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COMMENTARY
WHO guidelines for treatment of tuberculosis: the missing links
Muhammad Atif • Syed Azhar Syed Sulaiman •
Asrul Akmal Shafie • Irfhan Ali •
Mohamed Azmi Hassali • Fahad Saleem
Received: 22 December 2011 / Accepted: 15 May 2012 / Published online: 16 June 2012
� Springer Science+Business Media B.V. 2012
Abstract Worldwide, the treatment of tuberculosis is
based on evidence-based guidelines developed by the
World Health Organization (WHO) for national tubercu-
losis programs. However, the importance of health related
quality of life, the adequate management of side effects
associated with antituberculosis drugs and the elaboration
of tuberculosis treatment outcome categories are a few
issues that need to be addressed in forthcoming WHO
guidelines for the treatment of tuberculosis.
Keywords Antihistamines �Health related quality of life �Side effects � Sputum induction � Treatment outcomes �Tuberculosis �WHO Guidelines
Impacts on practice
• Incorporation of patient reported outcomes would help
health care professionals to identify patients with
altered mental and physical health.
• Stratifying patients with altered physical and/or mental
health is of critical importance in countries where highly
individualised approach cannot be applied because of
either limited resources or a higher incidence rate of
tuberculosis.
• Sputum induction for non-sputum producers would
help to spot the tuberculosis cases that require close
clinical and therapeutic monitoring.
• Rational selections of anti-histamines for treating itchiness
and skin rashes associated with anti tuberculosis agents
have a significant impact on a patient’s routine life.
Background
In directly observed treatment short course (DOTS) imple-
mented countries, the treatment of tuberculosis (TB) is based
on the guidelines developed by the Stop TB Department of the
World Health Organization (WHO) [1]. The principal purpose
of these guidelines is to help national TB control programs
(NTPs) in setting TB treatment policy to optimise patient cure.
A further purpose is to guide clinicians working in both public
and private sectors [1]. The stop TB Department of WHO
revises NTP guidelines every 3–5 years, or as needed because
of new evidences [1]. The authors would like to point out few
crucial issues that need to be addressed in the upcoming WHO
guidelines for management of the tuberculosis (TB).
Importance of measuring health related quality
of life in tuberculosis patients
WHO defines ‘‘health’’ as a state of complete physical,
mental and social well-being and not merely the absence of
M. Atif (&)
Discipline of Clinical Pharmacy, School of Pharmaceutical
Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia
e-mail: [email protected]
S. A. S. Sulaiman
School of Pharmaceutical Sciences, Universiti Sains Malaysia,
Penang, Malaysia
A. A. Shafie � M. A. Hassali � F. Saleem
Discipline of Social and Administrative Pharmacy,
School of Pharmaceutical Sciences, Universiti Sains Malaysia,
Penang, Malaysia
I. Ali
Head of Respiratory Department, Penang General Hospital,
Penang, Malaysia
123
Int J Clin Pharm (2012) 34:506–509
DOI 10.1007/s11096-012-9657-8
disease or infirmity [2]. Although there are many types of
equipments and instruments to measure clinical and bio-
physiological parameters of health, researchers and clini-
cians have now realised that these only measure interme-
diate outcomes that might not reflect the patient’s
understanding of their own well-being. Individual’s per-
ception of their physical, mental and social health could be
measured in terms of Health Related Quality of Life
(HRQoL) [3]. This measurement could be used to predict
how a patient’s well being is influenced by certain physi-
ological, psychosocial, sociological, economic and spiritual
factors [4]. It is now known that patients with chronic ill-
nesses place a high value on their mental, social and
physical wellbeing [5]. As far as TB is concerned, a
patient’s HRQoL can be compromised in various aspects.
For example, in some communities TB patients have to
face social rejection and isolation because they are con-
sidered to be a source of infection for healthy individuals
[6–8]. Similarly, in a few studies TB patients themselves
reported that they experience negative emotions such as
anxiety and fear [6, 7]. Stigmatisation and negative emo-
tions resulting from illness may lead to the long term
impairment of a patient’s psychosocial well-being [9]
which could lead to work absenteeism, resulting in loss of
productivity and monthly income [4].
A valid and reliable disease-specific instrument is
important to guarantee the accuracy, precision and general-
isability of the results. Ironically, SF-36, a generic instru-
ment was found to be more valid [9], despite the plethora of
questionnaires now available to measure HRQoL in TB [9–
11]. Nonetheless, at present, much of the attention within TB
management is spent on microbiological cure, and the
impact of this condition on HRQoL is either undervalued or
seldom considered [6]. Whilst more research is required to
find more valid specific tools for tuberculosis patients,
monitoring even their generic HRQoL would help health
care professionals to target the specific mental and physical
health components that are adversely affected by the disease
or treatment. It is therefore suggested that WHO should
incorporate HRQoL evaluation of TB patients into forth-
coming guidelines for national TB control programs. This
would help health care professionals to apply the tools in
their setting. Stratifying such patients is of critical impor-
tance in countries where a highly individualized approach
cannot be applied due to either limited resources or a greater
incidence rate than the other countries.
An insight into the reporting treatment outcome
in pulmonary tuberculosis
Treatment outcomes of pulmonary tuberculosis are repor-
ted on the basis of six outcome categories; ‘‘cure’’,
‘‘treatment completed’’, ‘‘treatment failure’’, ‘‘died’’,
‘‘default’’ and ‘‘transferred out’’ (Table 1).
‘‘Cure’’ and ‘‘treatment completed’’ are further classified
as ‘‘treatment success’’ [1] where-as ‘‘treatment failure’’,
‘‘died’’, ‘‘defaulted’’ and ‘‘transferred out’’ are classified as
‘‘treatment failure’’. Reporting ‘‘treatment completed’’,
‘‘treatment failure’’, ‘‘death’’, ‘‘default’’ and ‘‘transferred
out’’ is easy but case is different for declaring a patient as
‘‘cured’’. According to WHO [1], a pulmonary tuberculosis
patient can be declared as ‘‘cured’’ once his/her sputum
smear or culture was positive at the beginning of the
treatment but who was smear- or culture-negative in the
last month of treatment and on at least one previous
occasion. In actual practice, meeting this criterion is quite
difficult. Usually after regular intake of anti-TB drugs for
2–3 months, patients are unable to produce sputum
throughout the remaining period of their treatment. As a
result, a specimen is not available for Acid Fast Bacilli
smear staining and culture. One possible solution to cope
with this challenge is by inducing sputum [12, 13] with
sterile saline using ultrasonic nebuliser [12–15] at set time
points suggested by WHO [1]. However, selecting the most
suitable normal saline concentration is still under debate.
One school of thought advocates the use of higher nebu-
lised saline concentrations which might increase diagnostic
yield by increasing the volume of induced sputum due to
increased osmotic pressure [16]. Contrary to this, others
Table 1 Treatment outcome categories of tuberculosis according to
World Health Organization guidelines (fourth edition)
Outcome Definition
Cure A patient whose sputum smear or culture was
positive at the beginning of the treatment but who
was smear- or culture-negative in the last month
of treatment and on at least one previous occasion
Treatment
completed
A patient who completed treatment but who does
not have a negative sputum smear or culture
result in the last month of treatment and on at
least one previous occasion
Treatment
failure
A patient whose sputum smear or culture is positive
at 5 months or later during treatment. Also
included in this definition are patients found to
harbor a multidrug-resistant (MDR) strain at any
point of time during the treatment, whether they
are smear-negative or -positive
Died A patient who dies for any reason during the course
of treatment
Default A patient whose treatment was interrupted for 2
consecutive months or more
Transfer out A patient who has been transferred to another
recording and reporting unit and whose treatment
outcome is unknown
Treatment
success
A sum of cured and completed treatment
Int J Clin Pharm (2012) 34:506–509 507
123
have suggested that higher nebulized saline concentrations
might be associated with greater risk of adverse events
during the procedure [17]. A recent meta-analysis has
suggested that higher saline concentrations are not associ-
ated with better diagnostic yield in sputum induction [18].
Gonzalez-Angulo and co-workers [18] has further sug-
gested investigating the use of low nebulised saline con-
centrations in an effort to minimize adverse events.
Other alternatives to sputum induction are gastric aspi-
rates, bronchoalveolar lavage (BAL) [15] and bronchos-
copy. Gastric aspirates and BAL are often negative on
direct smears and thus culture is required [19]. Bronchos-
copy is more a invasive and expensive technique [12] and
patients often refuses to go through this painful process. Li
and co-workers [12] reported that the cost of sputum
induction per patient is only 2.5 % of that for bronchos-
copy. Based on these evidences, we can say that sputum
induction is a safe and cost-effective technique to cope
with the challenge of classifying a patient in the ‘cure’
category. Recent WHO guidelines do not advise sputum
induction in those patients who deny sputum production
during TB treatment [1]. It is therefore suggested that the,
WHO guidelines should recommend either sputum induc-
tion or an alternative as a routine procedure for non-sputum
producing patients. This investigation may have high
public health significance in pulmonary cases as this would
allow us to identify cases that require close clinical and
therapeutic monitoring. This measure would also ensure
minimum chances of relapse and transmission to other
individuals in a community.
Management of itchiness and skin rashes associated
with anti-tuberculosis agents
Another important issue in the management of TB is the
common side effects associated with anti TB drugs [1].
Among these side effects, itching, nausea, and vomiting are
most common. It is now well known that side effects are
most common reason for treatment default. Management of
side effects definitely puts an extra financial burden on
health care system and therefore the medical professional
choose the cheapest medications available which have an
acceptable level of efficacy. Chlorpheniramine maleate is
the most commonly prescribed low-cost drug with known
efficacy for management of itchiness and skin rashes.
Although very effective, it is associated with sedation,
which is its drawback. In some cases, patients default on
TB treatment just because of sedation the associated with
first generation anti-histamines rather than actual side
effect [20]. Therefore, non-sedative drugs including fexo-
fenadine [21] and loratidine [22], which have comparable
anti-histamine efficacy [23] seem to be superior over first
generation anti-histamines. Although costly, the use of
these drugs can reduce the chances of default especially in
patients with an active lifestyle. Moreover, these drugs can
be cost effective for those patients who stop taking medi-
cation in the middle of treatment just because of the side
effects of anti-histamines and later are registered as new
cases upon the recurrence of TB signs and symptoms.
Authors are of the opinion that the WHO guidelines should
clearly indicate the patient characteristics which demand
that only second generation anti-histamines can be pre-
scribed to ensure the patient’s quality of life and compli-
ance to TB treatment.
Conclusion
Psychometric evaluation of TB patients, rational use of
anti-histamines for the management of itchiness and skin
rashes associated with anti-TB drugs and methods of spu-
tum induction for achieving highest cure rate are a few
issues that need be addressed in the impending NTP
guidelines.
Funding Authors would like to thank Institute of Postgraduate
Studies (IPS) at University Sains Malaysia for their financial support
in carrying out this work through USM-RU-PRGS (1001/PFARM-
ASI/844011).
Conflicts of interest None.
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