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Tools to implement the World Health Organization End TB Strategy: Addressing common challenges in high and low endemic countries

Open AccessPublished:February 27, 2020DOI:https://doi.org/10.1016/j.ijid.2020.02.042

      Highlights

      • Latent tuberculosis (TB) is an important reservoir for developing active TB.
      • Screening, for instance with an interferon-gamma release assay, will identify the majority of people with latent TB.
      • Molecular epidemiology is key to understand transmission dynamics between nationals and migrants.
      • The development of public–private partnerships is needed to mobilize the resources needed to achieve the End TB goal.

      Abstract

      Aim

      The purpose of this viewpoint is to summarize the advantages and constraints of the tools and strategies available for reducing the annual incidence of tuberculosis (TB) by implementing the World Health Organization (WHO) End TB Strategy and the linked WHO TB Elimination Framework, with special reference to Oman.

      Methods

      The case-study was built based on the presentations and discussions at an international workshop on TB elimination in low incidence countries organized by the Ministry of Health, Oman, which took place from September 5 to September 7, 2019, and supported by the WHO and European Society of Clinical Microbiology and Infectious Diseases (ESCMID).

      Results

      Existing tools were reviewed, including the screening of migrants for latent TB infection (LTBI) with interferon-gamma release assays, clinical examination for active pulmonary TB (APTB) including chest X-rays, organization of laboratory services, and the existing centres for mandatory health examination of pre-arrival or arriving migrants, including examination for APTB. The need for public–private partnerships to handle the burden of screening arriving migrants for active TB was discussed at length and different models for financing were reviewed.

      Conclusions

      In a country with a high proportion of migrants from high endemic countries, screening for LTBI is of high priority. Molecular typing and the development of public–private partnerships are needed.

      Keywords

      Introduction

      Tuberculosis (TB) is one of the top 10 causes of death worldwide and the most important cause of death from an infectious disease, surpassing HIV/AIDS. In 2018, TB caused an estimated 1.5 million deaths (range 1.4–1.6 million), including 251 000 deaths among HIV-positive persons (). The severity of national TB epidemiology varies significantly among countries. Worldwide in 2019, there were fewer than 10 new cases per 100 000 population in most high-income countries, 150–400 in most of the 30 high TB burden countries, and above 500 in six countries ().
      The World Health Organization (WHO) End TB Strategy aims to end the global TB epidemic by 2035, reducing global TB incidence and mortality rates by 90% and 95%, respectively, in 2035 when compared to 2015 (
      • World Health Organization
      The End TB Strategy.
      ;
      • Uplekar M.
      • Weil D.
      • Lonnroth K.
      • Jaramillo E.
      • Lienhardt C.
      • Dias H.M.
      • et al.
      WHO’s new end TB strategy.
      ;
      • Lönnroth K.
      • Migliori G.B.
      • Abubakar I.
      • D’Ambrosio L.
      • de Vries G.
      • Diel R.
      • et al.
      Towards tuberculosis elimination: an action framework for low-incidence countries.
      ). In September 2018, the goal of ending TB was elevated to the highest level at the first-ever UN High Level Meeting on TB in New York, which brought together heads of states and governments, who made bold commitments to accelerate the TB response. Oman is a signatory of the UN High-Level Political Declaration on TB ​(
      • WHO
      Moscow declaration to End TB.
      )​.
      The WHO End TB Strategy was developed in parallel with the Sustainable Development Goals (SDGs), and interventions should be anchored in the SDGs (
      • Lönnroth K.
      • Migliori G.B.
      • Abubakar I.
      • D’Ambrosio L.
      • de Vries G.
      • Diel R.
      • et al.
      Towards tuberculosis elimination: an action framework for low-incidence countries.
      ;
      • Lönnroth K.
      • Raviglione M.
      The WHO’s new End TB Strategy in the post-2015 era of the sustainable development goals.
      ). It has been estimated that one quarter of the world population are latently infected with TB, having a latent TB infection (LTBI) (
      • Houben R.M.G.J.
      • Dodd P.J.
      The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling.
      ), and a recent meta-analysis of prevalence surveys confirmed that 20–25% globally have LTBI (
      • Cohen A.
      • Mathiasen V.D.
      • Schön T.
      • Wejse C.
      The global prevalence of latent tuberculosis: a systematic review and meta-analysis.
      ). This is a challenge for both high and low endemic countries, but it is evident that to reach the goal of TB elimination, the reservoir of LTBI has to be eliminated or reduced significantly (
      • World Health Organization
      Global action framework for TB research.
      ;
      • Petersen E.
      • Chakaya J.
      • Jawad F.M.
      • Ippolito G.
      • Zumla A.
      Latent tuberculosis infection: diagnostic tests and when to treat.
      ;
      • Rosales-Klintz S.
      • Bruchfeld J.
      • Haas W.
      • Heldal E.
      • Houben R.M.G.J.
      • van Kessel F.
      • et al.
      Guidance for programmatic management of latent tuberculosis infection in the European Union/European Economic Area.
      ;
      • Centis R.
      • D’Ambrosio L.
      • Zumla A.
      • Migliori G.B.
      Shifting from tuberculosis control to elimination: where are we? What are the variables and limitations? Is it achievable?.
      ).
      In view of the progress made in several low-incidence countries, the WHO joined forces with the European Respiratory Society to adapt the WHO End TB Strategy and develop a framework for TB elimination in these countries. Take-up of the WHO TB Elimination framework has been slow (
      • Matteelli A.
      • Rendon A.
      • Tiberi S.
      • Al-Abri S.
      • Voniatis C.
      • Carvalho A.C.C.
      • et al.
      Tuberculosis elimination: where are we now?.
      ) and there are few published country experiences, with the exception of Cyprus, Oman, and Latin America (
      • Al Yaquobi F.
      • Al-Abri S.
      • Al-Abri B.
      • Al-Abaidani I.
      • Al-Jardani A.
      • D’Ambrosio L.
      • Centis R.
      • Matteelli A.
      • Manissero D.
      • Migliori G.B.
      Tuberculosis elimination: a dream or a reality? The case of Oman.
      ).

      Oman as a pathfinder to TB elimination

      Oman is a low TB incidence country, with an annual incidence rate of less than 5.9 cases per 100 000 population in 2018 (Figure 1). Forty-five percent of the population are migrants from high-incidence countries, i.e. more than 100 cases per year per 100 000 population, accounting for 60% of the annual TB cases (Table 1; Figure 2). However, several studies have indicated that incidence rates based on notified cases may not fully reflect the burden due to under-reporting (
      • Snow K.J.
      • Sismanidis C.S.
      • Denholm J.
      • Sawyer S.M.
      • Graham S.M.
      The incidence of tuberculosis among adolescents and young adults: a global estimate.
      ;
      • Pandey S.
      • Chadha V.K.
      • Laxminarayan R.
      • Arinaminpathy N.
      Estimating tuberculosis incidence from primary survey data: a mathematical modeling approach.
      ;
      • Romanowski K.
      • Baumann B.
      • Basham C.A.
      • Ahmad Khan F.
      • Fox G.J.
      • Johnston J.C.
      Long-term all-cause mortality in people treated for tuberculosis: a systematic review and meta-analysis.
      ).
      Figure 1
      Figure 1Trend in tuberculosis incidence in Oman—1981–2018.
      Table 1New tuberculosis cases in Omani nationals and migrants.
      Year201020112012201320142015201620172018
      Omani nationals21423924518818418019014198
      Non-Omanis9498141146170147154122145
      Nationals per 10510.311.211.78.78.17.76.34.73.3
      Non-nationals per 1058.17.19.28.79.88.17.77.17.3
      Note: Estimated population January 1, 2019: 4 992 364 of which 2994 601 were Omani nationals and 1 997 763 were migrants ().
      Figure 2
      Figure 2Age-specific annual tuberculosis incidence in Omani nationals and non-Omanis.
      The purpose of this viewpoint is to summarize the advantages and constraints of the tools and strategies available for reducing the annual incidence of TB by implementing the WHO End TB Strategy and the linked WHO TB Elimination Framework, with special reference to Oman. In Oman, a reduction in annual TB incidence from 59 per million inhabitants (2018) to 1 per million by 2035 has to be achieved, which is the threshold defining TB elimination (
      • Lönnroth K.
      • Migliori G.B.
      • Abubakar I.
      • D’Ambrosio L.
      • de Vries G.
      • Diel R.
      • et al.
      Towards tuberculosis elimination: an action framework for low-incidence countries.
      ). It may be possible to advance the elimination date if modelling and effective implementation of key interventions, including the roll-out of TB preventive treatment, are conducted.

      Methods

      The case-study was built based on the presentations and discussions at an international workshop on TB elimination in low incidence countries organized by the Ministry of Health, Oman, which took place from September 5 to September 7, 2019, and supported by the WHO and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).
      The meeting reviewed existing tools, including the screening of migrants for LTBI with interferon-gamma release assays (IGRAs), clinical examination for active pulmonary TB (APTB) including chest X-rays (CXR), the organization of laboratory services, and the existing centres for mandatory health examination of arriving migrants including examination for APTB. The need for public–private partnerships to handle the burden of screening arriving migrants for active TB was discussed at length and different models for financing were reviewed.
      The TB elimination framework programme for Oman has opened many topics for applied research. It has also allowed the evaluation of models for public–private partnerships, community support in the treatment LTBI, the evaluation of screening methods for LTBI through long-term follow-up, and comparison of different regimens for the treatment of LTBI, for instance 4 weeks and 12 weeks rifapentin/isoniazid (or rifampicin/isoniazid).
      A writing team of global TB experts was invited to summarize the available evidence for the different areas with a non-systematic approach and to discuss this evidence based on Oman-specific data. Several rounds of discussion were organized to reach consensus on the final document.

      Background

      In 1981, the annual incidence of TB in Oman was over 90 per 100 000 population (Figure 1). Following rapid economic development in the 1980s, the incidence declined significantly to 20 per 100 000 population in 1991 and 10 per 100 000 population in 2010 (
      • Ministry of Health
      Annual statistical report.
      )​. Over the same period, the proportion of migrants from high TB endemic countries in Africa and Asia increased to around 45% of the population. Up until 2017, the national policy for TB control was based on the screening of migrants on arrival for APTB with a CXR. Since 2017, investigations for APTB have also included sputum microscopy, culture, and PCR if there is a clinical or radiological suspicion of TB. Pre-arrival screening is also conducted in Gulf Collaboration Council certified centres in the country of origin of migrants for around 90% of the migrants.
      The proportions of APTB cases among Omani nationals and non-nationals have been changing, with a decreasing number in Omanis and an increasing number diagnosed in non-Omanis (Table 1). The stable incidence rate for migrants and the slow decrease in rate for Omani nationals over the last 10 years potentially reflect Mycobacterium tuberculosis (Mtb) transmission from the migrant population (
      • Aldridge R.W.
      • Zenner D.
      • White P.J.
      • Williamson E.J.
      • Muzyamba M.C.
      • Dhavan P.
      • et al.
      Tuberculosis in migrants moving from high-incidence to low-incidence countries: a population-based cohort study of 519 955 migrants screened before entry to England, Wales, and Northern Ireland.
      ), but that assumption needs to be confirmed by genotyping. TB in migrants comprises either reactivation of LTBI, diagnosed some years after entry, or cases missed by the pre-entry or at-entry screening.
      It is often held that new cases of TB that occur some years after entry could be the result of the reactivation of LTBI (
      • Aldridge R.W.
      • Zenner D.
      • White P.J.
      • Williamson E.J.
      • Muzyamba M.C.
      • Dhavan P.
      • et al.
      Tuberculosis in migrants moving from high-incidence to low-incidence countries: a population-based cohort study of 519 955 migrants screened before entry to England, Wales, and Northern Ireland.
      ;
      • Lillebaek T.
      • Andersen A.B.
      • Bauer J.
      • Dirksen A.
      • Glismann S.
      • de Haas P.
      • et al.
      Risk of Mycobacterium tuberculosis transmission in a low-incidence country due to immigration from high-incidence areas.
      ;
      • Lönnroth K.
      • Mor Z.
      • Erkens C.
      • Bruchfeld J.
      • Nathavitharana R.R.
      • van der Werf M.J.
      • et al.
      Tuberculosis in migrants in low-incidence countries: epidemiology and intervention entry points.
      ;
      • Zenner D.
      • Hafezi H.
      • Potter J.
      • Capone S.
      • Matteelli A.
      Effectiveness and cost-effectiveness of screening migrants for active tuberculosis and latent tuberculous infection.
      ;
      • Kamper-Jørgensen Z.
      • Andersen A.B.
      • Kok-Jensen A.
      • Bygbjerg I.C.
      • Thomsen V.O.
      • Lillebaek T.
      Characteristics of non-clustered tuberculosis in a low burden country.
      ,
      • Kamper-Jørgensen Z.
      • Andersen A.B.
      • Kok-Jensen A.
      • Kamper-Jørgensen M.
      • Bygbjerg I.C.
      • Andersen P.H.
      • et al.
      Migrant tuberculosis: the extent of transmission in a low burden country.
      ). Previous studies have shown that screening for active TB at entry detects only a small number of TB cases, but will miss cases reactivating after entry if screening for LTBI is not included (
      • Abubakar I.
      • Lipman M.
      • Anderson C.
      • Davies P.
      • Zumla A.
      Tuberculosis in the UK—time to regain control.
      ;
      • Kruijshaar M.E.
      • Abubakar I.
      • Stagg H.R.
      • Pedrazzoli D.
      • Lipman M.
      Migration and tuberculosis in the UK: targeting screening for latent infection to those at greatest risk of disease.
      ), indicating that screening aimed only at identifying APTB cases at entry may miss an unknown proportion of cases who are developing TB at a later point.
      The Ministry of Health has estimated that Oman has to reduce the incidence by around 10% per year to reach the goal of a 90% reduction in the incidence rate by 2035. To reduce the current incidence of 59 cases per million population (Table 1) to less than 1 per million by 2035 will pose significant challenges. The age distribution among non-Omanis is younger than in Omanis, where older cases are likely more commonly due to reactivation of LTBI (Figure 2).
      Oman fulfils the first three goals of the pillars of the End TB Strategy (Table 2) and partly also the fourth, “Preventive treatment of persons at high risk, and vaccination against tuberculosis”, by including universal bacillus Calmette–Guérin (BCG) immunization at birth and preventive treatment of contacts of known active TB cases. The current strategy does not include the screening of migrants from highly endemic countries for LTBI.
      Table 2Pillars of the End TB strategy.
      Integrated, patient-centred care and prevention
      1. Early diagnosis of tuberculosis including universal drug-susceptibility testing, and systematic screening of contacts and high-risk groups
      2. Treatment of all people with tuberculosis including drug-resistant tuberculosis, and patient support
      3. Collaborative tuberculosis/HIV activities, and management of comorbidities
      4. Preventive treatment of persons at high risk, and vaccination against tuberculosis
      Bold policies and supportive systems
      5. Political commitment with adequate resources for tuberculosis care and prevention
      6. Engagement of communities, civil society organizations, and public and private care providers
      7. Universal health coverage policy, and regulatory frameworks for case notification, vital registration, quality and rational use of medicines, and infection control
      8. Social protection, poverty alleviation and actions on other determinants of tuberculosis
      Intensified research and innovation
      9. Discovery, development and rapid uptake of new tools, interventions and strategies
      10. Research to optimize implementation and impact, and promote innovations
      Points 5–8 of the TB Elimination Framework are partly fulfilled in Oman, in that there is political commitment and universal government-funded healthcare coverage and regulatory frameworks for case notification, vital registration, quality and rational use of medicines, and infection control.
      Regarding points 9 and 10, regarding ‘intensified research and innovation’, this paper will discuss the strategies and tools available to reduce the incidence in Oman by 10% per year.
      A previous modelling study, which reviewed seven different screening programmes for migrants, found that screening with an IGRA followed by a short regimen (3 months) of either rifampicin/isoniazid or rifapentine/isoniazid was the most cost-effective algorithm in the United Kingdom (
      • Kowada A.
      Cost effectiveness of interferon-gamma release assay for tuberculosis screening using three months of rifapentine and isoniazid among long-term expatriates from low to high incidence countries.
      ;
      • Abubakar I.
      • Drobniewski F.
      • Southern J.
      • Sitch A.J.
      • Jackson C.
      • Lipman M.
      • et al.
      Prognostic value of interferon-γ release assays and tuberculin skin test in predicting the development of active tuberculosis (UK PREDICT TB): a prospective cohort study.
      ). Risk groups among Omani nationals need to be identified (
      • Katelaris A.L.
      • Jackson C.
      • Southern J.
      • Gupta R.K.
      • Drobniewski F.
      • Lalvani A.
      • et al.
      Effectiveness of BCG vaccination against Mycobacterium tuberculosis infection in adults: a cross-sectional analysis of a UK-based cohort.
      ), for instance the elderly, families with previous TB cases, geographical clustering, and prisons (
      • Noppert G.A.
      • Yang Z.
      • Clarke P.
      • Davidson P.
      • Ye W.
      • Wilson M.L.
      Contextualizing tuberculosis risk in time and space: comparing time-restricted genotypic case clusters and geospatial clusters to evaluate the relative contribution of recent transmission to incidence of TB using nine years of case data from Michigan, USA.
      ). A study from Japan found that overall population density, age, and being a healthcare worker (HCW) were risk factors for TB (
      • Murakami R.
      • Matsuo N.
      • Ueda K.
      • Nakazawa M.
      Epidemiological and spatial factors for tuberculosis: a matched case-control study in Nagata, Japan.
      ).

      Specific interventions for national TB control and elimination programmes in the End TB era

      Multisectoral collaboration and political commitment

      TB is a disease of poverty and deprivation, which can only be controlled by involving multiple stakeholders and addressing the need of marginalized groups with a high incidence, as recently reviewed by the The Lancet Commission on TB (
      • Reid M.J.A.
      • Arinaminpathy N.
      • Bloom A.
      • Bloom B.R.
      • Boehme C.
      • Chaisson R.
      • et al.
      Building a tuberculosis-free world: the Lancet Commission on tuberculosis.
      ). The often long incubation period, the latent stage with no symptoms, and the lack of access to proper diagnostics and management hamper control efforts. Political commitment is key to addressing the complex interaction between socio-economic problems and healthcare provision (
      • Matteelli A.
      • Rendon A.
      • Tiberi S.
      • Al-Abri S.
      • Voniatis C.
      • Carvalho A.C.C.
      • et al.
      Tuberculosis elimination: where are we now?.
      ).
      One example is the Zero TB Initiative, which creates support for local stakeholders helping to mobilize financial and technical resources. Examples are the mobile units in rural areas of South Africa providing treatment, and mobile CXR units in Karachi, Pakistan (

      Zero TB Initiative. https://www.zerotbinitiative.org/. [Accessed 18 December 2019].

      ). Such outreach is key to reach marginalized populations and will benefit from a mixture of private funded and public initiatives.
      The government will support policies, which inform migrants in their own language of their right to seek medical care, the signs and symptoms of TB, and the right to free treatment in Oman without the risk of being repatriated in the case of APTB. The End TB Strategy was reiterated in the Moscow Declaration adopted at the first WHO Global Ministerial Conference on ending TB in 2017, where ministers of health (
      • Zumla A.
      • Petersen E.
      The historic and unprecedented United Nations General Assembly High Level Meeting on Tuberculosis (UNGA-HLM-TB)—‘United to End TB: an urgent global response to a global epidemic’.
      ) including the minister for Oman, declared “We reaffirm our commitment to end the TB epidemic by 2030” (
      • WHO
      Moscow declaration to End TB.
      ). The Moscow Declaration called for the development of a multisectoral accountability framework, which was reiterated in the UN High Level Meeting Political Declaration by heads of state.

      Managing LTBI in migrants

      Similar to other countries in the Gulf Cooperation Council, Oman is characterized by a local population with a low incidence of TB and a large population of migrants with a higher incidence of TB. Managing LTBI in this population is a clear priority. The topic was discussed with focus on both screening and diagnostic challenges, as well as on treatment (
      • Shete P.B.
      • Boccia D.
      • Dhavan P.
      • Gebreselassie N.
      • Lönnroth K.
      • Marks S.
      • et al.
      Defining a migrant-inclusive tuberculosis research agenda to end TB.
      ;
      • Wild V.
      • Jaff D.
      • Shah N.S.
      • Frick M.
      Tuberculosis, human rights and ethics considerations along the route of a highly vulnerable migrant from sub-Saharan Africa to Europe.
      ;
      • Shedrawy J.
      • Siroka A.
      • Oxlade O.
      • Matteelli A.
      • Lönnroth K.
      Methodological considerations for economic modelling of latent tuberculous infection screening in migrants.
      ;
      • Zenner D.
      • Hafezi H.
      • Potter J.
      • Capone S.
      • Matteelli A.
      Effectiveness and cost-effectiveness of screening migrants for active tuberculosis and latent tuberculous infection.
      ;
      • Kunst H.
      • Burman M.
      • Arnesen T.M.
      • Fiebig L.
      • Hergens M.P.
      • Kalkouni O.
      • et al.
      Tuberculosis and latent tuberculous infection screening of migrants in Europe: comparative analysis of policies, surveillance systems and results.
      ;
      • Dara M.
      • Sulis G.
      • Centis R.
      • D’Ambrosio L.
      • de Vries G.
      • Douglas P.
      • et al.
      Cross-border collaboration for improved tuberculosis prevention and care: policies, tools and experiences.
      ). A study from the Netherlands found that the most important predictor for developing active TB was known exposure, but being foreign-born was an independent risk factor (
      • Erkens C.G.
      • Slump E.
      • Verhagen M.
      • Schimmel H.
      • Cobelens F.
      • van den Hof S.
      Risk of developing tuberculosis disease among persons diagnosed with latent tuberculosis infection in the Netherlands.
      ), and 72% of new TB cases were foreign-born (
      • van de Berg S.
      • Erkens C.
      • van Rest J.
      • van den Hof S.
      • Kamphorst M.
      • Keizer S.
      • et al.
      Evaluation of tuberculosis screening of immigrants in the Netherlands.
      ).

      Diagnosis of LTBI

      Mandatory health examinations of migrants in Oman take place at pre-entry, on arrival, and then every 2–4 years as part of visa renewal. A CXR is included in these medical examinations, potentially identifying cases of APTB.
      A pilot study from Oman found that 21% of migrants from Asia and 31% from Africa were IGRA-positive (

      Yaquobi F, Bader Al Rawahi, Nduku Ndunda, Badr Al Abri, Amina Al Jardani, Ali Al Maqbali, et al. Screening migrants from tuberculosis high endemic countries for latent TB in a low endemic setting. Submitted.

      ). Screening for LTBI is usually performed by tuberculin skin test (TST) or IGRA, which both detect cell-mediated immune responses against TB antigens (
      • Getahun H.
      • Matteelli A.
      • Abubakar I.
      • Aziz M.A.
      • Baddeley A.
      • Barreira D.
      • et al.
      Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries.
      ;
      • Goletti D.
      • Lee M.R.
      • Wang J.Y.
      • Walter N.
      • Ottenhoff T.H.M.
      Update on tuberculosis biomarkers: from correlates of risk, to correlates of active disease and of cure from disease.
      ,
      • Goletti D.
      • Lindestam Arlehamn C.S.
      • Scriba T.J.
      • Anthony R.
      • Cirillo D.M.
      • Alonzi T.
      • et al.
      Can we predict tuberculosis cure? What tools are available?.
      ). These tests cannot distinguish active TB from LTBI. Even though IGRAs have several advantages compared to TST, they are more expensive, rely on blood sampling, and require a diagnostic laboratory (
      • Pai M.
      • Denkinger C.M.
      • Kik S.V.
      • Rangaka M.X.
      • Zwerling A.
      • Oxlade O.
      • et al.
      Gamma interferon release assays for detection of Mycobacterium tuberculosis infection.
      ). In immunocompetent subjects, IGRAs have a very high negative predictive value (NPV; >99%) but as the tests rely on the cell-mediated immune responses, there is a risk of false-negatives from immunosuppression. For the QuantiFERON-TB Gold (QFT) test, there is also increasing awareness that a grey zone range (at least 0.20–0.70 IU/ml) should be used around the cut-off (0.35 IU/ml) to avoid both false-negative results due to recent exposure or immunosuppression and also false-positive results (
      • Pai M.
      • Denkinger C.M.
      • Kik S.V.
      • Rangaka M.X.
      • Zwerling A.
      • Oxlade O.
      • et al.
      Gamma interferon release assays for detection of Mycobacterium tuberculosis infection.
      ). It should be noted that the false-negative rate of an IGRA in patients with active TB has been reported to be approximately 12% (
      • Nguyen D.T.
      • Teeter L.D.
      • Graves J.
      • Graviss E.A.
      Characteristics associated with negative interferon-γ release assay results in culture-confirmed tuberculosis patients, Texas, USA, 2013–2015.
      ). Thus IGRA screening for LTBI may not identify all cases of active TB. However, conversely, a study from the UK found that pre-entry screening was strongly and independently associated with fewer APTB cases among new migrants (
      • Berrocal-Almanza L.C.
      • Harris R.
      • Lalor M.K.
      • Muzyamba M.C.
      • Were J.
      • O’Connell A.M.
      • et al.
      Effectiveness of pre-entry active tuberculosis and post-entry latent tuberculosis screening in new entrants to the UK: a retrospective, population-based cohort study.
      ).

      Management of LTBI in migrants to Oman

      A pragmatic approach to reduce TB incidence could be to select the migrants with a strongly positive IGRA of >4 IU/ml and offer them preventive therapy of 3 months of combined rifampicin or rifapentin and isoniazid.
      Two studies (
      • Winje B.A.
      • White R.
      • Syre H.
      • Skutlaberg D.H.
      • Oftung F.
      • Mengshoel A.T.
      • et al.
      Stratification by interferon-γ release assay level predicts risk of incident TB.
      ;
      • Andrews J.R.
      • Nemes E.
      • Tameris M.
      • Landry B.S.
      • Mahomed H.
      • McClain J.B.
      • et al.
      Serial QuantiFERON testing and tuberculosis disease risk among young children: an observational cohort study.
      ) found that individuals with a strongly positive (>4 IU/ml) IGRA test had a relative risk of 30 of developing APTB within the next 2 years. A study from the UK found an approximately five-times higher risk compared to baseline for developing APTB in subject with a TST >15 mm, positive T-Spot.TB, or positive IGRA (
      • Abubakar I.
      • Drobniewski F.
      • Southern J.
      • Sitch A.J.
      • Jackson C.
      • Lipman M.
      • et al.
      Prognostic value of interferon-γ release assays and tuberculin skin test in predicting the development of active tuberculosis (UK PREDICT TB): a prospective cohort study.
      ). However, a follow-up study found that higher thresholds for QFT, T-Spot.TB, and TST modestly increased the positive predictive value (PPV) for incident TB, but markedly reduced sensitivity (
      • Gupta R.K.
      • Lipman M.
      • Jackson C.
      • Sitch A.
      • Southern J.
      • Drobniewski F.
      • et al.
      Quantitative interferon gamma release assay and tuberculin skin test results to predict incident tuberculosis: a prospective cohort study.
      ).
      In 2018, 943 377 migrants were examined in the medical migrant examination centres in Oman, and 33% (311 314) of them were new arrivals. The study of IGRA reactivity in migrants (

      Yaquobi F, Bader Al Rawahi, Nduku Ndunda, Badr Al Abri, Amina Al Jardani, Ali Al Maqbali, et al. Screening migrants from tuberculosis high endemic countries for latent TB in a low endemic setting. Submitted.

      ) showed that 22.4% had a positive IGRA, i.e., 69 734 out of the 311 314 new arrivals. Should all 69 734 receive treatment for latent TB?
      Migrants usually stay in Oman for an average of 4 years and it can be argued that with a low or median reactivity (0.35–4 IU/ml) and without known risk factors for developing active TB, the persons should be informed about their status of LTBI and advised to seek treatment at their own expense. However, we could consider prioritizing for treatment only migrants with a strongly positive QFT of >4 IU/ml or those with risk factors (such as immunosuppression) and a positive QFT (>0.35 IU/ml). This strategy would reduce the number of persons offered treatment from 69 734 to 17 224 (24%). This is still a high number, but distributed in the major cities the task should be manageable in a public–private partnership programme.

      Extending the service by developing public–private partnerships

      In 2018, 3 million of the estimated 10 million people with TB worldwide were ‘missed’ by national TB programmes (NTPs) (). Two-thirds of them are thought to access TB treatment of questionable quality from public and private providers who are not engaged by the NTPs. The quality of care provided in these settings is often not known or substandard (). To close these gaps, the WHO and partners have launched a new roadmap to scale up the engagement of public and private healthcare providers (
      • World Health Organization
      Public–private mix for TB prevention and care: a roadmap.
      ). Also in Oman, the future challenges of the TB control programme need resources provided by the private health sector, both in diagnostics and the management of LTBI.
      The government is committed to providing treatment for both LTBI and active TB, to both Omani nationals and migrants. This will be done either in public or private facilities.
      Involvement of the private sector in the diagnosis and management of LTBI requires a quality control programme for the diagnostic tests used and regular reporting of treatment outcomes, including compliance. The government needs to develop models for cost covering of services – diagnostic and clinical – provided in the private sector within the framework of universal health coverage (UHC), as has already been done successfully in countries such as Pakistan, Bangladesh, India, and Indonesia. UHC means that all people have access to the health services they need, when and where they need them, without financial hardship, and this is part of the SDGs (

      World Health Organization Universal Health Coverage. WHO, Geneva, 2019. https://www.who.int/health-topics/universal-health-coverage#tab=tab_1. [Accessed 26 November 2019].

      ). UHC was addressed by a high-level meeting at the United Nations General Assembly (UNGA) on September 23, 2019 (

      World Health Organization Universal Health Coverage. United National General Assembly 23rd September 2019. https://www.who.int/news-room/events/detail/2019/09/23/default-calendar/un-high-level-meeting-on-universal-health-coverage. [Accessed 26 November 2019].

      ). The Oman Minister of Health, at a side event held on multisectoral action to end TB by the WHO and the Russian Federation at the UNGA, stressed the need for greater commitment in reaching vulnerable groups such as migrants. He called for greater partnership across all sectors, including the private sector, to reach this goal.
      The private health sector in Oman is capable of and willing to handle screening for LTBI and follow-up treatment. The key is the financial model. There are two options: (1) an insurance paid model where the employer responsible for the migrant worker has insurance that covers the diagnosis and management of LTBI; and (2) a model where the private sector clinics are reimbursed by the government after the price for the service has been negotiated. The incentives that could be offered could include accreditation and positive branding of collaborative private sector health facilities, as well as access to new tools such as rapid diagnostic tests and new drugs that are currently only available in the public sector.

      Developing molecular characterization by whole genome sequencing (WGS) to uncover transmission routes and define clusters and detect genotype resistance

      A single study from Oman used spoligotyping to explore the genetic population structure and clustering of Mtb isolates among nationals and immigrants (
      • Al-Maniri A.
      • Singh J.P.
      • Al-Rawas O.
      • Al Busaidi S.
      • Al Balushi L.
      • Ahmed I.
      • et al.
      A snapshot of the biodiversity and clustering of Mycobacterium tuberculosis in Oman using spoligotyping.
      ). The study found a predominance of the strain families commonly found on the Indian sub-continent. A high proportion of immigrant strains were in the same clusters as Omani strains (
      • Al-Maniri A.
      • Singh J.P.
      • Al-Rawas O.
      • Al Busaidi S.
      • Al Balushi L.
      • Ahmed I.
      • et al.
      A snapshot of the biodiversity and clustering of Mycobacterium tuberculosis in Oman using spoligotyping.
      ). However, spoligotyping has a very low discriminatory power compared to WGS.
      Genotyping Mtb strains from TB patients over time provides detailed information on the Mtb transmission dynamics (
      • Folkvardsen D.B.
      • Norman A.
      • Andersen ÅB.
      • Michael Rasmussen E.
      • Jelsbak L.
      • Lillebaek T.
      Genomic epidemiology of a major mycobacterium tuberculosis outbreak: retrospective cohort study in a low-incidence setting using sparse time-series sampling.
      ;
      • Andrés M.
      • van der Werf M.J.
      • Ködmön C.
      • Albrecht S.
      • Haas W.
      • Fiebig L.
      Survey study group. Molecular and genomic typing for tuberculosis surveillance: a survey study in 26 European countries.
      ), and it is possible to determine transmission among and between nationalities (
      • Kamper-Jørgensen Z.
      • Andersen A.B.
      • Kok-Jensen A.
      • Bygbjerg I.C.
      • Thomsen V.O.
      • Lillebaek T.
      Characteristics of non-clustered tuberculosis in a low burden country.
      ). This information can be used to optimize the public health management of TB, e.g. by directing the TB control efforts to specific risk-groups (
      • Karmakar M.
      • Trauer J.M.
      • Ascher D.B.
      • Denholm J.T.
      Hyper transmission of Beijing lineage Mycobacterium tuberculosis: systematic review and meta-analysis.
      ). A study from Copenhagen found a prevalence rate of APTB of 3% in homeless people identified by sputum culture (
      • Jensen S.G.
      • Olsen N.W.
      • Seersholm N.
      • Lillebaek T.
      • Wilcke T.
      • Pedersen M.K.
      • et al.
      Screening for TB by sputum culture in high-risk groups in Copenhagen, Denmark: a novel and promising approach.
      ).
      Specifically in Oman, WGS will be useful to determine the amount of transmission between migrant workers and Omanis and to identify high-risk groups and hotspots for active TB transmission within the country.
      In addition, systematic use of WGS on all Mtb isolates will allow the emergence of drug resistance to be monitored and, if implemented from early liquid culture, could allow the cost of phenotypic drug sensitivity tests on strains that are fully wild-type for first-line drugs to be reduced. This strategy will be fully compliant with pillar 1: early diagnosis of TB including universal drug-susceptibility testing, and systematic screening of contacts and high-risk groups. The Oman Central Public Health Laboratory has received a grant from the Oman Research Council on “Understanding TB transmission and epidemiology using molecular and geo-spatial methods”, and this will be incorporated into the routine surveillance in the future.

      Patient-centred care including treatment support

      The key challenge with programmatic LTBI screening is compliance with preventive treatment (
      • Frieden T.R.
      • Sbarbaro J.A.
      Promoting adherence to treatment for tuberculosis: the importance of direct observation.
      ;
      • Newell J.N.
      • Baral S.C.
      • Pande S.B.
      • Bam D.S.
      • Malla P.
      Family-member DOTS and community DOTS for tuberculosis control in Nepal: cluster-randomised controlled trial.
      )​. A recent review of LTBI treatment in migrants found an overall poor level of compliance (
      • Greenaway C.
      • Pareek M.
      • Abou Chakra C.N.
      • Walji M.
      • Makarenko I.
      • et al.
      The effectiveness and cost-effectiveness of screening for latent tuberculosis among migrants in the EU/EEA: a systematic review.
      ), and one possibility is to extend the community-based treatment support to cover preventive treatment of LTBI. Adherence to preventive treatment of LTBI infection in Oman was found to be 42% among HCWs (
      • Khamis F.
      • Al-Lawati A.
      • Al-Zakwani I.
      • Al-Abri S.
      • Al-Naamani J.
      • Al-Harthi H.
      • et al.
      Latent tuberculosis in health care workers exposed to active tuberculosis in a tertiary care hospital in Oman.
      ). During 2 years of community-based care delivery in Muscat Governorate, 18 out of 27 Omani pulmonary TB patients included in 2017 and all Omani nationals with pulmonary TB (n = 16) in 2018, except two new cases, were on community-based care delivery. There was a significant reduction in average length of hospital stay for pulmonary TB patients when compared to previous years (27 days in 2017 and 28 days in 2018, compared to 61 days in 2016).
      This may help with the acceptability of preventive treatment among recipients and may contribute to reduce in-hospital transmission (
      • Migliori G.B.
      • Nardell E.
      • Yedilbayev A.
      • D’Ambrosio L.
      • Centis R.
      • Tadolini M.
      • et al.
      Reducing tuberculosis transmission: a consensus document from the World Health Organization Regional Office for Europe.
      ). Even though community preventive treatment support is not presently offered to people with LTBI, some form of support to ensure adherence that is either family or community based would be desirable. This could be enhanced through the use of digital and video technology. To increase compliance, the 3-month course with a rifapentin or rifampicin/isoniazid combination is much preferred.

      TB in high-risk groups

      Healthcare workers

      The United States recently (2019) revised its recommendations for the surveillance of TB in HCWs, because the risk was determined to be very low (
      • Sosa L.E.
      • Njie G.J.
      • Lobato M.N.
      • Bamrah Morris S.
      • Buchta W.
      • et al.
      Tuberculosis screening, testing, and treatment of U.S. Health Care Personnel: recommendations from the National Tuberculosis Controllers Association and CDC, 2019.
      ). The new recommendations include baseline (pre-placement) TB screening with an individual risk assessment and symptom evaluation for all personnel, and testing with an IGRA or TST for personnel with known exposure to TB. A recent study from Korea including 3920 HCWs tested with an IGRA found that 893 (22.8%) had LTBI (
      • Han S.S.
      • Lee S.J.
      • Yim J.J.
      • Song J.H.
      • Lee E.H.
      • Kang Y.A.
      Evaluation and treatment of latent tuberculosis infection among healthcare workers in Korea: a multicentre cohort analysis.
      ). The study also found that the acceptance rate for treatment of LTBI was 64.6% with 3 months of rifampicin/isoniazid or 4 months of rifampicin.

      TB in children

      TB cases in Omani children are shown in Table 3. Children pose unique challenges to TB control programmes, as infection in this age group is considered a sentinel event indicating recent transmission.
      Table 3Tuberculosis cases in children.
      YearOmaniNon-OmaniTotal
      20109110
      20119211
      201212012
      201310414
      2014617
      20159110
      2016628
      2017718
      2018606
      The importance and priority of children as a special high-risk group was highlighted in the WHO End TB Strategy (
      • World Health Organization
      The End TB Strategy.
      ). A recent study estimated that 70% of active TB in children in West Africa is not diagnosed (
      • TDR (Special Programme for Research and Training in Tropical Diseases)
      Improving detection of TB in children: a smarter solution.
      ).
      The main interventions to prevent new cases in children are vaccination with the bacillus Calmette-Guérin (BCG) vaccine, contact tracing and screening for active TB, and treatment of LTBI (
      • Thomas T.A.
      Tuberculosis in children.
      ). BCG immunization has been terminated in many low endemic countries due to more side effects than potentially prevented TB cases. A modelling study of the preventive effect of BCG vaccination found that a 92% BCG coverage at birth reduced TB deaths in the global birth cohort by 2.8% (0.1–7.0%, confidence interval) by age 15 years, and that a 100% coverage at birth reduced TB deaths by 16.5% (0.7–41.9%, CI) (
      • Roy P.
      • Vekemans J.
      • Clark A.
      • Sanderson C.
      • Harris R.C.
      • White R.G.
      Potential effect of age of BCG vaccination on global paediatric tuberculosis mortality: a modelling study.
      ).
      The WHO has strongly recommended treatment for LTBI in children under 5 years of age who are household contacts of pulmonary TB cases (WHO, 2018). The performance of screening tests like the TST and IGRA is poorly documented in children below 2 years of age (Box 1).
      Fact box.
      The End TB targets are:
      • 1
        A 95% reduction by 2035 in number of TB deaths compared with 2015;
      • 2
        A 90% reduction by 2035 in TB incidence rate compared with 2015;
      • 3
        Zero TB-affected families facing catastrophic costs due to TB by 2035 (
        • World Health Organization
        Global action framework for TB research.
        ).
      There is an increasing need for microbiological (culture) confirmation of TB disease, which is limited by the paucibacillary nature of TB in children. Furthermore, the newer rapid molecular tests are positive in the minority of children, generally <25–40% of children with TB disease (
      • World Health Organization
      Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary TB in adults and children. Policy update.
      ;
      • Jenkins H.E.
      • Tolman A.W.
      • Yuen C.M.
      • Parr J.B.
      • Keshavjee S.
      • Pérez-Vélez C.M.
      • et al.
      Incidence of multidrug-resistant tuberculosis disease in children: systematic review and global estimates.
      ).

      Screening algorithms and cost-effectiveness

      Current LTBI screening is limited by the relatively low PPV of available tests (
      • Rangaka M.X.
      • Wilkinson K.A.
      • Glynn J.R.
      • Ling D.
      • Menzies D.
      • Mwansa-Kambafwile J.
      • et al.
      Predictive value of interferon- γ release assays for incident active tuberculosis: a systematic review and meta-analysis.
      ). Although the PPV appears better for some IGRA tests compared with the TST (
      • Abubakar I.
      • Drobniewski F.
      • Southern J.
      • Sitch A.J.
      • Jackson C.
      • Lipman M.
      • et al.
      Prognostic value of interferon-γ release assays and tuberculin skin test in predicting the development of active tuberculosis (UK PREDICT TB): a prospective cohort study.
      ,
      • Gupta R.K.
      • Lipman M.
      • Jackson C.
      • Sitch A.
      • Southern J.
      • Drobniewski F.
      • et al.
      Quantitative interferon gamma release assay and tuberculin skin test results to predict incident tuberculosis: a prospective cohort study.
      ), defining reactivation risk varies significantly by population group. The selection of the population group determines the efficiency and cost-effectiveness of the approach (
      • Zenner D.
      • Hafezi H.
      • Potter J.
      • Capone S.
      • Matteelli A.
      Effectiveness and cost-effectiveness of screening migrants for active tuberculosis and latent tuberculous infection.
      ). Thus screening those at highest risk of reactivation, such as persons with immunosuppression, is most cost-effective (
      • Greenaway C.
      • Pareek M.
      • Abou Chakra C.N.
      • Walji M.
      • Makarenko I.
      • et al.
      The effectiveness and cost-effectiveness of screening for latent tuberculosis among migrants in the EU/EEA: a systematic review.
      ), and this has led to the recommendation to focus on these high-risk groups for LTBI control (
      • WHO
      Moscow declaration to End TB.
      ; ECDC, 2018). In the context of TB elimination and the large estimated numbers of persons with LTBI (
      • Houben R.M.G.J.
      • Dodd P.J.
      The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling.
      ), strategies need to include further groups.
      There is a conditional recommendation for screening of a number of groups, including recent migrants from high incidence countries (
      • World Health Organization
      Guidelines on the management of latent tuberculosis infection.
      ). A way forward is stratification by epidemiological risk factors (country of origin, time since arrival), demographic factors (age groups), co-morbidities, or social risk factors. There is no consensus on thresholds (
      • Greenaway C.
      • Pareek M.
      • Abou Chakra C.N.
      • Walji M.
      • Makarenko I.
      • et al.
      The effectiveness and cost-effectiveness of screening for latent tuberculosis among migrants in the EU/EEA: a systematic review.
      ), and practices vary significantly between countries (
      • Kunst H.
      • Burman M.
      • Arnesen T.M.
      • Fiebig L.
      • Hergens M.P.
      • Kalkouni O.
      • et al.
      Tuberculosis and latent tuberculous infection screening of migrants in Europe: comparative analysis of policies, surveillance systems and results.
      ). The decision on thresholds will depend on preferences and choices around the population impact of screening, individual risks and benefits, and cost-effectiveness. The UK has chosen its incidence threshold of 150 per 100 000 for the LTBI programme based on cost-effectiveness studies (
      • Pareek M.
      • Watson J.P.
      • Ormerod L.P.
      • Kon O.M.
      • Woltmann G.
      • White P.J.
      • et al.
      Screening of immigrants in the UK for imported latent tuberculosis: a multicentre cohort study and cost-effectiveness analysis.
      ).

      Modelling

      Part of the End TB Framework is to empower a strong and self-sustained TB research community in low- and middle-income countries with a high TB burden. In Oman, the next revision of the National TB Strategic Plan will include a national research plan.
      The scale of the possible interventions will create a substantial burden, both in terms of financial costs and population or healthcare system impact. It is therefore critical that interventions are designed rationally, and optimized with regards to maximal impact and minimal burdens. Mathematical modelling provides important tools for the assessment of potential strategies, and allows for comparison of a wide range of possible approaches with relatively minimal resource implications.
      In the specific context of Oman, mathematical modelling approaches could be used to consider the optimal screening algorithms for latent and active TB in migrants and nationals, and to evaluate the efficiency of different strategies. This could include the selection of the most appropriate tests, testing frequency, and cost-effective approaches to TB incidence reduction. One obvious task for a modelling analysis is to look at active TB in Omani nationals in order to provide data indicating whether screening for latent TB of part of the Omani population would be beneficial. Modelling can identify high-risk groups in the community, whether nationals or migrants.

      Research

      There is a need for operational research aimed at optimizing the cost-effectiveness of the different interventions, identifying high-risk groups in the community, follow-up of persons with LTBI without treatment, and stratification of the risk of developing active TB based on the strength of the IGRA level or TST reactivity (
      • Goletti D.
      • Lindestam Arlehamn C.S.
      • Scriba T.J.
      • Anthony R.
      • Cirillo D.M.
      • Alonzi T.
      • et al.
      Can we predict tuberculosis cure? What tools are available?.
      ;
      • Kik S.V.
      • Schumacher S.
      • Cirillo D.M.
      • Churchyard G.
      • Boehme C.
      • Goletti D.
      • et al.
      An evaluation framework for new tests that predict progression from tuberculosis infection to clinical disease.
      ).
      An obvious research project would be to compare 3 months of preventive treatment with 1 month (
      • Swindells S.
      • Ramchandani R.
      • Gupta A.
      • Benson C.A.
      • Leon-Cruz J.
      • Mwelase N.
      • et al.
      One month of rifapentine plus isoniazid to prevent HIV-related tuberculosis.
      ). The existing mandatory health investigation including a CXR every 2–4 years will ensure that follow-up is done if the migrant stays in Oman. This will allow studies on the effectiveness and cost-effectiveness of active TB screening in combination with LTBI or LTBI only.
      The extension of treatment support services to cover LTBI in order to increase compliance and a general switch from 6 or 9 months of isoniazid to 3 months of rifapentin or rifampicin/isoniazid are needed. The planned screening of migrants with mandatory follow-up every 2 years will also allow Oman to generate data on the efficacy of the screening assay and efficacy of the treatment offered, as it is expected that most active TB cases will develop after arrival.
      Models for public–private partnerships to enlarge affordable coverage for all, need to be developed, tried, and validated. A recent study from Australia compared central and decentralized management in TB programmes and concluded that central programmes were better suited to change and challenges (
      • Degeling C.
      • Carroll J.
      • Denholm J.
      • Marais B.
      • Dawson A.
      Ending TB in Australia: organizational challenges for regional tuberculosis programs.
      )

      Conclusions

      Fulfilling the WHO End TB Strategy and the WHO TB Elimination Framework requires a comprehensive package of strategies. This review of the challenges of achieving TB elimination in a low endemic country like Oman with a high number of migrants from high TB endemic countries, clearly shows that screening for LTBI and the treatment of either all cases with LTBI or high-risk cases, is a key intervention to reduce new cases. In more high-endemic settings, the identification of high-risk groups and screening these for LTBI, followed by preventive treatment, is an initial strategy.
      Molecular typing of all new cases in both nationals and migrants is needed to identify clusters and fully understand the transmission chains.
      The development of public–private partnerships is needed to handle the burden of screening and treating migrants for LTBI. This requires political decisions and quality control of diagnostics and management in private healthcare facilities. With high-level political commitment in Oman to eliminate TB, the country could be among the first to achieve TB elimination and serve as a pathfinder for the region and the world.

      Conflict of interest

      The authors declares no conflict of interest.

      Acknowledgements

      This paper is based on the presentations and discussions at an international workshop on TB elimination in low-incidence countries, which took place from September 5 to September 7, 2019, and was hosted by the Ministry of Health, Oman and supported by the WHO and ESCMID. Financial support was received from Qiagen , Cepheid , Advanced Healthcare Solutions , Pfizer , and MSD . This article is part of a supplement entitled Commemorating World Tuberculosis Day March 24th, 2020: “IT'S TIME TO FIND, TREAT ALL and END TUBERCULOSIS!” published with support from an unrestricted educational grant from QIAGEN Sciences Inc.

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