Tuberculosis: improving case finding and contact tracing

Raquel Duarte

Tuberculosis: improving case finding and contact tracing

Porto, 2011

Raquel de Almeida Ferreira Duarte Bessa de Melo

Tuberculosis: improving case finding and contact tracing

Dissertação de candidatura ao grau de Doutor apresentada à Faculdade de Medicina da Universidade do Porto

Porto 2011

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Art.º48, §3º – “A Faculdade não responde pelas doutrinas expendidas na dissertação.”

(Regulamento da Faculdade de Medicina da Universidade do Porto – Decreto-Lei nº 19337 de 29 de Janeiro de 1931)

- iii - Corpo Catedrático da Faculdade de Medicina do Porto

Professores Catedráticos Efectivos

Doutor Manuel Alberto Coimbra Sobrinho Simões Doutor Jorge Manuel Mergulhão Castro Tavares Doutora Maria Amélia Duarte Ferreira

Doutor José Agostinho Marques Lopes

Doutor Patrício Manuel Vieira Araújo Soares Silva Doutor Daniel Filipe Lima Moura

Doutor Alberto Manuel Barros da Silva Doutor José Manuel Lopes Teixeira Amarante Doutor José Henrique Dias Pinto de Barros

Doutora Maria Fátima Machado Henriques Carneiro Doutora Isabel Maria Amorim Pereira Ramos Doutora Deolinda Maria Valente Alves Lima Teixeira Doutora Maria Dulce Cordeiro Madeira

Doutor Altamiro Manuel Rodrigues Costa Pereira Doutor Rui Manuel Almeida Mota Cardoso Doutor António Carlos Freitas Ribeiro Saraiva Doutor Álvaro Jerónimo Leal Machado de Aguiar Doutor José Carlos Neves da Cunha Areias Doutor Manuel Jesus Falcão Pestana Vasconcelos

Doutor João Francisco Montenegro Andrade Lima Bernardes Doutora Maria Leonor Martins Soares David

Doutor Rui Manuel Lopes Nunes

Doutor José Eduardo Torres Eckenroth Guimarães Doutor Francisco Fernando Rocha Gonçalves

- iv - Doutor José Manuel Pereira Dias de Castro Lopes Doutor Manuel António Caldeira Pais Clemente

- v - Professores Jubilados ou Aposentados

Doutor Abel Costa Sampaio da Costa Tavares Doutor Abel Vitorino Trigo Cabral

Doutor Alexandre Alberto Guerra Sousa Pinto Doutor Amandio Gomes Sampaio Tavares Doutor António Augusto Lopes Vaz

Doutor António Carvalho Almeida Coimbra Doutor António Fernandes da Fonseca

Doutor António Fernandes Oliveira Barbosa Ribeiro Braga Doutor António Germano Pina Silva Leal

Doutor António José Pacheco Palha

Doutor António Luis Tomé da Rocha Ribeiro

Doutor António Manuel Sampaio de Araujo Teixeira Doutor Belmiro dos Santos Patricio

Doutor Candido Alves Hipólito Reis

Doutor Carlos Rodrigo Magalhães Ramalhão Doutor Cassiano Pena de Abreu e Lima Doutor Daniel Santos Pinto Serrão

Doutor Eduardo Jorge Cunha Rodrigues Pereira

Doutor Fernando de Carvalho Cerqueira Magro Ferreira Doutor Fernando Tavarela Veloso

Doutor Francisco de Sousa Lé

Doutor Henrique José Ferreira Gonçalves Lecour de Menezes

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Doutor Joaquim Germano Pinto Machado Correia da Silva Doutor José Augusto Fleming Torrinha

Doutor José Carvalho de Oliveira

Doutor José Fernando Barros Castro Correia Doutor José Luis Medina Vieira

Doutor José Manuel Costa Mesquita Guimarães Doutor Levi Eugenio Ribeiro Guerra

Doutor Luis Alberto Martins Gomes de Almeida Doutor Manuel Augusto Cardoso de Oliveira Doutor Manuel Machado Rodrigues Gomes Doutor Manuel Maria Paula Barbosa

Doutor Maria da Conceição Fernandes Marques Magalhães Doutor Maria Isabel Amorim de Azevedo

Doutor Maria José Cerqueira Gomes Braga Doutor Serafim Correia Pinto Guimarães

Doutor Valdemar Miguel Botelho dos Santos Cardoso Doutor Walter Friedrich Alfred Osswald

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Ao abrigo do Art.º 8º do Decreto-Lei n.º 388/70 fazem parte desta dissertação as seguintes publicações:

1. Duarte R, Neto M, Carvalho A, Barros H. Improving tuberculosis contact tracing: the role of house and workplace evaluation. Int J Tuberc Lung Dis. In press.

2. Duarte R, Santos A, Mota M, Carvalho A, Marques A, Barros H. Involving community partners in the management of tuberculosis among drug users. Public Health 2011;

125: 60-62.

3. Soares F, Pinto C, Duarte R. Who misses the second step of evaluation in tuberculosis contact screening? Eur Resp J. In press.

4. Duarte R, Miranda A, Braga R, Carvalho A, Rola J, Marques A, Barros H. Tuberculosis in a shopping centre, Portugal, 2004-5. Euro Surveill. 2008 Oct 16; 13 (42).

5. Duarte R, Tavares E, Miranda A, Carvalho A. Tuberculosis in a child - search for the infected adult nearby; case report, Portugal, 2007. Euro Surveill. 2009 Sep 10; 14 (36).

6. Miranda A, Magalhães A, Alves A, Braga R, Valente I, Duarte R. A population-based molecular epidemiology study of tuberculosis in Vila Nova de Gaia, Portugal, using the optimized 15 MIRU-VNTR loci typing system. Submitted

7. Duarte R, Carvalho C, Pereira C, Bettencourt A, Carvalho A, Villar M, Domingos A, Barros H, Marques A, Costa P, Mendonça D, Martins B. HLA class II alleles as markers of tuberculosis susceptibility and resistance in healthcare workers. Rev Port Pneumol.

2011;17(1):15-19.

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Esta investigação foi realizada no Centro Diagnóstico Pneumológico de Vila Nova de Gaia, no Centro Hospitalar de Vila Nova de Gaia/Espinho e no Serviço de Higiene e Epidemiologia da Faculdade de Medicina da Universidade do Porto.

- ix - Júri da Prova de Doutoramento

Doutor José Agostinho Marques Lopes (Presidente) Faculdade de Medicina, Universidade do Porto

Doutor Maurício Lima Barreto

Instituto de Saúde Colectiva, Universidade Federal da Bahia

Doutora Emília de Jesus da Encarnação Valadas Faculdade de Medicina, Universidade de Lisboa

Doutor José Henrique Dias Pinto de Barros Faculdade de Medicina, Universidade do Porto

Doutora Carla Maria de Moura Lopes

Faculdade de Medicina, Universidade do Porto

Doutora Ana Azevedo Cardoso Oliveira

Faculdade de Medicina, Universidade do Porto

- xi - Agradecimentos

Tive sorte. No decorrer da minha vida, várias pessoas tiveram papéis importantes que foram ditando o meu percurso.

Os meus pais que me ensinaram a ser persistente, a ter objectivos e a tentar cumpri-los. O Renato que me tem apoiado em todas as decisões – algumas influenciadas por ele. Os meus filhos que sempre viram a mãe atarefada com uma e outra coisa e até acham isso normal. A minha sogra, sem a qual muitas noites teriam sido ocupadas com outras tarefas que não a ciência.

Todos eles me deram o apoio familiar necessário para que me pudesse dedicar a trabalhar no que gosto – tuberculose.

Mas como tudo começou?

Verdadeiramente, a culpa é do Renato. Foi ele que me instigou a concorrer à vaga de Monitora para a disciplina de Saúde Comunitária. Fui aceite.

Conheci o Professor Doutor Calheiros que me entusiasmou na área da saúde Comunitária e me aconselhou a seguir a Pneumologia e posteriormente a fazer o Mestrado em Saúde Pública.

Na Pneumologia o Dr. Filipe Rodrigues e o Dr. Sapage incutiram-me o gosto pela tuberculose, enquanto uma outra médica, a Dra. Aurora Carvalho me adoptou. Ganhei na Pneumologia uma amiga com quem sempre pude contar.

Durante o mestrado conheci o Professor Doutor Henrique de Barros. Foi ele que me disse um dia “se não escreveres, não existes”. Ensinou-me a ser exigente comigo mesma, a ser metódica e a fazer mais e melhor a cada dia que passa.

Durante o mestrado conheci a Dra. Maria Neto, médica de Saúde Pública. Por coincidência, começamos a trabalhar na área da tuberculose ao mesmo tempo. Eu no Centro Diagnóstico Pneumológico e ela como Autoridade de Saúde em Vila Nova de Gaia. Estabelecemos parcerias e tentamos optimizar estratégias. Pouco tempo depois conheci a Dra. Ana Maria Correia, outra médica de Saúde Pública. Algum tempo depois a Dra. Ana Maria Correia é convidada para Coordenadora do programa de luta contra a tuberculose da região Norte e convida-me para consultora. Com ela aprendi muito sobre coordenação, definição de estratégias, avaliação dos resultados e actuação no terreno.

Que mais podia eu fazer, se não uma tese em tuberculose e concorrer ao Grau de Doutor em Saúde Pública?

No momento em que iniciei este percurso pude sempre contar com todos.

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Há contudo pessoas que tiveram um lugar preponderante neste percurso. O Professor Doutor Agostinho Marques foi um dos mais importantes impulsionadores do inicio deste projecto, acreditando em mim e incentivando-me a andar para a frente. A ele agradeço o exemplo, a sua posição séria, aberta e independente com que nos ensina Medicina, que nos chama à razão, que nos mostra que afinal não sabemos tudo.

Não posso deixar de agradecer especialmente ao Professor Doutor Henrique Barros, que no meio de milhares de afazeres, milhares de telefonemas, mails, faxs, conseguiu sempre ouvir as minhas dúvidas, voltar-me a pôr no caminho certo sempre que andei à deriva e me ajudou a levar este projecto até ao fim.

Para terminar, um agradecimento especial ao meu pai e à Mélanie que me ajudaram no resumo em Francês – uma língua que tenho de voltar a utilizar.

A todos, o meu muito obrigada.

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I hereby declare that I contributed to this thesis by designing the interventions, collecting part of the data and handling the data collected. No portion of the work referred to in this thesis has been submitted in support of an application for other degree or qualification of this or any university, or institution of learning.

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C ^ONTENTS

CHAPTER ONE - INTRODUCTION AND AIMS ... 1

INTRODUCTION ... 3

Tuberculosis ... 4

Tuberculosis in the world ... 5

Strategies ... 7

What is missing? ... 8

How can case detection be improved? ... 9

The frontier: host versus Mycobacterium ... 13

Can the elimination targets be achieved? ... 14

Vertical versus horizontal programs ... 15

Why performing the present study? ... 17

References ... 19

AIMS ... 25

CHAPTER TWO - STRATEGIES TO INCREASE CASE FINDING AND TREATMENT COMPLIANCE ... 27

PAPERS ... 29

Improving tuberculosis contact tracing: the role of household and workplace evaluation ... 31

Involving community partners in the management of tuberculosis among drug users ... 46

Who misses the second step of evaluation in tuberculosis contact screening? ... 52

CHAPTER THREE - PUBLIC HEALTH CONTRIBUTION OF MOLECULAR EPIDEMIOLOGY TO ADDRESS TUBERCULOSIS ... 58

PAPERS ... 60

Tuberculosis in a shopping centre, Portugal, 2004-5 ... 62

Tuberculosis in a child - search for the infected adult nearby ... 68

A population-based molecular epidemiology study of tuberculosis in Vila Nova de Gaia, Portugal, using the optimized 15 MIRU-VNTR loci typing system. ... 74

CHAPTER FOUR - HOST GENETIC BACKGROUND AND DEVELOPMENT OF CLINICAL TUBERCULOSIS ... 95

PAPERS ... 97

HLA class II alleles as markers of tuberculosis susceptibility and resistance in healthcare workers. ... 99

CHAPTER FIVE - GENERAL DISCUSSION AND CONCLUSIONS ... 107

DISCUSSION ... 109

Contact investigation ... 110

What is the cost of an enlarged contact tracing strategy? ... 113

Latent TB treatment compliance ... 115

TB case detection among drug users ... 116

Adherence to two-step evaluation ... 119

Understanding TB transmission and its implications ... 119

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Genetic factors determining susceptibility to TB ... 121

References ... 123

CONCLUSIONS ... 132

CHAPTER SIX – ABSTRACT ... 134

ABSTRACT... 136

RESUMO ... 141

RÉSUMÉ ... 147

C ^HAPTER O ^NE - I NTRODUCTION AND AIMS

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Introduction

Infectious diseases are the second leading cause of death and the leading cause of disability in terms of adjusted life-years worldwide¹. Despite earlier predictions to the contrary¹, infectious diseases remain a dominant feature of public health considerations in the 21st century. The continual evolution of emerging and re-emerging diseases, particularly the development of the human immunodeficiency virus pandemic in developing countries, impacts seriously on infectious disease frequency in the present century¹.

History has taught us the importance of complex multi-level interactions between a disease host and many other factors, ranging from mutations in pathogens to ecological, social, and demographical changes across the globe, aggravated by degradation of welfare and health- care systems in the poorest regions of the world, the re-emergence of latent epidemics, and the appearance of new epidemics².

Technological progress has improved the arsenal of responses to infectious diseases. A large and intensive research effort is devoted to the design of better drugs and vaccines, and we now know details on the molecular structure of a variety of pathogens. Unfortunately, despite remarkable advances at the molecular level, we still cannot predict how most infections spread, and remain unable to construct efficient vaccine and/or quarantine intervention policies to efficiently mitigate or stop disease transmission^2,3. These problems are attributable principally to the following three causes: (a) continuous and diverse mutation of pathogens, particularly viruses, in response to selection pressures; (b) the complexity of disease host- pathogen and host-host transmission mechanisms; and (c) the complexity of interactions among individuals, and variations in social behavior^2,3.

Apart from immune deficiency virus (HIV) and pandemic influenza, which have had an extraordinary impact on global health, continual evolution of many emerging and re-emerging infectious diseases is evident, and the potential for global spread of such diseases varies.

Some pathogens (such as Ebola virus) are highly virulent but have remained restricted, and have thus posed more of a medical problem than a global public health threat¹. Other pathogens, such as multidrug-resistant malarial parasites, have infected large numbers of

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humans but have remained geographically restricted. This has caused serious local public health problems, but no global public health threat¹. Multidrug-resistant TB and vancomycin- resistant Staphylococcus aureus and enterococci are examples of emerging infections that do not immediately attack large numbers of individuals, but nonetheless have a serious impact on public health throughout the world^1,3.

Because of the high mobility and fast worldwide connections of present-day life, infectious diseases are now spreading geographically much faster than at any time in recorded history.

Today, air travel means that an outbreak or epidemic in one part of the world can become, in only a few hours, an imminent threat elsewhere. Such problems intensify the need for development of a worldwide capacity for public health surveillance and response³.

Tuberculosis

The most prevalent form of tuberculosis (TB) results from infection with Mycobacterium tuberculosis and can cause death or chronic illness unless properly treated. In the vast majority of patients, infection is acquired by inhalation of airborne infected droplet nuclei derived from the sputum of an adult with respiratory TB⁴.

Only a small proportion of those infected develop active TB, but particular factors such as infection with human immunodeficiency virus, or the presence of other immunosuppressive conditions, increase the likelihood of progression to disease. TB most commonly affects the lungs but can cause disease in any part of the body^4,5.

Nowadays, treatment consists of a combination of antibiotics, usually isoniazid, rifampicin, pyrazinamide, and ethambutol, that need to be taken regularly (daily or three times a week) for a considerable time (at least 6 months). The range of effective antibiotics is becoming seriously compromised by the emergence of drug-resistant bacilli⁶.

Drug-resistant TB is essentially a man-made phenomenon. From a microbiological perspective, each form of drug resistance is caused by a genetic mutation that causes the drug to become ineffective against mutant bacilli. An inadequate or poorly administered treatment regimen permits a drug-resistant strain to become dominant in a patient infected with TB (Table 1)⁷.

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Traditional, short-course chemotherapy for patients infected with drug-resistant strains can increase the level of drug resistance. This is termed the “amplifier effect”. Ongoing transmission of established drug-resistant strains in a population is a further important source of new drug-resistant TB outbreaks⁷.

Health care providers:

Inadequate regimens

Drugs:

Inadequate supply/quality

Patients:

Inadequate drug intake Inappropriate guidelines

Noncompliance with guidelines Absence of guidelines

Poor training

No monitoring of treatment Poorly organized or funded TB control programs

Poor quality

Unavailability of certain drugs (lack of stock or delivery disruptions)

Poor storage conditions Wrong dosage or combination

Poor adherence

Poorly administered DOT (directly observed treatment) Lack of information

Lack of money (no treatment available free of charge) Lack of transportation Adverse effects Social barriers Malabsorption

Substance dependency disorders Table 1: Causes of inadequate anti-TB treatment⁷.

The emergence of resistance to drugs used to treat TB, and, particularly, the development of multi-drug resistant TB, has become a significant public health problem and an obstacle to effective global TB control^7,8.

Tuberculosis in the world

International targets for TB control seek to ensure that, by 2015, the global incidence rate should be declining; that the global prevalence and death rates of 1990 should be halved; that at least 70% of smear-positive cases are detected and subjected to in directly observed treatment with short course (DOTS) programs; and that at least 85% of smear-positive patients are successfully treated (90% according to the updated plan in 2010) ^8,9.

- 6 - TB incidence rate

An estimated 9.4 million incident cases of TB were recorded in 2009, up from 9.24 million in 2006, 8.3 million in 2000, and 6.6 million in 1990. Most cases in 2009 occurred in Asia (55%) and Africa (31%)⁸.

Although the number of incident TB cases is increasing in absolute terms, the number of cases per capita is falling as a result of population growth. The estimated global incidence rate, which peaked around 2003/2004 (142 cases per 100,000), has fallen slowly (at less than 1%

per year) since that time ⁸.

However, decline in TB incidence rates will not be reflected in all countries. Indeed, the incidence rates are falling in five of the six World Health Organization Regions, but with the exception of the South-East Asia Region (where the incidence rate is stable).

TB prevalence and death rate

Although TB prevalence has fallen globally in all six WHO regions⁸, the set targets of halving the 1990 prevalence are unlikely to be achieved. The exception is the Region of the Americas where the Stop TB Partnership’s target has been achieved.

Projections suggest further that the Western Pacific and Eastern Mediterranean regions are on track to achieve the target by 2015, and the European Region could get close.

On current projections, the African and South-East Asian regions will not achieve the target⁸. In 2009, 14 million cases of TB were reported globally⁸. An estimated 1.3 million deaths occurred among HIV-negative patients with newly acquired TB, and 0.38 million deaths among incident TB cases who were HIV-positive⁸.

Detection rate

The global detection rate under DOTS was 63% in 2009, a small increase from 61% in 2008 and 7% short of the 70% target. The highest rates of case detection in 2009 are estimated to be in

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the European Region (80%; range, 74–85%) and the Region of the Americas (79%; range, 74–

85%), followed by the Western Pacific Region (70%; range, 64–78%). The African Region has the lowest estimated rate of case detection (50%; range, 48–53%)⁸.

Success rate

Globally, the rate of treatment success for new smear-positive patients in the 2008 cohort attained the target of 85%⁸. Among WHO regions, three met or exceeded the 85% target: the Eastern Mediterranean Region, the South-East Asia Region and the Western Pacific Region.

The treatment success rate was lower in the African (80%), American (77%), and European (66%) Regions⁸.

Infection with HIV and multi-drug resistance are claimed to be the principal reasons why international targets are not attained, especially in the African and European Regions⁸. Major progress is evident in implementation of interventions in HIV-positive TB patients.

Strategies

An important document, the Stop TB Strategy, was promulgated in 2006 with the aim of achieving global TB control¹⁰. Developed by the WHO, the report identified interventions needed to achieve international targets and relied principally on the detection and treatment modality termed “directly observed treatment with short course” (DOTS)¹⁰. This emphasizes passive case finding and tracing of contacts of index cases.

Strategic programs to control TB have not had a major effect on disease incidence, at least on a large scale. One possible reason is that patients are not diagnosed and treated sufficiently early^11,12,13.

Using mathematical models, Styblo, Bumgarner, and Dowdy quantified the expected effect of detection and treatment of TB cases and found that disease incidence could be reduced by 5-

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10% per year by detecting at least 70% of cases and successfully treating 85% of those diagnosed11,12,13,14

. However, a gradual improvement in case detection results in a more rapid decline in TB incidence (a 3% annual decline in disease frequency is evident when the case detection rate rises by 1% per year)¹¹. Further, once the target levels of case detection are achieved, disease incidence stabilizes within 10 years, unless case detection continues to improve. Case detection rates of over 70% are best achieved by increasing the frequency of diagnostic attempts. These findings suggest that the current goals of TB control are unlikely to be met without continued improvements in case detection, thus beyond the current target levels¹¹.

To halve the disease prevalence rate by 2015, TB control programs must meet global targets for detection (70%) and treatment success (85%), and must also reduce the incidence rate by at least 2% annually. To halve the death rate, the incidence must decrease more steeply, by at least 5-6% annually^11,13.

What is missing?

DOTS uses passive case finding to detect TB cases, through health education and tracing of the contacts of index cases. This program recruits patients who would at any rate have been detected and treated in the public health system^11,14.

Some groups have limited or no access to health services and others approach the public health system because they experience symptoms, but are wrongly diagnosed¹⁴. It is known that improvements in case detection can identify 10-fold more patients than does DOTS¹⁵. Another problem is the time from the onset of symptoms until diagnosis. Analysis of TB transmission dynamics and treatment delay has stressed that the lag time to diagnosis is one the most importants obstacles inhibiting control of the TB epidemic^16,17.

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It is generally considered that, for TB control to be effective, the target diagnostic delay should not be more than 3-4 weeks¹⁷. In a systematic review by Sreeramareddy, it was observed that this limit was exceeded by about 4 weeks in high-income countries and 5 weeks in countries with low incomes¹⁶.

How can case detection be improved?

Several reasons for low case detection rates and delays in treatment have been advanced, including a poor understanding of TB in the general population, insufficient knowledge on where care is available, weak health service infrastructure, barriers to health care access, poor- quality diagnosis, limited human resources, and a lack of knowledge about TB among health care providers14,15,16,17

. The various TB control strategies suggest that the first requirements for improved case detection include recognition of symptoms by those affected, promotion of active health-seeking behavior, diagnosis and treatment in an appropriate place, and notification of the case. This pathway is that of “passive case detection”, and is the principal approach applied in countries with high TB burdens^8,10. In such places, national TB programs do not actively search for cases, but rather wait for patients with TB symptoms to seek care.

Active case finding involves the use of pro-active approaches to screen high-risk groups who do not actively seek health care despite the presence of TB symptoms. This approach involves contact investigations, and pre-symptom interactions with high-risk populations or groups at clinical risk¹⁸.

Contact investigations

Assessment of those who are likely to have recently become infected with M. tuberculosis is very important. The risk of progress of such subjects to active TB is greatest within the first 1-2 years after infection⁵.

In many areas of low TB incidence, pro-active investigation, with emphasis on household contacts, is an integral part of TB control, contributing to case finding and to disease prevention by treatment of latent TB infection. According to the United States Centers for

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Disease Control and Prevention, contact investigation is a high-priority aspect of effective TB control, and played an important role in achieving a 44% decrease in the incidence of TB in the United States of America between 1993 and 2004^18,19. However, the question of whether contact investigations are useful in high- or intermediate-prevalence disease burden settings remains controversial; contact investigation has historically been viewed as an expensive, low- priority endeavor.

Morrison and Pai systematically reviewed pooled data on the case yield of household contact investigations conducted in low- and middle-income countries, to develop an evidence base for formulating appropriate policies. The pooled yield of cases among household contacts was 4.5% for all forms of active TB, 2.3% for confirmed TB, and 51.4% for latent TB infection. These yields are remarkably high ²⁰.

Management of contacts is guided by three principles. First, the rates of TB are known to be high in contacts, presumably because such subjects have been recently infected ²¹. Second, this incidence can be reduced using preventative therapy²². Third, the organisms causing disease or infection in the contact are assumed to be the same that gave rise to disease in the index case and, thus, to be susceptible to the same antimicrobial agents²².

Contact tracing in general serves to identify individuals with TB or latent TB infection among the contacts of a TB patient. Adequate treatment and follow-up can then reduce morbidity and mortality caused by TB among newly infected individuals and, finally, reduce further transmission .

The effect of contact investigation on TB incidence has been well demonstrated in the United States of America. Upon a resurgence of TB in the mid 1980s, more funds were earmarked for enhanced program activities²³. These funds were directed toward improvements in completion of TB therapy and the intensification of other core TB control activities, such as investigation of contacts of TB cases. The increase in the median number of contacts identified through contact investigations, and the fall in the proportion of cases for whom no contacts were identified, were associated with a drop in TB incidence²³.

Contact tracing is regarded as effective to identify recently infected individuals and has become an essential component of the TB elimination strategy in most low-incidence countries18,24,25,26

. However, no uniform contact tracing strategy has been developed. Some groups use the stone-in-the-pond principle, a commonly used strategy that categorizes

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contacts as being at high, medium, or low risk, on the basis of an assessment of the likelihood of transmission (e.g., with consideration of personal, timing, and location factors)21,26,27,28

. Others investigate only close contacts^29,30 or household contacts alone³¹, whereas some investigators approach workplace contacts³². Thus, the optimal level of investment in contact tracing remains unknown.

Armbruster created a model to study the impact of screening and contact tracing in control of endemic infectious disease³³. The cited author concluded that contact tracing is cost-effective only when disease prevalence is below a threshold value. This threshold depends on the relative cost per case found by screening in comparison with contact tracing. The second conclusion of the study was that, for a given contact tracing policy, the screening rate needed to achieve a certain disease prevalence, or to identify a specified number of cases, is a decreasing function of disease prevalence. As the incidence of disease increases above a threshold (and contact tracing is discontinued), the screening rate jumps, in a discontinuous manner, to a higher level³³.

To reduce the resources spent on contact tracing, some groups use cost efficiency analysis to exclude low-risk groups from contact investigation and to initiate preventative therapy in high- risk groups, without screening³⁴. Others have created a decision tree that predicts the presence of latent TB infection or active TB among contacts. The tree is used to determine that contacts are investigated only if (1) the case to which they were exposed had cavitary disease, or (2) the total exposure time over 1 month was greater than 120 hours, or (3) the contact was less than 15 years of age. Such decisions eliminate 17-25% of initial contacts identified. This strategy substantially reduces the numbers of contacts examined and saves considerable resources. Although the work is encouraging, the cited authors acknowledged that some subjects who recently acquired TB are likely to be missed³⁵.

Other efforts have been made to better target contact investigation, to increase cost effectiveness. Prioritization of screening, and the targeting of those who should receive latent TB infection treatment, are important challenges today, when public health programs compete for resources and ever-decreasing budgets. However, such savings need to be weighed against the cost of potentially missing a contact recently infected with TB.

How is contact notification processed?

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In many countries, a diagnosis of infectious TB is reported to public health officials. This triggers a public health intervention that includes identification of close personal contacts.

These contacts are then notified that they are at risk of infection.

In countries that do not have case-reporting systems, or where case reporting does not result in identification and notification of contacts by public health authorities, patients are usually encouraged to personally notify their contacts. This is the case in Portugal.

A problem arises when patients are unwilling to participate in contact identification and notification. Public health authorities and TB programs must develop clear policies to deal with such instances, taking into consideration that all procedures must aim to protect both patients and their contacts from stigmatization and other social harm that is associated with TB in many settings.

Vulnerable populations

TB is causally linked to poverty and low socioeconomic status. Factors such as malnutrition, lack of education, and poor housing and sanitation, compounded by other risk elements such as alcohol and drug abuse, affect both vulnerability to TB and access to care^1,2,3,4.

One important target of TB programs is to ensure that the most vulnerable groups have access to diagnosis and treatment. Such subjects, which include drug users, the homeless, and illegal immigrants, are those who will not readily seek health care. However, these groups include the subjects who are most likely to contract infection, to develop disease, and to have poor treatment outcomes. If TB is not effectively diagnosed and treated in these groups, an epidemic can develop, placing the entire population at risk.

To develop an effective method of case finding, Ahmad et al. formulated a mathematical model to optimize TB case location in the context of the Indonesian public health system, by comparing three possible interventional strategies. The first sought to reduce the number of TB patients who do not seek care. The second attempted to decrease the delay in seeking treatment; and the third engaged non-DOTS providers to refer TB-suspect patients to DOTS services^36,37. The model predicted that intervention to reduce the proportion of TB patients who never seek care would have the biggest impact on prevention of death from TB, whereas

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an intervention resulting in more referrals of TB-suspect subjects to DOTS facilities would yield higher cure rates.

Molecular epidemiology: a new tool for public health

The capacity to genotype M. tuberculosis isolates, developed in the early 1990s, helped to clarify the patterns of transmission and opened new fields in TB prevention and control.

Primary typing of bacterial isolates can be achieved by PCR-based methods (spoligotyping and MIRU-VNTR) or by assessment of IS6110 restriction fragment length³⁸.

Today, molecular epidemiology and genotyping are being considered for use in outbreak investigation, contact tracing, identification of instances of laboratory cross-contamination (i.e., false-positive cultures) ³⁹, and evaluation of the performance of disease prevention and control programs^40,41. As reduction of recent transmission is a major focus of TB prevention and control, clustering of M. tuberculosis isolates may identify the proportion of incident cases attributable to recent transmission. Genotyping can be used to detect such clustering, thus revealing the impact of interventions aimed at reducing recent transmission.

The frontier: host versus Mycobacterium

M. tuberculosis is one of the most successful human pathogens, surviving in latent foci of infection in one-third of humanity, yet causing lung necrosis in a sufficient number of individuals to ensure continued disease transmission. Much effort has been devoted to identification of factors relevant to persistence of infection, and the ones required to allow infection to progress to overt disease⁵.

An analysis of factors determining the risk of overt disease following infection must consider both the virulence of the causative organism and the immune defenses of an infected patient⁵. Until recently, immunological studies on TB focused on immune reactivity in those with the disease, but attention is now devoted to understanding why the majority of infected subjects remain healthy. In this context, it is important to determine whether those who remain

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healthy are genetically endowed with high-level resistance to TB, or whether resistance is attributable to environmental or other exogenous factors that are subject to change.

Each stage of the host response to M. tuberculosis is under genetic control, including the initial encounter of mycobacteria with macrophages, epithelial cells, and dendritic cells of the lung;

induction of the T cell response; and bacterial killing by activated macrophages within granulomas⁵. Although environmental factors are important determinants of progression to disease, a host genetic component underlies susceptibility to TB, and this may vary in different populations. Studies on ethnic variations in disease susceptibility have provided substantial evidence that human genetic variation is an important determinant of the outcome of infection⁴². Only a minority of patients has obvious identifiable risk factors for TB; these include HIV infection, diabetes, or use of immunosuppressive drugs. In the remainder of patients, a complex interaction between genetic and environmental factors causes development of clinical TB. Assessment of the contribution of host genetic resistance factors to TB is a major research challenge. Elucidation of the functional significance of susceptibility gene polymorphisms will lead to new strategies for control and prevention of the disease.

The currently available tools do not permit identification of the subset of latently infected subjects who will develop active disease. Further studies in this area could lead to tests that could alter treatment algorithms, and provide more accurate prognostic information. In addition, such studies may lead to novel molecular insights into TB pathogenesis.

Can the elimination targets be achieved?

A TB control strategy aims to reduce the incidence of infection via case finding and curative treatment of disease transmitters to create a new generation with a lower frequency of infection caused by such transmission. Any TB elimination strategy requires, in addition, a reduction of infection prevalence achieved by identification and treatment of those already latently infected with viable M. tuberculosis, and who may thus develop reactivated TB in the future.

Using mathematical modeling, Dye showed that the goal of eliminating TB by the mid-century is most likely to be achieved if current treatment programs can be coupled with new

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approaches to reduce the vast reservoir of latent human infection⁴³. Apart from treatment of active TB, two other possible approaches to TB control are evident. The first is to prevent infection by (pre-exposure) vaccination, and the second is to stop progression from latent infection to active disease using preventative therapy⁴³. In Dye’s mathematical model, a far greater impact was evident when interventions that blocked both the fast (progressive primary TB) and slow (reactivation of latent infection) routes to development of active TB were combined. Treatment of latent TB was relatively ineffective when used alone, but was both powerful and synergistic when employed in combination with treatment of active TB. If such combined approaches were implemented intensively, the incidence of TB could be forced below the elimination threshold by 2050⁴³.

Vertical versus horizontal programs

For decades, global health experts and policymakers have been debating the merits of disease- specific initiatives versus broader efforts to strengthen health systems. This is the old vertical- versus-horizontal argument. Both approaches have strengths and weaknesses, which vary depending on the disease addressed and the particular societal context^44,45,46. The disease under discussion, the target group, the capabilities of the health care system, production specificities, and contextual factors all need to be considered when choosing a suitable approach. The urgency of service provision must also be reviewed^45,46.

The benefits of vertical programs are a focus on the need for control of a particular disease in a defined population, the use of specialist staff (who generally manage just a single condition), the availability of dedicated resources, and operation in a project mode in which clear objectives are to be achieved over defined (and often short) time scales. Consequently, it is suggested that such vertical programs tend to be more efficient than are horizontal approaches, in terms of achieving objectives^45,46. The biggest barrier to vertical approaches is human resource availability^45,46,47. Shortages of well-trained doctors, nurses, and health administrators are major problems when it is sought to control specific diseases (except perhaps at the expense of other important health programs). In such instances, vertical programs may fragment care, dissipate funds and resources, and potentially create

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inefficiencies, resulting in missed opportunities to treat multiple issues in an integrated fashion45,46,47,48

.

In contrast, horizontal approaches focus on the individual, employ generalist personnel who deal with multiple symptoms and conditions, respond to user needs as well as demands, and are more holistic in scope^45,46,47.

There is, however, no reason why vertical and horizontal approaches should not coexist^45,46. A vertical program may serve as an interim strategy to efficiently deal with a particular problem, combined with explicit efforts to strengthen the health system and to eventually achieve program integration. Such an approach would ensure that, in the short term, program objectives and efficiency are not compromised, and the scale of operations could be gradually expanded by a strengthening of the overall health system, the capacity of which would be augmented to cope with other needs ⁴⁶.

Health initiatives, whether focused on one disease or with a broader objective, always aim to improve health outcomes. Thus, it is not helpful to set one approach against another. Rather, we need to ask why TB prevention programs do not work. What is missing?

In 1966, Mahler identified the conditions for effective implementation of national TB programs in developing countries, still under discussion^44,45. TB strategies need to be closely aligned with general economic development within the community. The natural history of TB clearly shows an association of the disease with poverty^1,2,3,4. This means that TB programs need to work closely with organizations whose efforts address poverty, and must encourage approaches to poverty reduction⁴⁴. Treatment of TB must be much better integrated with treatment of co- morbidities such as HIV, diabetes, viral hepatitis, and alcohol and substance abuse. This integration requires co-operation and partnership with those working on other diseases⁴⁴. To prevent serious errors in the care of TB patients, aggressive professional education and support for physicians and institutions treating patients with TB are required. Rapid availability of expert clinicians and those who can effectively monitor treatment should be a priority of public health departments. As the treatment of TB becomes more complex (because of microbial drug resistance and HIV infection), consultation with specialists experienced in the treatment of such cases should be routine⁴⁹.

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In many settings, particularly if human and financial resources are available, the most efficient manner in which to avoid treatment errors and poor outcomes is to have all patients with TB treated by a central health department, or in a center of excellence in TB treatment. This strategy should be encouraged, if at all possible⁴⁹.

In regions with large caseloads and/or few public resources, a public-private partnership to achieve TB control is essential. However, active monitoring of all patients by a trained quality- assurance team is imperative to optimize care for patients with TB⁴⁹.

The best measure of performance of a health care system is the impact of that system on health outcomes. No single set of best practices can be considered to serve as a model of improved performance. However, health care systems that function well share certain characteristics. They have procurement and distribution systems that deliver intervention to those in need. They are staffed with sufficient numbers of trained health care workers who are motivated and have appropriate skills. They operate under a sustainable financing system⁴⁷.

Why performing the present study?

Early identification and treatment of patients are major issues in tuberculosis control.

Mathematical models suggest that the current goals for tuberculosis control are unlikely to be met without continued improvement in case finding, thus beyond current target levels. Such strategies rely on active screening of individuals that do not seek health care, and should include tuberculosis contacts and high risk populations.

A large variety of contact tracing or population screening strategies are applied across and even within countries. Not every investigation into tuberculosis can reasonably be conducted using the same strategy. The questions of who needs to be assessed, and why a certain strategy has been chosen, should be first posed and then clearly answered. It is therefore important to obtain more insight into processes in individual countries or regions.

This thesis seeks to assist in the design of an effective strategy that identifies subjects at higher risk for disease in societies with an intermediate incidence of tuberculosis. To address this public health problem, we conducted a set of studies trying to focus in three main questions:

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Can we find strategies to improve case finding and treatment compliance among individuals at high risk for tuberculosis (those with latent tuberculosis infection, contacts of tuberculosis patients and drug users)?

Can molecular epidemiology contribute to the control of tuberculosis?

What is the role of our genetic background (HLA-DRB1 and HLA-DQB1 alleles) in the development of active disease after exposure to Mycobacterium tuberculosis exposure?

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Aims

We sought to provide information allowing the design of the most effective strategy for identifying subjects at higher risk for TB in societies with an intermediate incidence of the disease. To approach this public health problem, we conducted a set of studies with the following specific objectives:

1. To compare strategies leading to increases in case finding and treatment compliance among individuals at high risk for TB (latent TB cases, contacts of TB patients, and drug users) - Papers I, II & III.

2. To assess the contribution of molecular epidemiology in the definition of TB clusters, and the appropriate actions indicated by the data – Papers IV, V & VI.

3. To evaluate interaction of subject genetic background (HLA-DRB1 and HLA-DQB1 alleles) and M. tuberculosis exposure in development of active disease – Paper VII.

C ^{HAPTER TWO} - S TRATEGIES TO INCREASE CASE

FINDING AND TREATMENT COMPLIANCE

Papers

Duarte R, Neto M, Carvalho A, Barros H. Improving tuberculosis contact tracing: the role of house and workplace evaluation. Int J Tuberc Lung Dis. In press.

Duarte R, Santos A, Mota M, Carvalho A, Marques A, Barros H. Involving community partners in the management of tuberculosis among drug users. Public Health 2011; 125:

60-62.

Soares F, Pinto C, Duarte R. Who misses the second step of evaluation in tuberculosis contact screening? Eur Resp J. In press.

Improving tuberculosis contact tracing: the role of household and workplace evaluation

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Improving tuberculosis contact tracing: the role of house and workplace evaluation R. Duarte^{1, 2,3}, M. Neto ⁴, A. Carvalho^1,2, H. Barros³

1Centro de Diagnóstico Pneumológico de Vila Nova de Gaia, Vila Nova Gaia, Portugal;

2Centro Hospitalar de Vila Nova de Gaia/Espinho, Laboratório de Tuberculose, Vila Nova de Gaia, Portugal

3 Faculdade de Medicina, Universidade do Porto, Portugal

4 Departamento de Saúde Pública, ARS Norte, Portugal

ABSTRACT

In Vila Nova de Gaia, Portugal, it was decided in 2004 to modify the tuberculosis (TB) contact screening strategy from targeting only close contacts identified by interview with the index patient (reflecting national policy) to include visits to the patient’s home and workplace.

The present study compares TB contact tracing during the periods 2001-2003 and 2004-2006 to answer three questions: (i) Does the new strategy increase TB screening compliance? (ii) Does the strategy identify more at-risk contacts? (iii) Does the strategy increase prevention of TB?

Home and workplace visits allowed identification of more at-risk contacts (8.4 per index patient) than did interview (2.5 per index patient) and improved compliance (87.3% of identified contacts were screened, compared to 67.6% previously). More patients with active TB and latent tuberculosis infection (LTBI) were detected (1.4/index patient compared with 0.75/index patient previously) and more TB cases were prevented.

The newly implemented contact-screening program featuring home and workplace evaluation of TB patient contacts improved compliance with screening procedures, identified more at-risk contacts, and should prevent more TB cases in the future.

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Contact tracing is effective to identify recently infected individuals and is an essential component of any tuberculosis (TB) elimination strategy^1-4. Tracing carries significant resource implications and public health authorities must establish screening strategies for individuals at higher risk of TB that balances the potential non-detection of at-risk subjects with the need to avoid unnecessary screening.

TB incidence in Portugal has been declining annually in the interval since 1985 (from 66.4 to 24.1 patients per 100,000 subjects from 1985 to 2009) but remains the highest in Western Europe⁵. In Portugal, a network of Chest Disease Centers (CDPs) within the National Health Service is responsible for management of TB patients at the primary care level; the Centers evaluate and treat suspected or confirmed TB patients, and perform contact screening.

In our local administrative area, Vila Nova de Gaia, a decision was taken in 2004 to modify the contact screening strategy from targeting only close contacts identified during interview of an index patient (this represents the national policy) to include home and workplace visits seeking to maximize the number of at-risk contacts detected and to increase compliance with screening.

The present study compares TB contact tracing during the periods 2001-2003 and 2004-2006 to answer three questions: (i) Does the new strategy increase TB screening compliance? (ii) Does the strategy identify more at-risk contacts? (iii) Does the strategy increase prevention of TB?

PARTICIPANTS AND METHODS

Organization of TB services

In Portugal, TB patient care is organized by outpatient clinics, designated CDPs, that are responsible for the evaluation and treatment of suspected or confirmed TB patients and also for contact screening within a given metropolitan area. The resources available within any

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Center reflect the local incidence of TB. Care is delivered by providers who work as salaried civil servants within the National Health Service; no specific fee-for-service is set. Home and workplace visits are activities of Public Health and Family Health Units, which are administratively independent of the CDPs. As part of their activities, Family Health and Public Health Units routinely perform home visits and provide home care, specifically addressing social and environmental risks.

Vila Nova de Gaia is a metropolitan area with a population of approximately 290,000, and a TB incidence of approximately 34 per 100,000 inhabitants. In Vila Nova de Gaia, the CDP has two chest physicians, one pediatrician, two general practitioners, three nurses, three technicians, and three administrative staff.

In Portugal, patients newly diagnosed with infectious TB are interviewed and asked to report the names of contacts in different spheres of daily activities (i.e., home, workplace, and social venues). Only those reported are screened. This was the policy of our institution until December 2003. In the interval since 2004, with the co-operation of public health professionals and family doctors, homes and workplaces are routinely visited, and other potential at-risk contacts are identified. Visitors are aware of the clinical situation of the patient, are asked to explain the purpose of the visit to every individual contacted, and to collect specific information related to TB risk. The resources of our CDP and the local Family Health and Public Health Unit did not change between the two time periods studied; no additional financial resources were allocated to the project. Thus, any increase in efficacy is a net productivity gain.

Identification of TB patient contacts and data collection

Contact investigations were triggered by every pulmonary TB diagnosis, as determined by positivity of broncho-alveolar lavage or sputum smears, and/or cultures positive for TB. An exposed contact was defined a subject exposed for more than 8 hours daily to the patient or who had over 40 hours of cumulative contact time.