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: pharmacist_atif@yahoo.com

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

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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

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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.

References

1. World Health Organization. Treatment of Tuberculosis Guide-

lines; 2009. Report No.: WHO/HTM/TB/2009/420. ISBN: 9789

241547833.

2. World Health Organization. Preamble to the constitution of the

World Health Organization as adopted by the International

Health Conference. International Health Conference; New York.

1946 [cited 1 May 2012]; Available from: http://whqlib

doc.who.int/hist/official_records/constitution.pdf.

3. Spilker B. Quality of life and pharmacoeconomics in clinical

trials. Philadelphia: Lippincott-Raven Philadelphia; 1996. ISBN:

0781703328.

4. Rajeswari R, Muniyandi M, Balasubramanian R, Narayanan PR.

Perceptions of tuberculosis patients about their physical, mental

and social well-being: a field report from south India. Soc Sci

Med. 2005;60(8):1845–53.

5. Sherbourne CD, Sturm R, Wells KB. What outcomes matter to

patients? J Gen Intern Med. 1999;14(6):357–63.

6. Marra CA, Marra F, Cox VC, Palepu A, Fitzgerald JM. Factors

influencing quality of life in patients with active tuberculosis.

Health Qual Life Outcomes. 2004;2(1):58.

7. Hansel NN, Wu AW, Chang B, Diette GB. Quality of life in

tuberculosis: patient and provider perspectives. Qual Life Res.

2004;13(3):639–52.

8. Macq J, Solis A, Martinez G, Martiny P, Dujardin B. An

exploration of the social stigma of tuberculosis in five. Health

Policy. 2005;74(2):205–17.

508 Int J Clin Pharm (2012) 34:506–509

123

9. Guo N, Marra F, Marra CA. Measuring health-related quality of

life in tuberculosis: a systematic. Health Qual Life Outcomes.

2009;7:14.

10. Dhuria M, Sharma N, Ingle GK. Impact of tuberculosis on the

quality of life. Indian J Commun Med. 2008;33(1):58–9.

11. Dhingra VK, Rajpal S. Health related quality of life (HRQL)

scoring (DR-12 score) in tuberculosis–additional evaluative tool

under DOTS. J Commun Dis. 2005;37(4):261–8.

12. Li LM, Bai LQ, Yang HL, Xiao CF, Tang RY, Chen YF, et al.

Sputum induction to improve the diagnostic yield in patients with

suspected pulmonary tuberculosis notes from the field. Int J

Tuberc Lung Dis. 1999;3(12):1137–9.

13. Parry CM, Kamoto O, Harries AD, Wirima JJ, Nyirenda CM,

Nyangulu DS, et al. The use of sputum induction for establishing

a diagnosis in patients with suspected pulmonary tuberculosis in

Malawi. Tuber Lung Dis. 1995;6(1):72–6.

14. Leigh TR, Hume C, Gazzard B, Parsons P, Husain OAN, Collins

JV. Sputum induction for diagnosis of Pneumocystis carinii

pneumonia. Lancet. 1989;334(8656):205–6.

15. Shata AM, Coulter JB, Parry CM, Ching’ani G, Broadhead RL,

Hart CA. Sputum induction for the diagnosis of tuberculosis.

Arch Dis Child. 1996;74(6):535–7.

16. Wills PJ, Hall RL, Chan W, Cole PJ. Sodium chloride increases

the ciliary transportability of cystic fibrosis and bronchiectasis

sputum on the mucus-depleted bovine trachea. J Clin Invest.

1997;99(1):9–13.

17. Schoeffel RE, Anderson SD, Altounyan RE. Bronchial hyperre-

activity in response to inhalation of ultrasonically nebulised

solutions of distilled water and saline. Br Med J (Clin Res Ed).

1981;283(6302):1285–7.

18. Gonzalez-Angulo Y, Wiysonge CS, Geldenhuys H, Hanekom W,

Mahomed H, Hussey G, Hatherill M. Sputum induction for the

diagnosis of pulmonary tuberculosis: a systematic review and

meta-analysis. Eur J Clin Microbiol Infect Dis. 2011 [Epub ahead

of print]. Available from: http://www.springerlink.com/content/

er6674p5785711rg/.

19. Crofton J, Horne NW, Miller F. Clinical tuberculosis. London:

The Macmillan Education Limited; 2008. ISBN: 140509737X.

20. Atif M, Sulaiman SAS, Shafie AA, Muttalif AR, Ali I, Saleem F.

Applying patient centered approach in management of pulmonary

tuberculosis: a case report from Malaysia. J Basic Clin Pharm.

2011;2(3):129–31.

21. Mason J, Reynolds R, Rao N. The systemic safety of fexofena-

dine HCl. Clin Exp Allergy. 1999;29(S3):163–70.

22. Mattila MJ, Paakkari I. Variations among non-sedating antihista-

mines: are there real differences? Eur J Clinical Pharmacol. 1999;

55(2):85–93.

23. Woodward JK. Pharmacology of antihistamines. J Allergy Clin

Immunol. 1990;86(4):606–12.

Int J Clin Pharm (2012) 34:506–509 509

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