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Evaluating the effectiveness of interventions for the prevention of tuberculosis ina low-incidence setting

Erkens, C.G.M.

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Evaluating the effectivenessof interventions for the prevention of tuberculosis in a low-incidence setting

connie erkens

connie erkensEvaluating the effectiveness of interventions for the prevention of tuberculosis in a low

-incidence setting

UITNODIGINGVoor het bijwonen

van de openbare verdediging van het proefschrift

DOOR

CONNIE ERKENS

Evaluating the effectiveness

of interventions for the prevention

of tuberculosis in a low-incidence

setting

op woensdag 29 maart 2017

11.00 uur in de Aula

van de Universiteit, Oude Lutherse Kerk,

Singel 411, 1012 XM Amsterdam

Aansluitend bent u van harte welkom op de

receptie op dezelfde locatie

paranimfen:Margreet Kamphorst

06-2569 8625

Marlies MensenMarliesmensen@hotmail.com

Kees BuddinghJohannes Mol Hendrika Jungius Bep

Bakhuys Jacoba van Beieren Jan MankesPetronella Rijfkogel Johanna Budde Esméevan Eeghen Gijs van Hall Estella Hertzveld Anna Berkhout Sonya Gaskell Saskia van

Uylen- burgh Jetje Brouwer JohannesHugen- holtz Adriana Alewijn Pieter Baan

Adolf van der Laar Trijntje van de SchaafJohan Stekelenburg PeterFaber Herman van Oenen

Wilma Vermaat Geertruida HubersAndries Kloos Aat Breur-Hitma Jan

Slauerhoff Louis Couperus Andries van DantzigCatherina van Lier Helperus van Lier Alexander van Oranje

Nassau Albert Pieter Hahn Jacques van Ginneken Marga Minco Paul van Ostaijen Jan Montyn P.A. de Génestet Gerard Bilders Karel

van de Woestijne Henk Westbroek Jan Wiegers Kees BuddinghJohannes Mol Hendrika Jungius Bep Bakhuys

Jacoba van Beieren Jan Mankes Petronella Rijfkogel Johanna Budde Esmée

van Eeghen Gijs van Hall Estella Hertzveld Anna Berk- hout Sonya Gaskell Saskia van

Uy- lenburgh Jetje Brouwer Johannes Hugenholtz

AdrianaAle-

wijn Pieter

Kees BuddinghJohannes Mol

HendrikaJungius Bep

Bak-

Kees Buddingh

Johannes Mol

Hendri-ka

Kees Bud-

dingh

Kees Buddingh

Johannes Mol Hendrika Jungius

Bep BakhuysJacoba

Kees Buddingh Johannes Mol Hendrika Jungius

Bep

Kees Buddingh Johannes Mol

Hen-

Kees Buddingh Johannes Mol

Hendri- ka Jungius Bep Bakhuys

Jacoba van Beieren JanMankes Petronella Rijfkogel

Johanna Budde Esmée van Eeghen Gijs van Hall Estella

Hertzveld Anna Berkhout SonyaGaskell Saskia van

Uylenburgh Jetje BrouwerJohannes Hugenholtz

Kees Buddingh Johannes Mol Hendrika Jungius Bep Bakhuys Jacoba van

Beieren Jan Mankes Petronella RijfkogelJohanna Budde Esmée van Eeghen

Gijs van Hall Estella Hertzveld Anna Berkhout Sonya

Gaskell Saskia van Uylenburgh

Kees Buddingh Johannes Mol Hendrika Jungius Bep Bakhuys

Jacoba van Beieren JanMa

Kees Buddingh Jo-hannes Mol Hendrika Jungius Bep

Bakhuys Jacoba van Beieren Jan Mankes Petronella RijfkogelJohanna Budde Esmée van Eeghen Gijs van

Hall Estella Hertzveld Anna Berkhout

Kees Buddingh Johannes Mol Hendrika Jungius Bep

Bakhuys Jacoba van Beieren Jan Mankes Petronella RijfkogelJohanna Budde Esmée van Eeghen Gijs van Hall Estella Hertzveld Anna

Berkhout Sonya Gaskell Saskia van Uylenburgh Jetje Brouwer Johannes Hugenholtz AdrianaAlewijn Pieter Baan Adolf van der Laar Trijntje van de Schaaf Johan Stekelenburg Peter Faber Herman van

Oenen Wilma Vermaat Geertruida Hubers Andries Kloos Aat Breur-Hitma Jan Slauerhoff Louis Couperus Andries vanDantzig Catherina van Lier Helperus van Lier Alexander van Oranje Nassau Albert Pieter Hahn Jacques van Ginneken Marga Minco

Paul van Ostaijen Jan Montyn P.A. de Génestet Gerard Bilders Karel van de Woestijne Henk Westbroek Jan Wiegers Kees Buddingh Johannes Mol Hendrika Jungius Bep Bakhuys Jacoba van Beieren Jan Mankes Petronella Rijfkogel Johanna Budde Esmée van Eeghen Gijs

van Hall Estella Hertzveld Anna Berkhout Sonya Gaskell Saskia van Uylenburgh Jetje Brouwer Johannes Hugenholtz Adriana AlewijnPieter Baan Adolf van der Laar Trijntje van de Schaaf Johan Stekelenburg Peter Faber Herman van Oenen Wilma Vermaat Geertruida

Hubers Andries Kloos Aat Breur-Hitma Jan Slauerhoff Louis Couperus Andries van Dantzig Catherina van Lier Helperus van Lier Alexandervan Oranje Nassau Albert Pieter Hahn Jacques van Ginneken Marga Minco Paul van Ostaijen Jan Montyn P.A. de Génestet Gerard BildersKarel van de Woestijne Henk Westbroek Jan Wiegers Kees Buddingh Johannes Mol Hendrika Jungius Bep Bakhuys Jacoba van Beieren Jan

Mankes Petronella Rijfkogel Johanna Budde Esmée van Eeghen Gijs van Hall Estella Hertzveld Anna Berkhout Sonya Gaskell Saskia vanUylenburgh Jetje Brouwer Johannes Hugenholtz Adriana Alewijn Pieter Baan Adolf van der Laar Trijntje van de Schaaf Johan

Stekelenburg Peter Faber Herman van Oenen Wilma Vermaat Geertruida Hubers Andries Kloos Aat Breur-Hitma Jan Slauerhoff Louis Cou- perus Andries van Dantzig Catherina van Lier Helperus van Lier Alexander van Oranje Nassau Albert Pieter Hahn Jacques vanGinne- ken Marga Minco Paul van Ostaijen Jan Montyn P.A. de Génestet Gerard Bilders Karel van de Woestijne Henk Westbroek Jan Wiegers Kees

Buddingh Johannes Mol Hendrika Jungius Bep Bakhuys Jacoba van Beieren Jan Mankes Petronella Rijfkogel Johanna Budde Esmée van Eeghen Gijs van HallEstella Hertzveld Anna Berkhout Sonya Gaskell Saskia van Uylenburgh Jetje Brouwer Johannes Hugenholtz Adriana Alewijn Pieter

Baan Adolf van der Laar Trijntje van de Schaaf Johan Stekelenburg Peter Faber Herman van Oenen Wilma Vermaat Geertruida Hubers AndriesKloos Aat Breur-Hitma Jan Slauerhoff Louis Couperus Andries van Dantzig Catherina van Lier Helperus van Lier Alexander van Oranje

Nassau Albert Pieter Hahn Jacques van Ginneken Marga Minco Paul van Ostaijen Jan Montyn P.A. de Génestet Gerard Bilders Karel van de WoestijneHenk Westbroek Jan Wiegers Kees Buddingh Johannes Mol Hendrika Jungius Bep Bakhuys Jacoba van Beieren Jan Mankes Petronella Rijfkogel Johanna Budde

Esmée van Eeghen Gijs van Hall Estella Hertzveld Anna Berkhout Sonya Gaskell Saskia van Uylenburgh Jetje Brouwer Johannes Hugenholtz AdrianaAlewijn Pieter Baan Adolf van der Laar Trijntje van de Schaaf Johan Stekelenburg Peter Faber Herman van Oenen Wilma Vermaat Geertruida Hubers

Andries Kloos Aat Breur-Hitma Jan Slauerhoff Louis Couperus Andries van Dantzig Catherina van Lier Helperus van LierAlexander van Oranje Nassau Albert Pieter Hahn Jacques van Ginneken Marga Minco Paul van

Ostaijen Jan Montyn P.A. de Génestet Gerard Bilders Karel van de Woestijne Henk Westbroek Jan Wiegers Kees Buddingh Johannes Mol Hendrika Jungius Bep Bakhuys Jacoba van Beieren

Jan Mankes Petronella Rijfkogel Johanna Budde Esmée van Eeghen Gijs van Hall EstellaHertzveld Anna Berkhout Sonya Gaskell Saskia van Uylenburgh Jetje Brouwer Johannes

Hugenholtz Adriana Alewijn Pieter Baan Adolf van der Laar Trijntje van de Schaaf Johan Stekelenburg Peter Faber Herman van Oenen Wilma Vermaat Geertruida Hubers Andries Kloos Aat Breur-Hitma JanSlauerhoff Louis Couperus Andries van Dantzig Catherina van Lier Helperus van Lier Alexander van Oranje Nassau Albert Pieter

Hahn Jacques van Ginneken Marga Minco Paul van Ostaijen Jan Montyn P.A. de Génestet Gerard Bilders Karel van deKees BuddinghJohannes Mol Hendrika Jungius Bep Bakhuys Jacoba van Beieren Jan Mankes Petronella Rijfkogel Johanna Budde Esmée van Eeghen Gijs van

Hall Estella Hertzveld Anna Berkhout Sonya Gaskell Saskia van Uylenburgh Jetje Brouwer Johannes Hugenholtz Adriana Alewijn Pieter Baan Adolf van der Laar Trijntje van de Schaaf Johan Stekelenburg Peter Faber Herman van Oenen Wilma Vermaat Geertruida Hubers Andries Kloos Aat Breur-Hitma Jan

Slauerhoff Louis Couperus Andries van Dantzig Catherina van Lier Helperus van Lier Alexander van Oranje Nassau Albert Pieter Hahn Jacques van Ginneken Marga Minco Paul vanOstaijen Jan Montyn P.A. de Génestet Gerard Bilders Karel van de Woestijne Henk Westbroek Jan Wiegers Woestijne Henk Westbroek Jan WiegersKees Buddingh Johannes Mol Hendrika

Jungius Bep Bakhuys Jacoba van Beieren Jan Mankes Petronella Rijfkogel Johanna Budde Esmée van Eeghen Gijs van Hall Estella Hertzveld Anna Berkhout Sonya Gaskell Saskia van Uylenburgh JetjeBrouwer Johannes Hugenholtz Adriana Alewijn Pieter Baan Adolf van der Laar Trijntje van de Schaaf Johan Stekelenburg Peter Faber Herman van Oenen Wilma Vermaat Geertruida Hubers Andries

Kloos Aat Breur-Hitma Jan Slauerhoff Louis Couperus Andries van Dantzig Catherina van Lier Helperus van Lier Alexander van Oranje Nassau Albert Pieter Hahn Jacques van Ginneken Marga MincoPaul van Ostaijen Jan Montyn P.A. de Génestet Gerard Bilders Karel van de Woestijne Henk Westbroek Jan WiegersKees Buddingh Johannes Mol Hendrika Jungius Bep Bakhuys Jacoba van Beieren Jan

Mankes Petronella Rijfkogel Johanna Budde Esmée van Eeghen Gijs van Hall Estella Hertzveld Anna Berkhout Sonya Gaskell Saskia van Uylenburgh Jetje Brouwer Johannes Hugenholtz AdrianaAlewijn Pieter Baan Adolf van der Laar Trijntje van de Schaaf Johan Stekelenburg Peter Faber Herman van Oenen Wilma Vermaat Geertruida Hubers Andries Kloos Aat Breur-Hitma Jan

Slauerhoff Louis Couperus Andries van Dantzig Catherina van Lier Helperus van Lier Alexander van Oranje Nassau Albert Pieter Hahn Jacques van Ginneken Marga Minco Paul van Ostaijen JanMontyn P.A. de Génestet Gerard Bilders Karel van de Woestijne Henk Westbroek Jan WiegersKees Buddingh Johannes Mol Hendrika Jungius Bep Bakhuys Jacoba van Beieren Jan Mankes Petronella Rijfkogel

Johanna Budde Esmée van Eeghen Gijs van Hall Estella Hertzveld Anna Berkhout Sonya Gaskell Saskia van Uylenburgh Jetje Brouwer Johannes Hugenholtz Adriana Alewijn Pieter Baan Adolf van der Laar Trijntjevan de Schaaf Johan Stekelenburg Peter Faber Herman van Oenen Wilma Vermaat Geertruida Hubers Andries Kloos Aat Breur-Hitma Jan Slauerhoff Louis Couperus Andries van Dantzig Catherina van Lier Helperus van

Lier Alexander van Oranje Nassau Albert Pieter Hahn Jacques van Ginneken Marga Minco Paul van Ostaijen Jan Montyn P.A. de Génestet Gerard Bilders Karel van de Woestijne Henk Westbroek Jan WiegersKeesBuddingh Johannes Mol Hendrika Jungius Bep Bakhuys Jacoba van Beieren Jan Mankes Petronella Rijfkogel Johanna Budde Esmée van Eeghen Gijs van Hall Estella Hertzveld Anna Berkhout Sonya

Gaskell Saskia van Uylenburgh Jetje Brouwer Johannes Hugenholtz Adriana Alewijn Pieter Baan Adolf van der Laar Trijntje van de Schaaf Johan Stekelenburg Peter FaberHerman van Oenen Wilma Vermaat Geertruida Hubers Andries Kloos Aat Breur-Hitma Jan Slauerhoff Louis Couperus Andries van Dantzig Catherina van

Lier Helperus van Lier Alexander van Oranje Nassau Albert Pieter Hahn Jacques van Ginneken Marga Minco Paul van Ostaijen Jan Montyn P.A.de Génestet Gerard Bilders Karel van de Woestijne Henk Westbroek Jan WiegersKees Buddingh Johannes Mol Hendrika Jungius Bep

Bakhuys Jacoba van Beieren Jan Mankes Petronella Rijfkogel Johanna Budde Esmée van Eeghen Gijs van Hall Estella Hertzveld AnnaBerkhout Sonya Gaskell Saskia van Uylenburgh Jetje Brouwer Johannes Hugenholtz Adriana Alewijn Pieter Baan Adolf van

der Laar Trijntje van de Schaaf Johan Stekelenburg Peter Faber Herman van Oenen Wilma Vermaat GeertruidaHubers Andries Kloos Aat Breur-Hitma Jan Slauerhoff Louis Couperus Andries van Dantzig Catherina van Lier

Helperus van Lier Alexander van Oranje Nassau Albert Pieter Hahn Jacques van Ginneken Marga Minco Paul van Ostaijen Jan Montyn P.A.de Génestet Gerard Bilders Karel van de Woestijne Henk Westbroek Jan WiegersKees Buddingh Johannes Mol Hendrika Jungius Bep Bakhuys Jacoba van

Bei- eren Jan Mankes Petronella Rijfkogel Johanna Budde Esmée van Eeghen Gijs van Hall Estella Hertzveld Anna Berkhout Sonya Gaskell Saskia van Uylenburgh JetjeBrouwer Johannes Hugenholtz Adriana Alewijn Pieter Baan Adolf van der Laar Trijntje van de Schaaf Johan Stekelenburg Peter Faber Herman van Oenen Wilma Vermaat

Geertruida Hubers Andries Kloos Aat Breur-Hitma Jan Slauerhoff Louis Couperus Andries van Dantzig Catherina van Lier Helperus van Lier Alexander van Oranje Nassau Albert PieterHahn Jacques van Ginneken Marga Minco Paul van Ostaijen Jan Montyn P.A. de Génestet Gerard Bilders Karel van de Woestijne Henk Westbroek Jan WiegersKees Buddingh Johannes Mol

Hendrika Jungius Bep Bakhuys Jacoba van Beieren Jan Mankes Petronella Rijfkogel Johanna Budde Esmée van Eeghen Gijs van Hall Estella Hertzveld Anna Berkhout Sonya Gaskell Saskia van Uylen- burgh Jetje Brouwer Johannes Hugenholtz Adriana Alewijn Pieter Baan Adolf van der Laar Trijntje

van de Schaaf Johan Stekelen- burg Peter Faber Herman van Oenen Wilma Vermaat Geertruida Hubers Andries Kloos AatBreur-Hitma Jan Slauerhoff Louis Couperus Andries van Dantzig Catherina van Lier Helperus van Lier

Alexander van Oranje Nassau Albert Pieter Hahn Jacques van Ginneken Marga MincoPaul van Ostaijen Jan Montyn P.A. de Génestet Gerard Bilders Karel van de

Woestijne Henk Westbroek Jan WiegersKees Buddingh Johannes Mol Hendrika Jungius Bep Bakhuys Jacoba van Beieren Jan

Mankes Petronella Rijfkogel Johanna Budde Esmée van Eeghen Gijs van Hall

Estella Hertzveld Anna Berkhout Sonya

Gaskell Saskia van Uylenburgh Jetje

Brouwer Jo-

hannes Hugen-holtz Adri-

ana Alewijn Pieter Baan Adolf van der Laar

Trijntje van de Schaaf Johan Stekelenburg Peter FaberHerman van Oenen Wilma

Vermaat GeertruidaHubers Andries

Kees Buddingh Johannes Mol Hendrika

Jungius Bep Bakhuys Jacoba vanBeieren Jan Mankes Petronella

Rijfkogel Johanna Budde Esmée vanEeghen Gijs van Hall Estella

Hertzveld Anna Berkhout Sonya Gaskell Saskia van Uylenburgh

Jetje Brouwer Johannes Hugenholtz

Adriana

Kees Buddingh

Johannes Mol

Hendri-ka

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dingh

Kees Buddingh

Johannes Mol Hendrika Jungius

Bep BakhuysJacoba

Kees Buddingh Johannes Mol Hendrika Jungius

Bep

Kees Buddingh Johannes Mol

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Kees Buddingh Johannes Mol

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Jacoba van Beieren Jan Mankes Petronella Rijfkogel

Johanna Budde Esmée vanEeghen Gijs van Hall Estella

Hertzveld Anna Berkhout SonyaGaskell Saskia van

Uylenburgh Jetje BrouwerJohannes Hugenholtz

Kees Buddingh Johannes Mol Hendrika Jungius Bep Bakhuys Jacoba van

Beieren Jan Mankes Petronella RijfkogelJohanna Budde Esmée van Eeghen

Gijs van Hall Estella Hertzveld Anna Berkhout Sonya

Gaskell Saskia vanUylenburgh

Kees Buddingh Johannes Mol Hendrika Jungius Bep Bakhuys

Jacoba van Beieren Jan Ma

Kees Buddingh Jo-hannes Mol Hendrika Jungius Bep

Bakhuys Jacoba van Beieren Jan Mankes Petronella RijfkogelJohanna Budde Esmée van Eeghen Gijs van

Hall Estella Hertzveld Anna Berkhout

Evaluating the effectiveness of interventions for the prevention

of tuberculosis in a low-incidence setting

Connie Erkens

Evaluating the effectiveness of interventions for the prevention of tuberculosis in a low-incidence setting

Thesis, University of Amsterdam (UvA), the Netherlands ISBN: 978-94-91602-93-1 http://dare.uva.nl/dissertaties Cover: Anna Tomson Lay-out: Anna Tomson Printed by: Print Service Ede Financial support for printing this thesis was provided by KNCV Tuberculosis Foundation and Vereniging voor Artsen Werkzaam in de Tuberculosebestrijding.

©2017 Connie Erkens, Leiderdorp, the Netherlands

Published articles were reprinted with permission of the publishers. No part of this thesis may be reproduced, stored or transmitted without prior permission of the author or when appropriate the publishers of the articles.

Evaluating the effectiveness of interventions for the prevention of tuberculosis in a low-incidence setting

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor

aan de Universiteit van Amsterdam

op gezag van de Rector Magnificus

prof. dr. ir. K.I.J. Maex

ten overstaan van een door het College voor Promoties ingestelde commissie,

in het openbaar te verdedigen in de Aula der Universiteit

op woensdag 29 maart 2017 te 11.00 uur

door

Conrada Gerardina Maria Erkens

geboren te Bergen op Zoom

Promotiecommissie

Promotor: Prof. dr. F.G.J. Cobelens Universiteit van Amsterdam

Copromotor: Dr. S. van den Hof KNCV Tuberculosefonds

Overige leden: Prof. dr. S.E. Geerlings Universiteit van Amsterdam

Prof. dr. L.J. Gunning-Schepers Universiteit van Amsterdam

Prof. dr. P.R. Klatser Universiteit van Amsterdam

Prof. dr. M. Prins Universiteit van Amsterdam

Dr. S.M. Arend Leids Universitair Medisch Centrum

Prof. I. Abubakar University College London

Faculteit der Geneeskunde

Contents

Chapter 1 Introduction .........................................................................................................................7

Chapter 2 Coverage and yield of entry and follow-up screening for tuberculosis among new

immigrants ...........................................................................................................................................19

Chapter 3 Added value of interferon gamma release assays for tuberculosis infection screening in

the Netherlands ...................................................................................................................................35

Chapter 4 The epidemiology of childhood tuberculosis in the Netherlands: still room for prevention.

.............................................................................................................................................................53

Chapter 5 Monitoring Latent Tuberculosis Infection diagnosis and management in the Netherlands

.............................................................................................................................................................69

Chapter 6 Risk of developing tuberculosis disease among persons diagnosed with latent tuberculosis

infection in the Netherlands ................................................................................................................85

Chapter 7 General Discussion ...........................................................................................................105

Summary ............................................................................................................................................117

Samenvatting .....................................................................................................................................123

List of abbreviations ...........................................................................................................................129

Authors contributions ........................................................................................................................131

Dankwoord ........................................................................................................................................143

7

Chapter 1 Introduction

8

Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. It presents most

commonly as a respiratory infection, but it can also affect other parts of the body. The classic

symptoms are cough, sometimes with blood-containing sputum, fever, night sweats, and weight

loss. When other organs are affected a wide range of symptoms can occur. Tuberculosis is

transmitted through the air, typically when people suffering from pulmonary TB cough or sneeze.

When inhaled, the bacteria are engulfed by alveolar macrophages and bronchial dendritic cells

which try to kill the bacteria. When they fail to do so, bacteria replicate and kill the macrophage

through apoptosis and necrolysis, releasing the bacilli and cytokines and chemokines, substances

that attract other immune-effector cells and trigger a complex delayed type hypersensitivity

reaction. A granuloma develops and bacilli can spread to the hilar lymph nodes and disseminate

through the body. The host immune response may clear the bacilli or induce a low metabolic and

slowly replicative ‘dormant’ state of the bacilli(1). Currently, Mycobacterium tuberculosis infection is

viewed as a continuous spectrum extending from sterilizing immunity to subclinical active disease

through to fulminant active disease(2). In the absence of diagnostic possibilities to detect bacilli

contained in a inactive form, latent tuberculosis infection (LTBI) is defined by immunological

evidence of sensitization against mycobacterial proteins in the absence of clinical signs and

symptoms of active disease. Based on cohort studies(3-5) it is postulated that the life time risk to

develop active TB after infection is 5-12%, but children younger than 2 years and immune

incompetent individuals have a higher risk(6).

Epidemiology Tuberculosis has been a major cause of disease and death for many ages. In the early 20th century TB

was the major cause of death among young adults in western industrialized countries. Nowadays

worldwide TB is causing more deaths than HIV and malaria each. The World Health Organization

(WHO) estimated 9 million people suffering from TB in 2014 and 1.5 million deaths caused by TB(7).

Fueled by the HIV epidemic, poverty and poor access to health services and adequate diagnosis, the

occurrence of TB in sub-Saharan Africa is comparable to the rates observed in western countries

around 1900. In the Netherlands the incidence of TB declined steadily to 5.1/100,000 in 2015. The

steady decline observed since the start of the TB surveillance in 1950 came to a halt in the late

eighties when there was a rise in the influx of immigrants from countries where TB was still

endemic. Since then, the TB incidence in the native Dutch population decreased faster than the

incidence in the immigrant population. Hence the proportion of TB among immigrants increased. In

the 2015, the incidence of TB among the foreign born population was 26 times higher than among

the Dutch born population and 72% of the TB patients were foreign born (Figure 1).

9

Figure 1 Tuberculosis incidence in population groups by ethnic group 1996-2015*

* Linear trend based on least squares fitting Source: Netherlands Tuberculosis Register, www.tbc-online.nl

TB control

History

Prevention and control of tuberculosis (TB) is one of the pillars of public health measures aimed to

improve and prolong the health of populations worldwide.

Preventive measures against TB were not undertaken until the late 19th century when Robert Koch

identified the TB bacillus and insight was gained in the mode of transmission. Even then, options for

prevention and control were limited to cough hygiene, sunlight and ventilation to reduce aerogenic

transmission. Options for antibiotic treatment were limited too, until streptomycin and isoniazid

were discovered after the Second World War. Until that time persons suffering from TB were

admitted in dedicated sanatoria for prolonged periods and subjected to a regime of rest, fresh air

and a protein rich diet to strengthen their immune systems. When TB drugs became available, early

case finding became a sensible thing to do: it was recognized that treatment of TB patients in an

early stage improved the chances of recovery and reduced risk of the transmission of the disease to

others. In the Netherlands, annual radiologic screening of the professional workforce and screening

of schoolchildren using the tuberculin skin test was continued until the late 1960s, when TB

incidence had decreased to less than 20 cases per 100,000 population. Careful assessment and

screening of close (household) contacts of infectious TB patients is still common practice and

generally regarded as the most effective measure to prevent TB(8-10), through early case finding as

well as treatment of contacts diagnosed with LTBI.

10

The emergence of drug resistance immediately after introduction of the first antibiotic

(streptomycin) used in TB treatment required therapy consisting of several drugs for a fixed period

with good adherence to treatment. Styblo showed in Tanzania in the 1980s that this could be

achieved by directly observed treatment (DOT): standardized short course treatment administered

under daily observation of a health care worker(11). DOTS (DOT combined with bacteriological

confirmation of the diagnosis) was recommended by the WHO as the main strategy to fight to TB,

with objectives of detecting and treating at least 70% of the new TB cases and of 85% of patients

completing the treatment(12).

TB control policy in the Netherlands

The pillars of Dutch TB control policy are based on the DOTS strategy recommended by WHO:

political commitment with increased and sustained financing; case detection through quality-

assured bacteriology; standardized treatment, with patient supervision and support; effective drug

supply and management system, and a monitoring and evaluation system, including impact

measurement. In addition a risk group approach is pursued, to enhance case finding and case

holding in vulnerable and risk populations(13). This approach was chosen in the early 1980s when, in

accordance with WHO recommendations, population-based screening programs were abolished(14)

(15). The objective of the risk group approach is to reduce morbidity and mortality as well as

transmission of TB through early detection of patients suffering from TB, and to prevent TB disease

in persons with a high risk of progression to active TB when infected. In 1995, the Committee for

Practical TB Control (CPT) and the National Health Council defined a risk group for TB as a

(sub)population with an incidence of >50 per 100,000 population, ∼10 times the rate in the general

Dutch population(16). Interventions for high-risk groups focused mainly on active case finding

through radiological screening among contacts of infectious TB patients, new immigrants and

asylum seekers from TB endemic areas, prisoners and drug users or homeless persons. Screening for

tuberculosis is mandatory for asylum seekers and for new immigrants from non-western countries

intending to stay longer than 3 months. Until 2007 a biannual follow-up screening for a period of 2

years was offered to all newly arriving migrants. In addition to active case finding, population groups

at risk for exposure to TB are targeted for screening for LTBI and preventive treatment. Target

groups include TB contacts, health workers and other professionals working with unscreened risk

groups for TB, and long-term travelers to countries where TB is endemic. In the clinical health sector,

patients with a high risk to develop TB when infected, such as HIV-infected individuals and persons

receiving immunosuppressant treatment are also targeted for LTBI screening.

Organization

The Public Municipal Health Services (PMHSs) have a pivotal role in TB control. PMHSs have been

performing prevention and control of TB in the Netherlands since 1993 when they took over this

responsibility from the local TB consultation bureaus as defined in the public health legislation(17)

and from 2008 onwards the Public Health Act(18). Health providers and laboratories are required by

law to notify TB patients nominally to the local PMHSs and take appropriate measures to prevent

further transmission. TB public health physicians and dedicated TB nurses in the PMHSs offer

support to the TB patient while on treatment, provide health education to the patient and the public

and offer advice on the necessary measures for infection control and contact investigation. In

addition, PMHSs offer (primary) preventive treatment to TB contacts with TB infection identified in

11

contact investigation, perform active case finding through screening of new immigrants and other

high risk groups for TB, and provide BCG-vaccination of new-born children with a parent born in a

country with estimated TB incidence >50 per 100,000 population. PMHSs provide information,

advice and guidance to local authorities, medical professionals, individuals and the public on a range

of TB issues related to diagnosis, screening, treatment, risk of transmission and need for preventive

measures. They also contribute to the understanding of the epidemiological TB situation through

maintaining the Netherlands TB register and submit anonymized data on TB and LTBI cases to the

national TB register. Policy development is coordinated at national level by the CPT consisting of

professionals active in TB control in the PMHSs, other public health institutions and professional

organizations. CPT guideline development and policy development relies on epidemiological

information derived from surveillance data, as well as scientific evidence based on the analysis of

monitoring and evaluation data into the effectiveness of interventions.

TB surveillance and monitoring of effectiveness of screening

In the Netherlands notification of infectious diseases to the Health Inspectorate has been mandatory

since 1865, but notification of tuberculosis was not mandatory until 1980, when TB became less

stigmatized(19). In the late 1980s it became apparent that the nominal information collected by the

Health Inspectorate did not render sufficient information to identify population groups at risk for TB,

and that it would be advisable to continue the systematic data collection performed by the TB

consultation bureaus(20). Moreover, it was perceived necessary to monitor the implementation of

WHO recommendations for standardized treatment regimens and DOTS in view of the worldwide

emerging problem of drug resistance (21). In 1993, PMHSs and KNCV Tuberculosis Foundation

started the Netherlands Tuberculosis register (NTR), supplementary to the mandatory notification of

nominal data to the Health Inspectorate. The goals of the NTR are: i) TB disease and LTBI

surveillance, ii) providing information for regional and national policy development, iii) providing

information for scientific research and training, iv) support quality control of TB preventive

interventions(22). Anonymized data on the diagnosis and treatment outcome for new and recurrent

TB patients and persons diagnosed with latent TB infection were initially collected through a paper

questionnaire. Data collection for TB as well as LTBI cases has encompassed anonymized case-based

demographic information, method of case finding, treatment regimen and treatment outcome. For

TB cases, disease location, risk factors, co-morbidity, laboratory and DNA-fingerprint results,

occurrence of serious adverse events, treatment supervision and adherence, and results of the

contact investigation are additionally recorded. In 2005 the paper NTR questionnaires were

integrated in the official central web-based notification system for infectious disease notification

and surveillance ‘Osiris’, hosted by the National Institute for Public Health and the Environment

(RIVM). Annually RIVM publishes in cooperation with KNCV Tuberculosis Foundation an annual

description of the TB situation and the yield of active case finding in the surveillance report

‘Tuberculose in Nederland’.

Thesis aim and objectives In general, good public health practice requires systematic monitoring and evaluation the

effectiveness of screening programs in order to inform policy development and prioritize risk groups

and to safeguard appropriate use of public resources(23). The well-coordinated national TB control

policy development, combined with a longstanding tradition of collecting epidemiological and

12

operational data to monitor TB control interventions, offers a unique opportunity to study the

effectiveness of internationally recommended TB control policies in low incidence settings. Thus the

studies included in this thesis were aimed at determining the effectiveness of specific TB control

interventions and screening algorithms in risk groups, and at identifying specific target groups with a

higher risk for TB or to progress to disease when infected with M. tuberculosis.

Specific objectives

Screening of immigrants

In the 1980s and 1990s immigrants from non-western countries and asylum seekers were targeted

for radiographic TB screening upon entry and bi-annual follow-up screening during the two years

after entry. TB screening of asylum seekers and other immigrants at entry was common practice in

other low-incidence countries (24-31), but few countries performed follow-up screening among

immigrants with a normal chest X-ray(29, 32). The effectiveness, in broad sense, of TB screening in

immigrants and asylum seekers has been disputed(25, 33-35). Particular concerns are cost-

effectiveness, the substantial resources required, the need for adequate access to diagnosis and

care and the assurance of continuum of care for all migrants. However, it has been shown that

screening contributes to reduction of severity of disease and duration of infectiousness, as well as to

decreased transmission potential (36).

In The Netherlands immigrants and asylum seekers have been regarded as distinct risk groups for

two reasons: i) asylum seekers undergo a different process for TB screening: they reside in the

dedicated reception facilities and are screened shortly after arrival. Whereas immigrants are

required individually to report to the PMHSs within 3 months after arrival in The Netherlands for TB

screening; ii) in the literature it was reported that asylum seekers are likely to be exposed to a

higher risk of infection after their departure from the country of origin(37). In 1993, a study

estimated a yield of the entry screening among asylum seekers in The Netherlands of 300-400 cases

of TB disease per 100,000 persons screened(38). This rate was lower than the rate observed among

asylum seekers and refugees in other low incidence countries(24, 29-31, 39, 40). The rate was

highest among persons from Somalia and Yugoslavia. From this finding the question arose if the

screening could be targeted to specific high-risk groups. Data on the yield of the TB screening of

immigrants were not known. Stimulated through a government research grant from ZonMW(41),

KNCV Tuberculosis Foundation and PMHSs started the Monitoring Screening of Immigrants (MSI)

project in 1996, and set up a national system to periodically assess the effectiveness of the Dutch

immigrant screening policy. The objective of the study using MSI data described in Chapter 2 was to

assess the prevalence, coverage and yield of the entry and follow-up screening and the risk to

develop TB in the first two years after entry, and to describe associated factors and characteristics of

immigrants detected with active TB disease or with a higher risk to develop active TB in order to

identify risk groups to which screening can be targeted.

Diagnostic algorithm for LTBI

Until 2007, the tuberculin skin test (TST) was used in the Netherlands for the diagnosis of latent TB

infection. In daily practice the TST has many limitations: the positive predictive value is low when

used in populations with a low likelihood of infection as well as in BCG-vaccinated populations.

13

Before 2007, skin tests with crude antigens of common nontuberculous mycobacteria were often

used in addition to TST to confirm LTBI. Moreover, varying cut-offs for the size of the TST-reaction

defining LTBI were recommended: a low cut-off of 5 mm and more for ‘vulnerable’ populations

where a high sensitivity was required, a cut-off of 10 mm and more for BCG-naïve populations, and a

high cut-off of 15 mm and more for BCG-vaccinated populations and other populations in which a

high specificity was required. Since 2000, interferon-gamma release assays (IGRA) came on the

market(42): blood tests based on ex-vivo stimulation of T-lymphocytes by specific antigens of

Mycobacterium tuberculosis. IGRAs were claimed to have an equal sensitivity, but higher specificity

than the TST, especially in BCG-vaccinated populations(43, 44). In addition, IGRAs had several

operational advantages over the TST: i) for the TST specific dexterity and experience is needed to

administer the test and interpret the reaction; ii) the TST-reaction needed to be measured within

72-96 hours. However, the cost of the two available commercial IGRAs and laboratory handling were

considerably higher than the cost of the TST. Cost-effectiveness studies supported the use of IGRAs

in high-income countries, with TST followed by an IGRA being the more cost-effective strategy(45). It

was not clear if this strategy would be the most cost-effective strategy for the Dutch setting, where

the majority of the target population for LTBI screening was not vaccinated with BCG and the

operational costs for IGRA were considerably higher than the cost for TST. Therefore, to guide the

choice for the optimal diagnostic algorithm for the Dutch TB control setting, it was decided that

IGRA would be recommended as confirmatory test after TST and the added value of IGRAs in terms

of numbers needed to treat and incremental costs would be evaluated prospectively after the

introduction for routine use by the PMHSs. The results of this evaluation are described in Chapter 3.

Effectiveness of TB control efforts in children

The WHO’s DOTS and StopTB strategies have focused mainly on improving detection and treatment

of infectious cases(46, 47). Recently it was recognized that as a consequence of this approach the

prevention and management of TB in children has been neglected by national TB programs(48, 49).

Although children with TB disease are generally considered non-infectious, TB infection and disease

in a child can be regarded as a sentinel event for ongoing transmission. In addition, young children

are more susceptible than adults to progression from TB infection to active disease and may suffer

severe TB-related morbidity and mortality. BCG vaccination, active case-finding of children in

contact with adults with TB and isoniazid preventive therapy to prevent progression of latent TB are

the basic elements of TB prevention in children and have been practiced in the Netherlands since

several decades, but the effectiveness of this approach had not been evaluated before. The

objectives of the study described in Chapter 4 were to analyze trends and characteristics of TB and

LTBI among children, to identify risk factors for delayed case finding of active TB in children and to

explore opportunities where TB prevention can be further improved.

Effectiveness and impact of LTBI diagnosis and treatment

Randomized clinical trials have demonstrated the safety and effectiveness of preventive

chemotherapy to reduce the risk of tuberculosis among persons with latent infection(50). In these

trials various preventive treatment regimens were shown to reduce the development of incident TB

by approximately 40-50%. However, under operational circumstances the effectiveness of

preventive treatment programs is influenced by other factors such as treatment acceptance and

treatment completion rates. In 2014, the World Health Organization (WHO) launched the End TB

14

Strategy to step up efforts for the elimination of tuberculosis worldwide. For low-incidence

countries, screening and providing preventive treatment for LTBI in populations at high risk for TB is

recommended as a key intervention(51-53). In its guidelines for LTBI management WHO

recommends routine monitoring and evaluation for initiation and completion of treatment,

occurrence of adverse events and development of active TB during and after the completion of

treatment for latent TB. Thus far few countries have routinely practiced LTBI treatment at scale, and

data on evaluation of LTBI management programs are sparse(34, 54). With the studies in Chapter 5

and 6 we aimed to evaluate the effectiveness of LTBI screening and preventive treatment performed

in the public health sector in the Netherlands, in terms of the annual number of cases identified with

LTBI in different target groups for LTBI screening, to determine factors associated with treatment

acceptance, successful outcome of preventive treatment and the occurrence of (severe) adverse

events and to assess the impact of the intervention in the different target groups.

Outline of the thesis and research questions:

In summary the overall aim of the thesis is to determine the effectiveness of specific TB control

interventions and screening algorithms and to further identify and prioritize target groups for the

interventions.

Specific study questions addressed this thesis are:

1. What is the yield and effectiveness of the screening of new immigrants to the Netherlands in terms of coverage, numbers and prevalence of cases detected, and proportion of the cases in the target group detected through screening, and which groups should be prioritized for screening? (Chapter 2)

2. What is the added value of interferon gamma release assays (IGRA) used as a confirmatory

test after tuberculin skin test (TST) in terms of numbers needed to treat in specific target

groups for LTBI screening in the Dutch setting, and what are the (incremental) costs and

the cost-effectiveness? (Chapter 3)

3. What is the burden of TB disease among children in the Netherlands, what proportion of

childhood TB cases is detected early through active case finding, how many children are

successfully targeted for preventive treatment, and what are the further opportunities for

prevention? (Chapter 4)

4. What is the performance of LTBI management in the public health sector in the

Netherlands, in terms of numbers of cases diagnosed, treatment acceptance, treatment

completion and the occurrence of severe adverse events? (Chapter 5)

5. What is the observed incidence of TB in different target groups for LTBI screening and in

groups receiving different treatment regimens and for which groups should LTBI screening

be prioritized? (Chapter 6)

The general discussion in Chapter 7 discusses the main conclusions, lessons learned and policy

implications of the studies for TB control in the Netherlands, the overall strengths and limitations of

these studies utilizing TB surveillance data and recommendations for future research.

15

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19

Chapter 2 Coverage and yield of entry and follow-up

screening for tuberculosis among new immigrants Connie Erkens, Erika Slump, Margreet Kamphorst, Sytze Keizer, Paul van Gerven, Robert Bwire,

Marcel Berkel, Martien Borgdorff and Suzanne. Verver

Published in European Respiratory Journal 2008; 32(1): 153–161 https://dx.doi.org/10.1183/09031936.00137907 Copyright © European Respiratory Journal.

20

Abstract

The aim of the present study was to determine the effectiveness of entry screening for tuberculosis

and biannual follow-up screening among new immigrants in the Netherlands. To achieve this, the

present authors analyzed screening, prevalence and incidence data of 68,122 immigrants, who were

followed for 29 months. Patients diagnosed within 5 months and 6–29 months after entry screening

were considered to be detected at entry and during the follow-up period, respectively. Coverage of

the second to fifth screening rounds was 59, 46, 36 and 34%, respectively. Yield of entry screening

was 119 per 100,000 individuals, and prevalence at entry was 131 per 100,000. Average yield of

follow-up screening was highest among immigrants with abnormalities on chest radiography (CXR)

at entry (902 per 100,000 individuals). When excluding these, yield of follow-up screening was 9, 37

and 97 per 100,000 screenings for immigrants from countries with tuberculosis incidences of 200 per 100,000, respectively. The incidence during follow-up in individuals with a

normal CXR was 11, 58 and 145 per 100,000 person-years follow-up in these groups. The proportion

of cases detected through screening declined per screening round from 91 to 31%. Yield of entry

screening was high. Overall coverage and yield of follow-up screening was low. Follow-up screening

of immigrants with a normal chest radiograph from countries with an incidence of

21

Introduction

In Western Europe, approximately half of the tuberculosis (TB) patients are of foreign origin [1]. In

the Netherlands, approximately 1,000–1,400 patients with active TB are diagnosed yearly, of whom

68% are foreign-born individuals [2]. In 2004, the incidence of all forms of TB among foreign-born

individuals was 52.4 per 100,000, 17 times the incidence in Dutch-born individuals (3.1 per 100,000

population). Active case finding in risk groups is an important strategy for TB control in low-

prevalence countries in the elimination phase [3]. In 1995, a risk group policy was formulated in the

Netherlands. The Committee for Practical TB Control and the National Health Council defined a risk

group for TB as a (sub)population with an incidence of 50 or more per 100,000 population,

approximately 10 times the rate in the general Dutch population [4].

Screening for active TB is mandatory for all immigrants from non-Western countries intending to

stay longer than 3 months in the Netherlands [5]; at the time of the study this included all countries

except the European Union, Australia, Canada, Iceland, Israel, Japan, Monaco, New Zealand,

Norway, Surinam, Switzerland and the USA. Immigrants applying for a residence permit in the

Netherlands are referred by the Immigration Department to the Municipal Health Services (MHSs)

for TB screening. Screening is performed by chest radiograph (CXR) in individuals aged >12 years.

Asymptomatic children aged

22

standardized and checked for inconsistencies. To validate data on TB patients in the MSI system,

data were compared with the Netherlands Tuberculosis Register (NTR) [2] using year of diagnosis,

year of birth, sex and nationality to match cases. If patients were registered in the MSI system and

not in the NTR or vice versa, the MHS was asked for clarification to improve completeness of the

database.

Definitions

The cohort was defined by date of entry screening. Coverage was defined as the number of

individuals screened divided by the number of individuals in the target population per screening

round. The yield was defined as the number of patients detected per 100,000 individuals screened

(for entry screening) and per 100,000 screenings (for follow-up screening). Prevalence was defined

as the total number of patients diagnosed (either through screening or passive case finding) per

100,000 individuals screened on entry. The incidence rate was defined as the total number of

patients diagnosed (either through screening or passive case finding) per 100,000 person-years

follow-up in the target population. Patients detected at entry screening or passively 704 days (23 months) between the first (entry) and the

last screening (regardless of attendance at previous screenings).

The result of the initial CXR was classified into five categories as follows: suspected active TB;

abnormality, possibly old TB; abnormality, no TB; no abnormalities; and unknown. For the purpose

of the analysis, the CXR result was aggregated in three groups: any abnormalities, no abnormalities,

and unknown. Active TB cases were classified by site of disease according to the revised

international definitions in TB control [21]. Patients were defined as detected passively when the

reason for medical examination leading to the diagnosis of active TB was not immigrant screening.

The majority of these patients were diagnosed through the healthcare system, due to presentation

of symptoms suggestive of TB.

Analysis

Stratified risk analysis was performed for age, sex, nationality grouped in countries or continents,

incidence groups according to World Health Organization (WHO) estimated incidence in the country

of origin in 2002, and abnormalities on the initial CXR. For the sake of brevity, countries of origin

with an incidence of 200 per 100,000 individuals were classified as low-,

medium- and high-incidence countries. Patient data are presented for all TB and pulmonary TB (PTB)

cases, since CXR is performed to detect PTB, but also frequently detects other forms of TB. Follow-

up screening and incidence is only presented for individuals aged >12 years (n=561,237), since no

follow-up screening was offered to children aged ≤12 years.

23

Figure 1. Flow chart of results of entry and follow-up screening (6–29 months).

Immigrants entry screening N=70 173

Complete recordsN= 68 122

Incomplete recordsN= 2 051

Tested with TST only (no CXR) and no TBN=1 654

CXR result unknown but no TBN=342

CXR abnormalN=1 620

CXR normalN-64 506

PTB n=76ETB n=5

PTB n=3

Age

24

Results

Table 1 Number of bacteriologically confirmed cases and percentage of total 0-5 months# 6-29 months# Total

Confirmed cases##

Total cases

% Confirmed cases##

Total cases

% Confirmed cases##

Total cases

%

PTB

Detected through screening

61 76 80 28 41 68 89 117 76

Passively detected 2 3 67 13 20 65 15 23 65

Total PTB cases 63 79 80 41 61 67 104 140 74

ETB

Detected through screening

0 5 0 1 6 17 1 11 9

Passively detected 2 5 40 10 30 33 12 35 34

Total ETB cases 2 10 20 11 36 31 13 46 28

PTB: pulmonary tuberculosis; ETB: extrapulmonary TB. #: after entering the Netherlands. ## bacteriolocally confirmed.

Study groups

Data were available from 27 MHSs on 70,173 new immigrants entering the Netherlands (fig. 1). A

total of 68,122 (97%) records were complete. The number of immigrants per MHS varied from 105

to 4,456 per cohort-year. In total, 187 TB patients were identified in the study group, of whom 74%

were bacteriologically confirmed (smear and/or culture positive) among PTB cases and 28% among

extrapulmonary TB cases (table 1). There were 89 prevalent cases and 98 incident cases 6–29

months after entering the country, of which one case was aged ≤12 years.

Coverage

The coverage of the second to fifth screenings was 59, 46, 36 and 34%, respectively (fig. 2). The

coverage in the four screening rounds varied considerably between MHSs, ranging from as low as

31, 23, 6 and 17% in one MHS to as high as 87, 77, 67 and 75% in another. The coverage among

individuals from Turkey and Morocco was 8–18% higher than in individuals from other countries. No

relevant differences were found between males and females or between other groups of

nationalities.

Entry yield and prevalence In total, 1,620 individuals were recorded with an abnormal CXR at entry requiring further

examination. Active TB was detected in 81 patients. The yield of screening at entry was 119 per

100,000 individuals screened for all forms of TB and 112 per 100,000 for PTB. A further eight

patients were detected passively within 5 months of entering the country. Including both passively

and actively detected patients, the prevalence of TB at entry was 131 per 100,000 (table 2). The

yield of entry screening was highest in age groups 25–34 and >45 years, and hardly differed between

males and females. The yield of the entry screening for all subgroups varied from 56 to 271 TB cases

per 100,000 individuals screened.

25

Table 2 Yield of screening and prevalence on entry# in the period 1998–2002 Screened

individuals

n

TB patients n

Yield" (95% CI)

Prevalence+

(95% CI)

Detected by screening

Found passively

Age in years

≤12 6885 8 1 116 (50–229) 131 (60–248)

13–24 25163 20 3 79 (49–123) 91 (58–137)

25–34 25009 41 3 164 (114–214) 176 (124–228)

35–44 8176 6 0 73 (27–160) 73 (27–160)

≥45 2883 6 1 208 (76–453) 243 (98–500)

Unknown 6 0 0

Sex

Male 28566 33 2 116 (76–155) 123 (82–163)

Female 39415 48 6 122 (87–156) 137 (101–174)

Unknown 141 0 0

Nationality

Morocco 11154 17 2 152 (89–244) 170 (103–266)

Turkey 9910 9 1 91 (42–172) 101 (48–186)

Africa (except Morocco)

7603 11 0 144 (72–258) 144 (72–258)

Asia (except Turkey) 19354 31 4 160 (104–217) 181 (121–241)

Central and Eastern Europe

12554 7 1 56 (22–115) 64 (28–125)

Other 5425 6 0 111 (41–241) 111 (41–241)

Unknown 2122 0 0

Incidence in country of origin1

200 11435 31 1 271 (176–366) 280 (183–377)

Unknown 2125 0 0

Entry cohort

1998 5608 9 0 160 (73–305) 160 (73–305)

1999 9417 11 2 117 (58–209) 138 (74–236)

2000 12055 10 4 83 (40–153) 116 (63–195)

2001 17930 24 1 134 (80–187) 139 (85–194)

2002 23112 27 1 117 (73–161) 121 (76–166)

Result chest radiography

Normal 66502 0 5 0 8 (2–18)

Any abnormalities 1620 81 3 4883 (3911–6089) 5185 (4076–6294)

Total 68122 81 8 119 (93–145) 131 (104–158)

TB: tuberculosis; CI: confidence interval. #: 0–5 months after entering the Netherlands; ": per 100,000 individuals screened; +: defined as number of cases detected through screening plus number of cases detected passively, divided by number of individuals screened; 1: estimated incidence of total TB per 100,000 individuals in 2002 according to the World Health Organization.

26

Figure 2. Coverage per screening round in 68,122 immigrants screened at entry, as a percentage of the target group screened.

Data are presented as averages: 59, 46, 36 and 34 for screening rounds 2–5, respectively. The error bars indicate the minimum and maximum coverage values observed in the Municipal Health Services.

Follow-up yield and incidence A total of 47 patients aged >12 years were detected during follow-up screening and 50 patients

were detected passively 6–29 months after entering the country. Of the 47 patients detected

through follow-up screening, 30 had a normal initial CXR. Among the 20 PTB patients detected

passively, two had abnormalities in the initial CXR (fig. 1). In 19 of the 50 TB patients detected

passively, the interval between the last screening and diagnosis was >7 months. The yield of follow-

up screening was highest among individuals with an abnormality in the initial CXR and who were not

diagnosed with TB in the first semester (tables 3 and 4). In 1,412 immigrants with abnormalities in

the CXR on entry, follow-up screening detected 17 cases (902 per 100,000 screenings; table 4). Even

in the low-incidence nationalities group a high number of cases was detected (411 per 100,000

screenings). The yield of follow-up screening among individuals with a normal CXR was 36 per

100,000 screenings and the incidence 6–29 months after entry was 53 per 100,000 person-years

follow- up (table 3). Among subgroups of immigrants from low-, medium- and high-incidence

countries, the yield was 9, 37 and 98 per 100,000 screenings, respectively (9, 28 and 89 per 100,000

for PTB cases), and the incidence was 11, 58 and 145 per 100,000 person-years follow-up,

respectively (7, 35 and 77 per 100,000 person-years for PTB cases).

The yield and incidence during the follow-up period were associated with the incidence in the

country of origin. Among individuals with a normal CXR, yield and incidence were higher in females

than in males. Yield and incidence were highest in the group aged 25–44 years. When the nationality

was unknown, yield and incidence were high, but the absolute number of patients of unknown

nationality was very low and, therefore, the confidence intervals were wide.

The yield of screening for all forms of TB for the second, third, fourth and fifth screening rounds was

48, 67, 66 and 30 per 100,000 individuals screened, respectively, and 45, 67, 40 and 23 PTB cases

per 100,000 individuals screened. In all incidence groups, the yield of screening declined in the last

two rounds, even in the high-incidence group, despite a continued high incidence (fig. 3).

5946

36 34

8777

67 75

31 23

6

170

25

50

75

100

2 3 4 5

round

% o

f ta

rget

gro

up

Maximum observed coverage in MHSs

Minimum observed coverage in MHSs

average

27

Table 3 Yield of screening and incidence of all tuberculosis (TB) cases during follow-up

period (6–29 months) for individuals with normal chest radiography at entry# Follow-up

person years

Screenings in rounds 2-

5

n

TB patients n Yield" (95% CI)

Incidence+ (95% CI)

Detected by screening

Found passively

Age years

13–24 57059 33237 7 16 21 (8–43) 40 (26–60)

25–34 57500 34693 14 21 40 (22–68) 61 (41–81)

35–44 18296 11910 8 5 67 (29–132) 71 (38–122)

0.45 6160 3811 1 2 26 (1–146) 49 (10–142)

Unknown 10

Sex

Male 56549 33232 10 19 30 (14–55) 51 (34–74)

Female 82194 50340 20 25 40 (24–61) 55 (39–71)

Unknown 283 79 0 0

Nationality

Morocco 23355 17365 5 10 29 (9–67) 64 (36–106)

Turkey 21575 15808 1 0 6 (0–35) 5 (0–26)

Africa (except Morocco)

15187 7998 5 8 63 (20–146) 86 (46–146)

Asia (except Turkey) 38097 21854 15 20 69 (38–113) 92 (61–122)

Central and Eastern Europe

25973 12821 2 4 16 (2–56) 23 (8–50)

Other 10603 5810 0 1 9 (0–53)

Unknown 4236 1995 2 1 100 (12–362) 71 (15–207)

Incidence in country of origin1

200 22003 12300 12 20 98 (50–170) 145 (95–196)

Unknown 4242 2004 2 1 100 (12–360) 71 (15–207)

Entry cohort

1998 11369 7340 3 4 41 (8–119) 62 (25–127)

1999 18455 12156 6 6 49 (18–107) 65 (34–114)

2000 24732 15663 6 8 38 (14–83) 57 (31–95)

2001 36664 21886 5 11 23 (7–53) 44 (25–71)

2002 47806 26606 10 15 38 (18–69) 52 (34–77)

Total 139026 83651 30 44 36 (23–49) 53 (41–65)

CI: confidence interval. #: n=558 529; ": per 100,000 screenings in rounds 2–5; +: defined as number of cases detected through screening plus number of cases detected passively, per 100,000 person-years follow-up; 1: estimated incidence of total TB per 100,000 individuals in 2002 according to the World Health Organization.

28

Table 4 Yield of screening and incidence of all tuberculosis (TB) cases during follow-up

period (6–29 months) for individuals with abnormal chest radiography at entry# Follow-up

person years Screenings in

rounds 2-5

n

TB patients n

Yield"

(95% CI)

Incidence+ (95% CI)

Detected by

screening

Found passively

Incidence in country of origin1

200 677 363 5 2 1377 (447–3215) 1034 (416–2130)

Total 3241 1884 17 6 902 (526–1445) 710 (450–1064)

CI: confidence interval. #: n=558 529; ": per 100,000 screenings in rounds 2–5; +: defined as number of cases detected through screening plus number of cases detected passively, per 100,000 person-years follow-up; 1: estimated incidence of total TB per 100,000 individuals in 2002 according to the World Health Organization.

The proportion of patients detected through screening declined with consecutive screening rounds

(fig. 4). There were no significant differences in age, sex or estimated incidence in country of origin

between patients found through screening or otherwise detected (data not shown).

Discussion

The present authors found that the yield of entry screening was 56–271 per 100,000 individuals

screened, depending on the subgroup analysed. Furthermore, it was shown that in individuals from

low-, medium- and high-incidence countries and with a normal CXR at entry, the yield of follow-up

screening during follow-up was 9, 37 and 98 per 100,000 screenings, respectively. Of the prevalent

cases, 91% were detected through screening. Of the incident cases during follow-up, 48% were

found through screening (67% of PTB cases). The proportion detected through screening was low in

the last two rounds. Abnormalities in CXR at entry were the most important predictor for

development of TB, irrespective of the incidence in the country of origin. Among those with any

abnormalities in CXR, 1.6% were diagnosed with active TB during follow-up.

Abnormalities in CXR are often fibrotic lesions due to healed TB and are a known risk factor for TB

activation [22, 23]. Immigrants with abnormalities in CXR at entry are usually either targeted for

more frequent follow-up screening and additional diagnostics or offered preventive therapy.

The present results suggest that, when accepting a cut-off value for the yield of 50 per 100,000

individuals screened, entry screening is useful to detect TB in all immigrants who are currently

targeted. Entry screening is also useful to identify an important risk group for intervention, this

being individuals with abnormalities in CXR. Follow-up screening can be targeted towards individuals

from high-incidence countries. However, the choice in the Netherlands of a cut-off value of 50 per

100,000 for the definition of a target group for screening is arbitrary. It may not be cost-effective to

screen all immigrants belonging to groups with a relatively low risk [14, 24]. The study of cost-

effectiveness was not the objective of the present study, but consideration of cost-effectiveness

may lead to a more effective use of resources. Limiting follow-up screening to individuals from high-

29

Figure 3. Yield (a and c) and incidence (b and d) of all cases of tuberculosis (TB; a and b)

and pulmonary TB (PTB; c and d) by screening round in individuals from countries with

an estimated TB incidence >200 per 100,000 and normal chest radiography at entry.

Screening rounds were performed 6–11, 12–17, 18–23 and 24–29 months after entry. Yield is expressed as n per 100,000 individuals screened and incidence as n per 100,000 person-years follow-up. Error bars represent 95% confidence intervals.

endemic countries will reduce by 40–45% the number of CXRs performed for screening of

immigrants and asylum seekers, an estimated total of 35,000 CXRs in 2007. It can be argued that

entry screening could also be restricted to individuals from high-incidence countries, but the present

results suggest that migrants are not representative of the total population in the country of origin.

For two nationalities, the present results could be compared with the WHO estimates. It was found

that among Moroccan and Turkish nationals the prevalence at entry (170 and 101 per 100,000,

respectively) was higher than expected from the WHO-estimated prevalence of TB in the country of

origin (86 and 44 per 100,000, respectively) [25]. However, incidence during follow-up in these

groups (68 and 13 per 100,000, respectively) was lower than the estimated incidence in the

countries of origin. This suggests that immigrants from these countries are a selected group with a

higher risk for active TB at entry, as are young adult age and lower socioeconomic status groups. In

the present study population, 38% of the population was aged 25–34 years, the group with the

highest prevalence of active TB. The lower incidence during follow-up can be explained by a lower

Yield all TB cases

96

147

5850

0

100

200

300

400

500

6-11 12-17 18-23 24-29

months

per

100,0

00 s

creend

Incidence all TB cases

229 241 220198

0

100

200

300

400

500

6-11 12-17 18-23 24-29

months

per

100,0

00 p

yrs

follo

w-u

p

Yield PTB

96

147

580

0

100

200

300

400

500

6-11 12-17 18-23 24-29

months

per

100,0

00 s

creend

Incidence PTB

137 14411099

0

100

200

300

400

500

6-11 12-17 18-23 24-29

months

per

100,0

00 p

yrs

follo

w-u

p

30

Figure 4. Pulmonary tuberculosis (PTB) cases per screening semester according to type

of case detection.

Screening rounds were performed 0–5, 6–11, 12–17, 18–23 and 24–29 months after entry. The percentage of total cases detected by screening at each round was 96, 71, 85, 46 and 43% for screening rounds 1–5, respectively.

risk of infection in the Netherlands. Early case finding through screening on entry in these groups is

likely to contribute to a lower risk of infection among immigrants in the Netherlands.

Other studies in low-incidence countries have reported a persistent high incidence of TB in

immigrants, although some found a decline over time [10, 13, 26–28]. The incidences found in the

present study were similar to those in another study in the Netherlands [29], where both regular

immigrants and asylum seekers were included. In the study by Vos et al. [29], it was found that

incidence remained high many years after immigration. In the present study, it was found that,

despite a high incidence throughout the follow-up period in the high- incidence group, the

proportion of patients detected through screening per consecutive screening round declined, and

the yield in the last two rounds was low. The duration of follow- up screening of 2 years is therefore

debatable for two reasons: the prolonged higher incidence after entry into the country and the

reduced effectiveness of the follow-up screening in the second year. Approximately half of the

patients with PTB detected passively could have been detected earlier, since the last screening was

>7 months before diagnosis; therefore, the yield of follow-up screening could be improved with a

better coverage.

The present yield of screening may have been affected by a selection bias, since individuals with

symptoms may be more likely to report for screening. Conversely, it is also likely that patients

detected passively belong to risk groups that are less likely to report for screening. Not all eligible

immigrants undergo entry screening [30]. It was estimated from routine surveillance and population

data that, in 2002, approximately 70% of the target immigrant population was screened on entry to

the Netherlands [31]. Furthermore, 35 patients from the NTR who were eligible for screening in the

study period, but never screened, were detected in the participating MHSs 6–29 months after entry

and, therefore, could not be included in the present study. These patients may represent an

31

immigrant population group with a different risk profile. Therefore, when the coverage of follow-up

screening improves, the absolute number of cases detected through screening will increase, but the

yield per 100,000 individuals screened may decrease. Therefore, interventions to increase the

coverage should address specific subgroups with the highest risk within the target population, such

as the younger age groups, and will need to be low cost to maintain the effectiveness of the

screening. It may also be more effective to ensure passive case finding among high-incidence

groups. The duration of the follow-up period could then be limited to a maximum of one year.

Alternatively, if it were possible to reduce the pool of latent infected individuals among immigrants,

the incidence caused by reactivation would be reduced and follow-up screening could be abolished

for all groups.

There are some other limitations concerning the coverage of screening and the representativeness

of the data in the present study. The low coverage of the follow-up screening rounds was

comparable to earlier studies [6, 24, 32]. The present authors underestimated coverage and,

therefore, incidence, since it was assumed that all immigrants were still in the Netherlands during

the follow-up period, while some may have left. The number of individuals who left the country

amounted to ≥15% in the 20 MHSs that registered intended length of stay in the present study and

to 26% in the first 2 years in a pilot study at one MHS in 1996 [6]. Marriage and labor are the most

important immigration motives for migrants coming to the Netherlands. During the period 1995–

2003, more than one third of the migrants came for marriage, 31% for labor, 13% for study and 9%

for family unification. Other reasons for migration, for 14% of migrants, were: being a family

member of a migrant; being an au pair; having an internship; and medical treatment [33]. Although

the data did not cover all MHSs in the country, the present authors believe the data are

representative for immigrants, other than asylum seekers, screened by MHSs in the Netherlands.

The participating MHSs are distributed uniformly over the country, giving a fairly even geographic

coverage and urban and rural distribution. In 2001 and 2002 the data covered 55–66% of the total

immigrants screened in the Netherlands. Furthermore, trends in coverage and yield are largely

comparable between cohorts (tables 2–4). However, the results may not be generalizable to asylum

seekers. First, the prevalence among immigrants at entry was lower than had been found for asylum

seekers in earlier studies [23, 34]. This can be explained by the differences in incidence in the

countries of origin between immigrants and asylum seekers. Secondly, asylum seekers may have

social circumstances that involve a higher risk of infection or breakdown. This may be related to the

process of asylum seeking [35]. The present study is also not generalizable to undocumented

immigrants, since, by definition, they are not a target group for screening.

Conclusions and recommendations

The yield of entry screening was high. Entry screening should be continued for all immigrant groups

that are currently screened. Follow-up screening for individuals from countries with a low or

medium incidence and with no abnormalities on their chest radiographs at entry has been abolished

as a result of the present study. The proportion of cases detected through screening declined per

screening round, and the coverage and yield of follow-up screening were low after the third round,

even in groups from high-incidence countries. This suggests that follow-up screening may be limited

to a period of one year. Coverage of follow-up screening needs to be increased, especially in

subgroups with the highest risk.

32

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