COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETES

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COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETESCollaborative framework
for care and control oftuberculosis and diabetes

Stop TB Department and
Department of Chronic Diseases and Health Promotion
World Health Organization, Geneva, Switzerland
andThe International Union Against Tuberculosis and Lung
Disease, Paris, FranceCollaborative framework for care and control of tuberculosis and diabetes.
WHO/HTM/TB/2011.15
1.Tuberculosis - prevention and control. 2.Tuberculosis - etiology.
3.Tuberculosis - complications. 4.Diabetes complications. 4.Diabetes mellitus- prevention and control. 5.Health programs and plans. 6.Guidelines. I.World
Health Organization. II.International Union against Tuberculosis and Lung
DiseaseISBN 978 92 4 150225 2(NLM classification: WF 200)

Provisional collaborative framework, 2011
Expiry date, 2015

© World Health Organization 2011
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Printed by the WHO Document Production Services, Geneva, Switzerlandii

COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETES

Contents

Acknowledgements
Abbreviationsiv
v

Executive summaryvii

1. Introduction
1.1 Rationale
1.2 Purpose
1.3 Target audience

1
1
3
5

2. Framework development process

7

3. Recommended collaborative activities for prevention and care ofdiabetes and tuberculosis
A. Establish mechanisms for collaboration
B. Detect and manage tuberculosis in patients with diabetes
C. Detect and manage diabetes in patients with tuberculosis

13

4.Indicators for evaluating collaborative activities

26

5. Implementing collaborative activities and evaluating their impact

27

Annexes
Annex I. Members of the Guideline GroupAnnex II. Summary grading of the evidence
Annex III. Key research questions for improving prevention, management andcare of diabetes and tuberculosis

28
28
30
34

References

35

14
19
23

Support material on the web: Detailed summary of studies included in thesystematic reviews (http://www.who.int/tb/publications/2011/en/index.html)
1. Associations between diabetes and tuberculosis infection, tuberculosis
disease and drug-resistant tuberculosis
2. Associations between diabetes and tuberculosis treatment outcomes
3. Summary of studies on screening for tuberculosis in diabetes patients andscreening for diabetes in tuberculosis patients, and studies on tuberculosis
preventive therapy in patients with diabetesiii

Acknowledgements

The development of this framework was coordinated by Anthony D. Harries
and Knut Lönnroth, who also wrote the first draft. The Guideline Group also
consisted of (in alphabetical order): Meghan A Baker, Mauricio Barreto, Nils
Billo, Richard Brostrom, Ib Christian Bygbjerg, Martin Castellanos, Saidi
Egwaga, Susan Fisher-Hoch, Christie Y. Jeon, Megan B. Murray, Toru Mori,
Salah-Eddine Ottmani, Kaushik Ramaiya, Gojka Roglic, Nigel Unwin, Vijay
Viswanathan, David Whiting, Lixia Wang and Wenhua Zhao. Annex I lists theprofessional affiliation and area of technical expertise for each group member.

Declaration of conflict of interests
Dr Vijay Viswanathan declared that he had received financial support for
consulting and research within the past three years from the World Diabetes
Foundation for a project on preventing diabetes among TB patients. No othermember of the group reported any conflicts of interest. Individuals affiliatedwith the World Diabetes Foundation who attended the expert meeting were
not engaged in developing this provisional framework.

Review by dateThis provisional collaborative framework is due for revision by 2015.

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COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETES

Abbreviations

DOTS

the basic package that underpins the Stop TB Strategy

HbA1c

glycated haemoglobinHIVhuman immunodeficiency virus

NTP

national tuberculosis control programme

OGTT

oral glucose tolerance testOR

odds ratio

PHC

primary health careRrifampicin

RR

relative risk

TB

tuberculosis

The Union

International Union Against Tuberculosis and Lung Disease

WDF

World Diabetes Foundation

WHO

World Health Organizationv

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COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETES

Executive summary

Diabetes triples the risk of developing tuberculosis (TB). Consequently, rates
of TB are higher in people with diabetes than in the general population, anddiabetes is a common comorbidity in people with TB. Diabetes can worsen
the clinical course of TB, and TB can worsen glycaemic control in people withdiabetes. Individuals with both conditions thus require careful clinicalmanagement. Strategies are needed to ensure that optimal care is provided topatients with both diseases: TB must be diagnosed early in people withdiabetes, and diabetes must be diagnosed early in people with TB.
Changes in lifestyle and diet have contributed to an increased prevalence ofdiabetes in many low-income and middle-income countries where the burden
of TB is high. The growing burden of diabetes is contributing to sustained highlevels of TB in the community, and the proportion of TB cases attributable todiabetes globally is likely to increase over time. This double burden of disease
is a serious and growing challenge for health systems.
Given the absence of international guidelines on the joint management andcontrol of TB and diabetes, the World Health Organization (WHO) and theInternational Union Against Tuberculosis and Lung Disease (the Union)
identified key questions to be answered and commissioned systematic
reviews of studies addressing those questions. A series of expert
consultations were organized to assess the findings of the systematic reviews
and a guideline group was established to develop this provisional
collaborative framework.
The framework aims to guide national programmes, clinicians and others
engaged in care of patients and prevention and control of diabetes and TB on
how to establish a coordinated response to both diseases, at organizationaland clinical levels. The framework is based on evidence collated fromsystematic reviews and existing guidelines on the diagnosis and managementof TB and diabetes. The systematic reviews confirmed the weak evidencebase for the effectiveness and cost-effectiveness of collaborativeinterventions. The framework is therefore provisional; several of its
recommendations are provisional pending better evidence. In order to provide

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advice on how to fill the knowledge gaps, the framework includes a list ofpriority research areas.
The framework includes the following provisional recommendations:
Establish mechanisms for collaboration
1. Joint coordination should be established at regional, district and/or local
levels (sensitive to country-specific factors), with representation from all
relevant stakeholders. A joint plan for activities should be drawn up andreflected in national plans for noncommunicable diseases and TB.
2. Surveillance of TB should be initiated among diabetes patients in settings
with medium to high burdens of TB.
3. Surveillance of diabetes should be initiated among TB patients in all
countries.
4. Where collaborative activities are being established, national programmes
should agree a core set of indicators and tools to collect data formonitoring and evaluating activities to improve care and prevention of bothdiseases. Diabetes programmes should explore the possibility of adapting
the DOTS system to monitor and report diabetes cases and treatment
outcomes.
Detect and manage TB in patients with diabetes
5. At a minimum, people with diabetes should be screened for chronic cough(that is, cough lasting more than 2 weeks) at the time of their diagnosis
with diabetes and, if possible, during regular check-ups. Those withpositive TB symptoms should be examined as per national guidelines.
Other diagnostic procedures (for example, for extrapulmonary TB) should
also be pursued rigorously as per national guidelines.
6. Screening for TB diseases on broader indications (for example, for all
people in whom diabetes is diagnosed, regardless of symptoms) should be
explored as part of the research agenda to improve the diagnosis of TB
among people with diabetes.
7. A referral system should be established so that patients suspected ofhaving TB are promptly referred to TB diagnostic and treatment centres,
and evaluated in accordance with guidelines of the national TB control
programme.

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8. Case-finding for TB should be intensified by increasing awareness of andknowledge about the interactions between diabetes and TB, including joint
risk factors, among health-care workers and the populations they serve.
9. Health-care facilities, including diabetes clinics, should have in place aninfection control plan that includes administrative and environmental
control measures to reduce transmission of TB within health-care settings.
These measures should adhere to WHO’s international guidelines for TB
infection control.
10. Treatment and case management of TB in people with diabetes should be
provided in accordance with existing TB treatment guidelines andinternational standards. The same TB treatment regimen should beprescribed for people with diabetes as for people without diabetes.
Detect and manage diabetes in patients with TB
11. Patients with TB should be screened for diabetes at the start of theirtreatment, where resources for diagnosis are available. The type ofscreening and diagnostic tests should be adapted to the context of local
health systems and the availability of resources, while awaiting additional
evidence on the best screening and diagnostic approach or approaches.
12. Management of diabetes in TB patients should be provided in line withexisting management guidelines.

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1. Introduction

1.1

RationaleIntersecting epidemics
Tuberculosis (TB) remains a considerable global public health concern,
mainly affecting poor and vulnerable populations (1). Every year, more than 9
million people fall ill with this infectious disease, and close to 2 million die fromit (1). Diabetes, a chronic metabolic disease that is increasing globally,
including in many settings with a high burden of TB, is associated with higher
risks of TB (2) and adverse TB treatment outcomes (3). The increase in thenumber of people with diabetes may further complicate care and control of
TB, especially in the many areas with high burden of both diseases (4, 5).
In 2010, WHO estimated that 285 million people were living with diabetes, ofwhom 7 million people developed the disease during that year and 3.9 million
deaths were attributed to diabetes (6, 7). Current predictions estimate that theprevalence of diabetes will reach 438 million by 2030 and that 80% of
prevalent cases will occur in the developing world (7). The increase is mainly
driven by changes in diet and levels of physical activity (8). In the poorest
countries, diabetes is more common among the better-off, but economic
development quickly reverses this trend so that people from lower
socioeconomic groups are more affected by diabetes; sequelae are worseamong the poor in all countries (9). People from lower socioeconomic groups
are therefore more vulnerable to both diseases (10).
Mutual risk factors
Intensified discussions and research over the past decade have focused on
the links between TB and diabetes (11, 12). Many hypotheses have been
postulated; the evidence base has grown for some but remains incomplete.
Theoretically, diabetes and TB may complicate each other at many levels.
Conceivably, people with diabetes may be more easily infected than nondiabetic people leading to a higher risk of latent TB infection, but the evidence
remains weak (13, 14). TB infection may progress at a faster rate in people
with diabetes than in those without diabetes (2, 15, 16). The clinicalpresentation of TB in people with diabetes may be altered and change the1sensitivity and specificity of conventional diagnostic algorithms. Among thosewith active TB, diabetes may adversely affect TB treatment outcomes bydelaying the time to microbiological response, reducing the likelihood of afavourable outcome, and increasing the risk of relapse or death (3). Diabetes
may also accelerate the emergence of drug-resistant TB, especially multidrugresistant TB (defined as strains of TB resistant to both rifampicin andisoniazid) among those receiving TB treatment, although the evidence islimited (17). Conversely, TB may trigger the onset of diabetes, and worsen
glycaemic control in existing diabetes. Finally, TB medications may interferewith the treatment of diabetes through drug interactions, and diabetes may
interfere with the activity of certain anti-TB medicines (18).
Gaps in care and control of TB
Over the past two decades, national TB control programmes worldwide have
implemented TB control through DOTS and the Stop TB Strategy with evident
success, including substantial increases in rates of case detection andimproved treatment outcomes (1). However, improvements are still needed totackle the following challenges:
First, countries must ensure complete and early case detection of all types ofTB. During 2005–2009, the global TB case detection rate stagnated at around
60% (19). In many countries these rates are even lower, and long delays fordiagnosis and treatment still occur in most countries (20), further aggravatingtransmission. Case detection of smear-negative TB and for multidrug
resistant-TB also must be substantially improved (1).
Second, while the rate of treatment success globally has surpassed the targetof 85%, treatment outcomes are suboptimal in many settings and for some
subpopulations (1). Where adverse treatment outcomes are frequent, reasons
may include poor adherence to treatment, high prevalence of drug-resistance
and/or vulnerability related to co-morbidities such as HIV, under-nutrition,
substance dependency, tobacco smoking-related conditions and diabetes.
Third, although rates of incidence, prevalence and death from TB are
decreasing globally, the rate of decline is much slower than forecast (1).
Given this slow rate of decline, the Millennium Development Goal target ofhalving TB prevalence and TB death rates by 2015, compared with theirlevels in 1990, may not be met in all WHO regions. Furthermore, the world asa whole, as well as in most regions, are far from the trend required to reachthe long-term rates of eliminating TB (defined as less than 1 incident case of
TB per one million population by 2050) (1). Additional interventions are
therefore required to meet the goals for TB control and elimination. Most
urgently, this should involve further efforts to improve TB case detection andtreatment outcomes, with the ultimate aim to get as close as possible to 100%

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case detection rate and treatment success rate. Moreover, new tools for TB
diagnosis, prevention and treatment are needed. Additional efforts should also
include prevention by intervening on known social determinants and risk
factors of TB, such as HIV/AIDS, smoking, malnutrition, alcohol dependency,
diabetes, crowded living conditions, and indoor air pollution to reduce people’svulnerability to TB disease (1, 21).
Synergies of collaborative activities
The link between diabetes and TB has potential additional implications for all
the above-mentioned challenges to TB control. First, given that people withdiabetes are at higher risk of TB, screening for TB in people with diabetes
may be warranted in populations with high TB prevalence to help improveearly case detection. Second, because diabetes may increase the risk ofadverse treatment outcomes in TB patients, special attention may be needed
to ensure high-quality TB treatment in people with diabetes. This requires
screening for diabetes among people with TB in settings where underdiagnosis of diabetes is common. Third, broad primary and secondary
prevention of diabetes will help prevent TB at the population level. Finally, TB
preventive therapy could potentially be indicated in people with diabetes who
have had recent exposure to TB.
Improved collaborative activities would also potentially improve care andprevention of diabetes. Under-diagnosis of the disease is common in lowincome and middle income countries, and could be improved by screening
people with TB for diabetes. Management of diabetes must be optimized ingeneral, and in particular during TB disease, as during all types of infections.
Improved management of diabetes could build on the successes of the DOTS
strategy, emphasizing support to patients and supervision of their treatment;
standardized protocols, a reliable supply of quality-assured medicines, regularmonitoring and evaluation, and management and administrative procedures;
as well as political commitment.

1.2

Purpose of the collaborative framework

The purpose of the collaborative framework is to assist policy-makers, publichealth practitioners and clinicians in understanding how to decrease the joint
burden of diabetes and TB. It responds to a growing concern about what
collaborative activities should be implemented and under what circumstances.
The framework is complementary to and in synergy with the established core
activities of prevention and care programmes for both diseases. The Stop TB
Strategy (22) and the International Standards for Tuberculosis Care (23) set
out the key elements of TB care and control. Similarly, a set of activities to3

prevent, diagnose and treat diabetes form the basis of strategies to control
diabetes (24).
The framework does not call for the institution of a new specialist or
independent control programme. Rather, it promotes enhanced collaboration
between diabetes and TB prevention and care programmes with the overall
aim of improving collaboration between disease control programmes, as apart of the broader agenda for strengthening health systems. Effective
collaboration between TB and HIV/AIDS programmes during the past
decades has helped avoid unnecessary duplication of service delivery
structures, and has promoted optimal and well-coordinated use of scarce
health-care resources. The proposed framework builds on the experience of
TB/HIV collaboration, and applies its key elements to TB and diabetes. The
elements could also be further applied to other risk factors for TB andassociated co-morbidities. WHO and its partners are reviewing the impact ofother TB risk factors and co-morbidities, such as tobacco smoking-related
conditions (25), under-nutrition (26), alcohol dependency (27) and substanceabuse (28).
Ideally, a future collaborative framework should encompass coordination
across all relevant programmes for infectious and noncommunicablediseases. However, the evidence base is still not strong enough for such acomprehensive framework.
Scientific evidence of the links between TB and diabetes is also incomplete
for certain aspects of the interaction, and there are insufficient data to support
specific guidance on several key elements of collaborative activities. Given
the lack of high-quality evidence, the framework does not include any
recommendations on diagnosis of latent TB infection and preventive treatmentof latent TB infection in people with diabetes. Nevertheless, sufficientevidence exists to formulate a set of broad recommendations, which would
have to be fine-tuned as more evidence becomes available.
For these reasons, the framework is provisional in nature, with existing
evidence from observational studies being used to support policy
recommendations. It is a rolling framework, which will be updated to reflect
new evidence and best practices. It should be reviewed and revised by 2015.
The framework is intended to help stimulate operational research. As betterscientific evidence and documented country experiences become available,
this framework should be further developed into global policy and guidelines
for collaborative activities.

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1.3

Target audience

This document is intended for decision-makers and public health practitioners(including managers of national TB control programmes, and initiatives forcare and prevention of diabetes), as well as development agencies,
nongovernmental organizations, researchers and funding agencies in the fieldof public health and disease control. The recommendations made in thisdocument may have important implications for the strategic directions andactivities of other ministries. The document also targets, indirectly, cliniciansworking at all levels of the health sector. However, the framework will neednational and local adaptation, including development of national clinicalguidance, as part of guidelines on TB and diabetes respectively.
The recommendations may not be equally relevant in all countries. The
relative importance of pursuing collaborative activities depends on thenational or local context, including the prevalence of both diseases, theavailability of diagnostic and treatment services for diabetes, the strength ofnational TB control programmes, competing priority areas and availability ofresources. The document may therefore be most relevant in countries withhigh TB burdens and high or rapidly increasing prevalence of diabetes.
Strong national TB control programmes and programmes for the prevention
and care of diabetes are ideal starting points to implement this framework.
Where such programmes already exist, the key actions are ensuring
coordination between programmes, introducing basic screening approaches
across both programmes, and initiating effective cross-referral between
services. Where both services are available within the same primary healthcare structure, such coordination should be relatively straightforward. The
exact division of roles between services will depend on the country context. In
principle, however, it should be possible to do basic screening for diabetes
among people with TB (for example, with random blood glucose) in a TB
facility, and to do simple symptom screening for TB in diabetes clinics, andrefer for TB diagnostic tests as required. TB treatment should in mostsituations be initiated in a TB facility, although the continuous treatment
support and supervision can be done in any facility. All parts of diabetes
management may not necessarily be done in a diabetes facility. For example,
health education and advice on self-management of treatment may be partly
incorporated into the service package that is delivered during the regular
health-care contacts that are a part of TB treatment, especially during thedirectly-observed treatment applied during the intensive phase (first twomonths), and sometimes beyond.

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If services for diabetes are not well developed, as is the case in several highTB burden countries, some of the recommendations in this framework may
not be appropriate. Nevertheless, the framework can be used to stimulate
collaborative efforts to strengthen diabetes services (as well as services fornoncommunicable diseases in general) with a view to creating the necessary
conditions for good, comprehensive, patient-centred care, that will benefit
both TB care and control, as well as care and prevention for diabetes andother noncommunicable diseases.

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2. Framework development process

In January 2009, WHO and the Union organized a meeting at WHO
headquarters in Geneva, Switzerland, to review existing evidence and identify
priority questions for systematic reviews of the links between diabetes and
TB. The meeting prioritized questions to be addressed based on (i) identified
gaps in evidence; (ii) relevance of the questions for policy and practiceprimarily in low-income and middle-income countries with high burdens of TB
and high or growing burdens of diabetes; (iii) potential for immediate
development of programmatic policy; and (iv) the likelihood that available
evidence could be obtained through systematic reviews. The prioritizedquestions are listed in box 1.

Box 1: Questions addressed through systematic reviews
1. Is diabetes associated with TB infection?
2. Is diabetes associated with active TB disease?
3. Is diabetes associated with positive sputum culture at 2–3 months?
4. Is diabetes associated with favourable TB treatment outcome?
5. Is diabetes associated with death during treatment period?
6. Is diabetes associated with recurrent TB disease?
7. Is diabetes associated with TB drug-resistance?
8. Does screening for TB among people with diabetes lead to more TB casedetection?
9. Does screening for diabetes among TB patients lead to more diabetes
detection?
10. Does hyperglycaemia initially found in TB patients resolve with TB
treatment?
11. Is chemoprophylaxis in diabetes effective in preventing TB?
12. Does screening for TB among people with diabetes lead to better
prevention of TB morbidity and mortality compared with no screening?
13. Does screening for diabetes among TB patients lead to better preventionof diabetes morbidity and mortality compared with no screening?

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The systematic reviews of the literature were commissioned from the Harvard
School of Public Health, USA, which had previously published a systematic
review addressing question 2: is diabetes associated with active TB disease?
(2). An updated review was conducted on the association of diabetes and TB
disease; new reviews were conducted to address the other questions. Studies
were searched for in (i) PubMed (from 1965 to June 2009); (ii) in EMBASE(from 1974 to June 2009); and (iii) conference proceedings of the Union (for2007 and 2008).
For the aims of identifying studies on the association between diabetes and
TB infection, the full text of studies including any of the following terms related
to TB infection in the abstract were examined: “latent”, OR “tuberculin skin”,
OR “PPD”, OR “interferon” OR “Mantoux” OR “Heaf” OR “Tine”. Any study
quantifying the association between diabetes and TB infection, or allowing thecomputation of a relative risk, were included in the final analysis. To identify
studies on the association between diabetes and TB, studies measuring theeffect of risk factors for active TB in full text were scanned to determine if
diabetes had been included as a risk factor. Studies measuring theassociation between diabetes and TB after adjusting for age were included in
the systematic review, as they had been for the previously publishedsystematic review (2).
In order to identify studies on the association of diabetes and drug-resistant
TB, studies including any of the following terms in the abstract were
examined: “drug-resistant”, “drug-resistance”, “multidrug-resistant”, “drugresistant” or “drug resistance”, “MDR TB” or “MDRTB”. The full text of studies
examining risk factors for drug-resistant TB was scanned to determine
whether diabetes had been assessed as a risk factor for TB. Studies thatquantified the association between diabetes and drug-resistant TB, or thatallowed the computation of a relative risk, were included.
To identify studies on the association between diabetes and TB treatment
outcomes, studies on diabetes and TB were searched for, as well as studies
on TB outcomes not necessarily mentioning diabetes in the abstract. Studies
providing or permitting the computation of an effect estimate of therelationship between diabetes and at least one of the following five TB
treatment outcomes were included: (i) proportion of treated patients with
culture conversion at 2–3 months; (ii) the combined outcome of treatment
failure and death; (iii) death; (iv) relapse; (v) or recurrent drug-resistant TB.
For the aims of summarizing studies on TB outcomes, the literature search
was expanded to include the WHO Regional Indexes (AIM (AFRO), LILACS(AMRO/PAHO), IMEMR (EMRO), IMSEAR (SEARO), WPRIM (WPRO))(http://www.globalhealthlibrary.net/php/index.php) and extended to 31

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December 2010 at the request of reviewers considering the systematic review
for publication.
To address whether screening for TB in people with diabetes or screening fordiabetes in people with TB will lead to detection of new cases, studies that
included any of the following root terms in the abstract: “screen*”, “detect*”,“diagnos*”, “chemoproph*”, “isoniazid*” and “prevent*” were searched.
a. To assess the yield of screening for TB disease among diabetics,
studies that actively screened a population of previously diagnosed
diabetics for active TB using any of the following methods ofidentification were included: X-ray consistent with TB, positive sputum
smear microscopy, positive mycobacterial culture, clinical diagnosis,
and response to anti-TB treatment. Studies that did not describe theage distribution of the screened population were excluded.
b. To assess the yield of screening for diabetes among TB patients,
studies were included that screened a population of patients with active
TB for diabetes using a blood glucose test, including random blood
glucose, fasting blood glucose, oral glucose tolerance test andmeasurement of haemoglobin A1c. Studies were excluded that did notdescribe the age distribution of the screened population, and studies
that only diagnosed impaired glucose tolerance.
c. To assess the efficacy of chemoprophylaxis in diabetics, studies that
had compared the incidence of TB in a diabetic population receiving TB
chemoprophylaxis to a control population also with diabetes were
included. The use of any standard anti-TB agent and analogs
administered for any duration of time was considered.
For the associations with TB infection and TB disease, the studies weregrouped by study design. For the associations with drug-resistant TB, thestudies were grouped by type of drug-resistance (any drug-resistance,
multidrug-resistance, or extensive drug resistance) and by primary or acquired
status. For studies on associations with TB outcomes, separate analyses
were performed for each of the outcomes. The heterogeneity of the effectestimates was assessed within these categories by the Cochran Q test andthe Higgins I (2) value. For subgroups with no heterogeneity, the findings by
fixed effects meta-analysis were summarized. When heterogeneity waspresent the Dersimonian-Laird random effects meta-analysis was performed.
The possibility of publication bias was examined by the Begg and Egger test
and by visually inspecting the funnel plot for asymmetry.
Studies on screening for TB among people with diabetes were grouped into
those that assessed TB prevalence and those that assessed TB incidence
through longitudinal follow-up. The prevalence or the incidence rates of TB
found in people with diabetes and controls were calculated where data were9

available. For follow-up studies, the annual TB incidences were summarized
by dividing the cumulative incidence by the number of years of follow-up. For
studies that provided the number of TB cases diagnosed by X-ray separatelyfrom those diagnosed by bacteriology, the latter definition was used to
calculate TB prevalence. Prevalence or incidence ratios and prevalence or
incidence differences were computed to assess the relative and absolutecontrast in yield of finding TB cases between the screened diabetic
populations and the comparison populations where available. Additionally, thenumber of people needed to screen to detect one additional case of TB in adiabetic population was calculated by taking the inverse of the prevalence or
incidence difference for each study.
The systematic reviews were completed by the end of August 2009. The
systematic reviews have resulted in peer-reviewed journal papers, which
describe the methods and results in detail and provide further information
about the reviewed studies (2, 3, 33). The main findings from the systematic
reviews are summarized in Box 1. Grading of the evidence (29) for each
respective question is presented in Annex II. Detailed summaries of thestudies included in the systematic reviews are provided on the WHO website:
http://www.who.int/tb/publications/2011/en/index.html.

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Box 2: Summary of findings in the systematic reviews
1. Diabetes is associated with an increased risk of active TB both in case-control studies and in cohort
studies. However, there is no evidence to suggest that diabetes increases susceptibility to TB infection. It
is not yet fully established that the risk of TB increases with poor glucose control, although thisassociation is plausible, and some indirect evidence supports this hypothesis. Full details are provided in
the previously published systematic review (2). The updated review identified three additional studies on
the association between diabetes and active TB published between March 2007 and May 2009. In
summary, there were four cohort studies where the pooled random effect relative risk of TB in diabetes
patients was 2.52 (95% CI 1.53–4.03). There were 10 case-control studies where the odds ratios ranged
from 1.16–7.81, with a random effects summary OR of 2.2. There were two studies that stratified diabetes
by glycaemic control and showed that higher blood glucose levels were associated with higher risk of TB.
Full details of these studies are provided in support material No. 1 at
http://www.who.int/tb/publications/2011/en/index.html
2. Diabetes appears to impact on several key TB treatment outcomes: it may increase the time to sputum
culture conversion, and it increases the risk of death and the risk of TB relapse. However, there is noevidence that diabetes increases the risk of recurrence caused by drug-resistant strains. Detailed
methodology and summary of reviewed studies are provided in the published systematic review (3). The
reasons for these adverse outcomes are not clear. Diabetes may be associated with decreased rifampicin
concentrations, which may result from drug–drug interactions between anti-TB drugs and oral
hypoglycaemic drugs. DM may also be a risk factor for hepatic toxicity of anti-TB drugs. Thus, lower antiTB drug concentrations and increased hepatic toxicity may lead to increased recurrent disease andincreased death rates respectively. Rifampicin, a known inducer of drug metabolizing enzymes in theliver, consistently decreases pharmacokinetic parameters of multiple oral diabetic agents, and this in turncan impair glucose control. This cumulative evidence suggests that increased attention should be paid to
the treatment of TB in people with diabetes, which may include diabetes testing, improved glucose control
and increased clinical and therapeutic monitoring. However, there is no evidence from trials assessing theeffectiveness and cost-effectiveness of such interventions. Full details of these studies are provided insupport material No. 2 at http://www.who.int/tb/publications/2011/en/index.html
3. In screenings studies, TB prevalence and incidence are consistently higher in people with diabetes
than in either the general population or in non-diabetic controls. However, the magnitude of this difference
varies between countries and there is a very limited evidence base from low-income countries and noneat all from sub-Saharan Africa. The burden of TB is higher in people with diabetes who are insulindependent compared with those who do not require insulin. The prevalence of diabetes is also higher in
TB patients than in healthy controls or the general population, but the data suggest that blood glucose
levels fall with TB treatment raising questions about when is the optimal time to screen for diabetes in TB
patients on anti-TB treatment. Intensified screening for TB among people with known diabetes would
potentially improve early TB case detection, but this approach has rarely been tested under programmaticconditions. The number needed to screen to detect one case of TB varies with underlying TB prevalence.
In settings in which TB prevalence is less than 25 per 100 000 persons, at least 1000 people withdiabetes would need to be screened, whereas in places with higher TB burden the number needed toscreen is considerably lower. For example, in India with an estimated TB prevalence of 283/100 000
people, screening 90 to 350 people with diabetes would yield one or more cases of TB. Detailed
methodology and summary of reviewed studies are provided in the published systematic review (33). Fulldetails of the included studies are provided in support material No. 3 at
http://www.who.int/tb/publications/2011/en/index.html
4. There is limited evidence from only two trials done 50 years ago that isoniazid preventive therapy
reduces the risk of TB in people with diabetes. However, the trials were poorly conducted and the true
benefit and risks of TB preventive therapy in people with diabetes remain unknown. Details are provided
in support material No. 3 at http://www.who.int/tb/publications/2011/en/index.html

11

The findings of the systematic review were presented and assessed at anexpert meeting held in November 2009 at The Union in Paris, France. The
meeting was attended by experts in the field of diabetes and TB; included
were representatives from WHO, The Union, the World Diabetes Foundation,
the International Diabetes Federation, academic institutions, and ministries ofhealth in low-income and middle-income countries. The main objectives of themeeting were to assess the results of the systematic reviews and to
determine whether there was enough evidence to make policy
recommendations about joint diagnosis and management of both diseases,
address research gaps and develop a research agenda around these gaps
(30). The experts assessed the quality of the systematic reviews, including thesearch strategy, inclusion/exclusion criteria, and interpretation andpresentation of findings. The research agenda is included in Annex III (31).
The results of the systematic review as well as the recommendations from themeeting were presented and discussed at the 40th Union World Conference
on Lung Health in December 2009.
Following the meeting, it was decided that there was enough evidence fromthe systematic review and existing guidelines on both diseases to allow a
provisional collaborative framework to be developed. The plan to develop a
collaborative framework was approved by the WHO Guideline Review
Committee, and a guideline group was established (29). The coordinators of
the work from WHO and The Union drafted the framework, including specificrecommendations. The draft was circulated to all members of the group anddiscussed in a series of conference calls. Altogether three iterations of theframework and recommendations were circulated to the group members; thefinal version was approved by all members.
There were no major
disagreements on the recommendations among the group’s members. The
recommendations were based in the findings in the systematic reviews, on
existing guidelines on TB and DM diagnosis and treatment, and on expert
opinions. The recommendations that are based on graded evidence emerging
from the systematic reviews have been graded as strong, weak, or
conditional. Other recommendations are not graded.
The draft was presented to WHO’s Strategic and Technical Advisory Groupfor TB on 28 September 2010. Several of the group’s recommendations wereconsidered in finalizing the provisional framework.

12

COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETES

3. Recommended collaborative
activities

The goal of the framework is to guide the development and implementation ofcollaborative activities aimed at decreasing the joint burden of diabetes and
TB in populations affected by both diseases. The objectives of thosecollaborative activities are:
A. To establish mechanisms of collaboration between diabetes and TB
programmes;
B. To improve detection and management of TB in patients with diabetes;andC. To improve detection and management of diabetes in TB patients.
The recommended activities are listed in table 1.
This document focuses on collaborative activities that address the interface ofthe diabetes and TB epidemics and that should be carried out as part of thehealth sector’s response to this dual disease burden. In all high TB burdencountries there is an established national TB control programme, which is the
key counterpart for such collaboration, while other local, national andinternational partners involved in TB care and control should also be involved.
National programmes or initiatives for prevention and care of diabetes are
generally less developed, at least in low-income and middle income countries
with high TB burdens. The counterpart(s) for collaboration may therefore be
more difficult to identify, and collaboration may have to start at a local andclinical level while national structures for diabetes prevention and care or fornoncommunicable diseases as a group are being developed further.

13

Table 1: Recommended collaborative activities

A. Establish mechanisms for collaboration
A.1. Set up means of coordinating diabetes and TB activities
A.2. Conduct surveillance of TB disease prevalence among people withdiabetes in medium and high-TB burden settings
A.3. Conduct surveillance of diabetes prevalence in TB patients in all
countries
A.4. Conduct monitoring and evaluation of collaborative diabetes and TB
activities

B. Detect and manage TB in patients with diabetes
B.1. Intensify detection of TB among people with diabetes
B.2. Ensure TB infection control in health-care settings where diabetes ismanagedB.3. Ensure high quality TB treatment and management in people withdiabetes

C. Detect and manage diabetes in patients with TB
C.1. Screen TB patients for diabetes
C.2. Ensure high-quality diabetes management among TB patientsA.

Establish mechanisms for collaboration

A.1. Set up means of coordinating diabetes and TB activities
Few countries have established formal coordination between programmes forprevention and care of diabetes and TB control programmes, although
integration of clinical care for both conditions may be in place at the local or
clinical level.
A coordinating body should be set up to ensure more effective collaboration
between existing programmes. As these cut across the interface between
noncommunicable diseases and communicable diseases, such a coordinating
body should also consider improved collaboration on other common comorbidities, such as respiratory illnesses, substance abuse and malnutrition,

14

COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETES

as well as metabolic problems related to treatment of HIV (32). If such acoordinating body already exists, coordination of activities for both diseases
may be incorporated into its terms of reference. The coordinating body should
include representatives from relevant Ministry of Health departments,
including those responsible for appropriate disease control programmes,
hospitals or curative care, national health insurance and private health careregulation, as well as of professional associations, patient groups for bothdiseases and civil society.
A key area for the joint coordinating bodies is to ensure joint planning
between the prevention and care services for diabetes and TB control
programmes. The joint plan should be reflected in the plan fornoncommunicable diseases including diabetes and the national TB control
plan, and encompass: development of guidelines and tools for bi-directional screening of TB
and diabetes and for treatment and management of the two diseases,
including clearly defined roles and responsibilities, and mechanisms forcross-referrals, at national and district levels;
 governance, standards and mechanisms for quality control; resource mobilization, including sufficient support for health-caredelivery in the field of laboratory, medicines and referral capacity; pre-service and in-service training; joint advocacy, communication and social mobilization addressing theneeds of individual patients and communities for clinical care andprevention of both diseases; research, especially operational research, on country-specific issues todevelop the evidence base for efficient and effective implementation ofcollaborative activities.
Mutual advocacy is an essential element of this coordination. National TB
control programmes should assist programmes for prevention and care ofdiabetes to advocate for improved prevention and care, and vice versa, using
the existing evidence on the link between the two diseases, and securingtranslation of new knowledge to best practice.
Recommendation 1
Joint coordination should be established at regional, district and/or
local levels (sensitive to country-specific factors), with representationfrom all relevant stakeholders. A joint plan for diabetes and TB activities
should be drawn up and reflected in the national plans on
noncommunicable diseases and TB respectively.
Remarks: No published studies on the feasibility and effects of joint
coordination of diabetes and TB services have been identified. However the15experts in the guideline group judged that this is an essential first step, which
would be acceptable and feasible in most settings. Coordination does notnecessarily mean additional resources for new infrastructure or manpower. It
can be achieved with existing resources, depending on the local situation, andmay be a part of coordination mechanisms for TB and other relevant TB comorbidities, such as HIV, chronic obstructive pulmonary disease andsubstance dependency.

A.2. Conduct surveillance of prevalence of TB disease in people withdiabetes in medium and high-TB burden settings
Data on TB burden among people with diabetes, and vice versa, are available
in only a few countries (33), from research studies. Surveillance is essential toinform planning and implementation. The two key methods for surveillance of
TB in diabetes patients are: (i) periodic (special) cross-sectional surveys
among representative groups of diabetes patients within a country; and (ii)data from routine TB screening in diabetes patients. The methods used
depend on the prevalence of both diseases in the country and the availabilityof resources. TB screening should follow the national TB guidelines of thecountry, although the special surveys may utilize other technologies than thestandard screening and diagnostic algorithms specified in such guidelines.
In settings where TB prevalence is low, the number of people with diabetes
that needs to be screened to detect one case of TB is very large; therefore,
surveillance of TB among people with diabetes may not be relevant andfeasible in such settings. The recommendation is therefore to conduct
surveillance in settings with an estimated TB prevalence exceeding
100/100 000 population.
Recommendation 2
There should be TB surveillance among diabetes patients in settings
with medium to high TB burden.
Remarks: No published studies were identified on the feasibility of TB
surveillance among diabetes patients. The experts agreed that such
surveillance would be of value in contributing to detection of additional TB
cases as well as in providing epidemiological data for decision-making on TB
screening among people with diabetes, with no risk of adverse consequences
for patients as long as adequate TB treatment resources are available.
However, where resources are limited, it may not be feasible to introduce TB
surveillance even where prevalence of the disease is high.

A.3.

16

Conduct surveillance of diabetes in TB patients in all countries

COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETES

Surveillance of diabetes in TB patients may involve (i) periodic (special) crosssectional surveys among a representative group of TB patients; and/or (ii)data from routine screening for diabetes among TB patients (see section C.1.
below). The method depends on the availability of resources and existing
structure of the health system and its capacity.
A simple postprandial blood glucose measurement with a glucometer 2 hours
after a meal is the preferred method for diagnosing diabetes in primary healthcare settings where ease of use, cheapness, speed, reliability andacceptability are paramount. This method will regularly identify more diabetes
patients than fasting and/or random blood sugar (FBS/RBS). However,
FBS/RBS can also be used, as long as it is understood that sensitivity is lower
than for postprandial blood glucose. Measurement of glycated haemoglobin(HbA1c) or the oral glucose tolerance test is effective but expensive and timeconsuming. Both assays, particularly the HbA1c, are useful in confirming a
glucometer reading (34).
In the 22 countries with a high burden of TB, the prevalence of diabetes
ranges from 2% to 9% in the general population (1). Given the increased risk
of TB among people with diabetes, its prevalence among people with TB is
generally 2–3 times higher than that of the general population. Therefore, thenumber of TB patients needed to screen to detect a case of diabetes, as well
as sample size required for periodic cross-sectional surveys, is small.
Surveillance of diabetes among people with TB should be feasible andaffordable in all countries where basic equipment and knowledge of diabetes
is available in primary health care.
Recommendation 3
There should be surveillance of diabetes among TB patients in all
countries.
Remarks: No published studies were identified on the feasibility of diabetes
surveillance among TB patients. However, the guideline group concluded thatsuch surveillance would be beneficial and feasible in most settings. Resource
requirements may be modest in most settings since diabetes testing in a
relatively small sample of TB patients would likely be sufficient. However,where resources are very limited, it may not be feasible to introduce testing.

A.4. Conduct monitoring and evaluation of collaborative diabetes and
TB activities
Monitoring and evaluation provides the means to regularly assess the quality,
effectiveness, coverage and delivery of collaborative activities. The DOTS

17

component of the Stop TB Strategy, allows structured, well-monitored
services to be delivered to millions of TB patients in some of the poorest
countries worldwide. The recommended monitoring strategy for national TB
control programmes already includes monitoring and reporting of HIVparameters, and this should similarly include monitoring and reporting of
diabetes prevalence among TB patients. Indicators for monitoringcollaborative TB and diabetes activities are further discussed in section 4
below.
The concept of using components of the DOTS model to manage diabetes
has already been proposed (35, 36), and diabetes clinics in urban areas inhigh-burden countries may pilot and evaluate this approach throughoperational research. In particular, diabetes clinics should assess whether
quarterly cohort reporting of incident cases, cumulative outcomes,
complications and survival analysis can lead to better management and care,and more rational forecasting and uninterrupted supplies of medicines. The
monitoring and evaluation of TB cases identified during screening needs to be
included into this model.
Recommendation 4
Where diabetes and TB collaboration is being established, programmes
for both diseases should agree on a core set of indicators and datacollection tools for the monitoring and evaluation of collaborative
activities. Diabetes programmes should explore the possibility ofadapting the DOTS system to monitor and report cases and treatment
outcomes.
Remarks: No published studies on the feasibility and effects of jointly
developing indicators for evaluation and monitoring of TB and diabetes wereidentified. However, many national TB control programmes have used astandard set of key indicators and routine data collection and reporting forms
for almost two decades, and their feasibility and utility has been establishedthrough regular national, regional and global reporting of TB control activities
and results (19). Improved management of diabetes could potentially build on
the successes of the DOTS strategy, emphasizing regular monitoring andevaluation.

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COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETES

B.

Detect and manage TB in patients with diabetes

B.1. Intensify detection of TB among people with diabetes
Early identification of TB symptoms and signs, followed by diagnosis andprompt treatment, increases the chances of survival, improves the quality oflife and reduces transmission of TB in the clinic and in the community.
Evidence shows that the prevalence of TB is considerably higher amongpeople with diabetes than in the general population (18). Therefore, thecurrent recommendation to screen for TB symptoms and identify people withcough for more than 2–3 weeks should be implemented rigorously in this risk
group. In practice, this means that clinicians need to be alert to the presenceof cough among people with diabetes, as well as be prepared to ask people
with diabetes about cough, at least at the time of their diagnosis, and atregular intervals, for example as a part of routine clinical follow-up.
Appropriate referral mechanisms for suspected or confirmed TB need to be
put in place, as well as routine systems for recording and reporting, withadequate training of all concerned staff. This should be developed as part of
the joint plan for collaborative activities.
There is currently insufficient evidence supporting more active screening
approaches, for example, regular screening of all people with diabetes for TB
disease using radiography, sputum smear microscopy or other tests, or to
conduct these investigations based on the presence of any TB symptom orsign. However, unexplained cough, long-lasting fever and/or other signs or
symptoms associated with TB should heighten clinical suspicion of TB in
people with diabetes, especially in high TB burden settings. The number
needed to screen, and the cost-effectiveness of screening, depends on theprevalence of TB among people with diabetes, the eligibility criteria forscreening, and the sensitivity, specificity and cost of the chosen screening
and diagnostic approach in the given setting. In settings where it is relevant topursue more active case detection strategies, and where resources permit,
comprehensive screening of people with diabetes should be explored as partof the research agenda for improved TB case detection. Operational researchis encouraged to determine (i) the most effective type of screening algorithm;(ii) how often screening should be conducted; and (iii) the most appropriate
TB screening tools.
Recommendation 5
At a minimum, people with diabetes should be asked about the presenceof cough (lasting more than 2 weeks) at the time of diabetes diagnosis,

19and if possible at each regular check-up for diabetes. Those withpositive symptoms should be examined as per national guidelines.
Other diagnostic procedures, such as those for extrapulmonary TB,
should also be pursued rigorously as per national guidelines.
Remark: The evidence for existing guidelines on TB screening and diagnosis
was not reviewed as part of the systematic review for this document.
However, this recommendation is fully in line with existing guidelines on TB
screening and diagnosis (37), and should therefore be highly acceptable inmost settings. Feasibility and resource implications are the same as forscreening of TB symptoms and diagnosis among other groups of patientsseeking care with TB symptoms.
Recommendation 6
Screening for active TB on broader indications (for example in all people
diagnosed with diabetes, regardless of symptoms) should be exploredas part of the research agenda for improved TB diagnosis among people
with diabetes.
Summary of assessment of graded evidence from the systematic
reviews
Overall quality of evidence

Very low

Balance of potential benefits and harms

Benefit

Disagreement among the panel

None

Acceptability

High

Feasibility

Dependent on setting

Resource implications

High

Strength of recommendation

STRONG

Remark: The direct evidence on screening for active TB among people withdiabetes is of very low quality. There are no published studies on thefeasibility and additional yield of routinely conducted TB screening amongpeople with diabetes. There are no studies on the impact of increased TB
screening among people with diabetes on TB morbidity or mortality. However,there is evidence of moderate quality that diabetes is associated with TB andthat its prevalence among people with diabetes is two to three times higher
than in the general population. The guideline group agreed to make this astrong recommendation while emphasizing that pursuing such screening is apart of the research agenda.
Recommendation 7
A referral system should be established so that patients with suspected
TB are promptly sent to TB diagnostic and treatment centres, and20

COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETES

evaluated in accordance with the Guidelines of the national TB control
programme.
Remark: Although no published studies were identified on establishing areferral system between TB and diabetes services, the guideline group’s
experts agreed that effective referral mechanisms are an essential element of
any health-care system.
Recommendation 8
Tuberculosis case-finding should be intensified by increasing theawareness and knowledge of the interactions between diabetes and TB,
including joint risk factors, among health-care workers and the
populations they serve.
Remark: No published studies specifically on the effectiveness of efforts toincrease awareness and knowledge of the interaction between TB anddiabetes were identified. The guideline group’s experts stressed that thisrecommendation should be an integral part of recommendations for training
and capacity building on care of both conditions.

B.2. Ensure TB infection control in health-care settings where diabetes
is managed
In diabetes clinics, where the risk of TB is higher than in the general
population, the risk of transmitting TB is increased, and the consequence oftransmission is more severe for a person with diabetes. Measures to reduce
TB transmission have been identified in WHO’s International Guidelines for
TB infection Control, and include administrative and environmental control
measures, which are aimed at generally reducing exposure to Mycobacterium
tuberculosis for health-care workers and patients (38).
Administrative measures include early recognition, diagnosis and treatment of
TB, particularly pulmonary TB, and separation of people with suspectedpulmonary TB from others until a diagnosis is confirmed or excluded.
Environmental protection should include maximizing natural ventilation withlarge, opened windows and doors, opening sky-lights for cross-ventilation andre-designing waiting rooms to be in the open air where possible (39).
Mechanical ventilation systems should be considered where affordable, and, if
used, regularly maintained.
Recommendation 9
Each health-care facility, including diabetes clinics, should have an
infection control plan (including a plan for TB infection control), which
includes administrative and environmental control measures to reducetransmission of TB within this setting. These measures should adhere toWHO’s International Guidelines for TB infection Control.
Remark: The evidence for existing guidelines on TB infection control was notreviewed as part of the systematic review for this document. However, this21

recommendation is fully in line with existing guidelines on TB infection control(38).

B.3. Ensure high-quality treatment and management of TB in people
with diabetes
Diabetes appears to impact negatively on the time to conversion of sputum
culture, and is associated with an increased risk of death and increased risk of
TB recurrence, although not recurrence caused by drug-resistant strains (3).
The reasons for these adverse outcomes are not clear but may be associatedwith poor control of diabetes affecting TB treatment outcomes and drug–druginteractions.
Given the apparent increased vulnerability among people with diabetes, it isessential that all standard aspects of TB treatment and case management are
optimized for this group. This includes correctly prescribed treatment
regimens, optimal patient support and supervision, and clinical monitoring as
per national guidelines and international standards. It also includes standard
diagnosis, treatment and management of multidrug-resistant TB.
Currently, there is insufficient evidence to support changing the recommended
standard TB treatment regimens or making specific recommendations forclinical case management of TB in people with diabetes. It is common clinicalpractice in some settings to extend the duration of TB treatment in people withdiabetes. However, there are no published trials on the effectiveness ofextending the duration of treatment.
Further research needs to be conducted to better understand drug–druginteractions and determine if any changes to drug choice and/or dosage are
required.
There is not enough evidence to support any policy recommendation to giveisoniazid preventive therapy, or any other preventive therapy, to diabetes
patients with latent TB infection in order to prevent progression to active
disease.
Recommendation 10
Treatment and case management of TB in people with diabetes should
be provided in accordance with existing TB treatment guidelines andinternational standards. The same TB treatment regimen should beprescribed to people with diabetes as for people without diabetes.

22

COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETES

Summary of assessment of graded evidence from the systematic
reviews
Overall quality of evidence

Low

Balance of potential benefits and harms

Benefit

Disagreement among the panel

None

Acceptability

High

Feasibility

High

Resource implications

Moderate

Strength of recommendation

STRONG

Remark: There is evidence of low quality for a higher risk of delayedbacteriological conversion, and there is evidence of low to moderate quality
for a higher risk of death and relapse among people with diabetes who aretreated for TB, compared with TB patients without diabetes. This suggeststhat it is particularly important to ensure high-quality TB treatment according
to existing standards in this group of patients. An extended period of TB
treatment for people with diabetes has been suggested and is arecommended consideration in some settings (40). However, there are no
published trials on the efficacy of extending the duration of TB treatment orother changes to the standard TB treatment regimens for people withdiabetes. Therefore, the evidence on special TB treatment regimens forpeople with diabetes is low. There is evidence of low quality of no association
between diabetes and drug-resistant TB. The guideline group’s experts
therefore agreed that there is no evidence to support special TB treatment
regimens for people with diabetes. Patients should be treated according toexisting guidelines on TB treatment until better evidence becomes available(23, 41).

C.

Detect and manage diabetes in patients with
Tuberculosis

C.1. Screen TB patients for diabetes
As discussed in section A.3. above, screening for diabetes among TB patientsshould be feasible in all countries where basic equipment and knowledge on
diabetes is available in primary health-care settings. However, the best
approach for screening, including timing and screening method used, has yet

23to be established. Further research should provide a clearer picture of the
optimal method and timing of screening for diabetes in TB centres.
As an infectious disease, TB may temporarily elevate blood glucose levels
and result in false-positive diagnoses of diabetes if investigations are
performed too early. However, delayed screening may be a missed
opportunity for early initiation of diabetes treatment and health education
during the intensive phase of TB treatment, which potentially would havepositive effects on both the management of diabetes and the results of TB
treatment. Furthermore, hyperglycaemia, even if temporary, may be a risk
factor for poor TB treatment outcomes. Testing at the time of diagnosis, in the
TB diagnostic facility, may be advisable also for practical reasons. Many TB
control programmes provide decentralized treatment to peripheral facilities
where laboratory investigations are difficult to perform. Screening for diabetes
is therefore recommended at the start of TB treatment, in the TB diagnostic
centre, and to confirm the diabetes diagnosis as part of the clinical follow upof elevated blood glucose.
Operational and other research should be carried out to determine the best
methods for diagnosing diabetes in TB patients, focusing on adults stratified
by type of disease (smear-positive pulmonary TB, smear-negative pulmonary
TB and extrapulmonary TB) and the most feasible and appropriate ways ofscreening.
Recommendation 11
TB patients should be screened for diabetes at the start of TB treatment,
where resources for diagnosis are available. Type of screening anddiagnostic tests should be adapted to the context of local healthsystems and the availability of resources, while awaiting additional
evidence on the best screening and diagnostic approach.
Overall quality of evidence

Low

Balance of potential benefits and harms

Benefit

Disagreement among the panel

None

Acceptability

High

Feasibility

Dependent on setting

Resource implications

Low

Strength of recommendation

STRONG

Remark: The direct evidence for diabetes screening among people with TB is
of low quality. Few published studies are available on the feasibility and24

COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETES

additional yield of routine screening for diabetes among people with TB. There
are no published studies on the impact of increased screening for diabetes
among people with TB on morbidity or mortality from the disease. However,there is evidence of moderate quality that diabetes is associated with TB andthat its prevalence among people with TB is two to three times higher than in
the general population. Where diagnosis and treatment of diabetes isavailable and accessible, screening among TB patients should be consideredas part of the basic clinical package. Existing guidelines for screening anddiagnosis should be followed (42). Specific screening and diagnostic
algorithms for diabetes among people with TB should be evaluated throughresearch studies. Resource implications from a general health service
perspective are judged to be low, since the number of TB patients to bescreened is relatively small in most settings.

C.2. Ensure high-quality management of diabetes among TB patients
Care of diabetes is underdeveloped in many low-income and middle-income
countries. Strengthening such services may be a necessary component ofcollaborative activities. Potentially, optimized care of diabetes among people
with TB could be an entry point for improved care of the disease in thegeneral health system. Although there are no published trials assessing if
improved glucose control reduces the risk of adverse TB treatment outcomes,
the existing evidence indirectly suggests that optimized management ofdiabetes in TB patients, including early diagnosis, optimized treatment andhealth education, and clinical and therapeutic monitoring, would improve TB
treatment outcomes and reduce the risk of recurrent TB. Optimized diabetes
management may also improve outcomes of other coinfections in diabetes,
accounting for as much as 24% of deaths in African patients (43).
Further research needs to be conducted to better understand drug–druginteractions and determine if any changes to drug choice and/or dosage are
required.
Recommendation 12
Management of diabetes in TB patients should be provided in line withexisting guidelines.
Remark: The evidence for existing guidelines on management of diabetes
was not reviewed as part of the systematic review for this document.
However, this recommendation is in line with existing guidelines on
management of the disease, including special considerations for people withworsened glucose control as an effect of an ongoing infection (44–46).

25

26

COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETES

4. Indicators for evaluating
collaborative activities

Monitoring a set of key process and outcome indicators would enablecountries, organizations and institutions to work towards common goals, andhelp to accelerate country-level implementation of collaborative activities. The
proposed indicators listed below may be monitored at clinic, district, province
and/or national levels. The choice among these indicators, and possible
additional indicators, depends on the local scope of collaborative TB anddiabetes activities.
Careful monitoring of these indicators would also be the basis for operational
research on the feasibility, effectiveness and cost-effectiveness of different
models of collaboration. Such operational research, which should ideally also
include qualitative research methods, will be a crucial complement to clinicalstudies when addressing the research questions listed in Annex II.
Proposed indicators
1. Joint TB and diabetes plan in place (Y/N)
2. Number and proportion of people with diagnosed diabetes that have been
screened for chronic cough.
3. Number and proportion of people with diagnosed diabetes that have beentested for TB (radiography, sputum smear microscopy, culture, etc).
4. Prevalence of TB among people with diabetes.
5. Number and proportion of people with TB that have been screened fordiabetes.
6. Prevalence of diabetes among people with TB.
7. TB treatment outcomes among people with diabetes.

27

5. Implementing collaborative activities
and evaluating their impact

The first set of recommendations in this framework concerns mechanisms forcollaboration, and suggests how stakeholders should work together to ensure
optimal coordination and local adaptation, and how to monitor progress using
the indicators suggested in section 4 (see sections 3A and 4). The
recommendation to set up joint coordination involves identification of barriers
and facilitating factors for implementation as well as local adaptation of therecommendations contained in sections 3B and 3C, which should translate
into specific national guidance within plans for diabetes and TB care andprevention respectively.
The framework will be disseminated through WHO regional and country
offices to Ministries of Health and relevant public health programmes, as wellas national and international partners involved in prevention and care of bothdiseases. The Union, the International Diabetes Federation and othertechnical agencies working in partnership with WHO will disseminate theframework through their respective networks.
Regular and joint evaluation of the guideline’s quality, usefulness and impact
will be done by WHO, the Union, the International Diabetes Federation andother partners.

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COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETES

Annex I.

Members of the Guideline Group

ExpertProfessional affiliation

Area of expertise

Professor
Mauricio
BarretoDr Meghan A
Baker

Instituto de Saude Coletiva,
Universidade Federal da Bahia,
Bahia, Brazil
Department of Epidemiology,
Harvard School of Public Health,Boston, MA, US
International Union against
Tuberculosis and Lung Disease,
Paris, France
US Centers for Disease Control
and Prevention, Regional Field
Medical Officer, US PacificRegion, Hawaii State TB
Controller
Department of International
Health, Immunology andMicrobiology, University of
Copenhagen, Denmark
Centro Nacional de Vigilancia
Epidemiológica y Control deEnfermedades, Mexico City,
MexicoNational Tuberculosis andLeprosy Programme, Dar-esSalaam, United Republic of
Tanzania

DM and TB research andepidemiology

Professor
Susan
Fisher-Hoch

School of Public Health,
University of Texas Health
Science Center, Houston, USA

Professor
Anthony D.
HarriesInternational Union against
Tuberculosis and Lung Disease,
Paris, France
2
London School of Hygiene andTropical Medicine, Keppel Street,
London, UK
Center for Infectious Disease
Epidemiologic Research,
Mailman School of Public Health,
Columbia University, New York,NY, U.S.

TB research in Africa and Asia.
DM in disadvantaged populations
and associations between DM &TB.
TB, HIV, and DM research andclinical practice

Dr Nils Billo

Dr Richard
Brostrom

Professor Ib
Christian
Bygbjerg
Dr Martin
Castellanos

Dr Saidi
EgwagaDr Christie Y
Jeon

TB and DM researcher,performed the systematic review
TB and public health expert

US CDC representative. TB andDM clinician and epidemiologist.
Developer of Pacific TB andDiabetes Guidelines.
Global Health expert; TB and DM
research; TB clinical practice

TB programme planner andimplementer, Mexico. TB
research
TB programme planner andimplementer, United Republic of
Tanzania. TB research

TB and DM research, performed
the systematic review

29

Dr Knut
Lönnroth

Stop-TB Department, World
Health Organization, Geneva,
Switzerland

TB epidemiology; research on TB
risk factors and co-morbidities;
health systems research

Professor
Megan B.
MurrayDepartment of Epidemiology,
Harvard School of Public Health,Boston, MA, US
Division of Global Health Equity,
Brigham & Women’s Hospital,
Boston, MA, US
Research Institute ofTuberculosis, Kiyose, Tokyo,
Japan
Stop-TB Department, World
Health Organization, Geneva,
Switzerland

TB and DM research andepidemiology, performed thesystematic review

Shree Hindu Mandal Hospital,
Dar Es Salaam, United Republicof Tanzania;
Department of Medicine,
Muhimbili University of Healthand Allied Sciences, Dar Es
Salaam, United Republic of
Tanzania
Department of Chronic Diseases
and Health Promotion, World
Health Organization, Geneva,
Switzerland
Faculty of Medical Sciences,
Cave Hill Campus, University of
the West Indies
M.V.Hospital for Diabetes andResearch Centre, Royapuram,
Chennai, India
International DiabetesFederation, Brussels, Belgium

TB and DM research and clinicalpractice, Hon General Secretaryof Association of Private HealthFacilities in Tanzania. Hon
General Secretary, Tanzania
Diabetes Association

Dr Toru Mori

Dr SalahEddine
Ottmani
Dr Kaushik
Ramaiya

Dr Gojka
RoglicProfessor
Nigel Unwin
Dr Vijay
Viswanathan
Dr David
Whiting
Dr Lixia
Wang

Dr Wenhua
Zhao

30

National Center for TB Control
and Prevention, China Centers
for Disease Control, Beijing,
China
National Center for Chronic
Disease control and Prevention
China Centers for Disease
Control, Beijing, China

TB research and epidemiology;
TB programme planner andimplementer, JapanTB epidemiology; research on TB
risk factors and co-morbidities

DM research and epidemiology

DM and TB research andepidemiology
TB and DM research andepidemiology
DM epidemiology and research,
representative of International
Diabetes Federation
TB programme planner andimplementer, China

NCD programme planner andimplementer, China

COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETES

Annex II. Summary grading of the evidence1

Summary of findings

Importance

Quality assessment
No. ofStudies

Design4

Cross-sectional
studies

Limitations

Inconsistency

Indirectness

Imprecision

Other
Effectconsiderations
Is diabetes associated with TB infection? (see support material 1 at http://www.who.int/tb/publications/2011/en/index.html)
Seriouslimitations

Consistent noassociation

Serious

SeriousNone

1.01 (0.78,
1.31)

Absolute

Quality

N/A

Low

Moderately
important

N/A

Moderate

Important

Is diabetes associated with active TB disease? (see support material 1 at http://www.who.int/tb/publications/2011/en/index.html)
4Cohort studies

Somelimitations

Consistent positive
associations, with large
heterogeneity

SeriousModerately
seriousNone

2.52 (1.53,
4.03)

10

Case-control studies

Somelimitations

LowModerate

8

Observational
studiesSomelimitations

Low

Moderately
important

13

Observational
studies

Seriouslimitations

Very Low

Important

Mostly positive
Moderately
Moderately
None
2.20 (1.78,
N/A
associations, with large
seriousserious2.73)
heterogeneity
Is diabetes associated with positive sputum culture at 2-3 months? (see support material 2 at http://www.who.int/tb/publications/2011/en/index.html)
Mostly positive
Moderately
Serious
None
RR range 0.79
N/A
associations, with large
serious
to 3.25
heterogeneity
Is diabetes associated with favourable treatment outcome? (see support material 2 at http://www.who.int/tb/publications/2011/en/index.html)
Mostly null findings withlarge heterogeneity

SeriousNot Serious

None

1

0.95 (0.91,
0.98)

N/A

Support material on the web (http://www.who.int/tb/publications/2011/en/index.html) include detailed summary tables of all reviewed studies and indicate foreach question the annex in which the details of the studies are included.

31

Is diabetes associated with death during treatment period? (see support material 2 at http://www.who.int/tb/publications/2011/en/index.html)
23

4

4

Observational
Serious
Mostly positive
SeriousModerately
None
1.85 (1.50,
studies with nolimitations
associations, with large
serious2.28)
adjustment forheterogeneity
confounders
Observational
Some
Consistent positive
Serious
SeriousNonestudies withlimitations
associations
4.95 (2.69,
adjustment for
9.10)
confounders
Is diabetes associated with relapse? (see support material 2 at http://www.who.int/tb/publications/2011/en/index.html)

N/A

Low

N/A

Moderate

Observational
studies

N/A

Moderate

Important

ImportantSomelimitations

Consistent positive
associations

Moderately
serious

SeriousNone

3.98 (2.11,
7.50)

Important

Is diabetes associated with drug-resistance? (see support material 2 at http://www.who.int/tb/publications/2011/en/index.html)
3

2

4

2

1

9

1

Observational
studies on primary
DR TB (any DR TB)
Observational
studies on acquired
DR TB
Observational
studies on any DR
TB without distinctionof primary or
acquired
Observational
studies on primary
MDR TB
Observational
studies on acquired
MDR TB
Observational
studies on MDR TB
without distinction ofprimary or acquired
Observational
studies on XDR TB

Somelimitations

Consistent noassociation

Serious

SeriousNone

1.01 (0.63,
1.63)

N/A

Low

Some
limitations

Consistent noassociation

Serious

SeriousNone

0.86 (0.39,
1.88)

N/A

Low

Serious
Limitations

Consistent noassociation

Serious

SeriousNone

1.02 (0.70,
1.49)

N/A

Very Low

Somelimitations

Consistent positive
association

Serious

SeriousNone

2.91 (1.26,
6.72)

N/A

Low

Some
limitations

No association

Serious

Serious

Small power

0.8 (0.2, 4.2)

N/A

Low

Serious
Limitations

Inconsistent

Moderately
seriousModerately
seriousNone

1.86 (1.39,
2.50)

N/A

Very Low

Somelimitations

No association

Serious

Serious

Small power

2.1 (0.64, 6.9)

N/A

Low

32

COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETESDoes screening for DM among TB lead to more TB case detection? (see support material 3 at http://www.who.int/tb/publications/2011/en/index.html)
10

Observational
studies on screening
for prevalent TB in
DM

Seriouslimitations

Large heterogeneity, but
consistently greater TB
prevalence than incomparison

Moderately
serious

SeriousSome studies
lack control
group

2

Observational
studies on screening
for incident TB in DM

Seriouslimitations

Large heterogeneity, but
consistently greater TB
incidence than incomparison

Serious

SeriousSome studies
lack control
group

5

Observational
studies on screening
for prevalent TB
infection in DM

Seriouslimitations

Some heterogeneity, but
mostly similar TB
infection prevalence as
in comparison

Serious

SeriousSome studies
lack control
group

7

Observational
studies on screeningfor DM after TB Tx
initiation

Seriouslimitations

Some heterogeneity, but
generally greater DM
prevalence than incomparison

Moderately
serious

SeriousSome studies
lack control
group

11

Observational
studies on screeningfor DM before TB Tx
initiation, or timing
unclearSeriouslimitations

Large heterogeneity, but
generally greater DM
prevalence than incomparison

Moderately
serious

SeriousSome studies
lack control
group

TB prevalencein DM higher
than incomparison,
where available
TB incidence inDM higher thanin comparison,
where available

N/A

Very Low

N/A

Very Low

TB infection
N/A
Very Low
prevalence inDM similar tocomparison
population,
where available
Does screening for DM among TB patients lead to more DM detection? (see support material 3 at http://www.who.int/tb/publications/2011/en/index.html)
DM prevalence
in TB higher
than incomparison,
where available
DM prevalence
in TB higher
than incomparison,
where available

N/A

Low

N/A

Very Low

ImportantModerately
important

Important

Does hyperglycaemia initially found in TB patients resolve with TB treatment? (see support material 3 at http://www.who.int/tb/publications/2011/en/index.html)
4

Observational
studies on screening
with multiple followup

Seriouslimitations

Consistent

Serious

Serious

No control
groups33

Prevalence ofhyperglycaemia
decreases with
TB treatment

N/A

Low

ImportantIs chemoprophylaxis intervention in DM effective in preventing TB? (see support material 3 at http://www.who.int/tb/publications/2011/en/index.html)
2

Observational
studies

Seriouslimitations

ConsistentStudies lacked
crucial details
on study design
and findings

Both report
reduced TB
incidence

Does screening for TB among DM lead to prevention of TB morbidity and mortality than not screening?
nostudy
Does screening for DM among TB lead to prevention of DM morbidity and mortality than not screening?
nostudy
DM = diabetes mellitus; TB = tuberculosis; Tx = treatment

34

N/A

Very Low

Moderately
important

COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETES

Annex III. Key research questions for improving theprevention, management and care of diabetes andtuberculosis (31)
Key research questions
Screening for Disease: Screening patients with DM
for active TB
 Screening patients with TB forDM
TB treatment outcomes inpatients with DM, including amore detailed assessment ofdeath during anti-TB treatment

Priority
High

High

Implementing and evaluating the“DOTS” model for standardized
case management of DM

High

Development and evaluation of apoint of care glycatedhaemoglobin test (HbA1c)

High

Rates of hospitalization andadditional medical costs
associated with diagnosis andmanagement of dual disease
Use of the community to improve
management and care ofpatients with DM and TB
Household contact tracing ofadult patients with smearpositive pulmonary TB

Study design and methodology
Prospective observational cohort studies of
DM patients routinely attending diabetic
clinics and screened for TB, and TB
patients starting anti-TB treatment andscreened for diabetes
Prospective observational cohort studies
using standardized TB regimens andstandardized treatment outcomes andfocusing on defined primary outcomes
Prospective observational cohort studies
determining when death occurs in relation
to start of TB treatment, the etiology andwhether case fatality is reduced by better
DM control
Operational research including quarterly
cohort reporting of new cases, treatment
outcomes of cumulative cases including
frequency of co-morbidities such as TB,
and survival analysis
Developmental work to develop a dipstickfor measuring HbA1c for use in rural areas,
which then needs to be tested for efficacy
and feasibility in the field

MediumCross-sectional studies

MediumOperational researchMediumRadiographic findings in DM
patients with TB

MediumModelling the effect of the DM
epidemic on the TB epidemic

Medium

TB preventive therapy in patientswith DM

Low

Prospective observational studies todetermine the yield of screening household
contacts for TB infection, active TB, HIV
and DM, and to assess whether DM
influences the establishment of TB infection
Systematic review of the literature andprospective cross-sectional studies if
further evidence is required to determine
the common radiographic patterns
Mathematical modelling studies

Randomized controlled trial assessing
efficacy and safety of isoniazid preventive
therapy in reducing risk of active TB in
patients with DM

DM = diabetes mellitus; HIV = human immunodeficiency virus; TB = tuberculosis

35

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COLLABORATIVE FRAMEWORK FOR CARE AND CONTROL OF TUBERCULOSIS AND DIABETESISBN 978 92 4 150225 241