INT J TUBERC LUNG DIS 19(2):137–140 Q 2015 The Union http://dx.doi.org/10.5588/ijtld.14.0543

PERSPECTIVES

Latent tuberculous infection: ethical considerations in formulating public health policy J. T. Denholm,*† A. Matteelli,‡ A. Reis§ *Victoria Tuberculosis Program, Melbourne Health, Parkville, †Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia; ‡Global Health Ethics Unit, Department of Knowledge, Ethics and Research, World Health Organization (WHO), Geneva, §TB/HIV and Community Engagement Unit, Global TB Program, WHO, Geneva, Switzerland SUMMARY

There is increasing interest in the introduction of public health policies relating to latent tuberculous infection (LTBI). However, there has been little previous systematic engagement with LTBI from an ethical perspective. This article offers a general overview of ethical issues in relation to LTBI, with particular focus on those aspects

relevant to the development and implementation of public health policy. Key characteristics of LTBI are discussed from an ethical perspective, with examples of challenging situations for policy makers. K E Y W O R D S : ethics; consent; migration; screening; risk

LATENT TUBERCULOUS INFECTION (LTBI) is defined as a state of persistent immune response to previously acquired Mycobacterium tuberculosis antigens without evidence of clinically manifested active tuberculosis (TB) disease.1 By its nature, LTBI does not directly cause harm; however, individuals with LTBI are at risk for morbidity and mortality related to future TB disease. While estimates are imprecise, it is believed that approximately one third of the world’s population has LTBI.2 The risk varies in different population groups, mainly reflecting underlying conditions that impair effective immune control.3,4 In addition, certain populations globally are at higher risk of having LTBI, largely due to contexts where exposure to infectious cases of TB is more common or intense, such as household contacts of pulmonary TB cases. The existence of identifiable populations at increased risk of reactivation TB suggests that public health strategies for systematic diagnosis and treatment of LTBI are required, at least under some conditions. In 2013, the World Health Organization (WHO) convened an expert group to provide public health approach guidance on evidence-based practices for testing, treating and managing LTBI in individuals with the highest risk of progression to active disease. While assessment of the evidence supporting testing and treatment strategies formed the core of this group’s activities, it was evident from the outset that there were significant ethical issues requiring consid-

eration. Engagement with ethical aspects of public health is critical for developing robust, appropriate and broadly acceptable policy. A review of the literature suggests that there has been little previous systematic reflection on LTBI from an ethical perspective. The present article offers a general overview of ethical issues in relation to LTBI, with particular focus on those aspects relevant to the development and implementation of public health policy, such as the recently released WHO guidelines.5

CHARACTERISTICS OF LATENT TUBERCULOUS INFECTION WITH ETHICAL SIGNIFICANCE LTBI has some distinctive characteristics that may have ethical significance. In particular, three characteristics of LTBI are highlighted here, as they offer insight into recurring themes that arise when considering policy: potentiality, uncertainty and vulnerability. A brief engagement with these concepts provides a background for specific ethical issues in subsequent policy development. Potentiality The biological nature of LTBI is imperfectly understood, and it is likely that LTBI and TB disease are part of a spectrum rather than clearly dichotomous.6 Nonetheless, from an individual perspective, LTBI is by definition an asymptomatic state, its importance

Correspondence to: Justin Denholm, Victoria Tuberculosis Program, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth Street, Melbourne, VIC 3000, Australia. Tel: (þ61) 3 9342 7481. Fax: (þ61) 3 9342 7277. e-mail: justin.denholm@ mh.org.au Article submitted 23 July 2014. Final version accepted 23 October 2014.

138

The International Journal of Tuberculosis and Lung Disease

arising from the risk of future development of active disease. Those with LTBI as currently defined have only potential, rather than actual, disease. Other elements of potentiality are also significant; for example, individuals with LTBI have no current risk of TB transmission, but do have a potential risk of future transmission should they develop the disease. Potentiality may limit or remove ethical obligations that would be imposed by TB. For example, as will be discussed further below, the merely potential future risk of community transmission would not justify restrictions on migration. However, potentiality does not necessarily remove all ethical obligations; health care workers, for instance, may have a professional obligation to appropriately manage their LTBI to prevent a foreseeable risk to patients. Uncertainty Given current limitations imposed by scientific and technological methodology, both diagnosis and treatment of LTBI involve a considerable degree of uncertainty. Existing diagnostic tests, for example, have poor predictive value for the identification of individuals who will actually develop TB in the future: many of those with a positive test will not fall ill with TB during follow-up, and so may not benefit from preventive treatment.7 Equally, no follow-up test currently available can identify whether treatment for LTBI has been successful for an individual.8 Finally, LTBI treatment has safety concerns: the rate of severe isoniazid-associated hepatotoxicity is estimated at 1 case per 1000 persons even when patients are carefully selected and clinically monitored.9 Uncertainty has ethical significance with regard to aspects such as the importance of appropriate communication for informed consent and the degree to which policy can be mandated or enforced in some settings. Communication of uncertainty and risk can be challenging, and such concepts need to be embedded in culturally appropriate forms to be adequately understood. Vulnerability Vulnerability has significance in ethical issues relating to TB generally, as the association with poverty and social marginalisation is well recognised.10 This is also a particularly relevant consideration in relation to LTBI. Individuals affected most by LTBI belong to population groups that are already frequently marginalised: prisoners, for example, as well as homeless persons, those using illicit drugs or those living with the human immunodeficiency virus/acquired immune-deficiency syndrome. Vulnerability is a critical consideration, as it may have a profound impact on power dynamics in health care, especially between marginalised individuals and health care providers. This impact may be substantial enough to affect the validity of consent, the dignity of individuals and/or the effective-

ness of public health interventions, and so introduce a key element into ethical considerations in relation to LTBI. Given these characteristics of LTBI, a critical overarching issue of ethical consideration when formulating policy is the establishment of a favourable individual risk-to-benefit ratio. Testing and treatment of LTBI introduce risk of harm to targeted groups and individuals, which may include inconvenience, social harms such as stigma, and the risk of physical harm from the adverse effects of preventive treatment. It is therefore essential that recommendations for testing individuals or groups are made on the basis of evidence that reasonably suggests that the risks are justified by the magnitude of benefit expected, a key principle of the WHO guidelines. This article therefore also focuses on ethical issues primarily relating to the individuals and groups being tested, rather than to broader societal questions. Although the risk of harm varies in different groups (for example, the risk of stigma and discrimination is greater when testing immigrants), the largest variations are in expected benefits: systematic testing and treatment should therefore be limited to those groups with substantial risk of progression.

FOCUSED ETHICAL ISSUES With these characteristics as background, we will now consider some specific issues encountered in public health policy on LTBI. While not intended as an exhaustive list, these issues have been selected both because of their current importance and because they illustrate key aspects of consideration for ethical policy development. Migration screening for LTBI Many low-prevalence countries have long-standing screening programs for active TB targeting potential migrants. There has recently been increasing interest in expanding these programs to include systematic screening and management of LTBI.11–13 While such programmes may be effective in reducing overall TB incidence in low-burden countries, the risks and burdens imposed by screening programmes, particularly those that are mandatory, should be balanced by maximising the benefits to the included group of potential migrants themselves. In establishing a screening programme for LTBI, a variety of considerations, including the choice of diagnostic tool and the timing of testing, may have ethical significance.14 In general terms, as LTBI does not present an immediate but merely a potential future risk to individuals and others, we would argue that exclusion or deferral of potential immigrants merely on the basis of LTBI would be disproportionate and unjustified. Mandatory testing for LTBI imposes little risk of physical harm in itself, while treatment introduces benefits for appropriately

Ethical considerations in LTBI policy

selected individuals. It would seem, then, that mandated testing followed by post-immigration medical review could offer the opportunity for future treatment and personal benefit, and would seem a reasonable way to balance sovereignty and dignity. Periodic LTBI screening for health care workers Health care workers (HCWs) are at increased risk of the acquisition of LTBI, presumably reflecting exposure to active disease in clinical settings.15 HCWs as a group may not be at increased risk of progression to active disease. However, the consequences of progression may be higher, due to concerns that HCWs may transmit infection to vulnerable patients and visitors. As explored in literature regarding mandatory vaccination policies, health care facilities and individual HCWs have professional obligations to act in a way that minimises risk of harm to patients.16 In relation to LTBI, then, periodic screening in a health care setting may be conducted for individual benefit to HCWs at risk, but may also be considered for the benefit of others who could be affected. This may raise additional challenges when the risk/benefit for an individual HCW may be unfavourable (for example, an older HCW with increased risk of side effects from LTBI treatment) but where the risk of secondary consequences are higher (e.g., in a clinical setting with heavily immunosuppressed patients). By and large, as with other groups, we would suggest that ethically appropriate policies should focus on maximising the benefits to those being targeted for testing and treatment, rather than other secondary benefits. Health care facilities considering mandatory testing for LTBI need to ensure that any considerations of protection for patients are based on genuine risk of transmission and do not impose unreasonable risks on HCWs. Education, consultation and community acceptability Public health policies relating to TB disease are generally well established, and their importance is likely to be at least broadly understood by communities in areas where TB is common. LTBI, however, has significantly less well-developed policy, and the nature and implications of this condition are frequently poorly understood by the affected communities. LTBI policy and practices will therefore require more substantial efforts to ensure that the public, and particularly members of the most affected communities, are encouraged to participate in their development and evaluation. This is likely to involve educational efforts regarding the nature of LTBI and its management.17 It is also likely to require more deliberate attempts to gauge the acceptability of novel strategies in diverse communities, including empirical assessment (for example, through community surveys or focus group interviews) and opportunities for continuous feedback and response. The extent to which these strategies are considered critical by affected communities may

139

depend on a variety of factors, particularly in relation to the degree of trust already established with public health authorities or other relevant organisations.18 Equity in testing and treatment Both LTBI and active TB represent a disproportionate burden for marginalised individuals and groups in society. Systematic policy on LTBI, therefore, may either address and correct this imbalance (through corresponding improvement in health outcomes), or exacerbate these issues (through the introduction of further stigma and exclusion). All aspects of testing and treatment policies should be evaluated to consider how they may reduce inequity rather than increase it. Two important and related general aspects of this consideration are cost and access. While ensuring appropriate access goes beyond financial outlay, escalating monetary costs could disproportionately reduce access to services.19 Wherever possible, financial burdens should be minimised and/or compensated for to ensure appropriate access. Some specific choices may also involve considerations of equity. For example, a need for multiple clinic or testing service appointments may limit access, and tests and testing protocols that require only a single visit may therefore be preferable. Assuming equivalent safety and efficacy, shorter treatment courses and those with less frequent follow-up will also result in reductions in inequity, and are therefore to be preferred where available. Informed consent While informed consent is a central tenet of medical ethics in general, explicit informed consent for TB diagnosis is not routine practice.20 However, several aspects of LTBI are worthy of special consideration. First, as discussed above, there is uncertainty regarding the risk of progression for individuals with a positive LTBI test result. Communication of this uncertainty is necessary for informed consent, which may be challenging for public health programmes. One topical situation highlighting these challenges arises when LTBI treatment is considered for contacts of multidrugresistant TB (MDR-TB). While some small studies have suggested reduction in risk with the use of targeted treatment for MDR LTBI, the degree and duration of risk reduction with specific regimens is uncertain.21,22 Public health policies should include recognition of this uncertainty to promote informed participation.

CONCLUSIONS We have highlighted a range of characteristics and ethical issues relevant to developing public health policy on LTBI. Each of these presents challenges and requires careful consideration in designing and establishing appropriate strategies, and responses to each will vary in different contexts. Nonetheless, they

140

The International Journal of Tuberculosis and Lung Disease

should not be neglected, to ensure that the strategies and policies are ethically defensible and receive buyin from relevant communities/stakeholders. The issues raised here should not, however, serve as a deterrent from engaging in LTBI public health policy development and implementation. Indeed, many of the characteristics and issues of significance highlight a strong moral imperative to offer effective diagnosis and treatment of LTBI for groups of vulnerable people at high risk for future development of disease. In the light of the characteristics of LTBI outlined here, it is critical that such policies are based on a favourable risk/benefit ratio for the individuals included. As policies relating to screening and treatment may introduce risk of harm to targeted groups and individuals (e.g., stigma and adverse effects),23 it is essential that recommendations are made on the basis of evidence which reasonably suggests that the risks are justified by the magnitude of benefit expected for participants. As with other types of public health policies, evaluation after implementation is critical, both to consider possible unexpected impact and to ensure that the evidence on which they are based remains current and relevant.24 As a variety of social and biological factors may influence the effectiveness of strategies relating to LTBI, it is particularly important that re-evaluation consider whether the harms and benefits of introduced policies remain appropriate for the groups and individuals to which they have been applied. We hope that the consideration of these ethical issues will stimulate additional research efforts, both to evaluate programmes operationally and to develop new tools and strategies for maximising the targeted impact of LTBI policies. Finally, while this article has offered a general overview of some ethical considerations relating particularly to public health policies on LTBI, we note the relatively limited evidence from the literature in this area. TB more broadly, and LTBI especially, have been underexplored from an ethical perspective. Continued reflection and deliberation around the challenging issues raised in this area of medicine and public health would assist in strengthening an effective and appropriate engagement with LTBI as part of the ongoing efforts towards eliminating the burden of TB globally. Conflicts of interest: none declared.

References 1 Mack U, Migliori G, Sester M, et al. LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement. Eur Respir J 2009; 33: 956–973. 2 Dye C, Scheele S, Dolin P, Pathania V, Raviglione M C. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. JAMA 1999; 282: 677–686.

3 Horsburgh C R, O’Donnell M, Chamblee S, et al. Revisiting rates of reactivation tuberculosis. Am J Respir Crit Care Med 2010; 182: 420–425. 4 Jeon C Y, Murray M B. Diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies. PLOS MED 2008; 5: e152. 5 World Health Organization. Guidelines for the management of latent tuberculosis infection. WHO/HTM/TB/2015.01. Geneva, Switzerland: WHO, 2015. http://www.who.int/tb/publications/ Hbi_document_pape/en Accessed December 2014. 6 Delogu G, Goletti D. The spectrum of tuberculosis infection: new perspectives in the era of biologics. J Rheumatol 2014; 91: 11–16. 7 Diel R, Loddenkemper R, Niemann S, Meywald-Walter K, Nienhaus A. Negative and positive predictive value of a wholeblood interferon-gamma release assay for developing active tuberculosis: an update. Am J Respir Crit Care Med 2011; 183: 88–95. 8 Adetifa I M, Ota M O C, Jeffries D J, et al. Interferon-c ELISPOT as a biomarker of treatment efficacy in latent tuberculosis infection. Am J Respir Crit Care Med 2013; 187: 439–445. 9 Nolan C, Goldberg S, Buskin S. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA 1999; 281: 1014–1018. 10 Farmer P. Rethinking medical ethics: a view from below. Develop World Bioethics 2004; 4: 17–41. 11 Ricks P M, Cain K P, Oeltmann J E, Kammerer J S, Moonan P K. Estimating the burden of tuberculosis among foreign-born persons acquired prior to entering the US, 2005–2009. PLOS ONE 2011; 6: e27405. 12 Greenaway C, Sandoe A, Vissandjee B, et al. Tuberculosis: evidence review for newly arriving immigrants and refugees. Can Med Assoc J 2011; 183: E939–E951. 13 Denholm J T, McBryde E S. Can Australia eliminate TB? Modelling immigration strategies for reaching MDG targets in a low-transmission setting. Aust NZ J Public Health 2014; 38: 78–82. 14 Denholm J T, McBryde E S, Brown G V. Ethical evaluation of immigration screening policy for latent tuberculosis infection. Aust NZ J Public Health 2012; 36: 325–328. 15 Baussano I, Nunn P, Williams B, Pivetta E, Bugiani M, Scano F. Tuberculosis among health care workers. Emerg Infect Dis 2011; 17: 488–494. 16 van Delden J J, Ashcroft R, Dawson A, Marckmann G, Upshur R, Verweij M. The ethics of mandatory vaccination against influenza for health care workers. Vaccine 2008; 26: 5562– 5566. 17 White M C, Duong T M, Cruz E S, et al. Strategies for effective education in a jail setting: the Tuberculosis Prevention Project. Health Promot Pract 2003; 4: 422–429. 18 Gilson L. Trust and the development of health care as a social institution. Soc Sci Med 2003; 56: 1453–1468. 19 Hill L, Blumberg E, Sipan C, et al. Multi-level barriers to LTBI treatment: a research note. J Immigrant Minority Health 2010; 12: 544–550. 20 World Health Organization. Guidance on ethics of tuberculosis prevention, care and control. WHO/HTM/TB/2010.16. Geneva, Switzerland: WHO, 2010. www.who.int/tb/ publications/2010/en/index.html 21 Denholm J T, Leslie D, Jenkin G A, et al. Long-term follow-up of contacts exposed to multidrug-resistant tuberculosis in Victoria, Australia, 1995–2010. Int J Tuberc Lung Dis 2012; 16: 1320–1325. 22 Seddon J A, Hesseling A C, Finlayson H, et al. Preventive therapy for child contacts of multidrug-resistant tuberculosis: a prospective cohort study. Clin Infect Dis 2013; 57: 1676–1684. 23 Childress J F, Faden R R, Gaare R D, et al. Public health ethics: mapping the terrain. J Law Med Ethics 2002; 30: 170–178. 24 Kass N E. An ethics framework for public health. Am J Public Health 2001; 91: 1776–1782.

Ethical considerations in LTBI policy

i

RESUME

Il y a un int´erˆet croissant vis-a-vis ` de l’introduction de politiques de sant´e publique relatives a` l’infection tuberculeuse latente (LTBI). Cependant, il y a eu peu d’engagement syst´ematique a` ce jour vis-a-vis ` de la LTBI d’un point de vue e´ thique. Cet article offre une vue d’ensemble des questions e´ thiques li´ees a` la LTBI avec un

accent particulier sur les aspects relatifs a` l’´elaboration et a` la mies en œuvre de politiques de sant´e publique. Les caract´eristiques majeures de la LTBI font l’objet d’une discussion e´ thique avec des exemples de situations d´elicates pour les responsables de politique.

RESUMEN

Se observa cada vez un mayor inter´es por la introduccion ´ de directrices de salud publica ´ en materia de infeccion ´ tuberculosa latente (LTBI). Sin embargo, hasta la fecha ha existido un escaso compromiso sistema´tico con esta afeccion ´ desde el punto de vista e´ tico. En el presente art´ıculo se ofrece un panorama general de los aspectos e´ ticos relacionados con la LTBI, con un inter´es especial

en los elementos que son importantes en la elaboracion ´ y la ejecucion ´ de las pol´ıticas de salud publica. ´ Se analizan las caracter´ısticas de esta afeccion ´ desde una perspectiva e´ tica, con ejemplos de situaciones que plantean dificultades a las instancias encargadas de formular las pol´ıticas.

Latent tuberculous infection: ethical considerations in formulating public health policy.

There is increasing interest in the introduction of public health policies relating to latent tuberculous infection (LTBI). However, there has been li...
66KB Sizes 4 Downloads 13 Views