9, -1.4), <0.001-0.7(-0.9, -0.6), <0.001
      ComorosKM15943935.64/40.2715216721.79/23.13-1.8(-1.8, -1.7), <0.001-1.9(-2, -1.8), <0.001-1.6(-1.7, -1.5), <0.001-2.3(-2.4, -2.2), <0.001-2(-2.1, -1.9), <0.001-1.2(-1.2, -1.1), <0.001
      CongoCG79178633.7/37.22150733429.41/32.25-0.6(-0.8, -0.5), <0.001-0.8(-1, -0.7), <0.001-0.4(-0.6, -0.3), <0.001-1.5(-1.7, -1.3), <0.001-0.5(-0.6, -0.4), <0.001-0.1(-0.2, -0.1), 0.003
      Cote d'IvoireCI421073935.99/40.14521859420.61/23.77-1.9(-2, -1.7), <0.001-2(-2.2, -1.9), <0.001-1.8(-1.9, -1.6), <0.001-2.8(-2.9, -2.7), <0.001-1.8(-2, -1.6), <0.001-0.9(-1.1, -0.8), <0.001
      Democratic Republic of CongoCD1269884334.46/38.382619873930.87/35.37-0.4(-0.5, -0.2), <0.001-0.6(-0.7, -0.4), <0.001-0.1(-0.3, 0), 0.035-0.9(-1.1, -0.7), <0.001-0.2(-0.3, -0.1), 0.0010.1(0.1, 0.2), 0.001
      Equatorial GuineaGQ15668638.29/42.1832642223.61/27.26-1.9(-2, -1.8), <0.001-2(-2.2, -1.9), <0.001-1.7(-1.8, -1.6), <0.001-2.9(-3, -2.7), <0.001-1.7(-1.8, -1.6), <0.001-1(-1.1, -1), <0.001
      EritreaER112137638.94/43.55149812322.98/26.09-1.8(-1.8, -1.7), <0.001-1.9(-2, -1.9), <0.001-1.6(-1.7, -1.5), <0.001-2.2(-2.3, -2.2), <0.001-1.8(-1.9, -1.7), <0.001-0.8(-0.9, -0.7), <0.001
      EswatiniSZ26945134.72/39.0925801223.17/25.75-1.2(-1.4, -1), <0.001-1.3(-1.6, -1.1), <0.001-1.1(-1.3, -0.8), <0.001-1.4(-1.6, -1.2), <0.001-1.5(-1.8, -1.3), <0.001-0.5(-0.7, -0.3), <0.001
      EthiopiaET1745755335.53/38.993312938631.83/35.25-0.4(-0.5, -0.3), <0.001-0.5(-0.5, -0.4), <0.001-0.4(-0.4, -0.3), <0.001-0.5(-0.6, -0.4), <0.001-0.5(-0.6, -0.4), <0.0010(0, 0.1), 0.11
      GabonGA29041730.44/33.2544775626.21/28-0.5(-0.6, -0.3), <0.001-0.7(-0.8, -0.5), <0.001-0.2(-0.4, -0.1), 0.003-1.2(-1.5, -1), <0.001-0.5(-0.7, -0.3), <0.001-0.1(-0.2, 0.1), 0.352
      GambiaGM28652530.26/34.4134317215.76/18.68-2.2(-2.3, -2), <0.001-2.3(-2.4, -2.2), <0.001-2.1(-2.2, -1.9), <0.001-3(-3.1, -2.9), <0.001-2.1(-2.3, -1.9), <0.001-1.2(-1.4, -1.1), <0.001
      GhanaGH582238440.32/43.81690671522.49/24.96-1.8(-1.9, -1.6), <0.001-1.9(-2, -1.7), <0.001-1.7(-1.8, -1.5), <0.001-2.8(-2.9, -2.8), <0.001-1.8(-2, -1.6), <0.001-0.9(-1.1, -0.8), <0.001
      GuineaGN233254439.53/43.16265543421.79/26.12-1.9(-2.1, -1.8), <0.001-2.1(-2.2, -1.9), <0.001-1.8(-1.9, -1.7), <0.001-2.8(-2.9, -2.7), <0.001-1.7(-1.9, -1.6), <0.001-0.8(-0.9, -0.7), <0.001
      Guinea-BissauGW38732640.16/44.0641761622.68/26.66-1.9(-2, -1.7), <0.001-2(-2.2, -1.8), <0.001-1.8(-1.9, -1.6), <0.001-2.9(-3, -2.8), <0.001-1.7(-1.9, -1.5), <0.001-0.8(-0.9, -0.7), <0.001
      KenyaKE575975225.89/30.381266063025.88/28.750.1(0, 0.1), 0.0070(0, 0), 0.7570.1(0.1, 0.1), <0.001-0.3(-0.4, -0.1), 0.001-0.1(-0.2, -0.1), <0.0010.3(0.2, 0.3), <0.001
      LesothoLS65382737.37/40.3655512727.12/28.89-0.9(-1.1, -0.7), <0.001-1.1(-1.2, -0.9), <0.001-0.8(-1, -0.6), <0.001-1.2(-1.4, -1.1), <0.001-1.2(-1.4, -1), <0.001-0.3(-0.4, -0.2), <0.001
      LiberiaLR72766438.54/42.293694120.1/23-2.3(-2.4, -2.2), <0.001-2.5(-2.6, -2.4), <0.001-2.1(-2.2, -2.1), <0.001-3.3(-3.4, -3.1), <0.001-2.2(-2.3, -2.1), <0.001-1.2(-1.3, -1.2), <0.001
      MadagascarMG398553034.79/39.56574314722.2/25.42-1.5(-1.6, -1.4), <0.001-1.6(-1.7, -1.6), <0.001-1.4(-1.4, -1.3), <0.001-1.7(-1.8, -1.6), <0.001-1.6(-1.7, -1.5), <0.001-0.7(-0.7, -0.6), <0.001
      MalawiMW214782623.52/29.35219707612.26/14.42-2.8(-3, -2.6), <0.001-2.8(-3, -2.6), <0.001-2.8(-3, -2.6), <0.001-3.1(-3.6, -2.5), <0.001-2.8(-2.9, -2.7), <0.001-1.9(-2, -1.9), <0.001
      MaliML321552238.9/42.9410911119.55/24-2.3(-2.4, -2.2), <0.001-2.4(-2.5, -2.4), <0.001-2.1(-2.2, -2.1), <0.001-3.1(-3.2, -2.9), <0.001-2(-2.2, -1.9), <0.001-1(-1.1, -0.9), <0.001
      MauritaniaMR73117536.89/40.6366619317.04/19.64-2.5(-2.7, -2.4), <0.001-2.7(-2.8, -2.5), <0.001-2.4(-2.5, -2.2), <0.001-3.3(-3.4, -3.3), <0.001-2.4(-2.7, -2.2), <0.001-1.5(-1.7, -1.3), <0.001
      MauritiusMU25177423.35/23.435533628.11/25.320.9(0.8, 1), <0.0010.8(0.7, 0.9), <0.0010.9(0.8, 1), <0.001-1.2(-1.3, -1), <0.0010.8(0.7, 0.8), <0.0011.1(1, 1.2), <0.001
      MozambiqueMZ474214437.84/42.32599589721.07/25.22-2(-2, -1.9), <0.001-2.1(-2.2, -2.1), <0.001-1.8(-1.9, -1.8), <0.001-2.2(-2.2, -2.1), <0.001-1.9(-2, -1.8), <0.001-0.9(-0.9, -0.8), <0.001
      NamibiaNA50847337.3/40.4146736619.95/21.89-2.1(-2.3, -1.9), <0.001-2.3(-2.5, -2.1), <0.001-2(-2.2, -1.7), <0.001-2.4(-2.6, -2.3), <0.001-2.3(-2.6, -2.1), <0.001-1.3(-1.4, -1.1), <0.001
      NigerNE299835539.36/43.89445174120.04/25.54-2.4(-2.5, -2.2), <0.001-2.5(-2.6, -2.3), <0.001-2.3(-2.4, -2.1), <0.001-3.1(-3.2, -3.1), <0.001-2(-2.2, -1.8), <0.001-1(-1.1, -0.9), <0.001
      NigeriaNG3111275336.02/38.634123597319.85/23.16-2.1(-2.2, -1.9), <0.001-2.2(-2.3, -2), <0.001-2(-2.1, -1.9), <0.001-2.8(-2.9, -2.7), <0.001-1.8(-1.9, -1.6), <0.001-1.1(-1.2, -1), <0.001
      RwandaRW253294636.84/41.68242103719.61/21.97-2.3(-2.5, -2.2), <0.001-2.5(-2.7, -2.3), <0.001-2.2(-2.3, -2), <0.001-2.9(-3.1, -2.7), <0.001-2.5(-2.7, -2.3), <0.001-1.4(-1.5, -1.2), <0.001
      Sao Tome and PrincipeST4049534.58/38.643393916.9/18.82-2.4(-2.5, -2.2), <0.001-2.5(-2.7, -2.4), <0.001-2.2(-2.4, -2.1), <0.001-3.3(-3.4, -3.2), <0.001-2.4(-2.6, -2.2), <0.001-1.6(-1.7, -1.4), <0.001
      SenegalSN266525336.52/40.8291559519.85/22.9-2(-2.2, -1.9), <0.001-2.1(-2.3, -2), <0.001-1.9(-2.1, -1.8), <0.001-2.9(-3, -2.9), <0.001-2(-2.2, -1.8), <0.001-1.1(-1.2, -1), <0.001
      SeychellesSC1929027.03/27.582939929.2/27.350.3(0.3, 0.4), <0.0010.3(0.2, 0.3), <0.0010.4(0.4, 0.5), <0.001-1.8(-1.8, -1.7), <0.0010.3(0.2, 0.4), <0.0010.6(0.6, 0.7), <0.001
      Sierra LeoneSL134204938.27/41.61164195520.47/23.8-2.1(-2.2, -1.9), <0.001-2.2(-2.4, -2.1), <0.001-1.9(-2.1, -1.8), <0.001-2.9(-3, -2.8), <0.001-1.9(-2.2, -1.7), <0.001-1(-1.2, -0.9), <0.001
      South AfricaZA1571644243.78/44.92369406343.41/43.43-0.1(-0.1, 0), 0.02-0.1(-0.2, 0), 0.0050(-0.1, 0), 0.11-0.1(-0.2, 0), 0.047-0.2(-0.2, -0.1), <0.0010(0, 0), <0.001
      South SudanGS199660135.47/39.97211994323.7/27.82-1.4(-1.5, -1.4), <0.001-1.5(-1.5, -1.4), <0.001-1.4(-1.4, -1.3), <0.001-1.5(-1.6, -1.5), <0.001-1.4(-1.5, -1.3), <0.001-0.5(-0.6, -0.5), <0.001
      TogoTG120947634.46/39.01149907619.48/22.3-1.9(-2.1, -1.8), <0.001-2(-2.2, -1.8), <0.001-1.8(-2, -1.7), <0.001-2.8(-3, -2.7), <0.001-1.9(-2.1, -1.7), <0.001-1.1(-1.3, -0.9), <0.001
      UgandaUG795830948.35/51.271390293135.1/39.83-1.1(-1.2, -1), <0.001-1.2(-1.3, -1.1), <0.001-1(-1.1, -0.9), <0.001-1.6(-1.8, -1.4), <0.001-0.8(-0.9, -0.7), <0.001-0.2(-0.3, -0.2), <0.001
      United Republic of TanzaniaTZ667397826.94/32.04687602712.56/14.67-2.6(-2.8, -2.4), <0.001-2.7(-2.9, -2.5), <0.001-2.5(-2.7, -2.3), <0.001-2.3(-2.8, -1.8), <0.001-2.8(-2.9, -2.7), <0.001-1.9(-2, -1.9), <0.001
      ZambiaZM280210336.94/41.59303571617.2/20.12-2.6(-2.7, -2.5), <0.001-2.7(-2.8, -2.5), <0.001-2.5(-2.6, -2.4), <0.001-3(-3, -2.9), <0.001-2.6(-2.8, -2.4), <0.001-1.5(-1.6, -1.3), <0.001
      ZimbabweZW201412120.2/23.22163535511.22/12.82-1.7(-2.1, -1.3), <0.001-1.7(-2.1, -1.3), <0.001-1.7(-2.1, -1.3), <0.001-1.6(-2, -1.2), <0.001-2(-2.4, -1.6), <0.001-0.8(-1.2, -0.5), <0.001
      WHO Region of the AmericasAMR17704176925.15/33.3419005225219.02/20.58-1(-1, -0.9), <0.001-0.8(-0.8, -0.7), <0.001-1.2(-1.2, -1.1), <0.001-2.2(-2.3, -2.2), <0.001-1.1(-1.1, -1), <0.001-0.7(-0.8, -0.7), <0.001
      Antigua and BarbudaAG1802630.35/31.341790220.46/18.72-1.4(-1.4, -1.3), <0.001-1.3(-1.3, -1.2), <0.001-1.5(-1.5, -1.4), <0.001-2.6(-2.6, -2.5), <0.001-1.6(-1.7, -1.5), <0.001-1.5(-1.6, -1.5), <0.001
      ArgentinaAR884495527.26/28.27794912417.89/17.31-1.3(-1.4, -1.3), <0.001-1.4(-1.5, -1.4), <0.001-1.3(-1.3, -1.2), <0.001-1.6(-1.6, -1.5), <0.001-1.5(-1.5, -1.5), <0.001-1.9(-1.9, -1.8), <0.001
      BahamasBS7909731.47/32.688351522.4/20.95-1.2(-1.2, -1.1), <0.001-1.1(-1.1, -1), <0.001-1.3(-1.3, -1.2), <0.001-2.4(-2.5, -2.2), <0.001-1.3(-1.3, -1.3), <0.001-1.3(-1.3, -1.3), <0.001
      BarbadosBB7721230.91/30.556021020.41/18.11-1.4(-1.4, -1.4), <0.001-1.4(-1.4, -1.3), <0.001-1.5(-1.5, -1.5), <0.001-2.7(-2.8, -2.6), <0.001-1.5(-1.5, -1.4), <0.001-1.6(-1.6, -1.6), <0.001
      BelizeBZ5719331.75/35.918873122.04/23.11-1.3(-1.3, -1.2), <0.001-1.1(-1.2, -1.1), <0.001-1.4(-1.5, -1.3), <0.001-2.4(-2.5, -2.3), <0.001-1.5(-1.5, -1.4), <0.001-1.3(-1.4, -1.2), <0.001
      BermudaBM1624927.74/26.31967415.23/13-2.1(-2.1, -2.1), <0.001-2.1(-2.1, -2.1), <0.001-2.1(-2.2, -2.1), <0.001-3.3(-3.4, -3.1), <0.001-2.1(-2.1, -2.1), <0.001-2.4(-2.4, -2.4), <0.001
      BoliviaBO214557234.66/38.5207746817.76/18.99-2.2(-2.3, -2.1), <0.001-2.3(-2.4, -2.2), <0.001-2.1(-2.2, -2), <0.001-3.5(-3.6, -3.5), <0.001-2.3(-2.4, -2.2), <0.001-2.1(-2.3, -2), <0.001
      BrazilBR4927397833.86/35.755607396526.25/24.86-0.9(-0.9, -0.8), <0.001-0.7(-0.7, -0.7), <0.001-1(-1.1, -1), <0.001-2.2(-2.3, -2.2), <0.001-1(-1.1, -1), <0.001-1.2(-1.2, -1.1), <0.001
      CanadaCA292748910.9/10.14380248010.52/9.3-0.2(-0.2, -0.2), <0.001-0.2(-0.2, -0.1), <0.001-0.2(-0.2, -0.2), <0.001-0.3(-0.4, -0.2), <0.001-0.3(-0.3, -0.3), <0.001-0.4(-0.5, -0.4), <0.001
      ChileCL333693125.7/26.93272097015.14/13.98-1.8(-1.8, -1.8), <0.001-1.9(-1.9, -1.9), <0.001-1.8(-1.8, -1.8), <0.001-2.2(-2.2, -2.1), <0.001-2.1(-2.1, -2.1), <0.001-2.6(-2.6, -2.5), <0.001
      ColombiaCO1102759534.85/37.011034470422.01/21.11-1.5(-1.6, -1.4), <0.001-1.1(-1.2, -1), <0.001-2(-2, -2), <0.001-2.7(-2.8, -2.7), <0.001-1.7(-1.8, -1.6), <0.001-1.8(-1.9, -1.7), <0.001
      Costa RicaCR81518527.54/29.6695076320.44/19.44-1.1(-1.3, -1), <0.001-0.8(-0.9, -0.7), <0.001-1.6(-1.7, -1.5), <0.001-2.3(-2.4, -2.2), <0.001-1.5(-1.6, -1.3), <0.001-1.5(-1.6, -1.4), <0.001
      CubaCU296267027.82/27.27200599117.82/15.63-1.5(-1.6, -1.5), <0.001-1.5(-1.6, -1.4), <0.001-1.6(-1.7, -1.6), <0.001-2.7(-2.7, -2.6), <0.001-1.6(-1.7, -1.5), <0.001-1.9(-2, -1.8), <0.001
      DominicaDM2297431.77/33.341704425.12/23.64-0.8(-0.8, -0.8), <0.001-0.8(-0.8, -0.7), <0.001-0.8(-0.9, -0.8), <0.001-2.1(-2.2, -1.9), <0.001-1(-1, -0.9), <0.001-1.1(-1.1, -1), <0.001
      Dominican RepublicDO255348536.62/39.44240913322.6/23-1.5(-1.5, -1.4), <0.001-1.4(-1.4, -1.3), <0.001-1.6(-1.6, -1.5), <0.001-2.8(-3, -2.7), <0.001-1.6(-1.6, -1.5), <0.001-1.6(-1.6, -1.5), <0.001
      EcuadorEC286192129.4/32.31246657014.3/14.73-2.4(-2.4, -2.3), <0.001-2.5(-2.5, -2.4), <0.001-2.3(-2.4, -2.3), <0.001-3.5(-3.7, -3.3), <0.001-2.5(-2.6, -2.5), <0.001-2.4(-2.5, -2.4), <0.001
      El SalvadorSV192698737.71/40.89148522124.17/24.23-1.5(-1.5, -1.4), <0.001-1.1(-1.1, -1), <0.001-2.1(-2.2, -2), <0.001-2.9(-3, -2.7), <0.001-1.6(-1.7, -1.6), <0.001-1.7(-1.8, -1.7), <0.001
      GrenadaGD2781633.23/35.92330422.88/21.65-1.1(-1.2, -1.1), <0.001-1(-1.1, -1), <0.001-1.2(-1.2, -1.2), <0.001-2.6(-2.7, -2.5), <0.001-1.4(-1.4, -1.4), <0.001-1.3(-1.4, -1.2), <0.001
      GuatemalaGT307123540.18/44.66486030927.98/29.84-1.2(-1.3, -1.2), <0.001-0.8(-0.8, -0.8), <0.001-1.8(-1.8, -1.7), <0.001-2.7(-2.8, -2.6), <0.001-1.3(-1.4, -1.3), <0.001-1.2(-1.3, -1.2), <0.001
      GuyanaGY28126737.58/40.1219963526.39/26.6-1(-1.1, -1), <0.001-0.9(-1, -0.9), <0.001-1.2(-1.2, -1.1), <0.001-2.3(-2.4, -2.2), <0.001-1.1(-1.2, -1), <0.001-1(-1.1, -1), <0.001
      HaitiHT269096343.93/47.09390744732.33/34.74-1(-1.1, -1), <0.001-0.9(-0.9, -0.9), <0.001-1.2(-1.2, -1.1), <0.001-2.5(-2.6, -2.5), <0.001-0.9(-0.9, -0.8), <0.001-0.7(-0.8, -0.6), <0.001
      HondurasHN173526938.26/43.18268680828.03/29.93-1(-1.1, -1), <0.001-0.6(-0.7, -0.6), <0.001-1.5(-1.6, -1.4), <0.001-2.3(-2.4, -2.3), <0.001-1.2(-1.3, -1.1), <0.001-1.1(-1.1, -1), <0.001
      JamaicaJM68180829.53/31.658272121/20.28-1.2(-1.3, -1.2), <0.001-1.1(-1.2, -1.1), <0.001-1.3(-1.4, -1.2), <0.001-2.4(-2.5, -2.3), <0.001-1.5(-1.5, -1.4), <0.001-1.5(-1.5, -1.4), <0.001
      MexicoMX2911177535.04/37.823177771225.86/25.47-1(-1, -0.9), <0.001-0.6(-0.7, -0.6), <0.001-1.4(-1.4, -1.4), <0.001-2(-2.1, -1.9), <0.001-1.2(-1.2, -1.1), <0.001-1.2(-1.2, -1.2), <0.001
      NicaraguaNI129499334.54/39.58143676922.52/23.52-1.6(-1.7, -1.4), <0.001-1.1(-1.3, -1), <0.001-2.1(-2.3, -1.9), <0.001-2.9(-3, -2.8), <0.001-1.8(-2, -1.7), <0.001-1.7(-1.9, -1.6), <0.001
      PanamaPA75475832.38/34.2587607721.45/21.52-1.3(-1.4, -1.1), <0.001-0.9(-1.1, -0.8), <0.001-1.7(-1.8, -1.6), <0.001-2.3(-2.4, -2.2), <0.001-1.3(-1.5, -1.2), <0.001-1.4(-1.5, -1.2), <0.001
      ParaguayPY130320633.24/36.82154007422.63/23.29-1.2(-1.3, -1.1), <0.001-1.1(-1.2, -0.9), <0.001-1.4(-1.5, -1.3), <0.001-2.7(-2.7, -2.6), <0.001-1.4(-1.6, -1.3), <0.001-1.3(-1.5, -1.2), <0.001
      PeruPE599650228.43/31.19452486113.56/13.61-2.6(-2.7, -2.5), <0.001-2.7(-2.7, -2.6), <0.001-2.5(-2.6, -2.5), <0.001-3.8(-3.9, -3.7), <0.001-2.8(-2.8, -2.7), <0.001-2.8(-2.9, -2.8), <0.001
      Puerto RicoPR92451426.06/26.1355445415.86/14.1-1.9(-1.9, -1.8), <0.001-1.8(-1.9, -1.8), <0.001-1.9(-2, -1.9), <0.001-3.1(-3.2, -3), <0.001-2(-2.1, -1.9), <0.001-2.2(-2.3, -2.2), <0.001
      Saint Kitts and NevisKN1194929.53/31.291156919.67/17.9-1.3(-1.3, -1.3), <0.001-1.3(-1.3, -1.2), <0.001-1.4(-1.4, -1.3), <0.001-2.7(-2.8, -2.6), <0.001-1.6(-1.6, -1.5), <0.001-1.5(-1.6, -1.5), <0.001
      Saint LuciaLC4305532.21/35.043901422.57/20.58-1.2(-1.2, -1.1), <0.001-1.1(-1.1, -1.1), <0.001-1.3(-1.3, -1.2), <0.001-2.7(-2.8, -2.6), <0.001-1.5(-1.5, -1.5), <0.001-1.7(-1.7, -1.7), <0.001
      Saint Vincent and the GrenadinesVC3419831.82/34.592748124.61/23.21-0.9(-0.9, -0.8), <0.001-0.8(-0.9, -0.8), <0.001-0.9(-1, -0.9), <0.001-2.3(-2.4, -2.2), <0.001-1.1(-1.2, -1), <0.001-1.2(-1.3, -1.2), <0.001
      SurinameSR13765336.44/38.2314488125.55/24.83-1.2(-1.3, -1.1), <0.001-1.1(-1.2, -1), <0.001-1.3(-1.4, -1.2), <0.001-2.5(-2.6, -2.5), <0.001-1.2(-1.3, -1.1), <0.001-1.3(-1.5, -1.2), <0.001
      Trinidad and TobagoTT39173733.21/34.8931902523.25/21.24-1.3(-1.4, -1.2), <0.001-1.2(-1.3, -1.1), <0.001-1.4(-1.4, -1.3), <0.001-2.8(-2.9, -2.7), <0.001-1.5(-1.6, -1.4), <0.001-1.6(-1.7, -1.5), <0.001
      United States of AmericaUS3250386613.02/12.313683851411.36/10.12-0.6(-0.7, -0.5), <0.001-0.5(-0.6, -0.4), <0.001-0.7(-0.8, -0.6), <0.0010(-0.1, 0.1), 0.958-1(-1.1, -0.9), <0.001-0.1(-0.1, 0), <0.001
      UruguayUY80074525.96/25.6957629217/16.06-1.5(-1.5, -1.4), <0.001-1.5(-1.6, -1.5), <0.001-1.4(-1.4, -1.4), <0.001-1.5(-1.6, -1.5), <0.001-1.5(-1.6, -1.5), <0.001-2(-2.1, -2), <0.001
      Venezuela (Bolivarian Republic of)VE629694134.43/37.03656184023.77/22.98-1.3(-1.4, -1.3), <0.001-1(-1, -0.9), <0.001-1.8(-1.9, -1.8), <0.001-2.7(-2.7, -2.6), <0.001-1.6(-1.6, -1.5), <0.001-1.5(-1.5, -1.5), <0.001
      WHO Eastern Mediterranean RegionEMR10684925429.15/30.6313068021418.32/16.49-1.6(-1.6, -1.5), <0.001-1.6(-1.7, -1.6), <0.001-1.6(-1.6, -1.5), <0.001-2.2(-2.3, -2.1), <0.001-1.7(-1.8, -1.6), <0.001-1.4(-1.5, -1.4), <0.001
      AfghanistanAF304116827.79/34.74592139816.06/21.36-2(-2.2, -1.8), <0.001-2.1(-2.3, -1.9), <0.001-1.9(-2.1, -1.7), <0.001-1.3(-2, -0.5), 0.001-2.1(-2.4, -1.8), <0.001-1.4(-1.6, -1.2), <0.001
      BahrainBH13026926.33/27.7420420114.28/12.08-2.2(-2.3, -2.2), <0.001-2.3(-2.4, -2.2), <0.001-2.3(-2.3, -2.2), <0.001-3.6(-3.7, -3.5), <0.001-2.8(-2.9, -2.7), <0.001-2.6(-2.7, -2.5), <0.001
      DjiboutiDJ16707035.89/41.0920600417.62/18.97-2.6(-2.9, -2.3), <0.001-2.8(-3.1, -2.5), <0.001-2.5(-2.8, -2.2), <0.001-3.2(-3.6, -2.7), <0.001-2.8(-3.1, -2.6), <0.001-1.8(-1.9, -1.6), <0.001
      EgyptEG2073903038.49/43.192659510727.43/29.64-1.1(-1.1, -1), <0.001-1.2(-1.2, -1.1), <0.001-1(-1, -0.9), <0.001-2.5(-2.7, -2.4), <0.001-1.1(-1.2, -1.1), <0.001-0.8(-0.8, -0.7), <0.001
      Iran, Islamic Republic ofIR1226155721.59/28.382269684427.36/26.031(0.8, 1.1), <0.0011(0.9, 1.1), <0.0010.9(0.8, 1.1), <0.0010.1(-0.4, 0.6), 0.6430.4(0.3, 0.5), <0.001-0.4(-0.5, -0.4), <0.001
      IraqIQ407115624.07/30.71574728213.96/15.53-2.1(-2.2, -1.9), <0.001-2.1(-2.2, -2), <0.001-2(-2.2, -1.9), <0.001-3.1(-3.2, -3), <0.001-2.5(-2.7, -2.3), <0.001-2.1(-2.3, -1.9), <0.001
      JordanJO1826845.02/6.582856202.51/2.71-2.7(-2.8, -2.5), <0.001-2.7(-2.8, -2.6), <0.001-2.6(-2.8, -2.5), <0.001-2.8(-2.9, -2.6), <0.001-3.1(-3.2, -3), <0.001-3.1(-3.2, -2.9), <0.001
      KuwaitKW32826919.09/20.3149792911.4/10.28-1.9(-2.1, -1.8), <0.001-1.7(-1.7, -1.6), <0.001-2.1(-2.2, -1.9), <0.001-2.9(-3, -2.8), <0.001-2.3(-2.4, -2.2), <0.001-2.3(-2.4, -2.2), <0.001
      LebanonLB73905923.32/26.5154750510.79/10.58-2.8(-2.9, -2.7), <0.001-2.7(-2.8, -2.7), <0.001-2.8(-2.9, -2.8), <0.001-3.9(-4, -3.8), <0.001-3.2(-3.3, -3.1), <0.001-3.2(-3.2, -3.1), <0.001
      LibyaLY90272122.07/27.9105963315.92/15.15-1.3(-1.4, -1.1), <0.001-1.1(-1.3, -1), <0.001-1.4(-1.5, -1.2), <0.001-2.8(-2.9, -2.6), <0.001-1.9(-2.1, -1.8), <0.001-2(-2.1, -1.9), <0.001
      MoroccoMA726331329.59/34.21638572718.06/17.85-1.7(-1.7, -1.6), <0.001-1.7(-1.8, -1.6), <0.001-1.6(-1.7, -1.5), <0.001-3.1(-3.1, -3), <0.001-2(-2.1, -1.9), <0.001-1.8(-1.9, -1.7), <0.001
      OmanOM42164522.44/26.7655669812.35/11.68-1.7(-2, -1.5), <0.001-1.8(-2, -1.6), <0.001-1.8(-2, -1.6), <0.001-3.4(-3.5, -3.3), <0.001-2.5(-2.7, -2.3), <0.001-2.4(-2.5, -2.3), <0.001
      PakistanPK3397176931.36/30.123074046714.12/13.61-2.8(-2.9, -2.7), <0.001-2.8(-2.9, -2.7), <0.001-2.8(-2.9, -2.6), <0.001-2.7(-2.8, -2.6), <0.001-2.8(-2.9, -2.7), <0.001-2.8(-2.9, -2.7), <0.001
      Palestine, see Occupied Palestinian territoryPS41860621.15/28.1461665712.76/15.09-1.7(-1.8, -1.6), <0.001-1.7(-1.8, -1.7), <0.001-1.6(-1.7, -1.5), <0.001-2.6(-2.7, -2.5), <0.001-2(-2.1, -1.9), <0.001-1.7(-1.8, -1.6), <0.001
      QatarQA11683926.87/26.3934988812.33/10.55-2.9(-3, -2.8), <0.001-2.9(-3, -2.7), <0.001-3(-3.1, -2.9), <0.001-4(-4.2, -3.9), <0.001-3.4(-3.5, -3.2), <0.001-3(-3.2, -2.9), <0.001
      Saudi ArabiaSA551881635.54/40.69625703017.73/16.23-2.4(-2.4, -2.3), <0.001-2.4(-2.5, -2.4), <0.001-2.4(-2.4, -2.3), <0.001-5(-5.2, -4.8), <0.001-2.9(-2.9, -2.8), <0.001-2.4(-2.5, -2.3), <0.001
      SomaliaSO177733325.93/30.69331500316.98/20.48-1.6(-1.8, -1.4), <0.001-1.9(-2.1, -1.8), <0.001-1.2(-1.5, -1), <0.001-1.6(-1.7, -1.5), <0.001-1.6(-1.9, -1.4), <0.001-0.7(-0.9, -0.5), <0.001
      SudanSD575189829.81/36.49679077417.12/20.71-1.8(-1.9, -1.8), <0.001-1.9(-1.9, -1.8), <0.001-1.8(-1.8, -1.7), <0.001-2.9(-3, -2.9), <0.001-1.9(-2, -1.8), <0.001-1.5(-1.6, -1.4), <0.001
      Syrian Arab RepublicSY287796523.2/30.28199775014.01/14.49-2(-2.2, -1.8), <0.001-2(-2.2, -1.8), <0.001-2(-2.2, -1.9), <0.001-3.3(-3.5, -3.1), <0.001-2.5(-2.7, -2.4), <0.001-2.4(-2.5, -2.3), <0.001
      TunisiaTN189885323.13/26.82151802513.31/12.4-1.9(-2, -1.9), <0.001-1.9(-1.9, -1.9), <0.001-2(-2, -1.9), <0.001-3.3(-3.3, -3.2), <0.001-2.4(-2.4, -2.4), <0.001-2.4(-2.5, -2.4), <0.001
      United Arab EmiratesAE70743938.74/39.92284770431.01/24.94-0.7(-0.7, -0.6), <0.001-0.8(-0.9, -0.6), <0.001-0.7(-0.8, -0.7), <0.001-3.1(-3.2, -3), <0.001-1.1(-1.1, -1), <0.001-0.9(-1, -0.9), <0.001
      YemenYE356179527.18/36.15554296818.11/22.44-1.6(-1.6, -1.5), <0.001-1.7(-1.7, -1.6), <0.001-1.5(-1.6, -1.4), <0.001-3(-3.1, -2.9), <0.001-1.8(-1.8, -1.7), <0.001-1.4(-1.5, -1.3), <0.001
      WHO European RegionEUR20620630224.32/23.2112512621913.58/12.48-2.1(-2.2, -2), <0.001-2.2(-2.3, -2.1), <0.001-2(-2.1, -1.9), <0.001-3.2(-3.3, -3.1), <0.001-2(-2.1, -1.9), <0.001-2.5(-2.6, -2.4), <0.001
      AlbaniaAL105818732.8/34.6144955816.74/15.33-2.2(-2.3, -2.1), <0.001-2.3(-2.3, -2.2), <0.001-2.2(-2.2, -2.1), <0.001-3.3(-3.4, -3.2), <0.001-2.5(-2.6, -2.4), <0.001-2.9(-3, -2.8), <0.001
      AndorraAD674712.59/11.3463437.68/6.51-1.8(-1.9, -1.7), <0.001-1.7(-1.8, -1.6), <0.001-1.8(-1.9, -1.7), <0.001-1.3(-1.5, -1.2), <0.001-1.7(-1.8, -1.6), <0.001-2.3(-2.5, -2.2), <0.001
      ArmeniaAM108323932.44/33.1157735419.36/17.91-1.7(-1.8, -1.6), <0.001-1.8(-1.9, -1.7), <0.001-1.7(-1.7, -1.6), <0.001-3(-3.1, -2.9), <0.001-1.8(-1.9, -1.8), <0.001-2.3(-2.4, -2.2), <0.001
      AustriaAT102992313.41/12.176782067.68/6.8-1.9(-1.9, -1.8), <0.001-1.9(-2, -1.8), <0.001-1.8(-1.9, -1.8), <0.001-1.4(-1.4, -1.3), <0.001-1.9(-1.9, -1.8), <0.001-2.3(-2.4, -2.2), <0.001
      AzerbaijanAZ255460735.74/37.24235268723.21/21.82-1.4(-1.6, -1.3), <0.001-1.5(-1.7, -1.3), <0.001-1.4(-1.5, -1.2), <0.001-2.8(-3, -2.5), <0.001-1.5(-1.7, -1.4), <0.001-1.8(-1.9, -1.6), <0.001
      BelarusBY325488531.52/30.39154505316.44/14.68-2.1(-2.3, -1.9), <0.001-2.2(-2.5, -2), <0.001-2(-2.2, -1.8), <0.001-3.1(-3.3, -2.9), <0.001-2.2(-2.3, -2), <0.001-2.7(-2.8, -2.5), <0.001
      BelgiumBE135802213.78/12.468485867.51/6.82-2.1(-2.2, -2.1), <0.001-2.1(-2.2, -2.1), <0.001-2.1(-2.1, -2.1), <0.001-1.6(-1.6, -1.5), <0.001-2.1(-2.1, -2), <0.001-2.5(-2.6, -2.4), <0.001
      Bosnia and HerzegovinaBA155761934.84/34.0561315318.73/16.45-2.4(-2.5, -2.2), <0.001-2.5(-2.7, -2.4), <0.001-2.3(-2.4, -2.1), <0.001-3.5(-3.7, -3.3), <0.001-2.4(-2.6, -2.3), <0.001-3(-3.1, -2.8), <0.001
      BulgariaBG270972231.58/29.59130007418.91/16.64-1.7(-1.8, -1.5), <0.001-1.8(-2, -1.6), <0.001-1.6(-1.7, -1.4), <0.001-2.5(-2.7, -2.4), <0.001-1.6(-1.8, -1.5), <0.001-2.2(-2.3, -2), <0.001
      CroatiaHR127017626.22/24.5759142414.04/12.45-2.2(-2.3, -2.1), <0.001-2.3(-2.4, -2.3), <0.001-2.1(-2.2, -2), <0.001-2.9(-2.9, -2.9), <0.001-2.2(-2.2, -2.1), <0.001-2.6(-2.7, -2.6), <0.001
      CyprusCY11653815.24/14.941008927.77/6.87-2.4(-2.5, -2.4), <0.001-2.5(-2.6, -2.4), <0.001-2.4(-2.5, -2.3), <0.001-2.4(-2.5, -2.3), <0.001-2.7(-2.8, -2.6), <0.001-3.1(-3.2, -3), <0.001
      Czech RepublicCZ282764727.8/26.47149997714.24/12.66-2.1(-2.2, -2.1), <0.001-2.3(-2.3, -2.2), <0.001-2(-2.1, -2), <0.001-3(-3.2, -2.9), <0.001-2.1(-2.2, -2.1), <0.001-2.5(-2.6, -2.4), <0.001
      DenmarkDK72434314.1/12.724494337.75/7.05-2.2(-2.2, -2.1), <0.001-2.2(-2.2, -2.2), <0.001-2.2(-2.2, -2.1), <0.001-1.5(-1.6, -1.5), <0.001-2.1(-2.2, -2.1), <0.001-2.3(-2.4, -2.3), <0.001
      EstoniaEE48093431.1/29.7919448014.97/13.53-2.7(-2.8, -2.5), <0.001-2.8(-3, -2.7), <0.001-2.5(-2.7, -2.4), <0.001-3.5(-3.7, -3.3), <0.001-2.7(-2.8, -2.5), <0.001-3.2(-3.4, -3), <0.001
      FinlandFI69606014.08/12.714057157.4/6.71-2.2(-2.3, -2.2), <0.001-2.3(-2.3, -2.2), <0.001-2.2(-2.3, -2.2), <0.001-1.7(-1.8, -1.6), <0.001-2.3(-2.3, -2.2), <0.001-2.5(-2.6, -2.4), <0.001
      FranceFR781989813.72/12.7947772527.29/6.73-2.3(-2.3, -2.2), <0.001-2.3(-2.3, -2.2), <0.001-2.2(-2.3, -2.2), <0.001-1.7(-1.8, -1.6), <0.001-2.2(-2.3, -2.2), <0.001-2.7(-2.8, -2.6), <0.001
      GeorgiaGE165890730.58/29.9779197221.89/20.19-0.9(-1, -0.8), <0.001-0.9(-1, -0.9), <0.001-0.8(-0.9, -0.7), <0.001-2(-2, -2), <0.001-0.8(-0.9, -0.7), <0.001-1.3(-1.4, -1.3), <0.001
      GermanyDE1144761914.48/12.866064147.85/6.95-2(-2.1, -2), <0.001-2.1(-2.2, -2), <0.001-2(-2.1, -1.9), <0.001-1.5(-1.5, -1.4), <0.001-2(-2.1, -1.9), <0.001-2.5(-2.5, -2.4), <0.001
      GreeceGR131609612.79/11.738175507.98/7.08-1.7(-1.7, -1.6), <0.001-1.7(-1.8, -1.7), <0.001-1.6(-1.7, -1.6), <0.001-1.4(-1.5, -1.3), <0.001-1.6(-1.7, -1.5), <0.001-2.3(-2.4, -2.3), <0.001
      HungaryHU312818230.46/28.72152194315.87/14.03-2.2(-2.2, -2.1), <0.001-2.3(-2.3, -2.3), <0.001-2(-2.1, -2), <0.001-3(-3.1, -2.9), <0.001-2.1(-2.2, -2.1), <0.001-2.5(-2.6, -2.5), <0.001
      IcelandIS2738810.98/10.84235516.91/6.4-1.6(-1.7, -1.5), <0.001-1.6(-1.7, -1.5), <0.001-1.6(-1.7, -1.5), <0.001-1.3(-1.4, -1.2), <0.001-1.7(-1.8, -1.6), <0.001-2.1(-2.3, -1.9), <0.001
      IrelandIE44565012.56/12.773348076.9/6.4-2.2(-2.2, -2.1), <0.001-2.2(-2.3, -2.2), <0.001-2.2(-2.2, -2.1), <0.001-2.2(-2.3, -2), <0.001-2.3(-2.4, -2.2), <0.001-2.7(-2.8, -2.7), <0.001
      IsraelIL65949513.57/14.376804787.46/7.53-2.1(-2.1, -2), <0.001-2.1(-2.2, -2.1), <0.001-2(-2.1, -2), <0.001-1.8(-1.9, -1.7), <0.001-2.1(-2.2, -2.1), <0.001-2.5(-2.6, -2.4), <0.001
      ItalyIT820963214.6/13.1155504019.27/8.17-1.6(-1.7, -1.6), <0.001-1.7(-1.8, -1.6), <0.001-1.6(-1.7, -1.5), <0.001-1.4(-1.5, -1.2), <0.001-1.5(-1.6, -1.4), <0.001-2.2(-2.3, -2.1), <0.001
      KazakhstanKZ525628832.83/33.79344608319.1/18.77-1.9(-2.2, -1.6), <0.001-2(-2.3, -1.7), <0.001-1.8(-2.1, -1.5), <0.001-3.1(-3.4, -2.7), <0.001-1.9(-2.1, -1.6), <0.001-2.1(-2.3, -1.8), <0.001
      KyrgyzstanKG147986534.11/36.55133483820.89/21.79-1.6(-1.8, -1.5), <0.001-1.7(-1.9, -1.6), <0.001-1.6(-1.7, -1.4), <0.001-2.8(-3, -2.6), <0.001-1.6(-1.8, -1.5), <0.001-1.7(-1.8, -1.6), <0.001
      LatviaLV83693931.93/30.4332815517.31/15.54-2.2(-2.3, -2), <0.001-2.3(-2.4, -2.2), <0.001-2(-2.1, -1.9), <0.001-3(-3.2, -2.8), <0.001-2.1(-2.3, -2), <0.001-2.7(-2.8, -2.5), <0.001
      LithuaniaLT109065330.14/29.0549495117.89/16-1.8(-1.8, -1.7), <0.001-1.9(-2, -1.8), <0.001-1.6(-1.7, -1.5), <0.001-2.6(-2.7, -2.5), <0.001-1.8(-1.9, -1.7), <0.001-2.4(-2.4, -2.3), <0.001
      LuxembourgLU5393114.33/12.75455277.44/6.59-2.3(-2.4, -2.1), <0.001-2.3(-2.4, -2.1), <0.001-2.2(-2.4, -2.1), <0.001-1.7(-1.8, -1.5), <0.001-2.3(-2.4, -2.1), <0.001-2.6(-2.8, -2.5), <0.001
      MaltaMT5075513.9/13.13351588.08/7.15-1.8(-1.9, -1.8), <0.001-1.9(-1.9, -1.9), <0.001-1.7(-1.8, -1.7), <0.001-1.6(-1.6, -1.6), <0.001-2.1(-2.1, -2), <0.001-2.4(-2.5, -2.3), <0.001
      MonacoMC384312.74/10.7427517.38/6.53-1.9(-2, -1.9), <0.001-1.9(-2, -1.9), <0.001-1.9(-1.9, -1.8), <0.001-1.1(-1.1, -1), <0.001-1.8(-1.8, -1.8), <0.001-2(-2.1, -1.9), <0.001
      MontenegroME16262326.41/26.099766215.92/14.42-1.8(-2, -1.6), <0.001-1.9(-2.1, -1.7), <0.001-1.7(-1.9, -1.5), <0.001-2.5(-2.7, -2.4), <0.001-1.9(-2.1, -1.7), <0.001-2.3(-2.5, -2.1), <0.001
      NetherlandsNL181750112.34/11.2612066127.11/6.39-2(-2, -2), <0.001-2(-2.1, -2), <0.001-2(-2, -1.9), <0.001-1.4(-1.5, -1.4), <0.001-2(-2, -1.9), <0.001-2.3(-2.3, -2.3), <0.001
      North MacedoniaMK66637433.64/33.3538762218.19/16.15-2.1(-2.2, -2.1), <0.001-2.3(-2.3, -2.2), <0.001-2(-2.1, -2), <0.001-3.2(-3.2, -3.1), <0.001-2.3(-2.3, -2.2), <0.001-2.6(-2.7, -2.5), <0.001
      NorwayNO56503913.49/12.513981367.52/6.86-2(-2.1, -2), <0.001-2.1(-2.2, -2), <0.001-2(-2.1, -1.9), <0.001-1.5(-1.6, -1.5), <0.001-2(-2.1, -2), <0.001-2.3(-2.4, -2.2), <0.001
      PolandPL1270797933.78/33.04661826317.39/15.46-2.3(-2.4, -2.2), <0.001-2.4(-2.5, -2.4), <0.001-2.2(-2.2, -2.1), <0.001-3.5(-3.6, -3.4), <0.001-2.4(-2.4, -2.3), <0.001-2.8(-2.9, -2.7), <0.001
      PortugalPT164758716.44/15.418707268.24/7.24-2.4(-2.5, -2.3), <0.001-2.5(-2.6, -2.4), <0.001-2.4(-2.4, -2.3), <0.001-2.2(-2.3, -2), <0.001-2.4(-2.5, -2.3), <0.001-3.1(-3.2, -3), <0.001
      Republic of MoldovaMD151267334.63/34.5277089121.09/18.7-1.6(-1.7, -1.5), <0.001-1.7(-1.8, -1.6), <0.001-1.5(-1.6, -1.4), <0.001-2.8(-2.9, -2.6), <0.001-1.7(-1.9, -1.6), <0.001-2.2(-2.3, -2.1), <0.001
      RomaniaRO790172434.23/33.24336614517.66/15.71-2.3(-2.3, -2.2), <0.001-2.4(-2.5, -2.3), <0.001-2.2(-2.2, -2.1), <0.001-3.3(-3.3, -3.2), <0.001-2.3(-2.3, -2.2), <0.001-2.8(-2.9, -2.7), <0.001
      Russian FederationRU4960531033.29/32.122727433318.81/16.98-2(-2.3, -1.7), <0.001-2.1(-2.4, -1.8), <0.001-1.9(-2.1, -1.6), <0.001-3.1(-3.5, -2.8), <0.001-2(-2.2, -1.8), <0.001-2.4(-2.7, -2.2), <0.001
      San MarinoSM279812.02/11.1623907.29/6.58-1.8(-1.8, -1.7), <0.001-1.7(-1.8, -1.7), <0.001-1.8(-1.8, -1.7), <0.001-1.3(-1.4, -1.2), <0.001-1.7(-1.7, -1.7), <0.001-2.3(-2.4, -2.2), <0.001
      SerbiaRS312237433.69/32.12145226716.76/15.19-2.4(-2.6, -2.3), <0.001-2.5(-2.6, -2.4), <0.001-2.4(-2.5, -2.2), <0.001-3.2(-3.3, -3.2), <0.001-2.4(-2.5, -2.3), <0.001-2.8(-2.9, -2.7), <0.001
      SlovakiaSK149978928.82/28.2684765115.75/13.93-2(-2.1, -1.9), <0.001-2.1(-2.2, -2), <0.001-1.8(-1.9, -1.7), <0.001-2.9(-3, -2.8), <0.001-2.1(-2.1, -2), <0.001-2.4(-2.4, -2.4), <0.001
      SloveniaSI50415225.87/24.5627171613.22/11.66-2.4(-2.5, -2.3), <0.001-2.5(-2.6, -2.4), <0.001-2.3(-2.4, -2.1), <0.001-3.2(-3.3, -3.1), <0.001-2.3(-2.4, -2.2), <0.001-2.9(-3, -2.8), <0.001
      SpainES30224387.87/7.3612887922.82/2.49-3.6(-3.6, -3.5), <0.001-3.6(-3.7, -3.5), <0.001-3.5(-3.6, -3.5), <0.001-2.7(-3.2, -2.1), <0.001-3.5(-3.6, -3.4), <0.001-4.3(-4.5, -4.2), <0.001
      SwedenSE185589521.92/19.89176164617.43/16.08-0.7(-0.7, -0.6), <0.001-0.7(-0.7, -0.6), <0.001-0.7(-0.7, -0.6), <0.001-0.1(-0.2, 0), 0.041-0.7(-0.7, -0.6), <0.001-0.9(-1, -0.8), <0.001
      SwitzerlandCH83482112.31/10.996329857.29/6.46-1.8(-1.8, -1.7), <0.001-1.8(-1.9, -1.7), <0.001-1.7(-1.8, -1.7), <0.001-1.3(-1.3, -1.2), <0.001-1.8(-1.8, -1.7), <0.001-2.1(-2.2, -2), <0.001
      TajikistanTJ182916235.33/39.17232775625.18/26.94-1.1(-1.1, -1), <0.001-1.1(-1.2, -1.1), <0.001-1(-1.1, -1), <0.001-2.3(-2.4, -2.2), <0.001-1.1(-1.2, -1.1), <0.001-1.1(-1.1, -1), <0.001
      TurkeyTR1994145434.27/37.951469411618.28/16.68-2.4(-2.5, -2.3), <0.001-2.5(-2.6, -2.3), <0.001-2.3(-2.5, -2.2), <0.001-4.3(-4.5, -4.2), <0.001-2.8(-3, -2.6), <0.001-2.7(-2.8, -2.5), <0.001
      TurkmenistanTM122706734.28/37.53109220421.96/22.22-1.5(-1.6, -1.3), <0.001-1.5(-1.7, -1.4), <0.001-1.4(-1.5, -1.2), <0.001-2.8(-2.9, -2.6), <0.001-1.5(-1.6, -1.4), <0.001-1.7(-1.9, -1.6), <0.001
      UkraineUA1712003732.92/31.39889671720.38/18.09-1.8(-1.9, -1.6), <0.001-1.9(-2, -1.7), <0.001-1.6(-1.8, -1.5), <0.001-2.8(-3, -2.6), <0.001-1.8(-1.9, -1.6), <0.001-2.2(-2.4, -2.1), <0.001
      United Kingdom of Great Britain and Northern IrelandGB786710713.88/12.7854109558.14/7.44-1.9(-1.9, -1.8), <0.001-1.9(-1.9, -1.9), <0.001-1.8(-1.9, -1.8), <0.001-1.4(-1.4, -1.3), <0.001-1.9(-1.9, -1.8), <0.001-2.2(-2.3, -2.2), <0.001
      UzbekistanUZ657860832.48/35.8705186821.39/21.93-1.3(-1.5, -1.2), <0.001-1.4(-1.5, -1.3), <0.001-1.3(-1.4, -1.2), <0.001-2.5(-2.7, -2.4), <0.001-1.5(-1.6, -1.3), <0.001-1.4(-1.5, -1.3), <0.001
      WHO South East Asian RegionSEA41030648632.3/31.2452474975726.46/24.69-0.8(-0.8, -0.7), <0.001-0.8(-0.9, -0.8), <0.001-0.7(-0.8, -0.7), <0.001-1.5(-1.6, -1.3), <0.001-0.6(-0.6, -0.6), <0.001-0.7(-0.7, -0.6), <0.001
      BangladeshBD2366637922.46/21.52115628037.38/7.33-3.8(-3.8, -3.7), <0.001-3.8(-3.8, -3.7), <0.001-3.7(-3.8, -3.6), <0.001-3.9(-3.9, -3.8), <0.001-3.5(-3.6, -3.4), <0.001-3.6(-3.7, -3.6), <0.001
      BhutanBT11446419.36/18.55428475.78/5.75-4.3(-4.4, -4.2), <0.001-4.4(-4.5, -4.3), <0.001-4.3(-4.4, -4.2), <0.001-4.5(-4.6, -4.3), <0.001-4.1(-4.2, -4), <0.001-4.1(-4.2, -4), <0.001
      Democratic People's Republic of KoreaKP688757333.82/34.891033782839.93/36.620.6(0.4, 0.8), <0.0010.4(0.2, 0.7), <0.0010.8(0.6, 1), <0.0010.6(0.1, 1.2), 0.0310.2(0, 0.4), 0.0170(-0.2, 0.2), 0.741
      IndiaIN27329827032.9/32.2436303316926.54/26.32-0.9(-1, -0.8), <0.001-0.9(-1, -0.9), <0.001-0.8(-0.9, -0.7), <0.001-1.3(-1.5, -1.1), <0.001-0.6(-0.7, -0.6), <0.001-0.8(-0.9, -0.8), <0.001
      IndonesiaID6445883535.65/36.859080109635.51/34.760(0, 0), 0.0020(-0.1, 0), <0.0010(0, 0), 0.529-1.8(-1.8, -1.7), <0.0010.1(0, 0.1), <0.0010.3(0.3, 0.3), <0.001
      MaldivesMV6121028.69/32.0611599223.67/22.59-0.8(-0.9, -0.7), <0.001-1(-1.1, -0.9), <0.001-0.7(-0.8, -0.5), <0.001-3.1(-3.3, -2.8), <0.001-1.3(-1.4, -1.1), <0.001-0.9(-1, -0.8), <0.001
      MyanmarMM1491691237.42/39.361955636936.44/36.38-0.1(-0.2, -0.1), <0.001-0.1(-0.2, -0.1), <0.001-0.1(-0.2, -0.1), <0.001-1.6(-1.8, -1.5), <0.001-0.1(-0.2, -0.1), <0.0010.1(0.1, 0.2), <0.001
      NepalNP776636141.36/39.32412572013.84/13.68-4.1(-4.2, -3.9), <0.001-4.1(-4.3, -4), <0.001-4(-4.1, -3.8), <0.001-4.5(-4.9, -4.1), <0.001-3.8(-3.9, -3.7), <0.001-3.4(-3.5, -3.4), <0.001
      Sri LankaLK351304620.83/21.14608730428.24/26.960.9(0.7, 1.1), <0.0010.8(0.6, 0.9), <0.0011.1(0.9, 1.3), <0.001-1.1(-1.4, -0.9), <0.0011(0.8, 1.1), <0.0011.3(1.1, 1.4), <0.001
      ThailandTH1534686627.49/27.431864465726.82/23.71-0.2(-0.3, -0.1), 0.003-0.2(-0.3, -0.1), <0.001-0.1(-0.2, 0), 0.028-2.3(-2.4, -2.3), <0.001-0.3(-0.4, -0.2), <0.0010(-0.1, 0.1), 0.849
      Timor-LesteTL27657036.9/40.3144197234.06/37.52-0.4(-0.4, -0.3), <0.001-0.4(-0.4, -0.3), <0.001-0.4(-0.4, -0.3), <0.001-1.6(-1.6, -1.5), <0.001-0.2(-0.2, -0.2), <0.0010.1(0.1, 0.1), <0.001
      WHO Western Pacific RegionWPR52869213534.37/34.1557830593730.13/29.98-0.5(-0.6, -0.3), <0.001-0.5(-0.7, -0.3), <0.001-0.4(-0.6, -0.3), <0.001-1.6(-1.8, -1.5), <0.001-0.7(-0.9, -0.5), <0.001-1(-1.2, -0.8), <0.001
      American SamoaAS1376329.43/32.91807233.18/34.120.4(0.4, 0.5), <0.0010.4(0.4, 0.5), <0.0010.5(0.4, 0.5), <0.0010.2(0.1, 0.3), <0.0010.2(0.2, 0.2), <0.0010.2(0.1, 0.2), <0.001
      AustraliaAU279925116.86/16.09261783510.79/9.88-1.5(-1.6, -1.5), <0.001-1.5(-1.6, -1.5), <0.001-1.5(-1.6, -1.5), <0.001-1.5(-1.5, -1.4), <0.001-1.6(-1.6, -1.5), <0.001-1.9(-2, -1.8), <0.001
      Brunei DarussalamBN9265536.82/39.9111229626.07/24.28-1.1(-1.2, -1.1), <0.001-1.1(-1.2, -1.1), <0.001-1.2(-1.2, -1.1), <0.001-2.5(-2.6, -2.5), <0.001-1.5(-1.5, -1.4), <0.001-1.6(-1.7, -1.6), <0.001
      CambodiaKH355048835.63/40.62496103330.54/31.47-0.6(-0.8, -0.5), <0.001-0.7(-0.8, -0.5), <0.001-0.6(-0.7, -0.5), <0.001-1.9(-2.3, -1.5), <0.001-0.9(-1, -0.8), <0.001-0.6(-0.6, -0.5), <0.001
      ChinaCN40464097634.28/34.8843968903330.73/26.59-0.4(-0.6, -0.2), 0.001-0.4(-0.6, -0.2), 0.001-0.3(-0.5, -0.1), 0.003-2.2(-2.5, -1.9), <0.001-0.7(-1, -0.5), <0.001-0.8(-1, -0.6), <0.001
      Cook IslandsCK456324.6/26.68475126.82/25.570.4(0.3, 0.4), <0.0010.3(0.3, 0.4), <0.0010.4(0.3, 0.4), <0.001-0.2(-0.2, -0.1), <0.0010.1(0.1, 0.1), <0.001-0.1(-0.1, -0.1), <0.001
      FijiFJ24727933.39/36.5133134137.07/37.570.4(0.4, 0.5), <0.0010.4(0.3, 0.5), <0.0010.5(0.4, 0.5), <0.0010.1(0.1, 0.2), <0.0010.2(0.2, 0.3), <0.0010.1(0.1, 0.1), <0.001
      GuamGU3361925.26/26.264986329.78/29.410.8(0.7, 1), <0.0010.8(0.7, 1), <0.0010.8(0.7, 1), <0.0010.6(0.4, 0.8), <0.0010.7(0.6, 0.8), <0.0010.6(0.5, 0.8), <0.001
      JapanJP4243675734.05/31.062260538117.82/15.72-2.3(-2.4, -2.2), <0.001-2.4(-2.5, -2.2), <0.001-2.2(-2.3, -2.1), <0.001-3(-3, -2.9), <0.001-2.1(-2.2, -2), <0.001-3(-3.1, -2.9), <0.001
      KiribatiKI2836939.62/43.194771641.25/43.610.2(0.2, 0.2), <0.0010.2(0.2, 0.2), <0.0010.2(0.2, 0.3), <0.0010.1(0.1, 0.1), <0.0010.1(0.1, 0.1), <0.0010(0, 0), <0.001
      Lao People's Democratic RepublicLA79071519.77/21.57105354415.07/15.79-0.9(-1, -0.9), <0.001-1(-1, -1), <0.001-0.9(-0.9, -0.9), <0.001-2.4(-2.5, -2.3), <0.001-1.1(-1.2, -1), <0.001-0.6(-0.7, -0.5), <0.001
      MalaysiaMY461777026.89/28.2803458826.12/25.52-0.1(-0.2, 0), 0.048-0.1(-0.2, -0.1), <0.0010(-0.1, 0.1), 0.837-1.9(-2, -1.9), <0.001-0.2(-0.3, -0.1), <0.0010.2(0.2, 0.3), <0.001
      Marshall IslandsMH1496433.82/40.142183039.24/40.920.5(0.4, 0.6), <0.0010.4(0.4, 0.5), <0.0010.5(0.5, 0.6), <0.0010(-0.1, 0.1), 0.6250.1(0.1, 0.2), <0.0010(0, 0), 0.84
      Micronesia, FederatedFM3535635.05/40.373705436.98/38.280.2(0.2, 0.2), <0.0010.2(0.1, 0.2), <0.0010.3(0.2, 0.3), <0.001-0.4(-0.5, -0.3), <0.001-0.1(-0.1, -0.1), <0.001-0.1(-0.2, -0.1), <0.001
      MongoliaMN81949639.34/42.6883755925.32/25.33-1.6(-1.7, -1.4), <0.001-1.6(-1.8, -1.5), <0.001-1.5(-1.7, -1.4), <0.001-3.4(-3.6, -3.1), <0.001-1.6(-1.7, -1.5), <0.001-1.8(-1.9, -1.6), <0.001
      NauruNR287129.16/33.63319731.17/34.20.3(0.1, 0.5), 0.0010.3(0.1, 0.5), 0.0020.3(0.1, 0.5), 0.0010.2(0, 0.5), 0.0640.2(0, 0.3), 0.0280.1(0, 0.3), 0.04
      New ZealandNZ64088519.08/18.5853714612.11/11.31-1.5(-1.6, -1.5), <0.001-1.5(-1.5, -1.5), <0.001-1.6(-1.6, -1.5), <0.001-1.6(-1.6, -1.5), <0.001-1.6(-1.6, -1.6), <0.001-1.8(-1.9, -1.7), <0.001
      NiueNU64828.55/30.7248529.41/28.360(0, 0.1), 0.1040(-0.1, 0), 0.0420.1(0.1, 0.1), <0.001-0.5(-0.6, -0.4), <0.001-0.2(-0.2, -0.2), <0.001-0.3(-0.4, -0.2), <0.001
      Northern Mariana IslandsMP1107325.06/25.351209528.79/26.250.7(0.6, 0.9), <0.0010.7(0.6, 0.9), <0.0010.7(0.5, 0.9), <0.0010.5(0.3, 0.8), <0.0010.5(0.4, 0.6), <0.0010.5(0.3, 0.6), <0.001
      PalauPW409327.2/28.39553431.05/28.320.5(0.5, 0.5), <0.0010.4(0.4, 0.5), <0.0010.5(0.5, 0.6), <0.0010(-0.1, 0.1), 0.7140.3(0.2, 0.3), <0.0010.1(0.1, 0.1), <0.001
      Papua New GuineaPG149685337.93/42.01377541539.52/42.580.2(0.2, 0.3), <0.0010.2(0.2, 0.2), <0.0010.3(0.2, 0.3), <0.0010.1(0.1, 0.2), 0.0010.1(0.1, 0.1), <0.0010.1(0, 0.1), <0.001
      PhilippinesPH1770926628.89/30.584066399137.12/38.220.9(0.8, 0.9), <0.0010.9(0.9, 1), <0.0010.9(0.8, 0.9), <0.0010.3(0.2, 0.3), <0.0010.8(0.7, 0.8), <0.0011.1(1, 1.2), <0.001
      Republic of KoreaKR1726370039.53/39.14981280018.52/15.56-2.6(-2.7, -2.6), <0.001-2.7(-2.7, -2.6), <0.001-2.6(-2.6, -2.6), <0.001-3.7(-4, -3.3), <0.001-2.9(-2.9, -2.8), <0.001-3.6(-3.7, -3.4), <0.001
      SamoaWS4919930.71/34.916751232.52/35.050.3(0.2, 0.3), <0.0010.2(0.2, 0.3), <0.0010.3(0.3, 0.4), <0.0010.1(-0.1, 0.2), 0.390.2(0.1, 0.2), <0.0010.1(0, 0.2), 0.001
      SingaporeSG109363436.48/34.6105299818.77/15.73-2.4(-2.5, -2.3), <0.001-2.5(-2.6, -2.4), <0.001-2.3(-2.4, -2.3), <0.001-3.4(-3.5, -3.3), <0.001-2.6(-2.7, -2.5), <0.001-3(-3.1, -3), <0.001
      Solomon IslandsSB11319334.64/40.322801735.89/39.70.2(0.1, 0.2), <0.0010.2(0.1, 0.2), <0.0010.2(0.1, 0.2), <0.001-0.1(-0.2, 0), 0.1560.1(0, 0.1), 0.0020(0, 0.1), 0.12
      TokelauTK53833.07/37.0843631.66/33.1-0.1(-0.1, -0.1), <0.001-0.1(-0.2, -0.1), <0.0010(-0.1, 0), 0.114-0.7(-0.7, -0.6), <0.001-0.3(-0.3, -0.3), <0.001-0.4(-0.5, -0.3), <0.001
      TongaTO2927231.07/35.33330433.29/35.740.3(0.2, 0.3), <0.0010.2(0.2, 0.3), <0.0010.3(0.3, 0.3), <0.0010(-0.1, 0.1), 0.8220.2(0.1, 0.2), <0.0010.1(0.1, 0.1), <0.001
      TuvaluTV332336.66/38.92422536.47/37.110.1(0, 0.1), 0.0020(-0.1, 0), 0.0270.2(0.2, 0.2), <0.001-0.1(-0.2, -0.1), <0.001-0.1(-0.1, -0.1), <0.001-0.1(-0.1, 0), <0.001
      VanuatuVU5222335.81/40.8311174838.93/42.090.4(0.3, 0.4), <0.0010.3(0.3, 0.4), <0.0010.4(0.3, 0.4), <0.0010.3(0.2, 0.4), <0.0010.2(0.1, 0.2), <0.0010.1(0.1, 0.1), <0.001
      VietnamVN3009534345.49/47.364157513843.75/41.92-0.1(-0.2, -0.1), <0.001-0.2(-0.2, -0.1), <0.001-0.1(-0.2, -0.1), <0.001-1.9(-2.2, -1.6), <0.001-0.2(-0.2, -0.2), <0.001-0.1(-0.1, 0), <0.001
      WHO: World Health Organization; AAPC: Average annual percent change; 95% CI: 95% confidence interval.
      Figure 1
      Figure 1Prevalence rate (1990 and 2019) and its trend (1990–2019) of latent tuberculosis infection worldwide. The top is the prevalence rate at country level in 1990 and the middle is the rate in 2019. The bottom is the average annual percent change in the prevalence of latent tuberculosis infection from 1990–2019.
      From 1990–2019, the prevalence rate of LTBI decreased in all the six WHO regions, ranging from 34.79% (ASR: 38.42%) to 23.51% (ASR: 4.86%) with AAPC of -1.4% (95% CI: -1.4, -1.3, P <0.001) in the AFR, from 25.15% (ASR: 33.34%) to 19.02% (ASR: 20.58%) with AAPC of -1.0% (95% CI: -1.0, -0.9, P <0.001) in the AMR, from 29.15% (ASR: 30.63%) to 18.32% (ASR: 16.49%) with AAPC of -1.6% (95% CI: -1.6, -1.5, P <0.001) in the EMR, from 24.32% (ASR: 23.21%) to 13.58% (ASR: 12.48%) with AAPC of -2.1% (95% CI: -2.2, -2.0, P <0.001) in the EUR, from 32.30% (ASR: 31.24%) to 26.46% (ASR: 24.69%) with AAPC of -0.8% (95% CI: -0.8, -0.7, P <0.001) in the SEA, and from 34.37% (ASR: 34.15%) to 30.13% (ASR: 29.98%) with AAPC of -0.5% (95% CI: -0.6, -0.3, P <0.001) in the WPR, respectively (Figure 2, Table 1). Region of WPR accounted for the most LTBI cases (32.1%) in 2019, followed by SEA (29.2%) and AFR (13.9%). The AFR had the highest prevalence rate (34.79%) in 1990, whereas the region of WPR had the highest rate with 30.13% in 2019. Pairwise comparisons among regions indicated that EUR decreased the most in the prevalence from 1990–2019 (-2.1%), followed by EMR (-1.6%), AFR (-1.4), AMR (-1.0%), SEA (-0.8%), and WPR (-0.5%).
      Figure 2
      Figure 2Prevalence trends of latent tuberculosis infection in six WHO regions, 1990–2019. AFR: African Region, AMR: Region of the Americas, EMR: Eastern Mediterranean Region, EUR: European Region, SEA: South East Asian Region, WPR: Western Pacific Region. AAPC: average annual percent change. *: P <0.05.

      Prevalence of LTBI in different countries and sex and age groups

      Prevalence ranged widely from 2.28% (Jordan) to 44.25% (Vietnam) in females and from 2.70% (Jordan) to 43.79% (South Africa) in males in 2019. The prevalence among females decreased in most countries with AAPC ranging from -4.4% (Bhutan) to -0.1% (Malaysia, Myanmar, South Africa, and Tokelau) (P <0.05), whereas it was stable in Indonesia, Kenya, Niue, and Tuvalu and increased in several countries with AAPC ranging from 0.2% (Kiribati, Micronesia, Papua New Guinea, Samoa, Solomon Islands, and Tonga) to 1.0% (Iran). Similar situations were observed among males, and the prevalence decreased in most countries with AAPC ranging from -4.3% (Bhutan) to -0.1% (Central African Republic, Democratic Republic of the Congo, Myanmar, Thailand, and Vietnam) (P <0.05). The prevalence was stable in Indonesia, Malaysia, South Africa, and Tokelau, whereas it increased in several countries with AAPC ranging from 0.1% (Kenya and Niue) to 1.1% (Sri Lanka) (Table 1). In most countries, males had higher disease burden than females.
      The prevalence also varied in different age groups at the country level. For example, the prevalence ranged from 1.71% (Jordan) to 45.47% (Nepal) among individuals aged 0–14 years, from 7.28% (Jordan) to 53.65% (Uganda) among individuals aged 15–59 years, and from 9.29% (Jordan) to 56.25% (Uganda) among those aged 60+ years in 1990. In most of the countries, adults aged 15+ years had higher prevalence rates than those aged 0–14 years in both 1990 and 2019. Additionally, compared with countries in other regions, countries in the EUR had relatively lower rates, especially among those aged 0–14 years (Supplementary Figure 2). Overall, the prevalence decreased among all the three age groups in the majority of the countries (Table 1).
      The prevalent cases of LTBI were concentrated among the population of adults aged 20–79 years (with the lowest prevalence rate of 11.35% occurring among females aged 20–24 years in the EUR in 2019) and decreased in both sexes among all the six WHO regions (Figure 3). Region of EUR had relatively lower prevalence rates than other regions during the same period. The prevalence increased among the adult population in the WPR from 2010–2015 and among those aged 10–24 years in SEA (Figure 3). Decreasing trends were observed among both sexes in all WHO regions, with AAPC ranging from -0.5% (WPR, 95% CI: -0.7, -0.3) to -2.2% (EUR, 95% CI: -2.3, -2.1) in females and from -0.4% (WPR, 95% CI: -2.1, -1.9) to -2.0% (EUR, 95% CI: -0.6, -0.3) in males (Supplementary Figure 3 and Table 1). Additionally, the prevalence rates increased after age-standardization in regions of AFR and AMR compared with those in other regions (Supplementary Figure 3).
      Figure 3
      Figure 3Age-, sex-, and year-specific prevalence rate of latent tuberculosis infection in six WHO regions, 1990–2019. The left part represents the data of females and the right part represents the data of males. The x-axis represents the year, the left y-axis shows the age groups by different WHO regions, and the right y-axis shows the reference for the gradation of color indicating the prevalence levels of latent tuberculosis infection, where the color of deep sky blue represents lower rates while the color of orange red represents relatively higher rates. The black contour lines with numbers represent the specific prevalence rates (20%, 30%, or 40%) of latent tuberculosis infection. AFR: African Region, AMR: Region of the Americas, EMR: Eastern Mediterranean Region, EUR: European Region, SEA: South East Asian Region, WPR: Western Pacific Region.

      Association between prevalence of LTBI and epidemic of TB

      Worldwide, one point of SDI increase contributed to a 25.97% (95% CI: 24.99, 26.95) decrease in the prevalence of LTBI, and every 1% increase in the prevalence of LTBI contributed to an increase of 5.23 (95% CI: 4.93, 5.53) per 100,000 and 1.41 (95% CI: 1.33, 1.49) per 100,000 in the incidence and mortality of TB, respectively. The association between the SDI and the prevalence of LTBI was negative among five of the six WHO regions, with negative values of β (-17.63 for AFR, -45.24 for AMR, -11.89 for EMR, -69.56 for EUR, and -27.26 for WPR, all P <0.05); however, it showed a positive correlation in the WPR (β: 11.27, P <0.05) (Figure 4). There were positive correlations (β: 5.20 for AFR, 1.18 for AMR, 4.45 for EMR, 2.60 for EUR, 1.89 for SEA, and 3.89 for WPR, all P <0.05) between the prevalence of LTBI and incidence of TB (Supplementary Figure 4). Positive correlations between the prevalence of LTBI and mortality of TB (β: 2.60 for AFR, 0.38 for AMR, 0.97 for EMR, 0.39 for EUR, 0.65 for SEA, and 0.68 for WPR, all P <0.05, Supplementary Figure 5) were also observed.
      Figure 4
      Figure 4Correlation between the sociodemographic index and the prevalence of latent tuberculosis infection in six WHO regions. Each line represents one country, starting at 1990 and ending at 2019. The blue lines are the fit lines of linear regression and shaded areas are 95% confidence limits. The values of beta and P are for the linear regressions of each region. AFR: African Region, AMR: Region of the Americas, EMR: Eastern Mediterranean Region, EUR: European Region, SEA: South East Asian Region, WPR: Western Pacific Region.

      Discussion

      Worldwide, the prevalence of LTBI decreased from 30.66% in 1990 to 23.67% in 2019. However, the pace of decline was relatively slow, and nearly one-fourth of the global population was latently infected with MTB in 2019. Consistent with these findings, even with limited data, the global LTBI prevalence was reported to be 32% in 1997 (
      • Dye C
      • Scheele S
      • Dolin P
      • Pathania V
      • Raviglione MC.
      Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country.
      ), 23.0% in 2014 (
      • Houben RM
      • Dodd PJ.
      The global burden of latent tuberculosis infection: A re-estimation using mathematical modelling.
      ), and 24.8% (by interferon-gamma release assay, IGRA) and 21.2% (by tuberculin skin test, TST) during 2005–2018 (
      • Cohen A
      • Mathiasen VD
      • Schön T
      • Wejse C.
      The global prevalence of latent tuberculosis: a systematic review and meta-analysis.
      ).
      Wide ranges of prevalence rates are observed at different geographical levels in this study. Previous studies also indicate the varied rates of LTBI among different populations in different countries (
      • Cohen A
      • Mathiasen VD
      • Schön T
      • Wejse C.
      The global prevalence of latent tuberculosis: a systematic review and meta-analysis.
      ;
      • Getahun H
      • Matteelli A
      • Chaisson RE
      • Raviglione M.
      Latent Mycobacterium tuberculosis infection.
      ;
      • Houben RM
      • Dodd PJ.
      The global burden of latent tuberculosis infection: A re-estimation using mathematical modelling.
      ). High prevalence rates of LTBI were documented, which were 31.2% (2010) in Ethiopia (
      • Legesse M
      • Ameni G
      • Mamo G
      • Medhin G
      • Bjune G
      • Abebe F.
      Community-based cross-sectional survey of latent tuberculosis infection in Afar pastoralists, Ethiopia, using QuantiFERON-TB Gold In-Tube and tuberculin skin test.
      ), 49% (2008–2009) in Uganda (
      • Kizza FN
      • List J
      • Nkwata AK
      • Okwera A
      • Ezeamama AE
      • Whalen CC
      • et al.
      Prevalence of latent tuberculosis infection and associated risk factors in an urban African setting.
      ), and 41.78% (2000–2018) in the Middle East and North Africa region (
      • Barry M.
      Prevalence of latent tuberculosis infection in the Middle East and North Africa: A systematic review.
      ). The rate was reported to be 10.0% in those aged 5–9 years and 17.9% in those aged 10–14 years in Bangladesh (2007–2009) (
      • Hossain S
      • Zaman K
      • Banu S
      • Quaiyum MA
      • Husain MA
      • Islam MA
      • et al.
      Tuberculin survey in Bangladesh, 2007–2009: prevalence of tuberculous infection and implications for TB control.
      ); 10.8% (2005) in Zambia; 30.3% (2005) in South Africa among those aged 4–18 years (
      • Shanaube K
      • Sismanidis C
      • Ayles H
      • Beyers N
      • Schaap A
      • Lawrence KA
      • et al.
      Annual risk of tuberculous infection using different methods in communities with a high prevalence of TB and HIV in Zambia and South Africa.
      ), 16.7% (2006–2007) among children aged 6–14 years (
      • Hoa NB
      • Cobelens FG
      • Sy DN
      • Nhung NV
      • Borgdorff MW
      • Tiemersma EW.
      First national tuberculin survey in Viet Nam: characteristics and association with tuberculosis prevalence.
      ); 36.8% (2015–2016) among adults in Vietnam (
      • Marks GB
      • Nhung NV
      • Nguyen TA
      • Hoa NB
      • Khoa TH
      • Son NV
      • et al.
      Prevalence of latent tuberculous infection among adults in the general population of Ca Mau, Viet Nam.
      ); and 19% (2013) in China (
      • Gao L
      • Lu W
      • Bai L
      • Wang X
      • Xu J
      • Catanzaro A
      • et al.
      Latent tuberculosis infection in rural China: baseline results of a population-based, multicentre, prospective cohort study.
      ). However, low rates were observed in some developed countries with low incidence of TB. For example, the rate was estimated to be 4.2% in 1999–2000 (
      • Bennett DE
      • Courval JM
      • Onorato I
      • Agerton T
      • Gibson JD
      • Lambert L
      • et al.
      Prevalence of tuberculosis infection in the United States population: the national health and nutrition examination survey, 1999–2000.
      ), 4.7% by TST, and 5.0% by IGRA in 2011–2012 (
      • Miramontes R
      • Hill AN
      • Woodruff Y RS
      • Lambert LA
      • Navin TR
      • Castro KG
      • et al.
      Tuberculosis Infection in the United States: Prevalence Estimates from the National Health and Nutrition Examination Survey, 2011-2012.
      ); 4.4% by TST and 4.8% by QFT-GIT in 2011–2012 (
      • Mancuso JD
      • Diffenderfer JM
      • Ghassemieh BJ
      • Horne DJ
      • Kao TC.
      The prevalence of latent tuberculosis infection in the United States.
      ); and 3.1% during 2011–2015 (
      • Haddad MB
      • Raz KM
      • Lash TL
      • Hill AN
      • Kammerer JS
      • Winston CA
      • et al.
      Simple estimates for local prevalence of latent tuberculosis infection, United States, 2011–2015.
      ) in the United States. It was also reported to be low in Australia (4.6% in 2006 and 5.1% in 2016) (
      • Dale KD
      • Trauer JM
      • Dodd PJ
      • Houben RMGJ
      • Denholm JT.
      Estimating the prevalence of latent tuberculosis in a low-incidence setting: Australia.
      ). In countries with incidence of TB well above the elimination threshold, preventing LTBI becomes the final frontier of disease elimination (
      • LoBue PA
      • Mermin JH.
      Latent tuberculosis infection: the final frontier of tuberculosis elimination in the USA.
      ) and it is still a struggle, with the prevalence of LTBI remaining minimally changed or relatively constant (
      • Mancuso JD
      • Diffenderfer JM
      • Ghassemieh BJ
      • Horne DJ
      • Kao TC.
      The prevalence of latent tuberculosis infection in the United States.
      ;
      • Miramontes R
      • Hill AN
      • Woodruff Y RS
      • Lambert LA
      • Navin TR
      • Castro KG
      • et al.
      Tuberculosis Infection in the United States: Prevalence Estimates from the National Health and Nutrition Examination Survey, 2011-2012.
      ).
      The prevalence rate of LTBI also varied in different WHO regions; the WPR had high prevalence rates and EUR had relatively low rates. Compared with other regions, higher prevalence rates were reported in regions of SEA, WPR, and AFR by other studies (
      • Dye C
      • Scheele S
      • Dolin P
      • Pathania V
      • Raviglione MC.
      Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country.
      ;
      • Houben RM
      • Dodd PJ.
      The global burden of latent tuberculosis infection: A re-estimation using mathematical modelling.
      ), which were consistent with this study; although, the specific rankings were different. Another study reported that SEA had the highest prevalence rate among the six regions (
      • Cohen A
      • Mathiasen VD
      • Schön T
      • Wejse C.
      The global prevalence of latent tuberculosis: a systematic review and meta-analysis.
      ) compared with WPR in this study. The differences of estimation between the results may be caused by different sources and methods used in the estimation of data.
      This study provides, to the best of our knowledge, the long-term trends in the prevalence of LTBI at different levels and reveals slight decreases in the prevalence worldwide at the country and the WHO regional levels. A previous review presented similar decreases, with the rate decreasing from 32% in 1999 to 21.2–24.0% in 2005–2018(
      • Cohen A
      • Mathiasen VD
      • Schön T
      • Wejse C.
      The global prevalence of latent tuberculosis: a systematic review and meta-analysis.
      ). The disparity in the prevalence rate of LTBI at different geographical levels could help target the highest risk countries or regions (
      • Collins JM
      • Stout JE
      • Ayers T
      • Hill AN
      • Katz DJ
      • Ho CS
      • et al.
      Prevalence of latent tuberculosis infection among non-U.S.-born persons by country of birth - United States, 2012–2017.
      ). For example, regions of WPR, SEA, and AFR accounted for the most LTBI cases and the decrease of cases in these regions would be more difficult but critical. Additionally, 18 of those 25 countries with no decrease of prevalence in this study are in the WPR, and most are island countries. The possible reason for this phenomenon is that these countries are undeveloped, with small land areas, have relatively concentrated population, and have a limited flow of population. By comparison, the levels of SDI in countries in the EUR are relatively higher than those in the AFR, SEA, and WPR (Figure 4). The WHO recommends increasing health financing and recruitment, development, training, and retention of the health workforce for the least developed countries and small islands and treatment of LTBI (). Males had higher prevalence of LTBI than females in most countries (
      • Gao L
      • Lu W
      • Bai L
      • Wang X
      • Xu J
      • Catanzaro A
      • et al.
      Latent tuberculosis infection in rural China: baseline results of a population-based, multicentre, prospective cohort study.
      ;
      • Kizza FN
      • List J
      • Nkwata AK
      • Okwera A
      • Ezeamama AE
      • Whalen CC
      • et al.
      Prevalence of latent tuberculosis infection and associated risk factors in an urban African setting.
      ;
      • Mancuso JD
      • Diffenderfer JM
      • Ghassemieh BJ
      • Horne DJ
      • Kao TC.
      The prevalence of latent tuberculosis infection in the United States.
      ;
      • Marks GB
      • Nhung NV
      • Nguyen TA
      • Hoa NB
      • Khoa TH
      • Son NV
      • et al.
      Prevalence of latent tuberculous infection among adults in the general population of Ca Mau, Viet Nam.
      ) and this coincided with the incidence of TB (,

      World Health Organization, Tuberculosis, 2021c. https://www.who.int/news-room/fact-sheets/detail/tuberculosis; Accessed October 15, 2021.

      ). Additionally, the prevalence of LTBI decreased more in females than in males in most regions. For different age groups, the adult population had higher rate of LTBI (
      • Barry M.
      Prevalence of latent tuberculosis infection in the Middle East and North Africa: A systematic review.
      ). Consistent with this finding, about 89% of people who develop active TB are adults who are in their peak productive years (

      World Health Organization. Global tuberculosis report 2020, Available at https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2020; Accessed March 9, 2021.

      ).
      Global incidence of TB decreased at about 2% per year (2015–2020), but the trajectory is mostly offtrack, with the fact that the cumulative decrease (11%) was only halfway to the strategic milestone of 20% decrease (). Additionally, the progress was hit hard by the COVID-19 pandemic, with increasing TB deaths and previous decreases in TB cases slowed (). The COVID-19 pandemic has fractured and strained health systems in many parts of the world, resulting in decreased access of patients with TB to medical services and a substantial decrease in TB testing and case notifications (
      • Kirby T.
      Global tuberculosis progress reversed by COVID-19 pandemic.
      ). To mitigate the impact of COVID-19, some challenges need to be addressed: improved TB (and COVID-19) case finding and real-time data reporting; sensitive and specific point-of-care diagnostics; and the development of cost-effective joint screening strategies, integrated screening for LTBI, estimation the effects of SARS-CoV-2 infection on individuals with active TB and on TB treatment outcomes, and improvement of the coverage of vaccination (SARS-CoV-2 and BCG) (
      • Dheda K
      • Perumal T
      • Moultrie H
      • Perumal R
      • Esmail A
      • Scott AJ
      • et al.
      The intersecting pandemics of tuberculosis and COVID-19: population-level and patient-level impact, clinical presentation, and corrective interventions.
      ).
      This study indicates that a higher prevalence of LTBI would contribute to higher incidence and mortality of TB. China, India, and Indonesia accounted for the most LTBI cases from 1990–2019, corresponding to the most incidence of TB cases in these countries in 2020 (). Although a positive correlation between the prevalence of LTBI and incidence of TB was revealed in this study, it varied by the WHO regions. In 2019, the incidence of TB was estimated as 217 per 100,000 in SEA and 29 per 100,000 in AMR (ratio: 7.18) (

      World Health Organization. Global tuberculosis report 2020, Available at https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2020; Accessed March 9, 2021.

      ). Relatively, the prevalence rate of LTBI was 26.46% in SEA and 19.2% in AMR (ratio: 1.38). The varied ratio indicates that there is uncertainty in the progression from LTBI to active TB and highlights the importance of LTBI and TB surveillance and management. There is a positive correlation between the SDI value and the prevalence of LTBI; therefore, progress such as surveillance, testing, and treatment for LTBI are inseparable from the improvement of socioeconomic conditions.
      Most countries have established surveillance systems for TB, whereas a few jurisdictions have estimates of local LTBI prevalence (
      • Haddad MB
      • Raz KM
      • Lash TL
      • Hill AN
      • Kammerer JS
      • Winston CA
      • et al.
      Simple estimates for local prevalence of latent tuberculosis infection, United States, 2011–2015.
      ). The diagnostic gap for TB varies widely globally: for example, >80% of all estimated cases were detected in the Philippines, whereas only one-third of cases were notified in Indonesia (
      • Dowdy DW
      • Grant AD
      • Dheda K
      • Nardell E
      • Fielding K
      • Moore DAJ.
      Designing and evaluating interventions to halt the transmission of tuberculosis.
      ). For the diagnosis and report of LTBI cases, the challenge would be more difficult, especially in the high burden countries of TB. The US Preventive Services Task Force found adequate evidence on the accurate screening test and treatment of LTBI (US
      • Preventive Services Task Force US
      • Bibbins-Domingo K
      • Grossman DC
      • Curry SJ
      • Bauman L
      • Davidson KW
      • Epling JW
      • García FA
      • Herzstein J
      • Kemper AR
      • Krist AH
      • Kurth AE
      • Landefeld CS
      • Mangione CM
      • Phillips WR
      • Phipps MG
      • Pignone MP
      Screening for latent tuberculosis infection in adults: US Preventive Services Task Force recommendation statement.
      ). Expanded programs for LTBI diagnosis and treatment may be considered for both individual clinical benefit and as part of public health programs (
      • Denholm JT
      • Millan-Marcelo JC
      • Fiekert K.
      Latent tuberculosis infection and the EndTB Strategy: ethical tensions and imperatives.
      ). Along with the reporting of LTBI cases, the testing of which could contribute to the finding of active TB cases, for example, there was 1 active TB case (0.1%) of the 833 IGRA-negative persons compared with the 2.3 % of 482 IGRA-positive individuals from a study conducted in Vietnam (
      • Marks GB
      • Nhung NV
      • Nguyen TA
      • Hoa NB
      • Khoa TH
      • Son NV
      • et al.
      Prevalence of latent tuberculous infection among adults in the general population of Ca Mau, Viet Nam.
      ). It could be reasonably foreseen that more benefits would be received among the high-risk populations in countries with high TB burdens. TB preventive treatment (TPT) is the main health care intervention available to decrease the risk of LTBI progression to active disease (), which has been included as a component among high-risk populations (
      • Uplekar M
      • Raviglione M.
      WHO's End TB Strategy: from stopping to ending the global TB epidemic.
      ). However, the use of TPT may have been hindered by limited provider awareness of the benefits and concerns about potential side effects, such as hepatotoxicity (
      • Haley CA
      • Schlossberg D
      Treatment of latent tuberculosis infection.
      ). It is also important to assess the effectiveness and feasibility of undertaking TPT among high-risk populations, such as contacts of persons with TB, people living with HIV, and people in congregate settings such as prisons and workplaces (
      • Getahun H
      • Matteelli A
      • Abubakar I
      • Aziz MA
      • Baddeley A
      • Barreira D
      • et al.
      Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries.
      ,
      • Getahun H
      • Matteelli A
      • Chaisson RE
      • Raviglione M.
      Latent Mycobacterium tuberculosis infection.
      ,

      Programme GT. WHO consolidated guidelines on tuberculosis: module 1: prevention: tuberculosis preventive treatment, 2020, https://apps.who.int/iris/bitstream/handle/10665/331525/9789240002906-eng.pdf; (accessed December 6, 2021).

      ,

      World Health Organization. The End TB Strategy-Global strategy and targets for tuberculosis prevention, care and control after 2015, 2018, Available at https://www.who.int/tb/strategy/End_TB_Strategy.pdf; Accessed September 17, 2019.

      ). The benefits of TPT should be also carefully balanced, especially regarding the mass, population-wide LTBI testing and treatment (

      Programme GT. WHO consolidated guidelines on tuberculosis: module 1: prevention: tuberculosis preventive treatment, 2020, https://apps.who.int/iris/bitstream/handle/10665/331525/9789240002906-eng.pdf; (accessed December 6, 2021).

      ). LTBI is paid more attention in countries with low incidence of TB, whereas more TB-related research is conducted by countries with high incidence of TB (
      • Chaw L
      • Chien LC
      • Wong J
      • Takahashi K
      • Koh D
      • Lin RT.
      Global trends and gaps in research related to latent tuberculosis infection.
      ). Innovations on improved testing, treatment, and management for LTBI are critical for more effective control of LTBI, especially for countries with high TB burden (
      • Cui X
      • Gao L
      • Cao B.
      Management of latent tuberculosis infection in China: exploring solutions suitable for high-burden countries.
      ).
      This study has several limitations. First, although the estimations by the GBD data are considered widely accepted, the reporting of the data is still improving and updating. The assessment for a few countries and the incidence of LTBI is limited by the paucity of data. Further longitudinal studies are needed to identify the incident LTBI cases. Second, the influence of different detection methods used across countries could not be ruled out. For example, TST and IGRA are known to have different sensitivities and specificities (
      • Lewinsohn DM
      • Leonard MK
      • LoBue PA
      • Cohn DL
      • Daley CL
      • Desmond E
      • et al.
      Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention clinical practice guidelines: diagnosis of tuberculosis in adults and children.
      ,

      Programme GT. WHO consolidated guidelines on tuberculosis: module 1: prevention: tuberculosis preventive treatment, 2020, https://apps.who.int/iris/bitstream/handle/10665/331525/9789240002906-eng.pdf; (accessed December 6, 2021).

      ) and may affect the LTBI data. Third, the heterogeneity and different spectrum of LTBI from low to high risk of progression to active disease were not assessed. MTB infection is viewed as a continuous spectrum extending from sterilizing immunity to subclinical active disease to fully active disease, and variations in levels of mycobacterial persistence and in host genetics can play a role in the outcome of disease development and progression (
      • Barry 3rd, CE
      • Boshoff HI
      • Dartois V
      • Dick T
      • Ehrt S
      • Flynn J
      • et al.
      The spectrum of latent tuberculosis: rethinking the biology and intervention strategies.
      ;
      • Zhang Y
      • Yew WW
      • Barer MR.
      Targeting persisters for tuberculosis control.
      ). Continued research to understand the host-organism interactions within the spectrum of disease is needed to develop better tools for identifying high-risk individuals for targeted prophylaxis (
      • Chee CBE
      • Reves R
      • Zhang Y
      • Belknap R.
      Latent tuberculosis infection: opportunities and challenges.
      ).

      Conclusions

      The prevalence rate of LTBI is still at a high level worldwide, and nearly one-quarter of the population are latently infected with MTB. Although the prevalence decreased worldwide in the last three decades, the decrease is minimal and slow. Region of WPR accounts for the most LTBI cases and has the highest prevalence rates in the past 20 years. More effort and progress in decreasing LTBI among the entire population should be made worldwide to achieve the WHO goal and targets of TB elimination.

      Declarations of interest

      The authors have no conflict of interest to declare.

      Author Contributions

      Conceiving and designing the study: K. Xu, Y. Zhang, S. Yang, and C. Ding. Accessing the data, and contributing to literature search: M. Hu, W. Guo, W. Hu, X. Li, S. Wang, and Y. Shangguan. Cleaning and analyzing the data: C. Ding, M. Hu, W. Guo, W. Hu, X. Li, S. Wang, and Y. Shangguan. Drafting the first version of the manuscript: C. Ding. Critically revising the manuscript: K. Xu, Y. Zhang, and S. Yang. All authors critically revised the manuscript and approved it for publication.

      Ethical Approval

      No ethical approval was obtained because the data included in this study were deidentified and publicly available.

      Funding

      This work was supported by the National Key Research and Development Program of China [grant number 2021YFC2301800]; the Medical and Health Science and Technology Project of Zhejiang Province [grant number 2022KY743]; and the National Science and Technology Major Project [grant number 2017ZX10105001 and 2018ZX10715014]. The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

      Acknowledgments

      This study was conducted as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), coordinated by the Institute for Health Metrics and Evaluation. The GBD was partially funded by the Bill & Melinda Gates Foundation.

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