Istc 3rded

INTERNATIONAL STANDARDS F OR
Tuberculosis Care
diagnosis treatment public health
3rd edition, 2014

Developed by TB CARE I with funding by the United States Agency for
International Development (USAID)
TB CARE I Organizations
Disclaimer:
The Global Health Bureau, Office of Health, Infectious Disease and Nutrition (HIDN), US
Agency for International Development, financially supports this publication through TB
CARE I under the terms of Agreement No. AID-OAA-A-10-00020. This publication is
made possible by the generous support of the American people through the United States
Agency for International Development (USAID). The contents are the responsibility of TB
CARE I and do not necessarily reflect the views of USAID or the United States Government.
Suggested citation:
TB CARE I. International Standards for Tuberculosis Care, Edition 3. TB CARE I, The
Hague, 2014.
Contact information:
Philip C. Hopewell, MD
Curry International Tuberculosis Center
University of California, San Francisco
San Francisco General Hospital
San Francisco, CA 94110, USA
Email: [email protected]
Available at the following web sites:

http://www.tbcare1.org/publications
http://istcweb.org
http://www.currytbcenter.ucsf.edu/international
http://www.who.int/tb/publications
To access a mobile version of ISTC, go to www.walimu.org/istc
INTERNATIONAL STANDARDS F OR
Tuberculosis Care
diagnosis treatment public health
3rd edition, 2014

Table of Contents
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Standards for Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Standards for Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Standards for Addressing HIV Infection and Other Co-morbid Conditions . . . 50
Standards for Public Health and Prevention . . . . . . . . . . . . . . . . . . . . . 57
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Annexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
I STC 3 r d e dition , 2014 table of contents

Acknowledgments
Development of the third edition of the International Standards for Tuberculosis Care was
guided by a steering committee of World Health Organization Global Tuberculosis Pro-
gramme staff and by an expert committee whose members were chosen to represent
perspectives and areas of expertise relevant to tuberculosis care and control. Both com-
mittees are listed below. The expert committees for editions 1 and 2 are in Annex 1.
Steering Committee (WHO)

• Haileyesus Getahun
• Chris Gilpin
• Malgosia Grzemska
• Ernesto Jaramillo
• Knut Lönnroth
• Mario Raviglione
• Mukund Uplekar
• Diana Weil
Expert Committee
• RV Asokan, India • Ernesto Jaramillo, WHO
• Erlina Burhan, Indonesia • Aamir Khan, Pakistan
• J.M. Chakaya, Kenya • Knut Lönnroth, WHO
• Gavin Churchyard, South Africa • G. B. Migliori, Italy
• Marcus Conde, Brazil • Dyah Mustikawati, Indonesia
• Charles Daley, USA • Madhukar Pai, Canada
• Saidi Egwaga, Tanzania • Rose Pray, USA
• Elizabeth Fair, USA • Mario Raviglione, WHO
• Paula Fujiwara, USA • Elizabeth Soares, Brazil
• Haileyesus Getahun, WHO • Mukund Uplekar, WHO (Co-Chair)
• Chris Gilpin, WHO • Dalene Von Delft, South Africa
• Steve Graham, Australia • Jan Voskens, Netherlands
• Malgosia Grzemska, WHO • Diana Weil, WHO
• Philip Hopewell, USA (Co-chair) • Gini Williams, UK
Elizabeth Fair (University of California, San Francisco) in addition to being a member of the
expert committee, provided scientific staffing and coordination.
Fran Du Melle (American Thoracic Society) provided administrative coordination as well as

guidance on dissemination and implementation.
Cecily Miller and Baby Djojonegoro (University of California, San Francisco) provided assis-
tance in organizing and preparing the document.
In addition to the committees, many individuals have provided valuable input. All comments
received were given serious consideration by the co-chairs, although not all were incorporated
into the document.
1 I STC 3 r d e dition , 2014 acknowledgments

List of Abbreviations
AFB Acid-fast bacilli
AIDS Acquired immunodeficiency syndrome
ART Antiretroviral therapy
ATS American Thoracic Society
BCG Bacille Calmette-Guérin
CDC Centers for Disease Control and Prevention
CI Confidence interval
COPD Chronic obstructive pulmonary disease
CPT Cotrimoxazole
CRI Colorimetric redox-indicator
DOT Directly observed treatment
DOTS The internationally recommended strategy for tuberculosis control
DR Drug-resistant
DST Drug susceptibility testing
EMB Ethambutol
FDA Food and Drug Administration (US)
FDC Fixed-dose combination
FHI 360 Formerly Family Health International
FM Fluorescence microscopy
HAART Highly active antiretroviral therapy
HIV Human immunodeficiency virus
IDSA Infectious Diseases Society of America
IGRA Interferon-gamma release assay
INH Isoniazid
IMAAI Integrated Management of Adolescent and Adult Illness
IMCI Integrated Management of Childhood Illness
IPT Isoniazid preventive therapy
IRIS Immune reconstitution inflammatory syndrome
ISTC International Standards for Tuberculosis Care
IUATLD International Union Against Tuberculosis and Lung Disease (The Union)
JATA Japan Anti-tuberculosis Association
KNCV KNCV Tuberculosis Foundation
LED Light emitting diode
LPA Line probe assay
LTBI Latent tuberculosis infection
M&E Monitoring and Evaluation
MDR Multidrug-resistant
MIC Minimal inhibitory concentration
2 I STC 3 r d e dition , 2014 list of abbreviations

MODS Microscopic observation drug susceptibility
MSH Management Sciences for Health
NAAT Nucleic acid amplification test
NALC N-acetyl L-cysteine
NaOH Sodium hydroxide
NIOSH National Institute for Occupational Services and Health
NNRTI Non-nucleoside reverse transcriptase inhibitors
NRA Nitrate reductase assay
NTM Non-tuberculous mycobacteria
NTP National tuberculosis control program
PCTC Patients’ Charter for Tuberculosis Care
PI Protease inhibitor
PLHIV People living with HIV
PPM Public-private mix
PZA Pyrazinamide
RIF Rifampicin
RR Risk ratio
STI Sexually transmitted infection
TB Tuberculosis
TBCTA Tuberculosis Coalition for Technical Assistance
TNF Tumor necrosis factor
TST Tuberculin skin test (Mantoux)
USAID United States Agency for International Development
WHO World Health Organization
XDR Extensively drug-resistant
ZN Ziehl-Neelsen staining
3 I STC 3 r d e dition , 2014 list of abbreviations

Preface to Edition 3
Development Process
The standards in Development of the first edition of the International Standards for Tuberculosis Care (ISTC)
was funded by the United States Agency for International Development (USAID) via the
the ISTC are all
Tuberculosis Coalition for Technical Assistance (TBCTA) and was guided by an expert
supported by committee of 28 members from 14 countries representing relevant perspectives and
existing WHO areas of expertise. The committee was co-chaired by Mario Raviglione of the World Health
Organization (WHO) and Philip Hopewell of the American Thoracic Society (ATS). The
guidelines and group first agreed on a content outline and then identified areas in which systematic
policy statements, reviews were needed. Six reviews, largely related to approaches to diagnosis, were con-
ducted and subsequently published in peer-reviewed publications.
many of which had
Development of Edition 2 of the ISTC was also funded by USAID via its TB Control Assis-
recently been tance Program (TBCAP). A new expert committee of 56 persons from 15 countries, plus
developed using WHO, chaired by Drs. Raviglione and Hopewell guided the process. Only one systematic
review, related to contact investigation (subsequently published), was identified.
rigorous
methodology. Edition 3 was again funded by USAID via TB CARE I and was developed using essentially
the same process. Development was led by Mukund Uplekar (WHO) and Philip Hopewell
(ATS). A steering committee from the staff of the Global TB Programme at the WHO iden-
tified areas in which revisions were needed. It was felt that no new systematic reviews
were needed for this edition. The standards in the ISTC are all supported by existing WHO
guidelines and policy statements, many of which had recently been developed using rig-
orous methodology, including systematic reviews. The draft document was then reviewed
by an expert committee of 27 members from 13 countries, co-chaired by Drs. Uplekar
and Hopewell. Subsequent drafts were also reviewed and approved by the expert com-
mittee. The final draft was reviewed and approved by the TB CARE I member organiza-
tions (ATS, FHI 360, the Japan Antituberculosis Association [JATA], KNCV Tuberculosis
Foundation [KNCV], Management Sciences for Health [MSH], the International Union
against Tuberculosis and Lung Disease [The Union], and WHO).
4 I STC 3 r d e dition , 2014 preface to edition 3

Key differences between ISTC Edition 2
and Edition 3
Edition 1 of the ISTC stated, “The Standards should be viewed as a living document that
will be revised as technology, resources, and circumstances change.” It has now been five
years since Edition 2 of the ISTC was published (2009); new information has emerged;
new approaches are now feasible; and new guidelines have been written. These changes
warrant an updating of the ISTC to be consistent with the concept of a “living document.”
It was also stated in Edition 1 that, “As written, the Standards are presented within a con-
text of what is generally considered to be feasible now or in the near future.” There is
continued recognition that not all of the standards in this edition can be met in all places
at this time. However, given the rapidity of technical advances and deployment of new
technologies and approaches, it is anticipated that compliance with the standards will be
possible in most places in the near future. It is hoped that having standards that are higher
than the minimum necessary will serve to stimulate more rapid improvements in tubercu-
losis care worldwide.
It must be emphasized that the basic principles that underlie the ISTC have not changed.
Case detection and curative treatment remain the cornerstones of tuberculosis care and
control and the fundamental responsibility of providers to ensure completion of treatment
is unchanged. Within these basic principles, however, there have been changes that are
of sufficient importance to be incorporated into the ISTC. The areas of change that are
addressed are summarized in Table 1.
An important companion document of which the reader should be aware is The Hand-
book for Utilizing the International Standards for Tuberculosis Care. The Handbook is
based mainly on experiences in countries that began utilizing the ISTC soon after it was
developed and provided documentation of these experiences. The findings from these
pilot countries are summarized briefly in the Introduction. The Handbook is available at
www.istcweb.org. A set of training modules based on the third edition of the ISTC is also
available on the same website. Summaries of the utilization handbook and the training
materials are in Annexes 2 and 3, respectively. Revisions of the Handbook and training
modules will be available online in October 2014.
A second companion document, the Patients’ Charter for Tuberculosis Care (PCTC), was
developed in tandem with the first edition of the ISTC and describes patient rights and
responsibilities. The ISTC and the PCTC are mutually reinforcing documents, serving to
define expectations from both the provider and the patient perspective. The PCTC is also
available at www.istcweb.org.

Table 1 .
Key differences between the 2009 and 2014 editions of the ISTC
Section Key Differences
Overall • Relevant WHO guidelines published since 2008 have been included.
• References have been reviewed and, where necessary, replaced with new references to
reflect current information.
• The wording has been tightened and made more concise throughout.
Introduction • Language has been added indicating that an additional purpose of the ISTC is to provide
support to the integrated, patient-centered care and prevention component of WHO’s global
strategy for tuberculosis prevention, care, and control after 2015. Engagement of all providers
is a critical component of the updated strategy and the ISTC will serve as a means of
facilitating implementation of the strategy, especially among private providers.
• Also noted is the importance of identifying individuals or groups at increased risk of
tuberculosis and utilizing appropriate screening methods and preventive interventions in
these persons or groups.
Standards for Diagnosis
Standard 1 • This is a new standard emphasizing the responsibility of providers to be aware of individual
and population risk factors for tuberculosis and to reduce diagnostic delay.
Standard 2 • Formerly Standard 1. The wording has been changed to include radiographic abnormalities
as an indication for evaluation for tuberculosis.
• The discussion of the standard emphasizes the importance of including not only cough, but
also fever, night sweats, and weight loss as indications for evaluation for tuberculosis.
Standard 3 • Formerly Standard 2. The current WHO recommendations for use of rapid molecular testing
as the initial microbiologic test in specified patients are now included.
• The WHO recommendation against using serologic assays for diagnosing tuberculosis is
emphasized.
Standard 4 • Previous Standard 4 now combined with Standard 1.

• The importance of microbiological diagnosis of extrapulmonary tuberculosis is emphasized.
• WHO recommendations for the use of rapid molecular testing for samples from
extrapulmonary sites are included.
Standard 5 • The WHO recommendations for use of rapid molecular testing for diagnosis of tuberculosis
among persons who are suspected of having the disease but have negative sputum smear
microscopy are presented.
Standard 6 • The WHO recommendations for the use of rapid molecular testing for the diagnosis of
tuberculosis in children are presented.

Table 1 .
Key differences between the 2009 and 2014 editions of the ISTC
Section Key Differences
Standards for Treatment
Standard 7 • No change
Standard 10 • The role of microscopy in monitoring response in patients who had the diagnosis established
by a rapid molecular test is described.
Standard 11 • This standard describes the use of Xpert® MTB/RIF in assessing for rifampicin resistance and
line probe assay for detecting resistance to both isoniazid and rifampicin.
Standard 12 • The standard has been changed to reflect the revised WHO recommendations for
programmatic management of drug-resistant tuberculosis.
Standards for Addressing HIV Infection and other Co-morbid Conditions
Standard 15 • The standard has been modified to reflect the current WHO recommendations for treating
HIV in PLHIV who have tuberculosis .
Standards for Public Health and Prevention

Summary
The purpose of the International Standards for Tuberculosis Care (ISTC) is to describe a
widely accepted level of care that all practitioners, public and private, should seek to
All providers achieve in managing patients who have, are suspected of having, or are at increased risk
of developing tuberculosis. The standards are intended to promote the effective engage-
who undertake ment of all providers in delivering high quality care for patients of all ages, including those
evaluation and with sputum smear-positive and sputum smear-negative pulmonary tuberculosis, extrapul-
monary tuberculosis, tuberculosis caused by drug-resistant Mycobacterium tuberculosis
treatment of complex (M. tuberculosis) organisms, and tuberculosis combined with HIV infection and
patients with other co-morbidities. Moreover, there is increasing recognition of the importance for pro-
viders to employ proven approaches to screening and prevention of tuberculosis in per-
tuberculosis must
sons at increased risk of developing the disease.
recognize that, not
The basic principles of care for persons with, or suspected of having, tuberculosis are the
only are they same worldwide: a diagnosis should be established promptly and accurately; standard-
delivering care to ized treatment regimens of proven efficacy should be used, together with appropriate
treatment support and supervision; the response to treatment should be monitored; and
an individual, they the essential public health responsibilities must be carried out. Prompt, accurate diagno-
are assuming an sis and appropriate treatment are the most effective means of interrupting transmission of
M. tuberculosis. As well as being essential for good patient care, they are the foundation
important public
of the public health response to tuberculosis. Thus, all providers who undertake eval-
health function. uation and treatment of patients with tuberculosis must recognize that, not only
are they delivering care to an individual, they are assuming an important public
health function that entails a high level of responsibility to the community and to
the individual patient.
Many national and international guidelines are directed toward and accessible to provid-
ers working for government tuberculosis control programs. Moreover, these providers are
subject to regular monitoring and evaluation. However, private providers are generally not
considered to be the main target for guidelines and recommendations and don’t undergo
assessments of the care they provide. Consequently, the ISTC is focused mainly on pri-
vate and non-program public sector providers. It should be emphasized, however, that
national and local tuberculosis control programs may need to develop policies and proce-
dures that enable non-program providers to adhere to the ISTC. Such accommodations
may be necessary, for example, to facilitate treatment supervision and contact investiga-
tions, as described in the ISTC.
8 I STC 3 r d e dition , 2014 summary

In addition to private sector health care providers and government tuberculosis programs,
both patients and communities are part of the intended audience. Patients are increas-
ingly aware of and expect that their care will measure up to a high standard. Having gen-
erally agreed upon standards will empower patients to evaluate the quality of care they are
being provided. Good care for individuals with tuberculosis is also in the best interest of
the community.
The standards in the ISTC are intended to be complementary to local and national tuber-
culosis control policies that are consistent with WHO recommendations. They are not
intended to replace local guidelines and were written to accommodate local differences in
practice. They focus on the contribution that good clinical care of individual patients with
or suspected of having tuberculosis makes to population-based tuberculosis control. A
balanced approach emphasizing both individual patient care and public health principles
of disease control is essential to reduce the suffering and economic losses from tuber-
culosis.
The ISTC is also intended to serve as a companion to and support for the Patients’ Char-
ter for Tuberculosis Care. The Charter specifies patients’ rights and responsibilities and
will serve as a set of standards from the point of view of the patient, defining what the
patient should expect from the provider and what the provider should expect from the
patient.
The ISTC should be viewed as a living document that will be revised as technology,
resources, and circumstances change. As written, the standards in the ISTC are presented
within a context of what is generally considered to be feasible now or in the near future.
The standards are as follows:

Standard 1. To ensure early diagnosis, providers must be aware of individual and group
risk factors for tuberculosis and perform prompt clinical evaluations and
appropriate diagnostic testing for persons with symptoms and findings
consistent with tuberculosis.
Standard 2. All patients, including children, with unexplained cough lasting two or more
weeks or with unexplained findings suggestive of tuberculosis on chest
radiographs should be evaluated for tuberculosis.
Standard 3. All patients, including children, who are suspected of having pulmonary
tuberculosis and are capable of producing sputum should have at least
two sputum specimens submitted for smear microscopy or a single spu-
tum specimen for Xpert® MTB/RIF* testing in a quality-assured laboratory.
Patients at risk for drug resistance, who have HIV risks, or who are seri-
ously ill, should have Xpert MTB/RIF performed as the initial diagnostic
test. Blood-based serologic tests and interferon-gamma release assays
should not be used for diagnosis of active tuberculosis.
*As of this writing, Xpert®MTB/RIF (Cepheid Corp. Sunnyvale, California, USA) is the only rapid
molecular test approved by WHO for initial use in diagnosing tuberculosis, thus, it is specifical-
ly referred to by its trade name throughout this document.

Standard 4. For all patients, including children, suspected of having extrapulmonary
tuberculosis, appropriate specimens from the suspected sites of involve-
ment should be obtained for microbiological and histological examination.
An Xpert MTB/RIF test is recommended as the preferred initial microbio-
logical test for suspected tuberculous meningitis because of the need for a
rapid diagnosis.
Standard 5. In patients suspected of having pulmonary tuberculosis whose sputum

smears are negative, Xpert MTB/RIF and/or sputum cultures should be
performed. Among smear- and Xpert MTB/RIF negative persons with clin-
ical evidence strongly suggestive of tuberculosis, antituberculosis treatment
should be initiated after collection of specimens for culture examination.
Standard 6. For all children suspected of having intrathoracic (i.e., pulmonary, pleural,
and mediastinal or hilar lymph node) tuberculosis, bacteriological confir-
mation should be sought through examination of respiratory secretions
(expectorated sputum, induced sputum, gastric lavage) for smear micros-
copy, an Xpert MTB/RIF test, and/or culture.

Standard 7. To fulfill her/his public health responsibility, as well as responsibility to the
individual patient, the provider must prescribe an appropriate treatment
regimen, monitor adherence to the regimen, and, when necessary, address
factors leading to interruption or discontinuation of treatment. Fulfilling
these responsibilities will likely require coordination with local public health
services and/or other agencies.
Standard 8. All patients who have not been treated previously and do not have other
risk factors for drug resistance should receive a WHO-approved first-line
treatment regimen using quality assured drugs. The initial phase should
consist of two months of isoniazid, rifampicin, pyrazinamide, and etham-
butol.* The continuation phase should consist of isoniazid and rifampicin
given for 4 months. The doses of antituberculosis drugs used should con-
form to WHO recommendations. Fixed-dose combination drugs may pro-
vide a more convenient form of drug administration.
*Ethambutol may be omitted in children who are HIV-negative and who have non-cavitary
tuberculosis.
Standard 9. A patient-centered approach to treatment should be developed for all

patients in order to promote adherence, improve quality of life, and relieve
suffering. This approach should be based on the patient’s needs and
mutual respect between the patient and the provider.
Standard 10. Response to treatment in patients with pulmonary tuberculosis (including

those with tuberculosis diagnosed by a rapid molecular test) should be
monitored by follow up sputum smear microscopy at the time of comple-
tion of the initial phase of treatment (two months). If the sputum smear is
positive at completion of the initial phase, sputum microscopy should be

performed again at 3 months and, if positive, rapid molecular drug sensi-
tivity testing (line probe assays or Xpert MTB/RIF) or culture with drug sus-
ceptibility testing should be performed. In patients with extrapulmonary
tuberculosis and in children, the response to treatment is best assessed
clinically.
Standard 11. An assessment of the likelihood of drug resistance, based on history of

prior treatment, exposure to a possible source case having drug-resistant
organisms, and the community prevalence of drug resistance (if known),
should be undertaken for all patients. Drug susceptibility testing should be
performed at the start of therapy for all patients at a risk of drug resistance.
Patients who remain sputum smear-positive at completion of 3 months of
treatment, patients in whom treatment has failed, and patients who have
been lost to follow up or relapsed following one or more courses of treat-
ment should always be assessed for drug resistance. For patients in whom
drug resistance is considered to be likely an Xpert MTB/RIF test should be
the initial diagnostic test. If rifampicin resistance is detected, culture and
testing for susceptibility to isoniazid, fluoroquinolones, and second-line
injectable drugs should be performed promptly. Patient counseling and
education, as well as treatment with an empirical second-line regimen,
should begin immediately to minimize the potential for transmission. Infec-
tion control measures appropriate to the setting should be applied.
Standard 12. Patients with or highly likely to have tuberculosis caused by drug-resistant
(especially MDR/XDR) organisms should be treated with specialized regi-
mens containing quality-assured second-line antituberculosis drugs. The
doses of antituberculosis drugs should conform to WHO recommenda-
tions. The regimen chosen may be standardized or based on presumed or
confirmed drug susceptibility patterns. At least five drugs, pyrazinamide
and four drugs to which the organisms are known or presumed to be sus-
ceptible, including an injectable agent, should be used in a 6–8 month
intensive phase, and at least 3 drugs to which the organisms are known or
presumed to be susceptible, should be used in the continuation phase.
Treatment should be given for at least 18–24 months beyond culture con-
version. Patient-centered measures, including observation of treatment,
are required to ensure adherence. Consultation with a specialist experi-
enced in treatment of patients with MDR/XDR tuberculosis should be
obtained.
Standard 13. An accessible, systematically maintained record of all medications given,

bacteriologic response, outcomes, and adverse reactions should be main-
tained for all patients.

Standards for Addressing HIV Infection and
other Co-morbid Conditions
Standard 14. HIV testing and counseling should be conducted for all patients with, or
suspected of having, tuberculosis unless there is a confirmed negative test
within the previous two months. Because of the close relationship of tuber-
culosis and HIV infection, integrated approaches to prevention, diagnosis,
and treatment of both tuberculosis and HIV infection are recommended in
areas with high HIV prevalence. HIV testing is of special importance as part
of routine management of all patients in areas with a high prevalence of HIV
infection in the general population, in patients with symptoms and/or signs
of HIV-related conditions, and in patients having a history suggestive of
high risk of HIV exposure.
Standard 15. In persons with HIV infection and tuberculosis who have profound immu-
nosuppression (CD4 counts less than 50 cells/mm3), ART should be initi-
ated within 2 weeks of beginning treatment for tuberculosis unless tuber-
culous meningitis is present. For all other patients with HIV and tuberculosis,
regardless of CD4 counts, antiretroviral therapy should be initiated within 8
weeks of beginning treatment for tuberculosis. Patients with tuberculosis
and HIV infection should also receive cotrimoxazole as prophylaxis for
other infections.
Standard 16. Persons with HIV infection who, after careful evaluation, do not have active
tuberculosis should be treated for presumed latent tuberculosis infection
with isoniazid for at least 6 months.
Standard 17. All providers should conduct a thorough assessment for co-morbid condi-
tions and other factors that could affect tuberculosis treatment response or
outcome and identify additional services that would support an optimal
outcome for each patient. These services should be incorporated into an
individualized plan of care that includes assessment of and referrals for
treatment of other illnesses. Particular attention should be paid to diseases
or conditions known to affect treatment outcome, for example, diabetes
mellitus, drug and alcohol abuse, undernutrition, and tobacco smoking.
Referrals to other psychosocial support services or to such services as
antenatal or well-baby care should also be provided.

Standards for Public Health and Prevention
Standard 18. All providers should ensure that persons in close contact with patients who
have infectious tuberculosis are evaluated and managed in line with inter-
national recommendations. The highest priority contacts for evaluation are:
• Persons with symptoms suggestive of tuberculosis

• Children aged < 5 years
• Contacts with known or suspected immunocompromised states,
particularly HIV infection
• Contacts of patients with MDR/XDR tuberculosis
Standard 19. Children < 5 years of age and persons of any age with HIV infection who
are close contacts of a person with infectious tuberculosis, and who, after
careful evaluation, do not have active tuberculosis, should be treated for
presumed latent tuberculosis infection with isoniazid for at least six months.
Standard 20. Each health care facility caring for patients who have, or are suspected of
having, infectious tuberculosis should develop and implement an appropri-
ate tuberculosis infection control plan to minimize possible transmission of
M. tuberculosis to patients and health care workers.
Standard 21. All providers must report both new and re-treatment tuberculosis cases
and their treatment outcomes to local public health authorities, in confor-
mance with applicable legal requirements and policies.

Introduction
Purpose
The ISTC is The fundamental purpose of the International Standards for Tuberculosis Care (ISTC) is to
describe a widely accepted level of care that all practitioners, public and private, should
intended to facilitate
seek to achieve in managing patients who have or are suspected of having tuberculosis,
the effective or are at increased risk of developing the disease. The ISTC is intended to facilitate the
engagement of all effective engagement of all care providers in delivering high quality care utilizing estab-
lished best practices for patients of all ages with all forms of tuberculosis. In addition,
care providers in providers must be aware of conditions and epidemiologic circumstances that impose an
delivering high increased risk of tuberculosis and of approaches to screening for tuberculosis and apply-
ing preventive therapies in these situations.1
quality care utilizing
The ISTC is also intended to provide support to the integrated, patient-centered tubercu-
established best losis care and prevention component of WHO’s proposed Global Strategy and Targets for
practices for Tuberculosis Prevention, Care and Control after 2015.2 Engagement of all providers is a
critical component of the updated strategy and the ISTC will serve as a means of facilitat-
patients of all ages
ing implementation of the strategy especially among non-program providers.3,4 The
with all forms of updated strategy presents the framework necessary for effective tuberculosis care and
tuberculosis. control and, when fully implemented, provides the elements essential for delivery of good
tuberculosis care and prevention.
Much of the information presented in the ISTC is derived from existing WHO docu-
ments. Thus, the ISTC serves as a compendium of recommendations and guidelines
developed by a rigorous, evidence-based process required by WHO.5 Taken together
these documents provide comprehensive guidance for best practices in tuberculosis
care and control.
In addition to the fundamental purpose of the ISTC, an important goal is to promote uni-
fied approaches to the diagnosis, management, and prevention of tuberculosis among all
care providers offering services for tuberculosis and to facilitate coordination of activities
and collaboration between tuberculosis control programs and non-program providers.
Given that public health authorities are responsible for normative functions, surveillance,
monitoring, evaluation, and reporting, it is crucial that there is coordination between con-
trol programs and non-program providers, especially in dealing with complicated issues
such as diagnosis and management of patients with drug-resistant tuberculosis. The
14 I STC 3 r d e dition , 2014 introduction

ISTC provides a common ground of understanding on which to build collaborations at
national, regional, or local levels, or even within individual institutions.
The basic principles of care for persons with, or suspected of having, tuberculosis are the
same worldwide: a diagnosis should be established promptly and accurately; standard-
ized treatment regimens of proven efficacy should be used, together with appropriate
treatment support and supervision; the response to treatment should be monitored; and
the essential public health responsibilities must be carried out. Additionally, persons at
increased risk of tuberculosis should be identified, evaluated, and preventive measures
applied when appropriate.1 The ways in which these principles are applied vary depending
on available technology and resources. However, prompt, accurate diagnosis and effec-
tive timely treatment are not only essential for good patient care; they are the key elements
in the public health response to tuberculosis and are the cornerstone of tuberculosis
control. Thus, all providers who undertake evaluation and treatment of patients with
tuberculosis must recognize that, not only are they delivering care to an individual, they
are also assuming an important public health function that entails a high level of respon-
sibility to the community, as well as to the individual patient.
Audience
The ISTC is addressed to all health care providers, private and public, who care for per-
sons with proven tuberculosis, with symptoms and signs suggestive of tuberculosis, or
with factors that place them at increased risk of developing the disease. In many instances
clinicians (both private and public) who are not part of a government-coordinated tuber-
culosis control program lack the guidance and systematic evaluation of outcomes pro-
vided by programs and, commonly, are not in compliance with the ISTC. Although gov-
ernment program providers are not exempt from adherence to the ISTC, non-program
providers are the main target audience. It should be emphasized, however, that public
tuberculosis control programs may need to develop policies and procedures that enable
non-program providers to adhere to the ISTC. Such accommodations may be necessary,
for example, to facilitate treatment supervision and contact investigations.6-8 In addition to
health care providers and government tuberculosis programs, both patients and commu-
nities are part of the intended audience. Patients are increasingly aware of and have the
right to care that measures up to a high standard, as described in the Patients’ Charter
for Tuberculosis Care (available at http://www.istcweb.org and at http://www.who.int/tb/
publications/2006/istc_charter.pdf). Having generally agreed upon standards will
empower patients to evaluate the quality of care they are being provided. Good care for
individuals with tuberculosis is also in the best interest of the community. Community
contributions to tuberculosis care and control are increasingly important in raising public
awareness of the disease, providing treatment support, encouraging adherence, reducing
the stigma associated with having tuberculosis, and demanding that health care providers
in the community adhere to a high standard of tuberculosis care.9 The community should
expect that care for tuberculosis will be up to the accepted standard and, thus, create a
demand for high quality services.

The standards Scope
focus on the The ISTC draws from a number of existing WHO guidelines and recommendations devel-
contribution that oped using modern rigorous methodology to provide its evidence base. In addition, gen-
erally we have cited summaries, meta-analyses, and systematic reviews of evidence that
good clinical care have examined and synthesized primary data, rather than referring to the primary data
of individual patients themselves. Throughout the document we have used the terminology recommended in
the Definitions and Reporting Framework for Tuberculosis, 2013 Revision.10
with or suspected
The ISTC is intended to be complementary to and provide support for local and national
of having
tuberculosis control policies that are consistent with WHO recommendations. They are
tuberculosis makes not intended to replace local guidelines and were written to accommodate local differ-
to population-based ences in practice while at the same time fostering a high standard of care. They focus on
the contribution that good clinical care of individual patients with or suspected of having
tuberculosis tuberculosis makes to population-based tuberculosis control. A balanced approach
control. emphasizing both individual patient care and public health principles of disease control is
essential to reduce the suffering and individual and community economic losses from
tuberculosis.
To meet the requirements of the ISTC, approaches and strategies determined by local cir-
cumstances and practices and developed in collaboration with local and national public
health authorities will be necessary. There are many situations in which local conditions,
practices, and resources will support a level of care beyond what is described in the ISTC.
The ISTC should be viewed as a living document that will be revised as technology,
resources, and circumstances change. As written, the standards are presented within a
context of what is generally considered to be feasible now or in the near future. Within the
standards priorities may be set that will foster appropriate incremental changes, such as
moving in a stepwise from no, or very limited, drug susceptibility testing to universal testing.
The ISTC is also intended to serve as a companion to and support for the Patients’ Char-
ter for Tuberculosis Care. The Charter specifies patients’ rights and responsibilities and
serves as a set of standards from the point of view of the patient, defining what the patient
should expect from the provider and what the provider should expect from the patient.
An additional use of the ISTC has been to serve as a model framework for adaptation (see
below) by countries or regions as has been done, for example, for the European Union
and India.11,12
There are several critical areas that are beyond the scope of the document. The ISTC
does not address the issue of access to care. Obviously, if there is no care available, the
quality of care is not relevant. Additionally, there are many factors that impede access
even when care is available: poverty, gender, stigma, and geography are prominent
among the factors that interfere with persons seeking or receiving care. Also, if the resi-
dents of a given area perceive that the quality of care provided by the local facilities is
substandard, they will not seek care there. This perception of quality is a component of
access that adherence to these standards will address.3
Also not addressed by the ISTC is the necessity of having a sound, effective tuberculosis
control program based on established public health principles. The level of care described

in the ISTC cannot be achieved without there being an enabling environment, generally
provided by an effective public health program supported by appropriate legal and regu-
latory framework and financial resources. The requirements of such programs are described
in publications from the WHO, the US Centers for Disease Control and Prevention (CDC),
and The International Union Against Tuberculosis and Lung Disease (The Union).13-16 Hav-
ing an effective control program at the national or local level with linkages to non-program
providers enables bidirectional communication of information including case notification,
consultation, patient referral, provision of drugs or services such as treatment supervision/
support for private patients, and contact evaluation. In addition, the program may be the
only source of quality-assured laboratory services for the private sector.
In providing care for patients with or suspected of having tuberculosis, or at risk of the
disease, clinicians and persons responsible for health care facilities should take measures
that reduce the potential for transmission of M. tuberculosis to health care workers and to
other patients by following local, national, or international guidelines for infection con-
trol.17-19 This is especially true in areas or specific populations with a high prevalence of
HIV infection. Detailed recommendations are contained in the WHO document, WHO Policy
on TB Infection Control in Health-care Facilities, Congregate Settings and Households.18
Rationale
Although in the past decade there has been substantial progress in the development and
implementation of the strategies necessary for effective tuberculosis control, the disease
remains an enormous global health problem.20,21 It is estimated that one-third of the
world’s population is infected with M. tuberculosis, mostly in developing countries where
95% of cases occur. In 2012, there were an estimated 8.6 million new cases of tubercu-
losis. The number of tuberculosis cases that occur in the world each year has been
declining slightly for the past few years, and the global incidence per 100,000 population
is decreasing at slightly more than 2%/year.21 Incidence, prevalence, and mortality are
now decreasing in all six of the WHO regions. In Africa, the case rate has only recently
begun to decrease but remains very high both because of the epidemic of HIV infection
in sub-Saharan countries and the poor health systems and primary care services through-
out the region. In Eastern Europe, after a decade of increases, case rates reached a pla-
teau in the early 2000’s and now have begun to decrease slightly. The increases in the
1990’s are attributable to the collapse of the public health infrastructure, increased pov-
erty, and other socio-economic factors complicated further by the high prevalence of
drug-resistant tuberculosis.22 In many countries, because of incomplete application of
effective care and control measures, tuberculosis case rates are either stagnant or
decreasing more slowly than should be expected. This is especially true in high-risk
groups such as persons with HIV infection, the homeless, and recent immigrants. The
failure to bring about a more rapid reduction in tuberculosis incidence, at least in part,
relates to a failure to fully engage non-tuberculosis control program providers in the pro-
vision of high quality care, in coordination with local and national control programs. Fos-
tering such engagement is an important purpose of the ISTC.6
It is widely recognized that many providers are involved in the diagnosis and treatment of
tuberculosis.23 Traditional healers, general and specialist physicians in private practice,

The failure to bring nurses, clinical officers, academic physicians, unlicensed practitioners, and community
organizations, among others, all play roles in tuberculosis care and, therefore, in tubercu-
about a more rapid losis control. In addition, other public providers, such as those working in prisons, army
reduction in hospitals, or public hospitals and facilities, regularly evaluate persons suspected of having
tuberculosis and treat patients who have the disease.
tuberculosis
Little is known about the adequacy of care delivered by non-program providers, but evi-
incidence relates to
dence from studies conducted in many different parts of the world show great variability
a failure to fully in the quality of tuberculosis care, and poor quality care continues to plague global tuber-
engage non- culosis control efforts even in low-prevalence, high-income settings.24,25 A global situation
assessment reported by WHO suggested that delays in diagnosis were common.26,27 The
tuberculosis control delay was more often in receiving a diagnosis rather than in seeking care, although both
program providers elements have been shown to be important.27,28 Even after a patient is found to have a
positive sputum smear, delays are common.29 The WHO survey and other studies also
in the provision of show that clinicians, in particular those who work in the private health care sector, often
high quality care, in deviate from standard, internationally recommended, tuberculosis management prac-
tices. These deviations include under-utilization of sputum smear microscopy for diagno-
coordination with
sis, generally associated with over-reliance on radiography; use of non-recommended
local and national drug regimens with incorrect combinations of drugs and mistakes in both drug dosage
control programs. and duration of treatment; and failure to supervise and assure adherence to treat-
ment.25,26,30-36 Recent evidence also suggests over-reliance on poorly validated or inappro-
priate diagnostic tests such as serologic assays, often in preference to conventional bac-
teriological evaluations.37 Because of the unreliability of these tests the WHO has taken
the unusual step of specifically recommending against their use.38
Together, these findings highlight flaws in health care practices that lead to substandard
tuberculosis care for populations that, sadly, are most vulnerable to the disease and are
least able to bear the consequences of such systemic failures. Any person anywhere in
the world who is unable to access quality health care should be considered vulnerable to
tuberculosis and its consequences.3 Likewise, any community with no or inadequate
access to appropriate diagnostic and treatment services for tuberculosis is a vulnerable
community. The ISTC is intended to reduce vulnerability of individuals and communities to
tuberculosis by promoting high quality care for persons with, or suspected of having,
tuberculosis.
There is also an ethical imperative, which applies equally to program and non-program
providers, to the provision of effective, appropriate tuberculosis care.39 Tuberculosis care
(including prevention) is a public good. The disease not only threatens the health of indi-
viduals, the health of the community is also at risk. It is generally agreed that universal
access to health care is a human right and governments have the ethical responsibility to
ensure access, a responsibility that includes access to quality-assured tuberculosis ser-
vices. In particular, tuberculosis disproportionately affects poor and marginalized people,
groups that governments and health care systems have an ethical obligation to protect.
Tuberculosis not only thrives on poverty, it breeds poverty by consuming often very limited
personal and family resources. Poor care compounds the costs that already impover-
ished individuals and families cannot afford and commonly results in persons being unable
to work for long periods while at the same time incurring catastrophic costs.40,41 Substan-
dard care, be it on the part of program or non-program providers, is unethical. The care and

control measures in the ISTC describe approaches to tuberculosis care, control, and
prevention that are consistent with the ethical standards articulated by the Guidance on
Ethics of Tuberculosis Prevention, Care, and Control developed by the WHO.39
Utilization of the ISTC

The ISTC is potentially a very powerful tool to improve the quality of tuberculosis care.
Because of the way in which the ISTC was developed and the international endorsements
it has received through the two previous editions, the document is authoritative and
broadly credible across categories of practitioners. This credibility is a major strength of
the ISTC and should be capitalized upon in its utilization. A variety of possible ways in
which the ISTC can be utilized is summarized in Annex 2.
Ideally, the ISTC should be used in conjunction with a set of tools developed by WHO,
Public-Private Mix for TB Care and Control: A Toolkit.6 The tools included in the Toolkit
present a framework for analyzing the role of all sectors in providing tuberculosis care and
control and a variety of tools to facilitate engagement of all providers. In addition, the ISTC
should be used in conjunction with the Patients’ Charter for Tuberculosis Care, which was
developed in tandem with the ISTC and specifies the rights and responsibilities of patients.
A third document developed by The Union, Management of Tuberculosis: A Guide to the
Essentials of Good Practice16, focuses on the critical roles of nurses and other health
workers in providing tuberculosis services and in managing tuberculosis control pro-
grams. Taken together these documents provide a framework and guidance that can be
used to develop a tailored, comprehensive multi-sectoral approach to tuberculosis care
and control at the local or national level, with each component having a set of defined
roles and responsibilities.
Adaptation of the ISTC

The ISTC has been developed for a global audience and it is expected and desirable that
regions and countries adapt and operationalize the document to suit their own circum-
stances. These circumstances include consideration of the epidemiology of tuberculosis
and the facilities and resources available in both the public and private sectors. The ulti-
mate goal of these adaptations should be to improve the quality of services for tubercu-
losis within a more limited setting. Ideally, a consultative process involving all relevant
stakeholders should be undertaken to ensure that the adaptation of the ISTC is appropri-
ate for the environment and provides appropriate guidance for implementation of the
practices described in the document. Moreover, broad input is necessary to ensure that
the document reflects the perspectives of all sectors of the health care system and cre-
ates a sense of ownership of and commitment to the principles and practices described
in the ISTC.
As with any set of guidelines, there should be establishment of an effective and standard-
ized monitoring and evaluation (M&E) system. To enable global M&E it is strongly sug-
gested that adaptations retain the title International Standards for Tuberculosis Care as
part of the adapted document’s title.

Standard 1. To ensure early diagnosis, providers must be aware of individual and group risk
factors for tuberculosis and perform prompt clinical evaluations and appropriate
diagnostic testing for persons with symptoms and findings consistent with tuber-
culosis.
Providers must Rationale and Evidence Summary
recognize that in Providers must recognize that in evaluating persons who may have tuberculosis they are
assuming an essential public health function that entails a high level of responsibility to the
evaluating persons community as well as to the individual patient. Early and accurate diagnosis is critical to
who may have tuberculosis care and control.42 Despite dramatically improved access to high quality
tuberculosis services during the past two decades21, there is substantial evidence that
tuberculosis they
failure to identify cases early is a major weakness in efforts to ensure optimal outcomes
are assuming an for the patient and to control the disease. Diagnostic delays result in ongoing transmission
essential public in the community and more severe, progressive disease in the affected person.
health function that There are three main reasons for delays in diagnosing tuberculosis: the affected person
either not seeking or not having access to care; the provider not suspecting the disease;
entails a high level and the lack of sensitivity of the most commonly available diagnostic test, sputum (or
of responsibility to other specimen) smear microscopy.27,28,42 Approaches to reducing these delays are, obvi-
ously, quite different. Reducing delays on the part of the affected person entails providing
the community as
accessible health care facilities, enhancing community and individual awareness, and
well as to the active case-finding in high risk populations—all of which are largely beyond the scope of
this document.9 Reducing provider delay is best approached by increasing provider
individual patient.
awareness of the risks for and symptoms of tuberculosis and of the appropriate and avail-
able WHO-approved diagnostic tests in their communities. Rapid molecular tests that
increase both the speed and the sensitivity for identifying Mycobacterium tuberculosis are
increasingly available and, in some situations as described in Standards 3, 5, and 6, are
the recommended initial diagnostic test.
Providers commonly fail to initiate appropriate investigations when persons with symp-
toms suggestive of tuberculosis, especially respiratory symptoms, seek care.29 Of partic-
ular note, in at least one study women were less likely to receive an appropriate diagnos-
tic evaluation than men.43 There must be a clinical suspicion of tuberculosis before proper
20 I STC 3 r d e dition , 2014 standards for diagnosis Standard 1

diagnostic tests are ordered. Clinical suspicion is prompted largely by the presence of
clinical symptoms, suggestive radiographic findings, and by awareness of co-morbidities
and epidemiological circumstances that increase the risk of tuberculosis in an individual
patient. These risks are summarized in the WHO guidelines for screening for tuberculo-
sis.1 Vulnerable groups such as persons living with HIV and other co-morbidities, children,
and populations at increased risk such as prisoners and persons living in high-incidence
urban areas require special attention, even in the absence of typical symptoms, as noted
subsequently.
Standard 2. All patients, including children, with unexplained cough lasting two or more weeks
or with unexplained findings suggestive of tuberculosis on chest radiographs
should be evaluated for tuberculosis.
Rationale and Evidence Summary
The most commonly reported symptom of pulmonary tuberculosis is persistent cough

that generally, but not always, is productive of mucus and sometimes blood (hemoptysis).
In persons with tuberculosis the cough is often accompanied by systemic symptoms
such as fever, night sweats, and weight loss. In addition, findings such as lymphadenop-
athy consistent with concurrent extrapulmonary tuberculosis, may be noted, especially in
patients with HIV infection. However, chronic cough with sputum production is not always
present, even among persons having sputum smears showing acid-fast bacilli. Data from
several tuberculosis prevalence surveys show that an important proportion of persons
with active tuberculosis do not have cough of 2 or more weeks that conventionally has
been used to define suspected tuberculosis.44-46 In these studies 10–25% of patients with
bacteriologically-confirmed tuberculosis do not report cough. These data suggest that
evaluation for tuberculosis, using a symptom review that includes, in addition to cough of
2 weeks or more, cough of any duration, fever, night sweats, or weight loss, may be indi-
cated in select risk groups, especially in areas where there is a high prevalence of the
disease and in high risk populations and individuals with increased susceptibility, such as
persons with HIV infection.1 Use of this broadened set of questions in a population of
PLHIV was found to have a negative predictive value of 97.7% for tuberculosis.47
Although many patients with pulmonary tuberculosis have cough, the symptom is not
specific to tuberculosis; it can occur in a wide range of respiratory conditions, including
acute respiratory tract infections, asthma, and chronic obstructive pulmonary disease.48
Having cough of 2 weeks or more in duration serves as the criterion for defining sus-
pected tuberculosis and is used in most national and international guidelines, particularly
in areas of moderate to high prevalence of tuberculosis, as an indication to initiate an
evaluation for the disease.16,49,50 In a survey conducted in primary health care services of
9 low- and middle-income countries with a low prevalence of HIV infection, respiratory
complaints, including cough, constituted on average 18.4% of symptoms that prompted
a visit to a health center for persons older than 5 years of age.51 Of this group, 5% of
patients overall were categorized as possibly having tuberculosis because of the pres-
ence of an unexplained cough for more than 2–3 weeks. This percentage varies some-
what depending on whether there is pro-active questioning concerning the presence of

cough. Respiratory conditions, therefore, constitute a substantial propor-
tion of the burden of diseases in patients presenting to primary health
care services.
Even in patients with cough of less than 2 weeks there may be an appre-
ciable prevalence of tuberculosis. An assessment from India demon-
strated that by using a threshold of ≥2 weeks to prompt collection of
sputum specimens, the number of patients with suspected tuberculosis
increased by 61% but, more importantly, the number of tuberculosis cases
identified increased by 46% compared with a threshold of >3 weeks.52 The
results also suggested that actively inquiring as to the presence of cough in all
adult clinic attendees may increase the yield of cases; 15% of patients who, with-
Missed out prompting, volunteered that they had cough, had positive smears. In addition, 7% of
patients who did not volunteer that they had cough but, on questioning, admitted to
opportunities for having cough ≥ 2 weeks had positive smears.
earlier detection of
In countries with a low prevalence of tuberculosis, it is likely that chronic cough will be due
tuberculosis lead to to conditions other than tuberculosis. Conversely, in high prevalence countries, tubercu-
increased disease losis will be one of the leading diagnoses to consider, together with other conditions, such
as asthma, bronchitis, and bronchiectasis that are common in many areas. Tuberculosis
severity for the should also be considered in the differential diagnosis of community acquired pneumonia,
patients and a especially if the pneumonia fails to resolve with appropriate antimicrobial treatment.53,54
Several features have been identified that suggest tuberculosis in patients hospitalized for
greater likelihood community acquired pneumonia. These are age less than 65 years, night sweats, hemop-
of transmission of tysis, weight loss, exposure to tuberculosis, and upper lobe opacities on chest radiograph.54
M. tuberculosis to Unfortunately, several studies suggest that not all patients with respiratory symptoms
receive an adequate evaluation for tuberculosis.26-30,32-35,43,55-58 These failures result in
family members
missed opportunities for earlier detection of tuberculosis and lead to increased disease
and others in the severity for the patients and a greater likelihood of transmission of M. tuberculosis to fam-
community. ily members and others in the community.
Although sputum (or other specimen) smear microscopy remains the most widely avail-
able test to establish a microbiological diagnosis, other more sensitive means of identify-
ing M. tuberculosis, particularly rapid molecular tests, are rapidly gaining acceptance as
their performance and applicability are increasingly understood.59,60 Table 2 presents a
succinct summary of the performance and evidence base for the various diagnostic tests
for tuberculosis.
In many settings chest radiographic examination is the initial test used for persons with
cough since it is a useful tool to identify persons who require further evaluation to deter-
mine the cause of radiographic abnormalities, including tuberculosis.1 Thus, radiographic
examination (film, digital imaging, or fluoroscopy) of the thorax or other suspected sites of
involvement may serve as the entry point for a tuberculosis diagnostic evaluation. Also,
chest radiography is useful to evaluate persons who are suspected of having tuberculosis
but have negative sputum smears and/or negative Xpert MTB/RIF. The radiograph is use-
ful to find evidence of pulmonary tuberculosis and to identify other abnormalities that may
be responsible for the symptoms. However, a diagnosis of tuberculosis cannot be estab-
lished by radiography alone. Although the sensitivity of chest radiography for the pres-

ence of tuberculosis is high, the specificity is low, as shown in Table 2. Reliance on the
chest radiograph as the sole test for the diagnosis of tuberculosis will result in both over-
diagnosis of tuberculosis and missed diagnoses of tuberculosis and other diseases. Thus,
the use of radiographic examinations alone to diagnose tuberculosis is unacceptable.
Scoring systems in which the likelihood of tuberculosis is estimated based on specific

radiographic criteria, each of which is given a preset value, have similar sensitivity and
specificity as radiographic assessment not using a scoring system.61 Such systems are
useful in ruling-out pulmonary tuberculosis, particularly for infection control purposes in
hospitals, but their low specificity precludes ruling-in tuberculosis.
Table 2 .
WHO-approved microbiologic tests for tuberculosis
Test Site Major Findings/results of Systematic Reviews
Diagnosis of Active Tuberculosis
Sputum smear Pulmonary • Fluorescence microscopy is on average 10% more sensitive than conventional
microscopy microscopy. Specificity of both fluorescence and conventional microscopy is
similar. Fluorescence microscopy is associated with improved time efficiency.62
• Same-day sputum smear microscopy is as accurate as standard smear
microscopy. Compared with the standard approach of examination of two smears
with light microscopy over 2 days, examination of two smears taken on the same
day had much the same sensitivity (64% for standard microscopy vs 63% for
same-day microscopy) and specificity (98% vs 98%)63-65
Nucleic acid Pulmonary and • Commercial, standardized NAATs have high specificity and positive predictive
amplification tests extra-pulmonary value, however, they have relatively lower (and highly variable) sensitivity and
(NAATs) [other than TB negative predictive value for all forms of TB, especially in smear-negative and
Xpert MTB/RIF] extrapulmonary disease.66-73
Xpert MTB/RIF Pulmonary TB • Xpert MTB/RIF used as an initial diagnostic test for detection of M. tuberculosis
and and rifampicin is sensitive and specific. Xpert MTB/RIF is also valuable as an
extrapulmonary add-on test following microscopy for patients who are smear-negative. An Xpert
TB and RIF MTB/RIF result that is positive for rifampicin resistance should be carefully
resistance interpreted and take into consideration the risk of MDR TB in a given patient and
the expected prevalence of MDR TB in a given setting.73
• When used as an initial test replacing smear microscopy Xpert MTB/RIF achieved
a pooled sensitivity of 88% and pooled specificity of 98%. The pooled sensitivity
was 98% for smear-positive, culture-positive cases and 68% for smear-negative
cases; the pooled sensitivity was 80% in people living with HIV.73
• For detection of rifampicin resistance Xpert MTB/RIF achieved a pooled sensitivity
of 94% and pooled specificity of 98%.73
Automated liquid Pulmonary TB • Automated liquid cultures are more sensitive than solid cultures; time to detection
cultures and rapid and is more rapid than solid cultures.72,74
MPT64-based extrapulmonary
• MPT64-based rapid immunochromatographic tests (ICT) for species identification
species TB; speciation
has high sensitivity and specificity.75
identification tests

Table 3 .
Performance of chest radiography as a diagnostic test for tuberculosis
Radiographic Finding (modified from Ref 1)
Pooled Sensitivity (%) Pooled Specificity (%)
Any abnormality compatible with TB (active or inactive) 98 (95–100) 75 (72–79)
Abnormalities suggestive of active TB 87 (79– 95) 89 (87–92)
After positive screening for symptoms (one study) 90 (81– 96) 56 (54–58)
Chest radiography scoring systems61 96 (93– 98) 46 ( 35–50)
Standard 3. All patients, including children, who are suspected of having pulmonary tuberculo-
sis and are capable of producing sputum should have at least two sputum speci-
mens submitted for smear microscopy or a single sputum specimen for Xpert®
MTB/RIF* testing in a quality-assured laboratory. Patients at risk for drug resis-
tance, who have HIV risks, or who are seriously ill, should have Xpert MTB/RIF
performed as the initial diagnostic test. Blood-based serologic tests and interfer-
on-gamma release assays should not be used for diagnosis of active tuberculosis.
* As of this writing, Xpert® MTB/RIF (Cepheid Corp. Sunnyvale, California, USA) is the only rapid molecular test
approved by WHO for initial use in diagnosing tuberculosis, thus, it is specifically referred to by its trade name
throughout this document.
To establish a diagnosis of tuberculosis every effort must be made to identify the causative
agent of the disease.76 A microbiological diagnosis can only be confirmed by culturing M.
tuberculosis complex or identifying specific nucleic acid sequences in a specimen from
any site of disease. Because the recommended initial microbiological approach to diag-
nosis varies depending on risks for drug resistance, the likelihood of HIV infection and the
severity of illness, clinical assessment must address these factors. Currently, WHO rec-
ommends that the Xpert MTB/RIF assay should be used rather than conventional micros-
copy, culture, and DST as the initial diagnostic test in adults and children suspected of
having MDR TB or HIV-associated tuberculosis.77 Although availability of rapid molecular
tests is rapidly increasing, in practice there are many resource-limited settings in which
rapid molecular tests or culture are not available currently. Microscopic examination of
stained sputum is feasible in nearly all settings and, in high-prevalence areas, finding acid-
fast bacilli in stained sputum is the equivalent of a confirmed diagnosis. It should be noted
that in persons with HIV infection sputum microscopy is less sensitive than in persons
without HIV infection; however, mortality rates are greater in persons with HIV infection
with clinically-diagnosed tuberculosis who have negative sputum smears than among
HIV-infected patients who have positive sputum smears.78,79

Data suggest that a combination of sputum smear microscopy and Xpert MTB/RIF can
substantially increase the diagnostic yield. Xpert MTB/RIF as an add-on test following a
negative smear microscopy result has a sensitivity of 68% and specificity of 99% com-
pared with culture. WHO recommendations also indicate that Xpert MTB/RIF may be
used as the initial test in all patients if resources are available.
More rapid methods of identifying growth of M. tuberculosis such as micro cul-

ture techniques (MODS) and thin layer agar have variable performance char-
acteristics and are not approved for general use by WHO at this time.76
Generally, it is the responsibility of government health systems (national

tuberculosis programs [NTPs] or others) to ensure that providers and
patients have convenient access to quality-assured diagnostic microbi-
ology laboratories. As with any laboratory test it is critical that tuberculo-
sis microbiological examinations be performed in a quality-assured labo-
ratory.
Failure to perform a proper diagnostic evaluation before initiating treat-

ment for tuberculosis potentially exposes the patient to the risks of unnec-
essary or wrong treatment with no benefit. Moreover, such an approach may
delay accurate diagnosis and proper treatment. This standard applies to adults,
adolescents, and children. With proper instruction and supervision many children
five years of age and older can generate a specimen. Thus, age alone is not sufficient
During the past justification for failing to attempt to obtain a sputum specimen from a child or adolescent.
few years Xpert
The optimum number of sputum specimens to establish a diagnosis has been examined
MTB/RIF has been in a number of studies that have served to support recommendations to decrease the
validated under field minimum number of sputum specimens examined from 3 to 2, assuming they are exam-
ined in a quality-assured laboratory. In a systematic review of 37 studies on the yield of
conditions and, in a sputum smear microscopy, it was found that, on average, the initial specimen was posi-
systematic review, tive in 85.8% of all patients ultimately found to have acid-fast bacilli detected, in an addi-
tional 11.9% with the second specimen, and a further 2.3% on the third specimen. In
shown to have studies that used culture as the reference standard, the mean incremental yield in sensi-
excellent tivity of the second specimen was 11.1% and that of the third was 3.1%.64
performance A re-analysis of data from a study involving 42 laboratories in four high-burden countries
showed that the incremental yield from a third sequential specimen ranged from 0.7% to
characteristics
7.2%.80 Thus, it appears that in a diagnostic evaluation for tuberculosis, at least two spec-
for detecting imens should be obtained. In some settings, because of practicality and logistics, a third
M. tuberculosis specimen may be useful, but examination of more than two specimens adds minimally to
the number of positive specimens obtained.64 Ideally, the results of sputum microscopy
and rifampicin should be returned to the clinician within no more than one working day from submission
resistance. of the specimen. Early detection of patients with infectious tuberculosis is an important
component of infection control in health care facilities, thus, sputum specimens should be
collected promptly from patients suspected of having the disease and laboratories should
quickly return the results.
A variety of methods have been used to improve the performance of sputum smear
microscopy.63,64,81 However, a comprehensive systematic review of 83 studies describing

the effects of various physical and/or chemical methods for concentrating and processing
sputum prior to microscopy found highly variable results.63 Moreover, processing increases
complexity and may be associated with increased infection risk to laboratory personnel.
For these reasons these methods are not recommended by WHO for regular use in
low-resource settings.
Fluorescence microscopy (FM), in which auramine-based staining causes the acid-fast

bacilli to fluoresce against a dark background, is widely used in many parts of the world.
A comprehensive systematic review of 45 studies, in which the performance of direct
sputum smear microscopy using fluorescence staining was compared with Ziehl-Neelsen
(ZN) staining using culture as the gold standard, indicates that FM is the more sensitive
method.62 This review showed that FM is on average 10% more sensitive than conven-
tional light microscopy. The specificity of FM was comparable to ZN microscopy. The
combination of increased sensitivity with little or no loss of specificity makes FM a more
accurate test, although the increased cost and complexity has restricted its use in many
areas. For this reason conventional FM has best been used in centers with specifically
trained and proficient microscopists, in which a large number of specimens are processed
daily, and in which there is an appropriate quality control program. However, lower cost,
light emitting diode (LED) fluorescence microscopes with performance characteristics
superior to conventional microscopes are now endorsed by WHO and are widely avail-
able.82
During the past few years Xpert MTB/RIF has been validated under field conditions and,
in a systematic review, shown to have excellent performance characteristics for detecting
M. tuberculosis and rifampicin resistance. The pooled sensitivity estimate was 98% for
specimens that were smear positive and 68% for smear-negative specimens.73 The over-
all sensitivity when used as an initial test in place of smear microscopy was found to be
89% with a specificity of 99%. Among persons with HIV infection the overall sensitivity
was 79% (61% for persons with smear-negative culture positive tuberculosis and 97% for
smear-positive specimens) and the specificity 98%. For detecting rifampicin resistance
the sensitivity was 95% and the specificity 99%. The obvious advantage of Xpert MTB/
RIF, in addition to its performance characteristics, is the rapidity with which an answer can
be obtained—about two hours if the specimen is tested upon receipt in the laboratory—
and its adaptability for use in more peripheral laboratories. It must be emphasized, how-
ever, that optimum benefit from any rapid molecular test can only be realized if the
response to the result is also rapid.
Assessment of the performance characteristics and the practicalities of implementation

(including costs) led WHO to issue recommendations for the use of Xpert MTB/RIF.83 The
WHO evidence synthesis process confirmed a solid evidence base to support widespread
use of Xpert MTB/RIF for detection of M. tuberculosis and rifampicin resistance.22, 59, 73, 83
Based on the evidence WHO recommended that Xpert MTB/RIF:
• should be used rather than conventional microscopy, culture, and drug susceptibil-
ity testing as the initial diagnostic test in individuals presumed to have MDR or
HIV-associated tuberculosis;
• may be used as a follow-on test to microscopy in adults where MDR and HIV is of
lesser concern, especially in further testing of smear-negative specimens;

• may be used rather than conventional microscopy and culture as the initial diagnos-
tic test in all adults presumed to have tuberculosis;
• should be used rather than conventional microscopy, culture, and drug susceptibil-
ity testing as the initial diagnostic test in children presumed to have MDR or HIV-as-
sociated tuberculosis;
• may be used rather than conventional microscopy and culture as the initial diagnos-
tic test in all children presumed to have tuberculosis.
Detection of rifampicin resistance in groups with a low prevalence of MDR TB should be

an uncommon finding and a second Xpert MTB/RIF test on a different sample from the
patient should be performed to exclude errors in performing the test. In patients with
repeated rifampicin resistance, a WHO recommended MDR TB regimen that includes
isoniazid should be initiated. Patients with discordant rifampicin resistance results by
Xpert MTB/RIF should be assumed to have susceptible organisms and be given a first-
line regimen. Discrepancies in the determination of rifampicin resistance by Xpert MTB/
RIF may require resolution by DNA sequencing.83-85
Using Xpert MTB/RIF does not eliminate the need for conventional microscopy, culture,
and drug susceptibility testing that are required to monitor treatment and to detect resis-
tance to drugs other than rifampicin.
Commercial line probe assay performance characteristics have been adequately vali-
dated in direct testing of sputum smear-positive specimens and on isolates of M. tuber-
culosis complex grown from smear-negative and smear-positive specimens. Direct use of
line probe assays on smear-negative clinical specimens is not recommended at present.86
Neither the tuberculin skin test nor Interferon-gamma release assays (IGRAs) have value
for diagnosing active tuberculosis in adults although the result may serve to increase or
decrease the diagnostic suspicion.38,87 Both sensitivity and specificity are generally low
and variable, especially among persons living with HIV.87 Commercial serological antibody
detection tests produce inconsistent and imprecise estimates of sensitivity and specific-
ity.88 For this reason WHO recommends against the use of these tests and the govern-
ments of India and Cambodia have banned their use.38
Standard 4. For all patients, including children, suspected of having extrapulmonary tuberculo-
sis, appropriate specimens from the suspected sites of involvement should be
obtained for microbiological and histological examination. An Xpert MTB/RIF test
on cerebrospinal fluid is recommended as the preferred initial microbiological test
in persons suspected of having tuberculous meningitis because of the need for a
rapid diagnosis.
Extrapulmonary tuberculosis (without associated lung involvement) accounts for at least

15–20% of tuberculosis in populations with a low prevalence of HIV infection.21,89 In pop-
ulations with a high prevalence of HIV infection, the proportion of cases with extrapulmo-
nary tuberculosis is higher. Because appropriate specimens may be difficult to obtain from
some of these sites, bacteriological confirmation of extrapulmonary tuberculosis is often

more difficult than for pulmonary tuberculosis. In spite of the difficulties,
however, the basic principle that bacteriological confirmation of the diag-
nosis should be sought still holds.
Generally, there are fewer M. tuberculosis organisms present in extrapul-

monary sites so identification of acid-fast bacilli by microscopy in specimens
from these sites is less frequent and rapid molecular tests and/or culture are
more important. Microscopic examination of pleural fluid in tuberculous pleuritis
detects acid-fast bacilli in only about 5–10% of cases, and the diagnostic yield is similarly
low in tuberculous meningitis although some studies have reported a higher sensitivity.90,91
Given the low yield of microscopy, both microbiological and histological or cytological
examination of tissue specimens, such as may be obtained by open or closed pleural
biopsy or needle biopsy of lymph nodes, are important diagnostic tests. A systematic
review showed the pooled sensitivity of Xpert MTB/RIF for the detection of TB in cerebro-
spinal fluid (compared with culture) was 79.5%. Although the sensitivity is not optimal, the
speed with which a result is returned makes the test highly useful and, thus, is the pre-
ferred initial test (although culture should be concurrently performed if sufficient specimen
is available). For lymph node tissue and aspirates the sensitivity of Xpert MTB/RIF was
84.9% compared with culture. In pleural fluid the sensitivity was only 43.7%, much greater
than the sensitivity of pleural fluid microscopy, but still not sufficiently sensitive to be used
as the sole test in the evaluation of pleural effusions.77
In view of these findings it is recommended that Xpert MTB/RIF may be used as a replace-
ment test for conventional microscopy, culture, and/or histopathology for testing of gas-
tric lavage fluid and specific non-respiratory specimens.77 However, patients suspected of
having extrapulmonary tuberculosis but with a single Xpert MTB/RIF-negative result
should undergo further diagnostic testing, and those with high clinical suspicion for TB
(especially children) should be treated even if an Xpert MTB/RIF result is negative or if the
test is not available. In patients who have an illness compatible with tuberculosis (pulmo-
nary and/or extrapulmonary) that is severe or progressing rapidly, initiation of treatment
should not be delayed pending the results of microbiological examinations. Even the best
test may not detect tuberculosis when there is a low bacillary load such as occurs in
tuberculous meningitis, in patients with HIV infection, and in young children. In these situ-
ations, or in critically ill patients where tuberculosis is suspected, clinical judgment may
justify empirical treatment while waiting for final test results, or even when test results are
negative.
In addition to the collection of specimens from the sites of suspected tuberculosis, exam-
ination of sputum and a chest radiograph may also be useful, especially in patients with
HIV infection, in whom asymptomatic or minimally symptomatic pulmonary tuberculosis
has been noted.92,93

Standard 5. In patients suspected of having pulmonary tuberculosis whose sputum smears are
negative, Xpert MTB/RIF and/or sputum cultures should be performed. Among
patients with sputum that is negative by smear and Xpert MTB/RIF who have clini-
cal evidence strongly suggestive of tuberculosis, antituberculosis treatment should
be initiated after collection of specimens for culture examination.
The designation of “sputum smear-negative tuberculosis” (now broadened to include

patients with a negative Xpert MTB/RIF test) presents a difficult diagnostic dilemma. In a
systematic review the sensitivity of sputum smear microscopy ranged from 31% to 69%,
thus, many cases may not be identified by smear microscopy alone.64 However, given the
nonspecific nature of the symptoms of tuberculosis and the multiplicity of other diseases
that could be the cause of the patient’s illness, it is important that a rigorous approach be
taken in diagnosing tuberculosis in a patient in whom at least two adequate sputum spec-
imens are negative by microscopy or one specimen is negative by Xpert MTB/RIF.
Ideally, Xpert MTB/ Because patients with HIV infection and tuberculosis frequently have negative sputum
smears, and because of the broad differential diagnosis, including Pneumocystis jiroveci
RIF and, if negative, pneumonia and bacterial and fungal lower respiratory infections, a systematic approach
culture should be to diagnosis is crucial. As indicated in Standard 3, persons who have HIV risks, or who
are seriously ill, Xpert MTB/RIF should be performed as the initial diagnostic test.
included in the
It is important to balance the need for a systematic approach, in order to avoid both over-
evaluation of
and under-diagnosis of tuberculosis, with the need for prompt treatment in a patient with
patients with an illness that is progressing rapidly. Over-diagnosis of tuberculosis when the illness has
negative sputum another cause will delay proper diagnosis and treatment of the true illness, whereas
under-diagnosis will lead to more severe consequences of tuberculosis, including disabil-
smears. ity and possibly death, as well as ongoing transmission of M. tuberculosis. It should be
noted that in making a diagnosis of smear-negative tuberculosis, a clinician who decides
to treat with a full course of antituberculosis chemotherapy should report this as a case of
sputum smear-negative pulmonary tuberculosis to local public health authorities (as
described in Standard 21).
Algorithms, including a widely used approach developed by WHO,94 may present a sys-
tematic approach to diagnosis. Performance of the WHO algorithm has been variable
under field conditions, and there is little information or experience on which to base
approaches to the diagnosis of smear-negative tuberculosis in persons with HIV infection
when culture or Xpert MTB/RIF is not routinely available.95-97
There are several points of caution regarding the use of algorithms for the diagnosis of
smear-negative tuberculosis. First, completion of all of the steps requires a substantial
amount of time; thus, it may not be appropriate for patients with an illness that is pro-
gressing rapidly. This is especially true in patients with HIV infection in whom tuberculosis
and other infections may be rapidly progressive. Second, several studies have shown that
patients with tuberculosis may respond, at least transiently, to broad spectrum antimicro-
bial treatment.98,99 Obviously such a response will lead one to delay a diagnosis of tuber-
culosis. Fluoroquinolones, in particular, are bactericidal for M. tuberculosis complex.
Empiric fluoroquinolone monotherapy for respiratory tract infections has been associated
with delays in initiation of appropriate antituberculosis therapy and acquired resistance to

the fluoroquinolones.100-102 Third, applying all the steps in an algorithm may be costly and
deter the patient from continuing with the diagnostic evaluation. Given all these concerns,
application of a complex sequence of diagnostic steps in patients with at least two nega-
tive sputum specimen examinations and/or one negative Xpert MTB/RIF test must be
done in a flexible manner. Ideally, the evaluation of smear-negative tuberculosis should be
guided by locally-validated approaches, suited to local conditions, and the needs (finan-
cial or otherwise) of the patient.
Ideally, Xpert MTB/RIF and, if negative, culture should be included in the algorithm for
evaluating patients with negative sputum smears. A positive Xpert MTB/RIF will greatly
reduce the time to diagnosis and initiation of appropriate treatment, possibly saving
money as well as staff time. Culture adds a significant layer of complexity and cost but
also increases sensitivity, which should result in case detection earlier in the course of the
disease.103,104 While, commonly, the results of culture are not be available until after a
decision to begin treatment has to be made, treatment can be stopped subsequently if
cultures from a reliable laboratory are negative, the patient has not responded clinically,
and the clinician has sought other evidence in pursuing the differential diagnosis. It must
be emphasized that, for seriously ill patients (particularly patients with HIV infection), a
clinical decision to start treatment often must be made without waiting for the results of
cultures. Such patients may die if appropriate treatment is not begun promptly. A rapid
molecular test such as Xpert MTB/RIF, although less sensitive than culture on liquid media
(but equal in sensitivity to culture on solid media), especially for smear-negative speci-
mens, has the clear advantage of providing a result very quickly, thus, enabling appropri-
ate treatment to be initiated promptly.85
The probability of finding acid-fast bacilli in sputum smears by microscopy is directly

related to the concentration of bacilli in the sputum. Sputum microscopy is likely to be
positive when there are at least 10,000 organisms per milliliter of sputum. At concentra-
tions below 1,000 organisms per milliliter of sputum, the chance of observing acid-fast
bacilli in a smear is less than 10%.105,106 In contrast, a properly performed culture, espe-
cially if liquid media are used, can detect far lower numbers of acid-fast bacilli (detection
limit is about 100 organisms per ml).104 The culture, therefore, has a higher sensitivity than
microscopy and, at least in theory, can increase case detection, although this potential
has not been demonstrated in low-income, high-incidence areas. Further, culture makes
it possible to identify the mycobacterial species and to perform full drug susceptibility
testing in patients in whom there is reason to suspect drug-resistant tuberculosis.104 The
disadvantages of culture are its cost, technical complexity, infrastructure requirements,
and the time required to obtain a result. In addition, ongoing quality assessment is essen-
tial for culture results to be credible.
In many countries, although culture facilities are not uniformly available, there is the capac-
ity to perform culture or rapid molecular testing in some areas. Providers should be aware
of the local capacity and use the resources appropriately, especially for the evaluation of
persons suspected of having tuberculosis who have negative sputum smears and for
persons with HIV infection or who are suspected of having tuberculosis caused by
drug-resistant organisms.

Traditional culture methods use solid media such as Lowenstein-Jensen and Ogawa.
Cultures on solid media are less technology-intensive and the media can be made locally.
However, the time to identify growth is significantly longer than in liquid media systems
such as the MGIT® system. Decisions to provide culture facilities for diagnosing tubercu-
losis depend on financial resources, infrastructure, trained personnel, and the ready avail-
ability of supplies and service for the equipment.
There is good evidence that liquid cultures are more sensitive and rapid than
solid media cultures and is the gold standard reference method.107 WHO has
issued policy guidance on the use of liquid media for culture and drug sus-
ceptibility testing in low-resource settings.108 This policy recommends
phased implementation of liquid culture systems as a part of a coun-
try-specific comprehensive plan for laboratory capacity strengthening
that addresses issues such as biosafety, training, maintenance of infra-
structure, and reporting of results. However, development of the capac-
ity to do cultures requires a well-functioning health care system, ade-
quate laboratory infrastructure, and trained personnel.
In June 2008, WHO endorsed the use of molecular line-probe assays for
rapid screening of patients at risk of MDR TB.86 This policy statement was
based in part on evidence summarized in systematic reviews,107 expert opin-
ion, and results of field demonstration projects. The recommended use of line
probe assays is currently limited to culture isolates and direct testing of smear-posi-
tive sputum specimens. Line probe assays are not recommended as a complete replace-
ment for conventional culture and drug susceptibility testing. Culture is still required for
smear-negative specimens, and conventional drug susceptibility testing is still necessary
to confirm resistance to drugs other than isoniazid and rifampicin.
Chest radiography may also play an important role in the evaluation of persons suspected
of having tuberculosis but who have negative sputum smears. Cough is a nonspecific
symptom; the chest radiograph can assist in determining the cause of the cough in per-
sons with negative sputum smear microscopy. Commonly, in areas where adequate
radiographic facilities are available the chest radiograph is obtained as the first test. Find-
ing an abnormality consistent with tuberculosis should prompt the ordering of sputum
specimens. Although the radiograph is a useful adjunct in diagnosing tuberculosis, as
noted above, the radiograph alone cannot establish a diagnosis. However, in combination
with clinical assessment, the radiograph may provide important circumstantial evidence
as to the diagnosis.109
It is important to note that, just as with the microbiology laboratory, radiography requires
quality control, both in terms of technical quality and interpretation. There are several
resources that are useful both for assuring technical quality of the radiograph and for
interpretation of the findings.109-111

Standard 6. For all children suspected of having intrathoracic (i.e., pulmonary, pleural, and
mediastinal or hilar lymph node) tuberculosis, bacteriological confirmation should be
sought through examination of respiratory secretions (expectorated sputum,
induced sputum, gastric lavage) for smear microscopy, an Xpert MTB/RIF test,
and/or culture.
The diagnosis of tuberculosis in children relies on a thorough assessment of all the evi-
dence derived from a careful history of exposure, clinical examination, and other relevant
investigations. Although most children with tuberculosis have pulmonary involvement,
they commonly have paucibacillary disease without evident lung cavitation but frequently
with involvement of intrathoracic lymph nodes. Consequently, compared with adults, spu-
tum smears from children are more likely to be negative. Although bacteriological confir-
mation of tuberculosis in children is not always feasible, it should be sought whenever
possible by sputum (or other specimen) examination with Xpert MTB/RIF, smear micros-
copy, and culture.77,112-116 Because many children less than five years of age do not cough
and produce sputum effectively, culture of gastric lavage obtained by naso-gastric tube or
induced sputum has a higher yield than spontaneous sputum.115,116 A trial of treatment
with antituberculosis medications is not recommended as a means of diagnosing tuber-
culosis in children. The decision to treat a child for tuberculosis should be carefully con-
sidered and once such a decision is made, the child should be treated with a full course
of therapy. The approach to diagnosing tuberculosis in children recommended by WHO
is summarized in Table 4.114
As a component of evaluating a child for tuberculosis, the social situation and nutritional
status of the child must be taken into account and the need for support services assessed.
The parent or responsible adult must be informed as to the importance of treatment in
order to be an effective treatment supporter.
Table 4 .
Guidance on approach to diagnose TB in children
1. Careful history (including history of TB contact and symptoms consistent with TB)
2. Clinical examination (including growth assessment)
3. Tuberculin skin testing
4. Chest X-ray if available
5. Bacteriological confirmation whenever possible
6. Investigations relevant for suspected pulmonary TB and suspected extrapulmonary TB
7. HIV testing

Several reviews have examined the effectiveness of various diagnostic tools,
scoring systems, and algorithms to diagnose tuberculosis in chil-
dren.112-115,117-119 Many of these approaches lack standardization and vali-
dation, and, thus, are of limited applicability. Though scoring systems and
diagnostic criteria remain widely used in the diagnosis of tuberculosis in
children, validation has been difficult due to lack of an established and
accessible gold standard.120 Estimates of sensitivity and specificity vary
widely, especially in populations with high HIV co-infection.120
In children the risk of tuberculosis is increased when there is an active

case (infectious, smear-positive tuberculosis) in the same house, or when
the child is malnourished, is HIV-infected, or has had measles in the past
few months. WHO’s Integrated Management of Childhood Illness (IMCI)121
program, which is widely used in first-level facilities in low- and middle-income
countries states that tuberculosis should be considered in any child with:
As a component of • Unexplained weight loss or failure to grow normally;
evaluating a child • Unexplained fever, especially when it continues for more than 2 weeks;
• Chronic cough;
for tuberculosis, the • Exposure to an adult with probable or definite pulmonary infectious tuberculosis.
social situation and
Findings on examination that suggest tuberculosis include:
nutritional status of
• Fluid on one side of the chest (reduced air entry, dullness to percussion);
the child must be • Enlarged non-tender lymph nodes or a lymph node abscess, especially in the
taken into account neck;
• Signs of meningitis, especially when these develop over several days and the
and the need for spinal fluid contains mostly lymphocytes and elevated protein;
support services • Abdominal swelling, with or without palpable lumps;
• Progressive swelling or deformity in the bone or a joint, including the spine.
assessed.
Stan

Standard 7. To fulfill her/his public health responsibility, as well as responsibility to the individ-
ual patient, the provider must prescribe an appropriate treatment regimen, monitor
adherence to the regimen and, when necessary, address factors leading to inter-
ruption or discontinuation of treatment. Fulfilling these responsibilities will likely
require coordination with local public health services and/or other agencies.
Failure of a Rationale and Evidence Summary
provider to ensure Effective treatment of tuberculosis prevents ongoing transmission of the infection and the
development of drug resistance and restores the health of the patient. As described in the
adherence could
Introduction, the main interventions to prevent the spread of tuberculosis in the commu-
be equated with, for nity are the early detection of patients with tuberculosis and provision of effective treat-
example, failure to ment to ensure a rapid and lasting cure. Consequently, treatment for tuberculosis is not
only a matter of individual health, as is the case with, for example, treatment of hyperten-
ensure that a child sion or asthma; it is also a matter of public health. Thus, all providers, public and private,
receives the full set who undertake to treat a patient with tuberculosis must have the knowledge to prescribe
a recommended treatment regimen and the means to assess adherence to the regimen
of immunizations. and to address poor adherence to ensure that treatment is completed.14,122 National and
local tuberculosis programs commonly possess approaches and tools, including incen-
tives and enablers, as well as other means of support, to ensure adherence with treat-
ment and, when properly organized, can offer these to non-program providers. Failure of
a provider to ensure adherence could be equated with, for example, failure to ensure that
a child receives the full set of immunizations. Communities and patients deserve to be
assured that providers treating tuberculosis are doing so in accordance with this principle
and are, thereby, meeting this standard.
34 I STC 3 r d e dition , 2014 standards for treatment Standard 7

Standard 8. All patients who have not been treated previously and do not have other risk factors
for drug resistance should receive a WHO recommended first-line treatment regi-
men using quality assured drugs. The initial phase should consist of two months of
isoniazid, rifampicin, pyrazinamide, and ethambutol.* The continuation phase should
consist of isoniazid and rifampicin given for 4 months. The doses of antituberculo-
sis drugs used should conform to WHO recommendations. Fixed-dose combina-
tion drugs may provide a more convenient form of drug administration.
*Ethambutol may be omitted in children who are HIV-negative and who have non-cavitary tuberculosis.
A large number of well-designed clinical trials have provided the evidence base for this
standard and several sets of treatment recommendations based on these studies have
been written in the past few years.14,16,122 All these data indicate that with the current treat-
ment options, a rifampicin-containing regimen is the backbone of antituberculosis che-
motherapy and is highly effective in treating tuberculosis caused by drug-susceptible M.
tuberculosis. It is also clear from these studies that the minimum duration of treatment for
smear- and/or culture-positive tuberculosis is six months. Regimens of less than six
months have an unacceptably high rate of relapse.123 Thus, the current international stan-
dard duration of treatment for tuberculosis is a minimum of six months.14,16,122 For the
six-month treatment duration to be maximally effective, the regimen must include pyrazin-
amide during the initial two-month phase and rifampicin must be included throughout the
full six months. Moreover, a systematic review of the outcome of treatment in the pres-
ence of single or poly-drug resistance (not multidrug resistance) demonstrated that fail-
ure, relapse, and acquisition of additional resistance were associated with shorter dura-
tion of rifampicin therapy.124
A retrospective review of the outcomes of treatment of tuberculosis in patients with HIV

infection showed that relapse is minimized by the use of a regimen containing rifampicin
throughout a six-month course of treatment.125 This finding was confirmed in a more rig-
orous systematic review of treatment of tuberculosis in patients with HIV infection show-
ing that better outcomes were associated with daily use of rifampicin in the initial phase of
treatment and with rifampicin duration of ≥ 8 months. However, these effects of rifampicin
duration were not seen in a small number of studies in which patients also received
antiretroviral treatment.126
There are several variations in the frequency of drug administration that have been shown
to produce acceptable results.14,16,122 Intermittent administration of antituberculosis drugs
enables supervision to be provided more efficiently and economically with no reduction in
efficacy, although daily administration provides a greater margin of safety. The evidence on
effectiveness of intermittent regimens has been reviewed.127-128 These reviews, based on
several trials, suggest that antituberculosis treatment may be given intermittently three times
a week throughout the full course of therapy or twice weekly in the continuation phase
without apparent loss of effectiveness except among individuals with advanced HIV infec-
tion.128-136 However, the WHO does not recommend the use of twice-weekly intermittent
regimens because of the potentially greater consequences of missing one of the two doses.
The evidence base for currently recommended antituberculosis drug dosages derives

from human clinical trials, animal models, and pharmacokinetic and toxicity studies. The
evidence on drug dosages and safety and the biological basis for dosage recommenda-
tions have been extensively reviewed in publications by WHO, ATS, the United States
Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of
America (IDSA), The Union, and others.14,16,122 The recommended daily and thrice weekly
doses are shown in Table 5.
Table 5 .
Doses of first-line antituberculosis drugs in adults and children
Recommended Dose in mg/kg Body Weight (Range)

Drug* Daily Three Times Weekly
Isoniazid**
Children 10 (7–15), maximum 300 mg /day ——
Adults 5 (4–6), maximum 300 mg /day 10 (8 –12), maximum 900 mg/dose
Rifampicin
Children 15 (10–20), maximum 600 mg /day ——
Adults 10 (8–12), maximum 600 mg/day 10 (8 –12), maximum 600 mg/dose
Pyrazinamide
Children 35 (30–40), maximum 2,000 mg /day ——
Adults 25 (20–30), maximum 2,000 mg /day 35 (30 –40), maximum 3,000 mg/dose
Ethambutol
Children 20 (15–25), maximum 1,000 mg /day ——
Adults 15 (15–20), maximum 1,600 mg /day 30 (25–35), maximum 2,400 mg/dose
* The recommended daily doses of all 4 antituberculosis medicines are higher in children who weigh less than
25 kg than in adults, because the pharmacokinetics are different (and to achieve the same plasma concentration
as in adults, the doses need to be increased)
**Same dosing for treatment of active disease and treatment of latent tuberculosis infection
Treatment of tuberculosis in special clinical situations such the presence of liver disease,
renal disease, pregnancy, and HIV infection may require modification of the standard reg-
imen or alterations in dosage or frequency of drug administration. For guidance in these
situations see the WHO and ATS/CDC/IDSA treatment guidelines.14,122
In a clinical trial comparing a fixed-dose combination (FDC) of isoniazid, rifampicin, eth-

ambutol, and pyrazinamide with a regimen of the same drugs given as separate pills,
there was no difference in treatment outcome or adverse effects.137 A systematic review
came to the same conclusion.138 However, because the FDC reduces the number of pills
taken daily in the intensive phase of treatment from 9–16 to 3– 4, patient convenience is
increased and the potential for medication errors is decreased.137,139-141

Standard 9. A patient-centered approach to treatment should be developed for all patients in
order to promote adherence, improve quality of life, and relieve suffering. This
approach should be based on the patient’s needs and mutual respect between the
patient and the provider.
The approach described in the standard is designed to encourage and facil-

itate a positive partnership between providers and patients, working
together to improve adherence. Adherence to treatment is the critical fac-
tor in determining treatment success.14,122 A successful outcome of treat-
ment for tuberculosis, assuming an appropriate drug regimen is pre-
scribed, depends largely on patient adherence to the regimen. Achieving
adherence is not an easy task, either for the patient or the provider. Anti-
tuberculosis drug regimens, as described above, consist of multiple
drugs given for a minimum of six months, often when the patient feels well
(except, perhaps, for adverse effects of the medications). Commonly,
treatments of this sort are inconsistent with the patient’s cultural back-
ground, belief system, and living circumstances. Consequently, it is not sur-
prising that, without appropriate treatment support, a significant proportion of
patients with tuberculosis discontinues treatment before completion of the planned
Interventions that
duration or is erratic in drug taking. Yet, failure to complete treatment for tuberculosis may
target adherence lead to prolonged infectivity, poor outcomes, and drug resistance.
must be tailored or Adherence is a multi-dimensional phenomenon determined by the interplay of several sets
customized to the of factors.13,142 In a systematic review of qualitative research on patient adherence to tuber-
culosis treatment, eight major themes were identified across the studies reviewed (Table
particular situation 6).142 These themes were then further refined into four sets of interacting factors that influ-
and cultural context ence adherence: structural factors including poverty and gender discrimination, the social
context, health service factors, and personal factors. From this synthesis it was concluded
of a given patient. that a group of factors was likely to improve patient adherence. These are listed in Table 7.
Despite evidence to the contrary, there is a widespread tendency to focus on patient-related

factors as the main cause of poor adherence.13,142 Sociological and behavioral research
during the past 40 years has shown that patients need to be supported, not blamed.13 Less
attention is paid to provider and health system-related factors. Several studies have evalu-
ated various interventions to improve adherence to tuberculosis therapy ( Table 7). Among
the interventions evaluated, DOT has generated the most debate and controversy.143,144 The
main advantage of DOT is that treatment is carried out entirely under close, direct supervi-
sion. This provides both an accurate assessment of the degree of adherence and greater
assurance that the medications have actually been ingested. When a second individual
directly observes a patient swallowing medications there is greater certainty that the patient
is actually receiving the prescribed medications. Also, because there is a close contact
between the patient and the treatment supporter, adverse drug effects and other complica-
tions can be recognized quickly and managed appropriately and the need for additional
social support can be identified. Moreover, such case management can also serve to iden-
tify and assist in addressing the myriad other problems experienced by patients with tuber-
culosis such as under-nutrition, poor housing, and loss of income, to name a few.

Table 6 .
Primary themes identified in a systematic review of qualitative research on adherence to

tuberculosis treatment
Organization of treatment and care for TB patients

• Access to services (urban ambulatory, distance, transport)
• Health center problems (long waiting hours, queues, physical condition of clinic)
• Treatment requirements (continuity, charging for drug, number of tablets, DOT, flexibility, and choice)
• Relationship between treatment provider and patient (poor follow up, increased contact, maltreatment of patients)
Interpretation of illness and wellness

• Individual interpretations of recovery
• Perceptions of TB
• Recognition of TB as a disease
Financial burden
• Conflict between work and treatment; costs of treatment; expenses exceeding available resources
• More pressing issues to attend to
• Increased expenditure on food
Knowledge, attitudes, and beliefs about treatment

• Limited understanding of treatment, duration, and consequences of default
• Beliefs about treatment efficacy
• Denial and difficulty accepting diagnosis
• Use of other medication, treatment requirements
Law and immigration

• Completion cards; impact on immigration status; fear of detention
Personal characteristics and adherence behavior

• Substance abuse • Residential mobility • Gender
• Mental illness • Religion • Structured environment

• Ethnic characteristics • Personal motivation • Personal agency
Side effects
• Real, anticipated, or culturally interpreted; insufficient information; insufficient communication; insufficient attention
Family, community, and household influence

• Peer influence • Providing for family • Marriage
• Stigma • Family support
Source: Munro SA, Lewin S A, Smith H J, Engel M E, Fretjheim, A, Volmink J. Patient adherence to tuberculosis treatment: a systematic review of qualitative
research. PLoS Med. 4: 2007; e238.

Table 7 .
Factors likely to improve TB treatment adherence
• Increase the visibility of TB programs in the community, • Increase the patient-centeredness of interactions
which may increase knowledge and improve attitudes between providers and clients
towards TB • Address structural and personal factors, for example
• Provide more information about the disease and compensating high cost of treatment and income loss
treatment to patients and communities through cash transfers, travel vouchers, food
assistance, micro-financing, and other empowerment
• Increase support from family, peers, and social
initiatives and preventing loss of employment though
networks
addressing employment policies.
• Minimize costs and unpleasantness related to clinic
• Provide more information about the effects of
visits and increase flexibility and patient autonomy
medication to reduce the risk of patients becoming
• Increase flexibility in terms of patient choice of nonadherent when experiencing treatment side
treatment plan and type of support effects
Source: Modified from Munro SA, Lewin S A, Smith H J, Engel M E, Fretjheim, A, Volmink J. Patient adherence to tuberculosis treatment: a systematic review of
qualitative research. PLoS Med. 4: 2007; e238.
The exclusive use of health facility-based DOT may be associated with disadvantages
that must be taken into account in designing a patient-centered approach. For example,
these disadvantages may include loss of income and time, stigma and discrimination,
physical hardship, and travel difficulties, all factors that can have an important effect on
adherence. Ideally a flexible mix of health facility- and community-based DOT, often with
a family member serving as a treatment supporter, should be available.145
In a Cochrane systematic review that synthesized the evidence from six controlled trials
comparing DOT with self-administered therapy,143,144 the authors found that patients allo-
cated to DOT and those allocated to self-administered therapy had similar cure rates and
rates of cure plus treatment completion. They concluded that direct observation of med-
ication ingestion did not improve outcomes. A more recent systematic review reached the
same conclusion.146 In contrast, programmatic assessments in several countries have
found DOT to be associated with high cure and treatment completion rates.147-150 It is likely
that these inconsistencies are due to the fact that primary studies are often unable to
separate the effect of DOT alone from the overall DOTS Strategy.13,144 In a retrospective
review of programmatic results, the highest rates of success were achieved with
“enhanced DOT” which consisted of “supervised swallowing” plus social supports, incen-
tives, and enablers as part of a larger program to encourage adherence to treatment.147
Such complex interventions are not easily evaluated within the conventional randomized
controlled trial framework.
Interventions other than DOT have also shown promise.147-150 Incentives, peer assistance
(for example, using cured patients), repeated motivation of patients, and staff training and
motivation, all have been shown to improve adherence significantly.13,142,147 In addition,
adherence may be enhanced by provision of more comprehensive primary care (as
described in the Integrated Management of Adolescent and Adult Illness),151,152 as well as
by provision of specialized services such as opiate substitution for injection drug users.

Providing every patient with a copy of the PCTC short version in their language may also
serve to improve adherence.
Systematic reviews and extensive programmatic experience demonstrate that there is no

single approach to case management that is effective for all patients, conditions, and
settings. Consequently, interventions that target adherence must be tailored or custom-
ized to the particular situation and cultural context of a given patient.13,142 Such an
approach must be developed in concert with the patient to achieve optimum adherence.
This patient-centered, individualized approach to treatment support is now a core ele-
ment of all tuberculosis care and control efforts. It is important to note that treatment
support measures, and not the treatment regimen itself, must be individualized to suit the
unique needs of the patient.
Mobile technologies may provide a means of implementing a “remote DOT” form of

supervision. Most health care workers and many patients in even the poorest countries
are familiar with mobile phone technologies and many use them regularly in their daily
lives. Voice messages, or possibly in the future video reminders, may serve both to sup-
port treatment and to monitor for adverse drug reactions.
In addition to one-on-one support for patients being treated for tuberculosis, community
support is also of importance in creating a therapeutic milieu and reducing stigma.9,153 Not
only should the community expect that optimum treatment for tuberculosis is provided,
but, also, the community should play a role in promoting conditions that facilitate and
assist in ensuring that the patient will adhere to the prescribed regimen.
A number of studies have shown that persons with tuberculosis may incur catastrophic
costs in seeking a diagnosis and appropriate treatment.40,41 Sickness insurance, disability
grants, and other social protection schemes are available in many countries, though they
may not cover the entire population. Persons with tuberculosis may be eligible for financial
support through such schemes, but may not be aware of them or have the capacity to
access them. Health care providers should assist patients to access existing schemes,
including help with administrative procedures, issuing sickness certificates, etc.
Standard 10. Response to treatment in patients with pulmonary tuberculosis (including those
with tuberculosis diagnosed by a rapid molecular test) should be monitored by
follow-up sputum smear microscopy at the time of completion of the initial phase
of treatment (two months). If the sputum smear is positive at completion of the ini-
tial phase, sputum microscopy should be performed again at 3 months and, if pos-
itive, rapid molecular drug sensitivity testing (line probe assays or Xpert MTB/RIF)
should be performed. In patients with extrapulmonary tuberculosis and in children,
the response to treatment is best assessed clinically.
Patient monitoring and treatment supervision are two separate functions. Patient monitor-
ing is necessary to evaluate the response of the disease to treatment and to identify
adverse drug reactions. To judge response of pulmonary tuberculosis to treatment, the
most expeditious method is sputum smear microscopy. Ideally, where quality-assured

laboratories are available, sputum cultures, as well as smears, should be per-
formed for monitoring.
Molecular tests, including Xpert MTB/RIF, are not suitable for patient mon-
itoring because these tests detect residual DNA from non-viable bacilli.154
However, Xpert MTB/RIF is useful for detecting rifampicin resistance in
patients who remain sputum smear positive after 3 or more months of
treatment. Patients whose diagnosis of tuberculosis is confirmed by
Xpert MTB/RIF and who have rifampicin susceptible organisms should
be monitored during treatment with sputum smear microscopy. For these
patients, microscopy should be performed at completion of the intensive
phase of treatment, five months into treatment and at the end of treatment
as per current WHO guidelines.14 Patients with TB and rifampicin resistance
confirmed by Xpert MTB/RIF and placed on MDR TB treatment should be
monitored by sputum smear and culture. If resources permit, monthly culture
throughout treatment is recommended.155,156
A positive sputum
Approximately 80% of patients with sputum smear-positive pulmonary tuberculosis
smear at the end of
should have negative sputum smears at the time of completion of the initial phase of
the initial phase of treatment (2 months of therapy).128 Patients who remain sputum smear-positive require
treatment should particular attention. A positive sputum smear at the end of the initial phase of treatment
should trigger an assessment of the patient’s adherence and a careful re-evaluation to
trigger an determine if co-morbid conditions, particularly HIV infection or other forms of immunosup-
assessment of the pression and diabetes mellitus, are present that might interfere with response to treat-
ment. However, a positive smear at the time of completion of the initial phase is not an
patient’s adherence indication to prolong this phase of treatment. If the sputum smear is positive at month
and a careful clinical two, sputum smear examination should be repeated at month three. Having a positive
sputum smear after completion of three months of treatment raises the possibility of drug
re-evaluation.
resistance and Xpert MTB/RIF, culture, and drug susceptibility testing should be per-
formed in a quality-assured laboratory.14
Chest radiographs may be a useful adjunct in assessing response to treatment but are
not a substitute for microbiologic evaluation. Similarly, clinical assessment can be unreli-
able and misleading in the monitoring of patients with pulmonary tuberculosis especially
in the presence of co-morbid conditions that could confound the clinical assessment.
However, in patients with extrapulmonary tuberculosis and in children, clinical evaluations
may be the only available means of assessing the response to treatment.

Standard 11. An assessment of the likelihood of drug resistance, based on history of prior treat-
ment, exposure to a possible source case having drug-resistant organisms, and the
community prevalence of drug resistance (if known), should be undertaken for all
patients. Drug susceptibility testing should be performed at the start of therapy for
all patients at a risk of drug resistance. Patients who remain sputum smear-positive
at completion of 3 months of treatment, patients in whom treatment has failed, and
patients who have been lost to follow up or relapsed following one or more
courses of treatment should always be assessed for drug resistance. For
patients in whom drug resistance is considered to be likely, an Xpert
MTB/RIF should be the initial diagnostic test. If rifampicin resistance
is detected, culture and testing for susceptibility to isoniazid, fluoro-
quinolones, and second-line injectable drugs should be performed
promptly. Patient counseling and education, as well as treatment
with an empirical second-line regimen, should begin immediately to
minimize the potential for transmission. Infection control measures
appropriate to the setting should be applied.
Drug resistance is largely man-made and is a consequence of suboptimal

regimens and treatment interruptions.25 Clinical errors that commonly lead to
the emergence of drug resistance include: failure to provide effective treatment
support and assurance of adherence; inadequate drug regimens; adding a single
Errors that lead to new drug to a failing regimen; and failure to recognize existing drug resistance. In addition,
co-morbid conditions associated with reduced serum levels of antituberculosis drugs
drug resistance
(e.g., malabsorption, rapid transit diarrhea, use of antifungal agents) and interruptions
include: failure to caused by adverse drug reactions may also lead to the acquisition of drug resistance.157
provide effective Programmatic causes of drug resistance include drug shortages and stock-outs, admin-
istration of poor-quality drugs and lack of appropriate supervision to prevent erratic drug
treatment support, intake.155-157 Transmission of drug-resistant strains of M. tuberculosis has been well
inadequate drug described in health care facilities, congregate settings, and in susceptible populations,
notably HIV-infected persons.158-162 However, multidrug-resistant (MDR) tuberculosis
regimens, adding a (tuberculosis caused by organisms that are resistant to at least isoniazid and rifampicin)
single new drug to may spread in the population at large as was shown in data from a number of countries,
including China, the Baltic States, and countries of the former Soviet Union.163-166
a failing regimen,
and failure to Drug resistance surveillance data suggest that more cases of MDR tuberculosis occur
among new cases of tuberculosis than among previously treated cases, although the pro-
recognize existing portion in the previously treated group is much higher.164 In 2010, 30 countries with anti-
drug resistance. tuberculosis drug resistance surveillance data were each estimated to have more than 700
multidrug-resistant tuberculosis cases among their notified cases each year. Patients who
had not had previous treatment comprised a median of 54% of the MDR cases. The
occurrence of MDR TB in a new patient is an indication that MDR organisms are spreading
in a community. Although case-finding efforts for MDR tuberculosis should first prioritize
previously treated patients for drug sensitivity testing, identification of all MDR TB cases
will require screening for drug resistance in a much wider group of patients.164
The strongest factor associated with drug resistance is previous antituberculosis treat-

ment, as shown by the WHO/IUATLD Global Project on Anti-TB Drug Resistance Surveil-
lance, started in 1994.22,166 In previously treated patients, the odds of any resistance are
at least 4-fold higher, and that of MDR TB at least 10-fold higher, than in new (untreated)
patients.155 Patients with chronic tuberculosis (sputum-positive after re-treatment) and
those who fail treatment (sputum-positive after 5 months of treatment) are at highest risk
of having MDR tuberculosis, especially if rifampicin was used throughout the course of
treatment.155 Persons who are in close contact with confirmed MDR tuberculosis patients,
especially children and HIV-infected individuals, also are at high risk of being infected with
MDR strains. In some closed settings prisoners, persons staying in homeless shelters and
certain categories of immigrants and migrants are at increased risk of MDR tuberculo-
sis.155,167 These factors are summarized and presented in descending order of level of risk
in Table 8.
By the mid-1990’s, most countries participating in the global survey of antituberculosis

drug resistance registered cases of MDR tuberculosis. Not surprisingly, in 2006, exten-
sively drug-resistant (XDR) tuberculosis (defined as tuberculosis caused by M. tuberculo-
sis resistant to at least isoniazid and rifampicin, as well as to any one of the fluoroquinolo-
nes and to at least one of three injectable second-line drugs [amikacin, capreomycin, or
kanamycin]) was described and rapidly recognized as a serious emerging threat to global
public health, as well as being deadly in the initial outbreak.168 Subsequent reports have
identified XDR tuberculosis in all regions of the world and, to date, treatment outcomes
have been significantly worse than MDR tuberculosis outcomes.168-171 In one cohort from
KwaZulu-Natal, 98% of XDR tuberculosis patients co-infected with HIV died, with a
median time of death of only 16 days from time of specimen collection.168 The two stron-
gest risk factors for XDR tuberculosis are:
1. Failure of a tuberculosis treatment which contains second-line drugs including

an injectable agent and a fluoroquinolone.
2. Close contact with an individual with documented XDR tuberculosis or with an indi-
vidual for whom treatment with a regimen including second-line drugs is failing or has
failed.
More recently, strains of M. tuberculosis with resistance patterns beyond XDR tuberculo-
sis have been described. The available evidence suggests that treatment outcomes are
worse when resistance patterns become more complicated.172-174

Table 8 .
Assessing risk for drug resistance
Risk Factors for Resistance Comments
Failure of re-treatment regimen Patients who are still sputum smear-positive at the end of a re-treatment regimen have
(a second course of treatment after perhaps the highest MDR TB rates of any group, often exceeding 80%.
failure, relapse, or default)
Close contact with a known Most studies have shown that tuberculosis occurring in close contacts of persons with
drug-resistant case MDR TB are also likely to have MDR TB.
Failure of the initial treatment Patients who fail to become sputum smear-negative while on treatment are likely to have
regimen drug-resistant organisms. However, the likelihood depends on a number of factors,
including whether rifampicin was used in the continuation phase and whether DOT was
used throughout treatment. Thus, a detailed history of drugs used is essential. This is
especially true for patients treated by private providers, often with non-standard regimens.
Relapse after apparently successful In clinical trials most patients who relapse have fully susceptible organisms. However,
treatment under program conditions an apparent relapse, especially an early relapse, may, in fact, be
an unrecognized treatment failure and thus have a higher likelihood of drug resistance.
Return after default without recent The likelihood of MDR TB varies substantially in this group, depending in part on the
treatment failure duration of treatment and the degree of adherence before default.
Exposure in institutions that have Patients who frequently stay in homeless shelters, prisoners in many countries, and health
outbreaks or a high prevalence of care workers in clinics, laboratories, and hospitals can have high rates of TB with any drug
TB with any drug resistance resistance pattern.
Residence in areas with high Drug-resistant TB rates in many areas of the world can be high enough to justify routine
drug-resistant TB prevalence DST in all new cases.
155
Modified from World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. WHO/HTM/TB/2008.402.
Drug susceptibility testing (DST ) to the first-line antituberculosis drugs should be per-
formed in laboratories that participate in an ongoing, rigorous quality assurance program.
DST for first-line drugs is currently recommended for all patients with a history of previous
antituberculosis treatment; patients who have failed treatment, especially those who have
failed a standardized re-treatment regimen, are the highest priority.156 Testing with Xpert
MTB/RIF is recommended for patients judged to be at risk for having MDR tuberculosis.85
Tests (other than Xpert MTB/RIF) for identifying drug resistance in M. tuberculosis are
shown in Table 9. It should be noted that in some instances phenotypic DST may miss
low level rifampicin resistance due to uncommon mutations in the rpoB gene, thus
accounting for discordance between genotypic and phenotypic methods of performing
DSTs.175,176 The determination of the specificity of a molecular DST method based only on
phenotypic DST as a reference may, therefore, underestimate the specificity of the molec-
ular DST. In light of these findings, it is currently unclear whether and to what extent Xpert
MTB/RIF might out-perform phenotypic DST methods for rifampicin resistance.77
Patients who develop tuberculosis and are known to have been in close contact with
persons known to have MDR tuberculosis also should have DST performed on an initial
isolate. Although HIV infection has not been conclusively shown to be an independent risk

factor for drug resistance, MDR tuberculosis outbreaks in HIV settings and high mortality
rates in persons with MDR tuberculosis and HIV infection justify routine DST in all HIV-in-
fected tuberculosis patients, resources permitting.159,160,162,168
All patients suspected of having XDR tuberculosis should have DST to isoniazid, rifampi-
cin, the second-line injectable agents, and a fluoroquinolone. When epidemiological or
other factors suggest that there is a risk for XDR tuberculosis in a person with HIV infec-
tion, liquid media or other validated rapid techniques for DST of first- and second-line
drugs is recommended. HIV-infected patients with XDR tuberculosis have been observed
to have a rapidly fatal course, thus, in patients (with or without HIV infection) who have a
severe or rapidly progressive illness an empirical treatment regimen, based on interna-
tional recommendations, should be initiated promptly, generally prior to having drug sus-
ceptibility test results.168
Table 9 .
WHO approved tests for identification of drug resistance
Tests Purpose Comments
Line probe assays: Rapid detection The GenoType MTBDR® assays have good sensitivity and specificity for rifampicin
GenoType of rifampicin resistance in AFB positive sputum samples and positive cultures.177 LPAs are
MTBDRplus assays resistance approved by WHO86
Colorimetric redox- Rapid detection WHO recommends NRA and CRI as interim solutions, pending the development of
indicator (CRI) of rifampicin capacities for genotypic DST.178,179
methods and nitrate and isoniazid
reductase assays resistance
(NRA)
Microscopic Rapid detection MODS is suitable for use at reference laboratory level;180 scaling-up and
Observation Drug of rifampicin decentralization to lower level laboratories is not recommended. The WHO
Susceptibility [MODS] and isoniazid recommends MODS as interim solution, pending the development of capacities for
resistance genotypic DST.
Phenotypic drug Detection of DST for isoniazid and rifamipicin shows good reliability and reproducibility when
susceptibility testing resistance to tested in commercial liquid and solid media. WHO recommends that among
methods for first-line first- and Rif-resistant or MDR TB cases, phenotypic testing for all fluoroquinolones (ofloxacin,
and second-line second-line moxifloxacin, levofloxacin) and second-line injectable agents (kanamycin, amikacin,
antituberculosis drugs and capreomycin) available to national TB programmes should be done.181
drugs:
Note: Genotypic methods for detection of second-line drug susceptibility are
available but not approved by WHO.182
Pyrosequencing for Rapid detection Pyrosequencing is a highly sensitive and specific tool for the detection of RIF
RIF resistance of rifampicin resistance in M. tuberculosis. Overall sensitivity and specificity were estimated at
resistance respectively 0.94 (95% CI 0.92– 0.96) and 0.98 (95% CI 0.97–0.99).183
Pyrosequencing is considered the reference method for genotypic DST methods.

Standard 12. Patients with or highly likely to have tuberculosis caused by drug-resistant (espe-
cially MDR/XDR) organisms should be treated with specialized regimens contain-
ing quality-assured second-line antituberculosis drugs. The doses of antitubercu-
losis drugs should conform to WHO recommendations. The regimen chosen may
be standardized or based on suspected or confirmed drug susceptibility patterns.
At least five drugs—pyrazinamide and four drugs to which the organisms are known
or presumed to be susceptible, including an injectable agent—should be used in a
6-8 month intensive phase and at least 3 drugs to which the organisms are known
or presumed to be susceptible, should be used in the continuation phase. Treat-
ment should be given for at least 18–24 months beyond culture conversion.
Patient-centered measures, including observation of treatment, are required to
ensure adherence. Consultation with a specialist experienced in treatment of
patients with MDR/XDR tuberculosis should be obtained.
Because randomized controlled treatment trials for MDR/XDR tuberculosis are difficult to
design, none has been conducted to evaluate currently available regimens of second-line
drugs. However, study designs similar to those used for new antiretroviral drugs in which
a new drug plus an optimized regimen, based on DST, is compared to the optimized
regimen are being used for studies of new drugs for MDR/XDR tuberculosis.184 In the
absence of clinical trial data, current recommendations for treating MDR/XDR tuberculo-
sis are based on observational studies, general microbiological and therapeutic principles,
extrapolation from available evidence from pilot MDR tuberculosis treatment projects,
expert opinion,155,156,169,185-193 and more recently, a carefully conducted individual patient
meta-analysis.194 The individual patient data meta-analysis examined the outcomes of
treatment for MDR tuberculosis and concluded that treatment success, compared with
failure/relapse or death, was associated with use of later generation fluoroquinolones, as
well as ofloxacin, ethionamide or prothionamide, use of four or more likely effective drugs
in the initial intensive phase, and three or more likely effective drugs in the continuation
phase.156,174,194 In addition, not surprisingly, outcomes in patients with XDR tuberculosis
were worse when there was resistance to additional drugs beyond those that comprise
the definition of XDR.172
There are three strategic options for treatment of MDR/XDR tuberculosis: standardized,
empiric, and individualized regimens. The approach is dependent on having access to
either reliable DST results for individual patients or population data on the prevalent resis-
tance patterns. The choice among the three approaches should be based on availability
of second-line drugs and DST for first- and second-line drugs, local drug resistance pat-
terns, and the history of use of second-line drugs.155,156,187,193 Basic principles involved in
the design of any regimen include the use of at least four drugs with either certain or highly
likely effectiveness, drug administration at least six days a week, drug dosage determined
by patient weight, the use of an injectable agent (an aminoglycoside or capreomycin) for
6–8 months, treatment duration of approximately 20 months, and patient-centered DOT
throughout the treatment course.
Based on their activity, efficacy, route of administration, tolerance, availability, and costs,
antituberculosis drugs can be classified in five groups.187 Group 1 consists of first-line

William: January, 2012. 19 years old, 33 kg MDR TB William: July, 2012. 19 years old, 59 kg
“My grandfather
lived with my family drugs: isoniazid, rifampicin, ethambutol, pyrazinamide, and rifabutin. Any of these drugs
should be used if it is thought that susceptibility remains. Only one drug should be selected
and he was very from Group 2 (injectable agents—kanamycin, amikacin, capreomycin, streptomycin) and
sick with cough Group 3 (fluoroquinolones), because of documented total or partial cross-resistance and
similar toxicities within the groups. Group 4 consists of less potent oral agents: ethion-
and losing weight.
amide, prothionamide, cycloserine, terizidone, p-aminosalicylic acid. Group 5 is com-
He had TB and posed of drugs for which antituberculosis action has not been documented in clinical tri-
was treated several als (except for thiacetazone): clofazimine, linezolid, amoxicillin/clavulanate, thioacetazone,
imipenem/cilastatin high-dose isoniazid, and clarithromycin. A drug that has been used
times but never got within a failing regimen should not be counted in the total of four drugs for re-treatment,
cured. He died. even if susceptibility is shown in the laboratory. The doses and adverse effects of sec-
ond-line drugs are described in detail the ATS/CDC/IDSA Treatment of Tuberculosis.122
Then I got sick.”
—William Standardized treatment regimens are based on representative drug resistance surveil-
lance data or on the history of drug usage in the country.155 Based on these assessments,
He has now regimens can be designed that will have a high likelihood of success. Advantages include
less dependency on highly technical laboratories, less reliance on highly specialized clini-
completed cal expertise required to interpret DST results, simplified drug ordering and logistics, and
treatment and is easier operational implementation. A standardized approach is useful in settings where
second-line drugs have not been used extensively and where resistance levels to these
working as a
drugs are consequently low or absent.
volunteer in the
Empiric treatment regimens are commonly used in specific groups of patients while the
TB program in DST results are pending.155,156 Empiric regimens are strongly recommended to avoid clin-
Dar es Salaam. ical deterioration and to prevent transmission of MDR strains of M. tuberculosis to con-
tacts while awaiting the DST results.155 Once the results of DST are known, an empiric
regimen may be changed to an individualized regimen. Ongoing global efforts to address
the problem of MDR tuberculosis will likely result in broader access to laboratories per-
forming DST and a faster return of results.
Individualized treatment regimens ( based on DST profiles and drug history of individual
patients or on local patterns of drug utilization ) have the advantage of avoiding toxic and
expensive drugs to which the MDR strain is resistant.155 However, an individualized
approach requires access to substantial human, financial, and technical (laboratory)
capacity. DSTs for second-line drugs are notoriously difficult to perform, largely because
of drug instability and the fact that critical concentrations for defining drug resistance are
very close to the minimal inhibitory concentration (MIC) of individual drugs.195 Laboratory
proficiency testing results are not yet available for second-line drugs; as a result little can
be said about the reliability of DST for these drugs. 195 Clinicians treating MDR tuberculosis

Often second-line patients must be aware of these limitations and interpret DST results with this in mind.
drugs are the last A shorter course standardized regimen used in Bangladesh has been described with
good results reported in a small observational study.196 Although promising, at this point
best hope for there is insufficient evidence to recommend the use of this regimen for treating MDR
patients with tuberculosis. A clinical trial is underway that should provide substantial new information
on which to base recommendations. Current advice from WHO is that a short regimen for
drug-resistant
MDR tuberculosis should be used only under operational research conditions.197
tuberculosis, and it
Substantial treatment support that may include financial assistance is commonly needed
is crucial that such to enable patients to complete a second-line regimen. MDR/XDR tuberculosis treatment
treatment be is a complex health intervention and medical practitioners are strongly advised to obtain
consultation with a specialist experienced in the management of these patients. Often
designed with the second-line drugs are the last best hope for patients with drug-resistant tuberculosis, and
active participation it is crucial that such treatment be designed for maximal effectiveness with the active
participation of the patient to overcome the challenges faced by both provider and patient
of the patient. with MDR/XDR tuberculosis.198 Physicians undertaking treatment of patients with MDR TB
must be committed to finding and administering a regimen using quality-assured drugs
for the full recommended duration of treatment. Commonly this requires collaboration
with public health tuberculosis control programs.
Two new second-line drugs, delaminanid and bedaquiline,199-201 have been introduced,
although as of this writing only bedaquiline has been approved by the US FDA. Given the
paucity of data describing outcomes and adverse events, the recommendation by WHO
states that bedaquiline may be added to a WHO-recommended regimen in adult patients
with pulmonary tuberculosis caused by MDR organisms.200 The recommendations also
specify fairly rigid conditions under which the drug should be used. Thus, informed con-
sent should be obtained from the patient and there should be careful monitoring for
adverse drug effects.
Of great concern, tuberculosis caused by organisms resistant to all drugs tested has been
described in India, but likely exists elsewhere as well.202,203 However, because of uncer-
tainties about the connection between second-line DST results and patient outcomes it is
not clear that there are no treatment options. Nevertheless, at least at this time there are
no specific recommended treatment options for such patients and symptomatic or palli-
ative care may be required. Although the number of such cases is likely to be small pro-
viders should be attuned to the possibility of such situations and be prepared to provide
appropriate palliative management to relieve suffering caused by the disease.

Standard 13. An accessible, systematically maintained record of all medications given, bacterio-
logic response, outcomes, and adverse reactions should be maintained for all patients.
Recording and reporting of data are fundamental components of care for patients with
tuberculosis and for control of the disease. Data recording and reporting are necessary to
monitor trends in tuberculosis at global, national, and subnational levels; to monitor prog-
ress in the treatment and in the quality of care for individual patients and groups (cohorts)
of patients; to ensure continuity when patients are referred between health care facilities;
to plan, implement, and evaluate programmatic efforts; and to support advocacy for ade-
quate funding for tuberculosis control programs.10 When high quality data are available,
successes can be documented and corrective actions taken to address problems
that are identified.204,205
There is a sound rationale and clear benefits for individual patients of a

well-maintained record keeping system. It is common for individual physi-
cians to believe sincerely, generally without documentation, that a majority
of the patients in whom they initiate antituberculosis therapy are cured.
However, when systematically evaluated, it is often seen that only a
minority of patients have successfully completed the full treatment regi-
men. The recording and reporting system enables targeted, individual-
ized follow-up to identify patients who are failing therapy. It also helps in
facilitating continuity of care, particularly in settings (e.g., large hospitals)
where the same practitioner might not be seeing the patient during every
visit. A good record of medications given, results of investigations such as
smears, cultures, and chest radiographs, and progress notes on clinical
improvement, adverse events, and adherence will provide for more uniform
monitoring and ensure a high standard of care.
Records are Records are important to provide continuity when patients move from one care provider
important to provide to another and enable tracing of patients who miss appointments. In patients who default
and then return for treatment, and patients who relapse after treatment completion, it is
continuity when
critical to review previous records in order to assess the likelihood of drug resistance.
patients move from Lastly, management of complicated cases (e.g., MDR tuberculosis) is not possible with-
out an adequate record of previous treatment, adverse events, and drug susceptibility
one care provider to
results. It should be noted that, wherever patient records are concerned, care must be
another and enable taken to assure confidentiality of the information, yet the records should be made avail-
tracing of patients able to the patient upon request.
who miss It is anticipated that electronic data systems will play an increasing role in tuberculosis
data collection and analysis.204 Most health care workers in even the poorest countries are
appointments. familiar with mobile phone technologies and many use them regularly in their daily lives.
The spread of mobile and web-based technologies is dramatically reducing the barriers to
implementing electronic systems that existed until the very recent past. In this context, it
is not surprising that there is growing use of and interest in electronic recording and
reporting of tuberculosis data.

Standards for Addressing
HIV Infection and Other
Co-morbid Conditions
Standard 14. HIV testing and counseling should be conducted for all patients with, or suspected
of having, tuberculosis unless there is a confirmed negative test within the previous
two months. Because of the close relationship of tuberculosis and HIV infection,
integrated approaches to prevention, diagnosis, and treatment of both tuberculosis
and HIV infection are recommended in areas with high HIV prevalence. HIV testing
Knowledge of a
is of special importance as part of routine management of all patients in areas with
person’s HIV status a high prevalence of HIV infection in the general population, in patients with symp-
influences the toms and/or signs of HIV-related conditions, and in patients having a history sug-
gestive of high risk of HIV exposure.
approach to a
diagnostic
Tuberculosis is strongly associated with HIV infection and is estimated to cause more than
evaluation and a quarter of deaths among persons with HIV.21,206 An autopsy study conducted among
treatment for adults with HIV infection who died at home in a South African setting found microbiologi-
cal evidence of tuberculosis in 34% and active tuberculosis in 19%.207 Similarly, an autopsy
tuberculosis.
study conducted in Kenya among adults with HIV infection who died after receiving a
median 10 months of antiretroviral therapy (ART ) found microbiological or histological
evidence of tuberculosis in 52% and tuberculosis was thought to be the cause of death
in 41% of people living with HIV who died within 3 months of ART initiation.208
Infection with HIV increases the likelihood of progression from infection with M. tubercu-
losis to active tuberculosis. The risk of developing tuberculosis in people living with HIV is
between 20 and 37 times greater than among those who do not have HIV infection.206
Although the prevalence of HIV infection varies widely between and within countries,
among persons with HIV infection there is always an increased risk of tuberculosis. The
wide differences in HIV prevalence mean that a variable percentage of patients with tuber-
culosis will have HIV infection as well. This ranges from less than 1% in low HIV prevalence
countries up to 50–77% in countries with a high HIV prevalence, mostly sub-Saharan
African countries.21 Even though in low HIV prevalence countries few tuberculosis patients
are HIV-infected, the connection is sufficiently strong and the impact on the patient suffi-
ciently great that provider-initiated HIV counseling and testing should always be con-
ducted in managing individual patients, especially among groups in which the prevalence
50 I STC 3 r d e dition , 2014 standards for co-morbid conditions Standard 14

Integrated care of HIV is higher, such as injecting drug users. In countries having a high prevalence of HIV
infection, the yield of positive results will be high and, again, the impact of a positive result
facilitates early on the patient will be great.209 Thus, the indication for HIV testing is strong; co-infected
detection and patients will benefit by access to antiretroviral therapy and by administration of cotrimox-
azole for prevention of opportunistic infections.209 Testing for HIV among presumptive
prompt treatment tuberculosis cases in sub-Saharan Africa also yields high HIV-positive results.210,211 In
of tuberculosis addition, in South Africa testing household contacts of patients with tuberculosis for both
HIV and tuberculosis resulted in detection of a large number of undiagnosed tuberculosis
resulting in a
cases and persons with HIV infection.212 A study in Thailand also showed higher HIV prev-
reduction of alence among contacts of tuberculosis patients living with HIV than among contacts of
mortality and HIV-negative tuberculosis patients.213
improved treatment Infection with HIV changes the clinical manifestations of tuberculosis.214,215 Further, in
comparison with non-HIV infected patients, patients with HIV infection who have pulmo-
success. nary tuberculosis have a lower likelihood of having acid-fast bacilli detected by sputum
smear microscopy.216 Moreover, data consistently show that the chest radiographic fea-
tures are atypical and the proportion of extrapulmonary tuberculosis is greater in patients
with advanced HIV infection compared with those who do not have HIV infection. Conse-
quently, knowledge of a person’s HIV status influences the approach to a diagnostic
evaluation for tuberculosis. For this reason it is important, particularly in areas in which
there is a high prevalence of HIV infection, that provider-initiated HIV testing and counsel-
ing be implemented for persons suspected of having tuberculosis and those known to
have tuberculosis.210,217 In addition, the history and physical examination should include a
search for indicators that suggest the presence of HIV infection. A comprehensive list of
clinical criteria/algorithms for HIV/AIDS clinical staging is available in the WHO document
WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immuno-
logical Classification of HIV-Related Disease in Adults and Children.218
Studies of integrated tuberculosis and HIV services have demonstrated that integrated
care facilitates early detection and prompt treatment of tuberculosis resulting in a reduc-
tion of mortality and improved treatment success.219-223 The integrated model of tubercu-
losis and HIV services in a single health facility also improves ART enrollment and ART
update, and supports early initiation of ART.209,219-223 Thus, integrated approaches to pre-
vention, diagnosis, and treatment of tuberculosis and HIV are strongly recommended in
areas of high HIV prevalence.
Standard 15. In persons with HIV infection and tuberculosis who have profound immunosup-
pression (CD4 counts less than 50 cells/mm3 ), ART should be initiated within 2
weeks of beginning treatment for tuberculosis unless tuberculous meningitis is
present. For all other patients with HIV and tuberculosis, regardless of CD4 counts,
antiretroviral therapy should be initiated within 8 weeks of beginning treatment for
tuberculosis. Patients with tuberculosis and HIV infection should also receive cotri-
moxazole as prophylaxis for other infections.
The evidence on effectiveness of treatment for tuberculosis in patients with HIV co-infection
versus those who do not have HIV infection has been reviewed extensively.14,122,125,126,224-227

These reviews suggest that, in general, the outcome of treatment for tuberculosis is the
same in HIV-infected and non-HIV-infected patients with the notable exception that death
rates are greater among patients with HIV infection, presumably due in large part to com-
plications of HIV infection. Tuberculosis treatment regimens are largely the same for
HIV-infected and non-HIV-infected patients; however, the results are better if rifampicin is
used throughout and treatment is given daily at least in the intensive phase.126
In patients with HIV-related tuberculosis, treating tuberculosis is the first priority.

In the setting of advanced HIV infection, untreated tuberculosis can progress
rapidly to death. As noted above, however, antiretroviral treatment may be
lifesaving for patients with advanced HIV infection. Therefore, all patients
with tuberculosis and HIV infection should receive antiretroviral therapy
as early as possible regardless of CD4 counts.228 Antiretroviral therapy
results in remarkable reduction in mortality and AIDS-related morbidity,
and greatly improves survival and quality of life of HIV-infected persons.
ART is associated with reduction of mortality risk that in different studies
has ranged from 54% to 95% in both resource-limited and high-income
settings.229 Recent clinical trials, STRIDE and SAPIT, showed reduction of
deaths and AIDS-related events by 42% and 68%, respectively, with early
ART in combination with tuberculosis treatment in persons with advanced
HIV infection.230,231 The CAMELIA trial found reduction of mortality by 34% when
ART was initiated 2 weeks compared with 8 weeks following initiation of tubercu-
ART should be losis treatment in patients with profound immunosuppression (median CD4 count of 25
initiated within 2 cells/mm3 ).232 Thus, evidence from these trials indicates that ART should be initiated
within 2 weeks after the start of tuberculosis treatment for patients with a CD4 count less
weeks after the start than 50 cells/mm3 and as early as possible within 8 weeks for the other HIV-positive
of tuberculosis tuberculosis cases.209 Caution should be given for early initiation of ART in HIV-positive
patients with tuberculous meningitis because of its association with higher rate of adverse
treatment for
events compared with initiation of ART 2 months after start of tuberculosis treatment.233
patients with a CD4
There are some important issues associated with concomitant therapy for tuberculosis
count less than 50 and HIV infection that should be considered. These include overlapping toxicity profiles for
cells/mm 3 and as the drugs used, drug-drug interactions (especially with rifampicin and protease inhibitors),
potential problems with adherence to multiple medications, and immune reconstitution
early as possible inflammatory reactions.122,214 There are few drug interactions with tuberculosis drugs and
within 8 weeks the nucleoside reverse transcriptase inhibitors (NRTIs) and no specific changes are rec-
ommended. However, rifampicin reduces drug levels of both non-nucleoside reverse tran-
for the other
scriptase inhibitors (NNRTI) and protease inhibitors through induction of the cytochrome
HIV-positive P450 liver enzyme system. Therefore, efavirenz should be used as the preferred NNRTI
tuberculosis cases. since its interactions with antituberculosis drugs are minimal. In several studies, ART with
standard-dose efavirenz and two nucleosides was well tolerated and highly efficacious in
achieving viral load suppression.14 In HIV-positive tuberculosis patients who need an ART
regimen containing a boosted protease inhibitor (PI), it is recommended to use a rifabu-
tin-based regimen.14 Patients should also be closely monitored to identify adverse drug
reactions and to observe for immune reconstitution inflammatory syndrome ( IRIS ).
Although some studies reported increased risk of IRIS when ART is started earlier, the mor-
tality benefit of earlier ART initiation outweighs the IRIS risk, which usually is self-limited.234

Patients with tuberculosis and HIV infection should also receive cotrimoxazole ( trimetho-
prim-sulfamethoxazole) as prophylaxis for other infections. Several studies have demon-
strated the benefits of cotrimoxazole prophylaxis, and this intervention is currently recom-
mended by the WHO as part of the TB/HIV management package.209,214,235-239
Standard 16. Persons with HIV infection who, after careful evaluation, do not have active tuber-
culosis should be treated for presumed latent tuberculosis infection with isoniazid
for at least 6 months.
Early identification of symptoms consistent with tuberculosis followed by prompt diagnos-

tic evaluation and appropriate treatment of the disease among people living with HIV
increases survival and improves quality of life. Thus, screening for symptoms among per-
sons with HIV infection is crucial for identifying both tuberculosis cases and persons who
should receive isoniazid preventive therapy.46,47,240,241 A comprehensive systematic review
and meta-analysis found that the absence of four symptoms: current cough, night sweats,
fever, or weight loss identified a large subset of PLHIV who are very unlikely to have active
tuberculosis.47 All persons with HIV infection should be regularly screened for tuberculosis
using the clinical algorithm with the four symptoms: current cough, night sweats, fever or
weight loss, at every visit to a health facility or contact with a health care worker.47,209,216,241
PLHIV who report any one of the symptoms should be evaluated for tuberculosis and
other diseases. Similarly, children living with HIV who have one of the following symp-
toms—poor weight gain, fever, current cough, or a history of contact with a person who
has infectious tuberculosis should be evaluated for tuberculosis and other conditions.209,241
The diagnostic evaluation for tuberculosis should be done in accordance with national
and international guidelines. In HIV-prevalent settings, Xpert MTB/RIF should be used as
the initial test.59,85 PLHIV who do not have any one of the four screening symptoms cited
above or a history of contact with a person who has infectious tuberculosis are unlikely to
have active tuberculosis (negative predictive value 97.7%, 95% CI 97.4–98.0) and, there-
fore, are candidates for IPT.47,241
Isoniazid, given to PLHIV in whom tuberculosis has been excluded reduces the risk of
tuberculosis by approximately 33% compared with placebo.242 The protective effect
decreases with time after treatment but may persist for 2–3 years. The benefit is most
pronounced in persons with a positive tuberculin skin test (~64% reduction) and is sub-
stantially less (14%) in persons with negative or unknown tuberculin skin test results. After
excluding active tuberculosis, isoniazid (approximately 5 mg/kg/day, 300 mg/day maxi-
mum for adults and 10 mg/kg/day up to 300 mg/day for children) should be given to
persons with HIV infection who are known to have latent tuberculosis infection or who have
been in contact with an infectious tuberculosis case. If performing a tuberculin skin test is
not possible, isoniazid is recommended for all PLHIV.209,241 There is a trend to lower tuber-
culosis incidence with a longer preventive therapy particularly in settings with high tuber-
culosis prevalence and transmission and among tuberculin skin test-positive PLHIV.243,244
In spite of there having been strong evidence-based recommendations for the use of IPT
in PLHIV since 1998, implementation for these recommendations has been very limited.

Screening for The reluctance to use IPT is based, particularly, on concerns with creating drug resistance
if active tuberculosis is not excluded. In a study conducted in Rio de Janeiro, Brazil, oper-
symptoms among ational training of physicians to screen for tuberculosis in public HIV clinics combined with
persons with HIV the use of tuberculin skin testing led to improved implementation of IPT.245 There was a
modest population level reduction in the incidence of tuberculosis (13% reduction) and
infection is crucial death (24% reduction). After adjustment for important covariates (age, CD4 count,
for identifying both antiretroviral treatment), there was a 27% reduction in incidence and a 31% reduction in
deaths. Adverse effects were minimal.
tuberculosis cases
and persons who Treatment of latent tuberculosis infection with a regimen of once weekly rifapentine and
isoniazid given for 3 months (12 doses) under direct observation has been shown in low
should receive tuberculosis incidence settings to be as effective as a 9-month isoniazid regimen in pre-
isoniazid preventive venting tuberculosis.246 Moreover, the treatment completion rate was significantly higher.
The weekly rifapentine/isoniazid regimen also showed less toxicity than other drug com-
therapy. bination or continuous isoniazid regimens.244,247 However, this regimen has not been eval-
uated in high-prevalence settings and thus cannot be recommended at this time in those
settings.
The combined use of IPT and antiretroviral therapy ( ART ) among PLHIV significantly
reduces the incidence of tuberculosis. The combined use of ART and IPT can reduce
tuberculosis incidence among PLHIV by up to 97% particularly among persons with pos-
itive tuberculin skin tests.248,249 Earlier initiation of ART at a CD4 cell count of more than
350/µl can reduce tuberculosis incidence by 60% and the reduction is 84% if ART is
started when the CD4 cell count is less than 200/µl.250 A recent clinical trial among PLHIV
who received ART showed that at 12 months isoniazid resulted in a 40% reduction of
tuberculosis incidence regardless of the tuberculin skin test result.251

Standard 17. All providers should conduct a thorough assessment for co-morbid conditions and
other factors that could affect tuberculosis treatment response or outcome and
identify additional services that would support an optimal outcome for each patient.
These services should be incorporated into an individualized plan of care that
includes assessment of and referrals for treatment of other illnesses. Particular
attention should be paid to diseases or conditions known to affect treatment out-
come, for example, diabetes mellitus, drug and alcohol abuse, undernutrition, and
tobacco smoking. Referrals to other psychosocial support services, or to such ser-
vices as antenatal or well-baby care should also be provided.
In addition to the location, severity, and extent of tuberculosis, a number of other factors
can affect the response to and outcome of treatment. These factors include concomitant
illnesses (such as diabetes mellitus), psychosocial issues, and socioeconomic barriers to
treatment completion. In working with a patient to treat tuberculosis, the provider must
assess and address other contributing factors to ensure that there is the greatest chance
of cure. Addressing co-morbid conditions commonly associated with tuberculosis can
decrease treatment default, prevent drug resistance, and decrease treatment failures and
deaths.
There are a number of conditions that are either risk factors for tuberculosis or are com-
mon in patients with the disease. Many of these can adversely affect treatment outcome.
These include HIV (discussed previously), other immunosuppressive disorders, diabetes
mellitus, malnutrition, alcoholism, other substance abuse, and tobacco use.252-256
Clinicians should take individual risk factors into account and carry out the necessary
tests to evaluate co-morbid conditions relevant to tuberculosis treatment response and
outcome. These should be provided free of charge to the patient.
Because of its increasing prevalence, diabetes mellitus is a particular concern.257 Diabetes

triples the risk of developing tuberculosis and can increase the severity of tuberculosis.258
Conversely, tuberculosis can worsen blood glucose control in persons with diabetes.
Tuberculosis must be considered in people with diabetes, and diabetes must be consid-
ered in people with tuberculosis. Individuals with both conditions require careful clinical
management to ensure that optimal care is provided for both diseases.259
The same tuberculosis treatment regimen should be prescribed for patients with diabetes
as for those without diabetes. However, because of the potential for reduced concentra-
tions of rifampicin, careful observation of clinical response is necessary.260 Where possi-
ble, patients with tuberculosis should be screened for diabetes at the start of their treat-
ment. Management of diabetes in patients with tuberculosis should be provided in line
with existing management guidelines.261
Coexisting non-infectious lung diseases, such as chronic obstructive pulmonary disease

(COPD), may increase the risk for tuberculosis and complicate management. Both clinical
and radiographic assessment of response may be confounded by coexisting lung dis-
ease. Tuberculosis is also a risk for the development of COPD and may be a major con-
tributor to this emerging problem in low–resource settings.262

Macro- and micronutritional deficiencies are both causes and consequences of
tuberculosis and therefore very common at the time of tuberculosis diagno-
sis. All tuberculosis patients should have a nutritional assessment including
weight and height in order to determine body mass index. Nutritional care
should be provided according to the nutritional status of the patient in line
with guidelines on nutritional care for people with tuberculosis. Nutritional
support, for example a food package, should be considered for patients
who do not have the financial means to meet their nutritional needs
during tuberculosis treatment.263
Social factors13,142 may also be important in influencing treatment response

and outcome, and interventions should be considered to mitigate their
impact. Homelessness, social isolation, migration for work, a history of
incarceration, and unemployment have all been cited as barriers to treatment
adherence and risk factors for poor treatment outcome.13,142 Having a diagnosis
of tuberculosis may serve as an entry point to health care and psychosocial services that
Having a diagnosis
can enhance treatment completion. Treatment support including psychosocial support is
of tuberculosis may a cornerstone of the best practices for tuberculosis treatment described in detail in Best
serve as an entry Practice for the Care of Patients with Tuberculosis: a Guide for Low-income Countries.16
By providing patients with referrals to accessible services for co-morbid conditions of any
point to health care kind, the provider enhances their chances for cure in the shortest possible time and con-
and psychosocial tributes to increasing the overall health of the community.
services that can It is recognized that not all necessary services are currently available in the areas most in
need of this support. To the extent these services are available, they should be fully utilized
enhance treatment
to support tuberculosis patient treatment. Where they are not available, plans to enhance
completion. relevant capacities should be incorporated into local, regional, and national tuberculosis
control strategies.
Other diseases and treatments, especially immunosuppressive treatments such as corti-

costeroids and tumor necrosis factor ( TNF) alpha inhibitors, increase the risk of tubercu-
losis and may alter the clinical features of the disease.264,265 Clinicians caring for patients
with diseases or taking drugs that alter immune responsiveness must be aware of the
increased risk of tuberculosis and be alert for symptoms that may indicate the presence
of tuberculosis. Isoniazid preventive treatment may be considered for such patients if
active tuberculosis is excluded.

Standards for Public Health
and Prevention
Standard 18. All providers should ensure that persons in close contact with patients who have
infectious tuberculosis are evaluated and managed in line with international recom-
mendations. The highest priority contacts for evaluation are:
• Persons with symptoms suggestive of tuberculosis

This inability to
• Children aged < 5 years
conduct targeted • Contacts with known or suspected immunocompromised states, particularly
contact HIV infection
• Contacts of patients with MDR/XDR tuberculosis
investigations
results in missed
The determination of priorities for contact investigation is based on the likelihood that a
opportunities to
contact: 1) has undiagnosed tuberculosis; 2) is at high risk of developing tuberculosis if
prevent additional infected; 3) is at risk of having severe tuberculosis if the disease develops; and 4) is at high
cases of risk of having been infected by the index case. The risk of acquiring infection with M.
tuberculosis is correlated with intensity and duration of exposure to a person with infec-
tuberculosis, tious tuberculosis, generally called an index case. A contact is any person who has been
especially among exposed to an index case. Commonly contacts are divided into two groups, household
and non-household. A person who shared the same enclosed living space for one or
children. more nights, or for frequent or extended periods during the day with the index case during
the 3 months before commencement of the current treatment episode, is defined as a
household contact. Non-household contacts may also share an enclosed space, such as
a social gathering place, workplace, or facility, for extended periods during the day with
the index case during the 3 months before commencement of the current treatment epi-
sode and thus also be at risk of having acquired infection with M. tuberculosis. Contact
investigation is considered an important activity, both to find persons with previously
undetected tuberculosis and persons who are candidates for treatment of latent tubercu-
losis infection.266-268
Unfortunately, lack of adequate staff and resources in many areas makes contact investi-
gation a challenging task. This inability to conduct targeted contact investigations results
in missed opportunities to prevent additional cases of tuberculosis, especially among
57 I STC 3 r d e dition , 2014 standards for public health Standard 18

children. Thus, more energetic efforts are necessary to overcome these barriers to opti-
mum tuberculosis control practices.
Two systematic reviews of studies on household contact investigations in low- and mid-
dle-income settings showed that, on average, about 4.5% and 3.1% respectively of the
contacts were found to have active tuberculosis.269,270 The median number of household
contacts that were evaluated to find one case of active tuberculosis was 19 ( range
14–300). The median proportion of contacts found to have latent infection was just over
50% in both studies. The median number of contacts that were evaluated to find one
person with latent tuberculosis infection was 2 (range 1–14). In the review by Fox et al,270
longer term follow up demonstrated that the incidence of tuberculosis remained above
the background rate for at least 5 years. Evidence from these reviews suggests that con-
tact investigation in high-incidence settings is a high-yield strategy for case finding. Based
on the evidence from the reviews, WHO developed recommendations for contact investi-
gation in low resource settings.8
A systematic review and meta-analysis of the yield of investigation of contacts of persons

with MDR/XDR tuberculosis found a pooled yield of 6.5% of contacts also had active
tuberculosis.271 Latent tuberculosis infection was found in 50.7%.
The main benefit of contact investigation for contacts of MDR/XDR index cases is early
detection of active tuberculosis that should result in decreasing transmission of MDR/XDR
organisms. In the systematic review, just over 50% of contacts with active tuberculosis
had drug susceptibility profiles that were concordant with the index case. Unfortunately,
there are no current recommendations for treatment of latent infection that is presumed
to be with MDR/XDR organisms.
Standard 19. Children < 5 years of age and persons of any age with HIV infection who are close
contacts of a person with infectious tuberculosis, and who, after careful evaluation,
do not have active tuberculosis, should be treated for presumed latent tuberculosis
infection with isoniazid for at least six months.
Children (particularly those under the age of five years) are a vulnerable group because of
the high likelihood of progressing from latent infection to active tuberculosis. Children,
especially if very young, are also more likely to develop disseminated and serious forms of
tuberculosis such as meningitis. For these reasons it is recommended that, after active
tuberculosis is excluded, children under the age of five years living in the same household
as a sputum smear-positive tuberculosis patient should be treated with isoniazid, 10 mg/
kg/day (up to a maximum of 300 mg), for 6 months on the presumption that they have
been infected by the index case. The screening of children for active tuberculosis can be
accomplished by a careful medical history and physical examination, as illustrated in Fig-
ure 1.114
Likewise, PLHIV are highly vulnerable to developing tuberculosis if infected and, thus,
should be carefully evaluated for the presence of active tuberculosis. Persons with HIV
infection should be evaluated and treated as described in Standard 16.241 Monitoring and

evaluation of IPT as a programmatic intervention should be undertaken as described in
Recommendations for Investigating Contacts of Persons with Infectious Tuberculosis in
Low- and Middle-income Countries.8
In persons other than children < 5 years of age and PLHIV, the tuberculin skin test and
interferon-gamma release assays may be used to identify those at increased risk for
developing active tuberculosis and who are therefore candidates for treatment of latent
infection once active tuberculosis is excluded.8 Because the public health benefit of treat-
ment for latent tuberculosis infection, other than for children and PLHIV, in low- and mid-
dle-income countries is not proven, it is not recommended as a programmatic approach.
However, as a part of care for individuals with risk factors for tuberculosis who are exposed
to a person with infectious tuberculosis, clinicians may choose to test for latent infection
with a tuberculin skin test or interferon-gamma release assay and, if the test is positive
and active tuberculosis is excluded, give treatment for latent tuberculosis infection as a
preventive intervention.8
F igure 1 .
Approach to evaluation and management of children in contact with an infectious case of

tuberculosis when a tuberculin skin test and chest radiograph are not available
Child in close contact with case of smear-positive PTB
Aged <5 years Aged ≥5 years
Well Symptomatic1 Symptomatic1 Well
6H2 No treatment3
If becomes If becomes
symptomatic symptomatic
Evaluate for TB disease
1. If tuberculosis is suspected evaluate as described in Standard 6

2. Treat with isoniazid 10 mg/kg/day for six months
3. No treatment should be given unless the child is HIV-infected in which case give isoniazid 10 mg/kg/day

Standard 20. Each health care facility caring for patients who have, or are suspected of having,
infectious tuberculosis should develop and implement an appropriate tuberculosis
infection control plan to minimize possible transmission of M. tuberculosis to patients
and health care workers.
M. tuberculosis is spread nearly exclusively via the air, thus, the simple act of sharing air
with a person who has infectious tuberculosis may result in transmission of the infection.
There have been a number of well-documented outbreaks of tuberculosis including MDR
and XDR tuberculosis that have occurred in health care facilities. Because of the concern
with transmission of both drug-resistant and drug susceptible M. tuberculosis to
patients and health care workers in facilities providing care for patients with
tuberculosis, infection control is now recognized to be of considerable impor-
tance.17-19,272-274
Infection control for tuberculosis consists of managerial activities at the

facility level and a hierarchy of three categories of control measures
including administrative controls (most important), environmental con-
trols, and the use of respirators (special masks designed to protect the
wearer).
Managerial Controls: Facility-level managerial activities constitute the

framework for setting up and implementing the other two categories of
controls and should include the following: identification and strengthening
of local coordinating bodies; development of a facility plan (including human
resources) for implementation of infection control measures; and policies and
procedures to ensure proper implementation of the control measures. In addition,
policies that minimize the use of health care facilities, both for inpatients and outpatients,
should be developed and implemented. Community approaches to providing care for
persons with, or suspected of having, tuberculosis should be emphasized as a means of
reducing visits to health care facilities.
Implementation of the control measures as a group reduces transmission of M. tubercu-

losis in health care facilities.275 However, in health care facilities, administrative controls
should be implemented as the first priority because they have been shown to be the most
important measures in reducing transmission of tuberculosis. Consequently, all facilities,
public and private, caring for patients with, or suspected of having, infectious tuberculosis
should implement the set of measures in a manner that is best suited to the conditions
that prevail in the facility, particularly local programmatic, climatic, and socioeconomic
conditions. For example, infection control requirements will be less in programs that man-
age most patients with tuberculosis in the community compared with programs that rou-
tinely utilize hospitalization. The interventions should be consistent with and complement
overall general infection control efforts and, particularly, those efforts targeting other air-
borne infections.
Administrative Controls: There are several administrative controls that are feasible in all
settings that, taken together, could be predicted to minimize the likelihood of transmission
occurring in the facility.275-278 Administrative measures include careful screening and early

identification of patients with, or suspected of having, tuberculosis and separating them
from other patients, especially from patients who are highly susceptible to tuberculosis.
Organizing patient flow through sections of facilities, for example, rapid identification of
coughing patients, systematic use of surgical masks for coughing patients, and directing
these patients away from crowded waiting areas (fast-tracking) can minimize the potential
for exposure and transmission. Separation of patients who are suspected of having tuber-
culosis will decrease risks to other patients and will enable health workers to take appro-
priate precautions. Patients with HIV infection and other forms of immunosuppression, in
particular, should be physically separated from patients with suspected or confirmed
infectious tuberculosis. Patients who have or are at risk of having MDR tuberculosis
should be separated from other patients, including other patients with tuberculosis. Hav-
ing a universally applied program in which patients taught proper cough etiquette will
serve to reduce dissemination of infectious aerosols.
Prompt collection of sputum specimens for microscopy or other microbiological evalua-

tions is an important step in infection control. Early identification of tuberculosis leads to
early initiation of treatment and a consequent prompt major reduction in infectiousness, if
the organisms causing the disease are not resistant to the drugs being used. In areas in
which there is a high prevalence of drug resistance, rapid drug susceptibility/resistance
testing would enable identification and appropriate treatment.276 Diagnostic delays can be
further minimized by using rapid molecular tests (including rapid drug susceptibility tests),
by reducing the laboratory turnaround time for sputum examination, and by carrying out
diagnostic investigations in parallel rather than in sequence.
All health workers should be given appropriate information and encouraged to undergo
regular screening for tuberculosis and HIV testing and counseling. Those who are HIV-in-
fected should be offered appropriate prevention and care services. Health workers with
HIV infection should not work in areas where exposure to untreated tuberculosis is likely
and especially should not be caring for patients with known MDR and XDR tuberculosis,
or in settings where drug resistance is likely. Such workers should be provided with jobs
in a lower risk area.
Environmental Controls: The choice of environmental controls is largely determined by

building design and intended use, construction details, local climatic and socioeconomic
conditions, and available resources. Effective ventilation should be given a high priority.
Ventilation effectively reduces the number of infectious particles in the air and may be
achieved by natural ventilation in some settings, by mixed natural and mechanical ventila-
tion, and by mechanical ventilation systems. The obvious benefit of natural ventilation as
an approach to infection control is that can be applied to all areas that have windows and
doors that open to the outside.277 However, around the clock natural ventilation cannot be
applied other than in tropical climates, and even in these areas, windows may be closed
during the night for security or comfort negating the effect of natural ventilation, thus, it is
of limited utility. In settings where optimal natural ventilation cannot be achieved, properly
placed and shielded upper room ultraviolet germicidal irradiation fixtures should be con-
sidered as a complementary control. This may be especially useful in cold climates where
outdoor ventilation is limited.

Disposable Particulate Respirators (masks): Particulate respirators protect the per-
son wearing the device by filtering particles out of the inspired air.278 Respirators that meet
or exceed Centers for Disease Control and Prevention/National Institute for Occupational
Services and Health (CDC/NIOSH)-certified N95 or CE-certified FFP2 standards (filter at
least 95% of airborne particles ≥ 0.3 µm in diameter) should be worn by health care pro-
viders in areas where the risk of transmission is high after appropriate training.17,19
Indications for using a respirator should be defined by the facility, but commonly include
procedures in which aerosols are generated, such as bronchoscopy, or exposure to per-
sons with untreated or ineffectively treated tuberculosis. In areas where drug resistance is
common, however, every patient with tuberculosis should be considered potentially to
have drug-resistant disease for purposes of infection control.
Standard 21. All providers must report both new and re-treatment tuberculosis cases and their
treatment outcomes to local public health authorities, in conformance with applica-
ble legal requirements, regulations, and policies.
Reporting tuberculosis cases to the local tuberculosis control program is an

essential public health function and in many countries is legally mandated.
Ideally, the reporting system design, supported by a legal framework, should
be capable of receiving and integrating data from several sources includ-
ing laboratories and health care institutions, as well as from individual
practitioners.
An effective reporting system that includes all providers enables a deter-

mination of the overall effectiveness of tuberculosis control programs, of
resource needs, and of the true distribution and dynamics of the disease
within the population as a whole, not just the population served by the
government tuberculosis control program. In most countries tuberculosis
is a notifiable disease. Such a system is useful not only to monitor progress
and treatment outcomes of individual patients, but also to evaluate the overall
performance of the tuberculosis control programs at the local, national, and
global levels, and to indicate programmatic weaknesses.
A regularly updated recording and reporting system allows for targeted, individualized
follow-up to help patients who are not making adequate progress (i.e., failing therapy).279
The system also allows for evaluation of the performance of the practitioner, the hospital
or institution, local health system, and the country as a whole. Finally, a system of record-
ing and reporting ensures accountability.
An additional important function of a recording and reporting system is to identify serious

adverse events resulting from antituberculosis drugs.280 This surveillance is especially
important as new drugs and regimens are introduced. In both the WHO and CDC recom-
mendations regarding the use of bedaquiline, it is strongly recommended that there be
ongoing surveillance and reporting of adverse events.200,281 Clinical experience with the
drug is limited, but because of the pressing need for new drugs to treat MDR TB,

An effective bedaquiline was released for use under specific conditions. There are many instances of
serious adverse effects of drugs being identified by post-marketing surveillance (phase IV
reporting system studies). Similarly there is little systematic information on the adverse effects of many of
that includes all the drugs and regimens used in treating MDR TB, thus pharmacovigilance is important in
this group as well.
providers enables a
Although, on the one hand reporting to public health authorities is essential, on the other
determination of the
hand it is also essential that patient confidentiality be maintained. Thus, reporting must
overall effectiveness follow predefined channels using standard procedures that guarantee that only autho-
of tuberculosis rized persons see the information. Such safeguards must be developed by local and
national tuberculosis control programs to ensure the confidentiality of patient information.
control programs,
of resource needs,
and of the true
distribution and
dynamics of the
disease.

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Annex 1
The steering committees responsible for editions 1 and 2 of the ISTC are listed below.
Edition 1
• Edith Alarcón (nurse, international technical agency, NGO)
• R. V. Asokan (professional society)
• Jaap Broekmans (international technical agency, NGO)
• Jose Caminero (academic institution, care provider)
• Kenneth Castro (national tuberculosis program director)
• Lakbir Singh Chauhan (national tuberculosis program director)
• David Coetzee (TB/HIV care provider)
• Sandra Dudereva (medical student)
• Saidi Egwaga (national tuberculosis program director)
• Paula Fujiwara (international technical agency, NGO)
• Robert Gie (pediatrics, care provider)
• Case Gordon (patient advocate)
• Philip Hopewell, Co-Chair (professional society, academic institution, care provider)
• Umesh Lalloo (academic institution, care provider)
• Dermot Maher (global tuberculosis control)
• G. B. Migliori (professional society)
• Richard O’Brien (new tools development, private foundation)
• Mario Raviglione, Co-Chair (global tuberculosis control)
• D’Arcy Richardson (nurse, funding agency)
• Papa Salif Sow (HIV care provider)
• Thelma Tupasi (multiple drug-resistant tuberculosis, private sector, care provider)
• Mukund Uplekar (global tuberculosis control)
• Diana Weil (global tuberculosis control)
• Charles Wells (technical agency, national tuberculosis program)
• Karin Weyer (laboratory)
• Wang Xie Xiu (national public health agency)
Edition 2
• Edith Alarcón (nurse, international technical agency, NGO)
• R. V. Asokan (professional society)
• Carmelia Basri (national tuberculosis program)
• Henry Blumberg (infection control, academic institution)
• Martien Borgdorff (international technical agency)
• Jose Caminero (training, academic institution, care provider)
• Martin Castellanos (national tuberculosis program director)
• Kenneth Castro (national tuberculosis program director)
• Richard Chaisson (prevention, academic institution)
• Jeremiah Chakaya (professional society)
• Lakbir Singh Chauhan (national tuberculosis program director)
• Lucy Chesire (patient advocate)
• Daniel Chin (donor agency)
• David Cohn (prevention, academic institution)
• Charles Daley (role of radiographic evaluation, academic institution)
77 I STC 3 r d e dition , 2014 annex 1

• Saidi Egwaga (national tuberculosis program director)
• Elizabeth Fair (case finding and contact investigation, academic institution)
• Paula Fujiwara (international technical agency, NGO)
• Haileyesus Getahun (TB/HIV, global tuberculosis control)
• Robert Gie (pediatrics, care provider)
• Case Gordon (patient advocate)
• Ruben Granich (TB/HIV, global tuberculosis control)
• Malgosia Grzemska (policy and liaison with WHO, global tuberculosis control)
• Mark Herrington (TB/HIV, NGO)
• Philip Hopewell, Co-Chair (professional society, academic institution, care provider)
• Ernesto Jaramillo (drug resistance, global tuberculosis control)
• Anwar Jusuf (professional society)
• Salmaan Keshavjee (drug resistance)
• Umesh Lalloo (drug resistance, professional society)
• Kitty Lambregts (drug resistance, international technical agency)
• Hadiarto Mangunnegoro (professional society)
• Divide Manissero (pediatric tuberculosis, regional tuberculosis control)
• Eugene McCray (TB/HIV, national tuberculosis control program)
• G. B. Migliori (professional society)
• Ed Nardell (infection control)
• Paul Nunn (drug resistance, global tuberculosis control)
• Rick O’Brien (diagnosis of smear-negative TB/role of new diagnostics, private
foundation)
• Madhukar Pai (diagnosis of smear-negative TB/role of new diagnostics, academic
institution)
• Mario Raviglione, Co-Chair (global tuberculosis control)
• D’Arcy Richardson (nursing, funding agency)
• KJ Seung (infection control)
• Joseph Sitienei (national tuberculosis program director)
• Pedro Suarez (role of radiographic evaluation)
• Thelma Tupasi (drug resistance, private sector, care provider)
• Mukund Uplekar (public private mix, global tuberculosis control)
• Maarten Van Cleef (international technical agency)
• Cheri Vincent (donor agency)
• Diana Weil (policy, global tuberculosis control)
• Karin Weyer (laboratory)
• Wang Xie Xiu (national public health agency)

Annex 2
Utilization of the ISTC
The ISTC is potentially a very powerful tool to improve the quality of tuberculosis care
globally. Because of the way in which the ISTC was developed and the international
endorsements it has received through the two previous editions, the document is broadly
credible across categories of practitioners and, thus, carries substantial authority. This
credibility and authority are major strengths of the ISTC and should be capitalized upon in
its utilization.
Based on experience with the first (2006) and second (2009) editions of the ISTC, there
are multiple uses for the document by both the public and private sectors. Many of these
are described in the Handbook for Utilizing the International Standards for Tuberculosis
Care which described utilization of the first edition of the ISTC (available at http://www.
istcweb.org). Some of the more frequent uses are summarized below:
Unifying Approaches to Tuberculosis Care Between the Public

and Private Sectors
One of the intended uses of the ISTC is as a tool to unify approaches to diagnosis and
treatment between the public and private sectors, especially in countries in which there is
a strong private sector. The ISTC, by articulating widely accepted, authoritative approaches
to tuberculosis care, can serve as a vehicle for bringing the two sectors together. As a prod-
uct of the collaboration fostered by the ISTC, several countries and regions have utilized
the ISTC as the framework for developing more local adaptations of the document.
Activities aimed at fostering public-private collaborations may be initiated by organizations

representing either sector. Prior to developing activities based on the ISTC, the initiating
organization must have a sound understanding of the individual standards and assess
their ability to be in compliance with the standards. This likely will require internal assess-
ment of capacity, planning, and development of specific strategies to address the stan-
dards. For example, if the goal is to involve the private sector more effectively, the NTP
must be willing to adjust and accommodate, where necessary, to the needs of private
providers. Planned ISTC activities should be clearly linked with the identified gaps to be
filled. Overall objectives should also be formulated in relation to national tuberculosis con-
trol objectives and targets.
Obtaining endorsements by influential local organizations, including governments and

professional societies, serves as a way of obtaining buy-in and commitment to the princi-
ples in the ISTC. Moreover, the influence of the ISTC is amplified with each endorsement
received, and local endorsement paves the way for further ISTC-related activities, as
described subsequently.
Mobilizing Professional Societies

Professional societies and their leaders are often influential members of the private medi-
cal community, have direct access to a large number of practicing clinicians, and have
influence that extends beyond their membership. The societies often include academic
physicians who are influential in their own right. Professional societies can provide a con-
venient means, sometimes the only means, to access the private sector systematically by

utilizing society journals, newsletters, and other communications. Strategic thinking needs
to be applied in determining the reasons for seeking professional society support, but the
ISTC can serve as a means to identify and focus on common goals and objectives and
can provide a framework for addressing and improving the quality of care delivered by
private providers.
Providing the Framework for Conducting a Feasibility Analysis

Because each of the major components of tuberculosis care is included in the ISTC, the
standards provide a broad framework for a systematic “feasibility analysis” of local capa-
bilities, and can serve as a vehicle for addressing any shortcomings. Conceptually, the
ISTC feasibility analysis is a way for programs and providers to take stock of the stan-
dards that are or are not being met in their country. The feasibility analysis can be applied
at any level in the health system national, state/provincial, district, or individual institutional
level. The level at which the analysis is performed depends in part on the organization and
funding of tuberculosis services. Conducting the analysis at a national level can provide
an overall mapping and assessment of tuberculosis services across the country; this can
be useful for general NTP planning purposes, for informing policy makers, and for advo-
cacy efforts. Conducting the analysis at a district or local level may enable those partici-
pating to discuss more specific problems and to devise more specific solutions. For
example, if the problem is limited access to laboratories, specific sharing of resources can
be suggested. Within an individual institution, the ISTC may be used to assess the avail-
ability and quality of essential tuberculosis services provided by the institution and by the
clinicians practicing within the institution.
Quality and Performance Assessment

Similar to the feasibility analysis, the ISTC can serve as a means for assessing the quality
of care. The individual standards within the ISTC can be utilized to measure the quality of
tuberculosis services delivered by any provider, program, or sector. A major purpose of
the ISTC is to improve the quality of tuberculosis care. Any or all of the standards may be
used as tools for monitoring and evaluation of quality. Such assessments, just as with the
feasibility analysis, can identify weaknesses in programs, institutions, or individual provid-
ers. Tailored interventions can then be employed to correct the weaknesses and improve
quality.
ISTC as an Advocacy Tool

Political commitment is a critical component of tuberculosis control, and its absence limits
implementation of control measures. There has been considerable success in bringing
high-level government attention and commitment to tuberculosis control. However, in
most countries, at all levels of government, there has been a failure to translate this high-
level political commitment into effective, country-level public policies that provide a frame-
work for sustained tuberculosis control programs and activities. The ISTC provides a set
of internationally recognized standards any government should seek to meet. In using the
ISTC feasibility analysis tools, NTPs can identify gaps in meeting the standards, providing
a powerful advocacy tool to seek improved tuberculosis care and control.

Engaging Patients and Communities
The ISTC relates to this component in two ways: First, because the ISTC is backed by an
international consensus and describes agreed upon elements of tuberculosis care that
should be available everywhere, patients worldwide should expect that their care is in
compliance with the ISTC. The ISTC, thus, provides patients with the backing they need
to insist that they receive high quality care. Similarly, communities should expect that the
care provided within their boundaries meets the standards, and thus is of high quality.
Second, the Patients’ Charter for Tuberculosis Care was developed in tandem with the
ISTC with the intent that they would be complimentary documents. The PCTC relies on
the ISTC as its technical support. The PCTC describes both patients’ rights and respon-
sibilities. Implicit in both the statements of patients’ rights and their responsibilities is that
they will receive care that is in conformance with the ISTC. Patients’ awareness of and
support for the ISTC and the PCTC can be used to provide leverage in dealings with pol-
icy makers and funding agencies, empowering them to be effective advocates for high
quality tuberculosis care.

Annex 3
ISTC Tuberculosis Training Modules
The ISTC Tuberculosis Training Modules are educational resource tools developed to
assist in the incorporation of the ISTC into training courses and curricula on tuberculo-
sis. The modules currently available are based on edition 2 of the ISTC. Updates mod-
ules based on edition 3 will be available in September, 2014. However, the descriptions
based on the 2009 update will be equally applicable to the modules based on edition 3.
All training material can be downloaded at www.istcweb.org.
The modules are comprehensive in their coverage of core topics in the clinical evalua-
tion and management of tuberculosis and the material is presented in a format that is
flexible and adaptable to various training needs. While the modules may be used as
core presentations for courses on tuberculosis, the ISTC Tuberculosis Training Modules
material should also be viewed as a tuberculosis “training resource library” offering easy
access to specific ISTC material, individual slides, images, or graphics as needed to
update or augment existing tuberculosis training materials.
The planning and development of the ISTC Tuberculosis Training Modules was guided
by members of the original ISTC steering committee and through significant input from
ISTC implementation pilot countries. Through an informal assessment of needs from
country-level input and steering committee members, a didactic PowerPoint slide for-
mat was chosen as most useful for easy adaptation for general training needs across a
spectrum of capacity-building activities. The target audience is practicing physicians,
both public and private. The modules may be adapted for pre-service trainees, nursing,
and other health care providers.

Organization of Modules
Core topics in tuberculosis diagnosis, treatment, and public health responsibilities are
covered in the modules, highlighting the relevant ISTC standards as they address the
basic principles of care for persons with, or suspected of having, tuberculosis.
ISTC Tuberculosis Training Modules cover the following content areas:
Training Module Slide Sets 2009
Clinical Presentation and Diagnosis of Tuberculosis Standards 1, 2, 3, 4, 5, 6
Microbiological Evaluation of Tuberculosis Standards 2, 3, 4, 5, 6, 10, 11
Pediatric Tuberculosis Standards 2, 3, 4, 6
Initial Treatment of Tuberculosis Standards 7, 8, 9, 10, 12,13
Fostering and Assessing Adherence to Treatment Standard 9,17
Drug-resistant Tuberculosis Standard 11, 12
Standards for Addressing HIV Infection and other Co-morbid Conditions
TB and HIV infection: Introduction and Diagnosis Standards 2, 3, 14
TB and HIV infection: Treatment Standards 8, 15,16
Standards for Public Health
Contact Evaluation Standards 18
Isoniazid Preventive Therapy Standards 16, 19
Tuberculosis Infection Control Standards 20
Additional Training Modules/Slides
Basic Chest Radiology for the TB Clinician
Introduction to the ISTC Standards

Additional Training and Evaluation Tools
Additional materials provided with the slidesets include instructor Teaching Notes, a
Facilitator’s Guide (includes sample ISTC course agendas), instructions for producing
Participant Manuals, and Evaluation and Training Tools (includes Training Module Test
Questions).
Teaching Notes: Each ISTC Tuberculosis Training Module contains Teaching Notes
to assist instructors by offering speaking points, background material, and interactive
tips. The Teaching Note Summary serves as a quick reference document containing a
complete set of Teaching Notes with “thumbnail” slide images for all modules.
Facilitator’s Guide: The Facilitator’s Guide explains the organization of the ISTC
Tuberculosis Training Modules and includes suggestions for effective course develop-
ment and facilitation, including:
• Sample course agendas

• Participant manual instructions
Test Questions: Questions based on module objectives are included which may be
used as Pre- and Post- test evaluation or alternately as interactive discussion tools for
module presentations.
Other Evaluation and Training Tools: Template forms for course evaluations and
training course administrative tools for registration and certification are also available.
Pilot Testing of the Training Modules

Draft versions of the ISTC Tuberculosis Training Modules have been pilot-tested in a vari-
ety of settings. The successful adaptation and incorporation of the ISTC material by these
pilot groups offers examples of how the ISTC Training Modules may be used.
Training curriculum for practicing physicians (private and public): Materials from
the ISTC Tuberculosis Training Modules were adapted for use in a comprehensive set of
training material developed to teach providers about new national tuberculosis guidelines
(which incorporated the ISTC) in the Caribbean. In-country educators piloted the material
in three separate trainings sessions.
Specialty workforce training: Select materials from the ISTC Tuberculosis Training
Modules were used by outside experts as part of a training course for physicians, nurses,
and clinical staff at a new national MDR-referral hospital in Tanzania.
Pre-service training: Collaboration between the National Tuberculosis and Leprosy Pro-
gram (NTLP) and six medical schools and Allied Health Sciences in Tanzania resulted in a
unified curriculum on tuberculosis integrating the ISTC. Materials from the ISTC Tubercu-
losis Training Modules were used in the development of the final curriculum.
Professional Societies: ISTC Tuberculosis Training Modules were adapted for use as
core material for an extensive country-wide training plan developed by a collaborative
effort of professional society members and the NTP as part of the ISTC task force mission
in Indonesia.

2009 Revisions and Online Access
The first version of the training material was released in 2008. The current 2009 version
has been updated to reflect the revisions within this document. New modules (radiology,
pediatrics, isoniazid preventive therapy, and infection control) have been added as well. All
training material can be downloaded at www.istcweb.org.

86 I STC 3 r d e dition , 2014
Photo Credits
Cover - top Page 37
Peru 1997 Ghana 2004
Photographer: Jad Davenport Photographer: Pierre Virot
Credits: WHO/TBP/Davenport Credits: WHO/TBP/Virot
Source: World Lung Foundation Source: World Lung Foundation
Cover - middle Page 41
India 2004 Photographer:Gary Hampton
Photographer: Gary Hampton Credits: WHO/TBP/Hampton
Credits: WHO/TBP/Gary Hampton Source: World Lung Foundation
Source: World Lung Foundation
Page 42
Cover - bottom Photographer: Phil Hopewell
Uganda 2003 Credits: Curry International TB Center,
Photographer: Gary Hampton UCSF
Credits: WHO/TBP/Gary Hampton Source: Photographer
Page 47
Page 4 Tanzania 2012
Ethiopia 2003 Photographer: Phil Hopewell
Photographer: Jan van den Hornbergh Credits: Curry International TB Center,
Credits: WHO/TBP/Jan van den Hornbergh UCSF
Source: World Lung Foundation Source: Photographer
Page 8 Page 49
Tanzania 2012 Photographer: Sarah England
Photographer: Phil Hopewell Credits: WHO/TBP/England
Credits: Curry International TB Center, Source: World Lung Foundation
UCSF
Page 50
Source: Photographer
Uganda 2003
Page 14 Photographer: Gary Hampton
Uganda 2003 Credits: WHO/TBP/Gary Hampton
Photographer: Gary Hampton Source: World Lung Foundation
Credits: WHO/TBP/ Gary Hampton
Page 52
Uganda 2003
Page 20 Photographer: Gary Hampton
Myanmar 2001 Credits: WHO/TBP/Gary Hampton
Photographer: Virginia Arnold Source: World Lung Foundation
Credits: WHO/TBP/Arnold
Page 56
Saipan 2009
Page 22 Photographer: Richard Brostrom
Thailand 2007 Credits: CNMI Tuberculosis Control Program
Photographer: Wanda Walton Source: Photographer
Credits: CDC/DTBE
Page 57
Tanzania 2012
Page 25 Photographer: Phil Hopewell
Uganda 2010 Credits: Curry International TB Center,
Credits: ©FIND/Ajay Thirumala UCSF
Page 28
Peru 1997 Page 60
Photographer: Jad Davenport Tanzania 2012
Credits: WHO/TBP/Davenport Photographer: Phil Hopewell
Source: World Lung Foundation Credits: Curry International TB Center,
UCSF
Page 31
Photographer: Gary Hampton
Credits: WHO/TBP/Hampton Page 62
Source: World Lung Foundation Peru 1997
Photographer: Jad Davenport
Page 33
Credits: WHO/TBP/Davenport
Photographer: Sarah England
Credits: WHO/TBP/England
Source: World Lung Foundation Back Cover
Bangladesh 2001
Page 34
Photographer: Sarah England
South Africa 2003
Credits: WHO/TBP/England
Photographer: Gary Hampton
Credits: WHO/TBP/Hampton
87 I STC 3 r d e dition , 2014 photo credits

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INTERNATIONAL STANDARDS F OR

3rd edition, 2014

Available at the following web sites:

3rd edition, 2014

I STC 3 r d e dition , 2014 table of contents

Steering Committee (WHO)

Fran Du Melle (American Thoracic Society) provided administrative coordination as well as

1 I STC 3 r d e dition , 2014 acknowledgments

2 I STC 3 r d e dition , 2014 list of abbreviations

3 I STC 3 r d e dition , 2014 list of abbreviations

4 I STC 3 r d e dition , 2014 preface to edition 3

5 I STC 3 r d e dition , 2014 preface to edition 3

Section Key Differences

Standards for Diagnosis

Standard 4 • Previous Standard 4 now combined with Standard 1.

6 I STC 3 r d e dition , 2014 preface to edition 3

Section Key Differences

Standards for Treatment

Standards for Addressing HIV Infection and other Co-morbid Conditions

Standards for Public Health and Prevention

7 I STC 3 r d e dition , 2014 preface to edition 3

8 I STC 3 r d e dition , 2014 summary

The standards are as follows:

Standards for Diagnosis

9 I STC 3 r d e dition , 2014 summary

Standard 5. In patients suspected of having pulmonary tuberculosis whose sputum

Standards for Treatment

Standard 9. A patient-centered approach to treatment should be developed for all

Standard 10. Response to treatment in patients with pulmonary tuberculosis (including

10 I STC 3 r d e dition , 2014 summary

Standard 11. An assessment of the likelihood of drug resistance, based on history of

Standard 13. An accessible, systematically maintained record of all medications given,

11 I STC 3 r d e dition , 2014 summary

12 I STC 3 r d e dition , 2014 summary

• Persons with symptoms suggestive of tuberculosis

13 I STC 3 r d e dition , 2014 summary

14 I STC 3 r d e dition , 2014 introduction

15 I STC 3 r d e dition , 2014 introduction

16 I STC 3 r d e dition , 2014 introduction

17 I STC 3 r d e dition , 2014 introduction

18 I STC 3 r d e dition , 2014 introduction

Utilization of the ISTC

Adaptation of the ISTC

19 I STC 3 r d e dition , 2014 introduction

Providers must Rationale and Evidence Summary

20 I STC 3 r d e dition , 2014 standards for diagnosis Standard 1

Rationale and Evidence Summary

The most commonly reported symptom of pulmonary tuberculosis is persistent cough

21 I STC 3 r d e dition , 2014 standards for diagnosis Standard 2

22 I STC 3 r d e dition , 2014 standards for diagnosis Standard 2

Scoring systems in which the likelihood of tuberculosis is estimated based on specific

WHO-approved microbiologic tests for tuberculosis

Test Site Major Findings/results of Systematic Reviews

Diagnosis of Active Tuberculosis

23 I STC 3 r d e dition , 2014 standards for diagnosis Standard 2

Performance of chest radiography as a diagnostic test for tuberculosis

Radiographic Finding (modified from Ref 1)

Pooled Sensitivity (%) Pooled Specificity (%)

Any abnormality compatible with TB (active or inactive) 98 (95–100) 75 (72–79)

Despite evidence to the contrary, there is a widespread tendency to focus on patient-related

1. Failure of a tuberculosis treatment which contains second-line drugs including