PCS GUIDELINES

Diagnosis & Management of

Drug-susceptible Tuberculosis

A National Clinical Guideline

2017
 Table of content

Content Page
Foreword
Message by the President, Pakistan Chest Society
Introduction
Evolution of TB infection and disease in humans
Factors modifying TB epidemiology
Anatomical Sites of Tuberculosis
Clinical presentation of TB
Definition
Diagnosis of Tuberculosis
Management of Tuberculosis
Principles of Chemotherapy
Drug Regimens
New Cases
Anti-TB Drugs – Mechanisms of Action
Clinical Information about Essential Anti-TB Drugs
Treatment Regimens In Special Situations
Annexures
Introduction
Tuberculosis causes a great deal of ill health and an enormous burden on the population of low-income
countries. The tuberculosis situation, like many other developing countries is very serious in Pakistan. It
is one of the major public health problems in Pakistan. Pakistan ranks 5th among TB high burden
countries worldwide which together accounts for 56% of the global total.

As per WHO estimates, Total cases of tuberculosis reported in 2016 in Pakistan were 366061 out of them
new and relapse cases were 356390 and retreatment were 8091(excluding relapse registered in 2015) with
prevalence of 397 per 100,000 population and incidence of 268 rate per 100,000 population and the
majority of the cases are in productive age group. Pakistan is also estimated to have 6th highest prevalence
of multidrug-resistant TB with 4.2% MDR-TB in new cases and 16% in retreatment TB cases.

Although high case detection rates have been achieved in the country under NTP, the delay in diagnosis,
unsupervised inappropriate and inadequate drug regimens, poor follow up and lack of social support
program for high risk populations are some of the reasons for not reaching the target cure rates and
emergence of Drug Resistant forms of Tuberculosis. Our country has currently annual death rate of 24 per
100,000* people attributed to Tuberculosis. We have achieved 50% mortality rate reduction in 2015 as
compared with 1990.

Cure of cases of active tuberculosis is the key to effective control of the disease. Proper treatment of
tuberculosis patients reduces suffering and prevents death from tuberculosis. The purpose of these
guidelines is to help doctors and related health workers in the identifications of TB suspects, diagnosis
and treatment of a TB patient and to underline their important or essential role in the control of
Tuberculosis in the community. These guidelines have been prepared to develop a consensus management
of tuberculosis preferably in programmatic settings in line with International Standards in Tuberculosis
Care.
What is Tuberculosis?
Tuberculosis is an infectious bacterial disease caused by Mycobacterium tuberculosis which most
commonly affects the lungs. Mycobacteria are small rod-shaped bacilli that can cause a variety of
diseases in humans. There are three main groups:

1. Mycobacterium tuberculosis complex: this group includes M. tuberculosis, M. bovis, M.

africanum, M. microti, and M. canetti. They all can cause “tuberculosis” in humans. The vast
majority of tuberculosis is caused by M. tuberculosis, with the other organisms being relatively
rare. Their treatment is similar (M. bovis is innately resistant to pyrazinamide and M. africanum
is resistant to thioacetazone). This guide only addresses disease caused by Mycobacterium
tuberculosis complex.
2. Mycobacterium leprae causes leprosy.
3. Non tuberculous mycobacteria (NTM): this group includes all the other mycobacteria that can
cause diseases in humans. NTM sometimes can cause clinical manifestations (in the lungs, skin,
bones, or lymph nodes) similar to those of tuberculosis. Most NTM exist in the environment, are
not usually spread from person to person and are often non-pathogenic in persons with intact
immune system or healthy lung tissue.

All mycobacteria are classical acid-fast organisms and are named so because of their ability to retain
stains used in evaluation of tissue or sputum specimens (Ziehl-Neelsen stain).

M. tuberculosis multiplies more slowly and causes disease weeks or even months to years after infection.
M. tuberculosis is a strictly aerobic bacterium. It therefore multiplies better in pulmonary tissue (in
particular at the apex, where oxygen concentration is higher) than in the deeper organs.

How Does Tuberculosis Develop?

Tuberculosis is transmitted from person to person via droplets from the throat and lungs of people with
the active respiratory disease. A healthy person might be infected by inhaling these tiny particles and
developing a primary complex in the lungs. Infection with Mycobacterium tuberculosis, in most healthy
people, often causes no symptoms since the person’s immune system acts to wall off the bacteria.
However, in some people the tuberculosis bacteria will spread from the primary lung lesion to other parts
of the body via the blood stream and lymphatics or by direct extension, and in this way may affect any
organ.

Evolution of TB infection and disease in humans

When a person inhales infectious droplets containing M. tuberculosis, most of the larger droplets become
lodged in the upper respiratory tract (nose and throat), where infection is unlikely to develop. However,
smaller droplet nuclei may reach the small air sacs of the lung (the alveoli), where infection may begin.

Primary infection

After transmission, M. tuberculosis multiplies slowly, in most cases in the terminal alveoli of the lungs
(primary focus) and in the lymph nodes of corresponding drainage areas: this represents the primary
infection. The primary focus and related hilar lymphadenopathy form the primary complex. In one to two
months, due to the action of lymphocytes and macrophages (cellular immunity), the primary focus will be
contained and encapsulated with a central zone of parenchymal necrosis (caseous necrosis). It is at this
moment that specific TB immunity appears, and a positive skin reaction to tuberculin is observed4,5. This
stage is usually asymptomatic; however, in some rare cases, hypersensitivity reactions may occur.

Note: A small area of granulomatous inflammation will occur in the alveoli, which is not usually
detectable on chest X-ray unless it calcifies or grows substantially. It is called a primary focus.

In the majority of cases (90 to 95% of non-HIV infected patients), the pulmonary lesions gradually heal.
In 5 to 10% of the cases, the pulmonary lesion will progress to active disease either by gradual
progression and/or spread via lymphatics or blood or by reactivation (often many years later) of primary
or secondary lesions.

Active TB

Before immunity is established, bacilli from the primary infectious focus or from a near-by lymph node
can be transported and disseminated throughout the body via the lymph system or the bloodstream.
Secondary foci containing bacilli can be born this way, particularly in the lungs, lymph nodes, serous
membranes, meninges, bones and kidneys. As soon as an immune response is mounted, most of these foci
spontaneously resolve. Yet, a number of bacilli may remain latent in the secondary foci for months or
even years. Different factors can reduce immunity (e.g. HIV infection) and lead to reactivation of the
bacilli and their multiplication in one or more of these foci. This reactivation or progression of the
primary or secondary foci results in “active TB disease”. While active TB may occur after months or
years without clinical signs following primary infection, it is estimated that half of the cases of active TB
appear in the year following infection.

Risk factors for developing active TB

The risk depends on a number of factors including those that lead to a weakened immune system,
damaged lungs, or the intensity and duration of exposure:

Host immune defences:

– HIV infection (risk multiplied by 20-40);

– Diabetes mellitus (risk multiplied by 3-5);

– Malnutrition;

– Prolonged therapy with corticosteroids (such as prednisolone) and other immuno - suppressive

therapies;

– Certain types of cancer (e.g., leukaemia, Hodgkin's lymphoma, or cancer of the head and neck);

– Severe kidney disease;

– Alcoholism;
– Substance abuse;

– Age:

• Young children (children under 5 have twice the risk and higher risks are observed for those under 6
months);

• Persons over sixty years have 5 times the risk;

– Pregnancy.

Conditions that damage the lung:

– Tobacco smoking;

– Silicosis.

Intensity of exposure (number of inhaled bacilli):

– Contagiousness of the source;

– Environment and proximity in which the exposure took place;

– Duration of exposure;

– Residents and employees of high-risk congregate setting.

Prognosis
TB is a severe and often deadly disease without treatment. After 5 years without treatment, the outcome
of smear-positive pulmonary TB (PTB) in HIV-negative patients is as follows:

– 50-60% die (case fatality ratio for untreated TB);

– 20-25% are cured (spontaneous cure);

– 20-25% develop chronic smear-positive TB.

With adequate treatment, the case fatality ratio (CFR) often falls to less than 2 to 3% under optimal
conditions. Similar CFRs are seen with untreated EPTB and smear-negative PTB, with an equivalent fall
in CFR with adequate treatment. Untreated TB in HIV-infected patients (not on antiretrovirals) is almost
always fatal. Even on antiretrovirals, the CFR is higher than in non-HIV infected patients.
FACTORS MODIFYING TB EPIDEMIOLOGY

There are four major factors that influence TB epidemiology: (1) socioeconomic development; (2) TB
treatment; (3) HIV infection; and (4) BCG vaccination.

Socioeconomic development

In European countries, the incidence and specific mortality of TB have diminished by 5 to 6% per year
since 1850. This progressive improvement dates back to before the era of vaccination and antibiotics and
was correlated with socioeconomic development (improvement of living conditions, nutritional status of
populations, etc.). TB is a disease of the poor: over 95% of cases occur in resource-constrained countries
and in poor communities. In industrialised countries, TB generally affects the most disadvantaged social
groups.

TB treatment

Diagnosing and initiating effective treatment in a patient early in the course of their TB disease, before
they can infect many people, is considered the most effective preventive measure against TB. Effective
treatment substantially reduces or eliminates disease transmission from smear-positive patients in less
than one month after initiation of treatment. Since the introduction of anti-TB treatment, a rapid reduction
of the annual risk of infection (ARI) has been observed in many industrialised countries, with the
infection risk diminishing by approximately 50% every 5 to 7 years during this period. This tendency was
observed in countries having a BCG vaccination programme, as well as, in those without one. This
reduction of the risk of infection is a direct consequence of detection programmes, diagnosis and
treatment.

HIV infection

Immunodeficiency induced by HIV infection is a major risk factor for progression of TB infection and
has a dramatic impact on the epidemiology of TB. While the lifetime risk of TB disease after infection is
approximately 10%, patients infected both with HIV and M. tuberculosis have an approximate risk of
10% annually. Approximately 12 to 14% of TB cases in the world are at present among HIV patients. The
African region accounts for 82% of the TB cases among HIV patients. The impact of HIV on TB
epidemiology can only increase with the spread of the HIV epidemic in Asia, where two-thirds of the
world's M. tuberculosis-infected population lives.

BCG vaccination

The effect of BCG vaccination is controversial. Two notions may be distinguished: the effectiveness of
BCG at an individual level and the epidemiological impact of this vaccination. Effectiveness of BCG at
an individual level Even though results of controlled surveys are contradictory (efficacy ranging from 0 to
80%), it is acknowledged that BCG, if administered before primary infection (as is done in the practice of
giving it at birth), confers a protection of 40 to 70% for a period of approximately 10 to 15
years13,14,15,16. Protection from the severe forms of TB in children (miliary and meningitis) is
estimated at 80%. Epidemiological impact of vaccination The analysis of public health statistics of some
European countries has shown that BCG vaccination reduces the number of active TB cases in
vaccinated subjects as compared to those unvaccinated. Models demonstrate that even moderately
effective vaccines could have a significant effect on reducing tuberculosis epidemics if they can be
coupled with moderate to high treatment rates. Despite some protection of the BCG vaccination, the
impact of BCG vaccination on TB transmission and the TB epidemic is generally considered quite
minimal and more effective vaccines are needed.

Other factors

Other modifying factors include infection control measures and isoniazid preventive therapy for latent
TB. The degree to which the TB epidemiology is affected by these measures is not known.

Anatomical Sites of Tuberculosis

For the purpose of registration and treatment TB is divided in two broad categories i.e 1. Pulmonary TB.
2. Exra Pulmonary TB.

Pulmonary Tuberculosis:

Tuberculosis affects the lungs in more than 80% of cases. Pulmonary tuberculosis in adults is often
sputum smear-positive and therefore highly infectious. Smear negative cases are 7-10 times less
infectious than smear positive cases.

Extra-Pulmonary Tuberculosis:

Affects various organs such as lymph nodes, pleura, pericardium, bones and joints, genito-urinary tract,
the nervous system, intestines, skin and many other parts of the body. Diagnosis is often difficult and
should preferably be made by Specialists using specific diagnostic tools to confirm the diagnosis.

Clinical presentation of Tuberculosis

• Pulmonary tuberculosis (PTB)

• Extrapulmonary tuberculosis (EPTB)

• Disseminated or miliary tuberculosis

• Clinical presentation in HIV-infected patients

• Summary of clinical presentations of tuberculosis

Pulmonary tuberculosis (PTB)

Certain signs of PTB are quite typical: prolonged cough (lasting more than 2 weeks) and sputum
production, while others are less so: weight loss, anorexia, fatigue, shortness of breath, chest pain,
moderate fever, and night sweats. Haemoptysis (blood in sputum) is a characteristic sign present in about
one third of patients. All these signs are variable and evolve in a chronic, insidious manner. History taking
and questioning the patient are therefore of the utmost importance.

Advanced forms and complications are not uncommon. These include:

 Respiratory insufficiency due to extensive lesions and destroyed lungs;

 Massive haemoptysis due to large cavities with hypervascularisation and erosion of vessels;
 Pneumothorax due to the rupture of a cavity in the pleural space.

In an endemic area, the diagnosis of PTB is to be considered, in practice, for all patients who have
experienced respiratory symptoms for more than 2 weeks.

Extrapulmonary tuberculosis (EPTB)

Starting from a pulmonary localisation (primary infection), M. tuberculosis can spread to other organs
during a silent phase, generally at the beginning of the infection. Active TB can develop in many other
parts of the body, in particular lymph nodes, meninges, vertebrae, joints, kidneys, genital organs and the
abdominal cavity. EPTB forms can develop at any age. Young children and HIV infected adults are more
susceptible. EPTB forms resent with a variety of clinical characteristics. However, a common
characteristic is the insidious evolution with gradual deterioration of the physical condition. Furthermore,
there is a lack of response to symptomatic or non-tuberculosis anti-infective treatments. EPTB may be
associated with a pulmonary localisation, which should be searched for whenever EPTB is diagnosed or
suspected.

1. Lymph node tuberculosis

Lymph node TB is a common presentation particularly in certain areas of Asia, where it represents up to
25% of TB cases. This form is more common in children and HIV infected patients. The presentation of
lymph node tuberculosis is non-inflammatory adenopathies, cold and painless, single or multiple, usually
bilateral, evolving in a chronic mode towards softening and fistulisation. Cervical lympadenothapy is
most frequent, followed by axillary and mediastinal forms. Diagnosis is mainly clinical, however fine
needle aspiration can be done if the diagnosis is in question. Adenopathies usually disappear in less than 3
months after treatment initiation. Paradoxical reactions may be observed at the beginning of treatment
(appearance of the lymph node getting worse with abscesses, fistulas or other lymph nodes appearing) and
often a change in the treatment is not needed.

Differential diagnosis includes malignancies (lymphoma, leukaemia, ear/nose/throat tumours, Kaposi

sarcoma) and other infections (bacterial, viral, non-tuberculosis mycobacteria, toxoplasmosis, HIV
infection, syphilis, African trypanosomiasis).
2. Tuberculous meningitis

Meningitis due to tuberculosis is most common in children below 2 years of age 5 and in HIV-infected
adults. Headaches, irritability, fever, and an altered mental status accompany the beginning of the disease,
often in a variable manner, which is progressive in nature. The meningeal syndrome (stiff neck, hypotonia
in infants, photophobia and headache) is present in most cases. Vomiting may be present. The impairment
of the third cranial nerve is a sign that can accompany TB meningitis (oculomotor paralysis). The main
differential diagnoses are other forms of meningitis where the cerebrospinal fluid (CSF) is clear – viral/
fungal meningitis or incompletely treated bacterial meningitis are the most common. TB meningitis is a
medical emergency, and any delay in diagnosis/treatment may result in irreversible neurological sequelae.

3. Tuberculosis of bones and joints

Tuberculosis of bones and joints is mostly found in children, probably because of better vascularisation
and oxygenation of osteo-articular structures during growth.

Arthritis: Often arthritis due to TB is a chronic monoarthritis, starting insidiously, with little or no pain
and accompanied by joint destruction. The joints most often affected are the hips, knees, elbows and
wrists. Half of the patients with TB arthritis have PTB at the same time.

Osteitis: This is the less frequent presentation of TB of the bones. It may be a primary osteitis or an
osteitis complicating arthritis. It affects long bones and is occasionally accompanied by cold abscesses.
Like arthritis, it is distinguished from common bacterial infections by the contrast of slight symptoms and
the extent of destruction detected by radiography.

Spondylodiscitis (TB of the spine or Pott's disease): TB of the spine affects vertebrae and disks,
bringing about destruction and deformation of the spine. A missed diagnosis of thoracic or cervical spinal
TB can result in paralysis. Dorsal localisation is the most frequent followed by lumbar and lumbosacral
areas. Localised pain may precede the appearance of the first radiological anomalies (destruction of an
inter-vertebral disk) by several months. A para-vertebral cold abscess may accompany osteo-articulary
lesions, yet neurological signs may complicate them. The diagnosis is often made based on the clinical
history and X-ray, as biopsy and culture is difficult to perform in resource-constrained settings.
Deterioration of physical condition and prolonged and insidious clinical history of osteitis or arthritis are
in favour of TB aetiology as opposed to bacterial osteomyelitis or brucellosis. The patient may have a
history of not responding to broad-spectrum antibiotics. months. A para-vertebral cold abscess may
accompany osteo-articulary lesions, yet neurological signs may complicate them.

4. Genitourinary tuberculosis

Renal involvement is frequent and may be asymptomatic for a lengthy period of time, with a slow
development of genitourinary signs and symptoms including: dysuria, urinary frequency, nocturia,
urgency, back and flank pain, abdominal pain, tenderness/swelling of the testes or epididymitis and
haematuria. General physical condition is preserved most of the time with only about 20% of patients
having constitutional symptoms.
Diagnosis is suspected in the presence of pyuria (white blood cells in the urine) and microor macroscopic
haematuria, which does not respond to broad-spectrum antibiotics. Examination of the urine aids in
diagnosis

In women, genital tract contamination can also happen by a haematogenous path. Abdominal pain,
leucorrhoea and vaginal bleeding are variable, non-specific signs of genital tract tuberculosis. Extension
may be found in the peritoneum with resulting ascites. The presenting complaint leading to the diagnosis
of genitourinary disease is often sterility. In men, genital localisation is secondary to renal localisation. It
is manifested most often by epididymitis with scrotal pain.

5. Abdominal tuberculosis

Abdominal TB commonly presents as ascites resulting from the peritoneal localisation of the infection.
The frequency of chronic ascites in tropical regions, with its many different causes, makes this relatively
uncommon form of TB a common diagnostic challenge. Diagnosis is assisted greatly by examination of
the ascitic fluid via paracentesis.

Besides ascites, clinical symptoms are non-specific: abdominal pain, diarrhoea and constitutional
symptoms (feve night sweats, malaise, weight loss). The ascites may mask weight loss.

6. Tuberculous pleural effusion

TB pleural effusion by itself is often asymptomatic, especially if less than 300 ml. When the effusion is
large, shortness of breath may be present. Sputum production and cough may only be present if there is
also pulmonary involvement, which is common. Constitutional symptoms such as fever, weight loss,
night sweats, anorexia and malaise may also be present. This form of TB is more frequent in young
adults. Diagnosis is assisted by examination of the pleural fluid via paracentesis.

7. Tuberculous pericardial effusion

Clinical signs of a tuberculous pericardial effusion include: chest pain, shortness of breath, oedema of the
lower limbs and sometimes ascites. The clinical examination may show pericardial friction rub, raised
jugular pressure and tachycardia. The radiography and ultrasounds are key elements for diagnosis.
Pericardiocentesis may be necessary in the event of acute heart failure resulting in haemodynamic
compromise. It must be performed by experienced personnel in wellequipped hospitals.

8. Cutaneous tuberculosis

The clinical presentation of cutaneous tuberculosis is chronic, painless, non-pathognomonic lesions,

ranging from small papula and erythema to large tuberculomas. The diagnosis is based on culture from a
biopsy.
Disseminated or miliary tuberculosis

Miliary TB is a generalised massive infection characterized by diffusion of bacteria throughout the body.
The disease may manifest as a miliary pattern or very small nodular shadows (“millet seeds”) in the lungs.
It can occur immediately after primary infection or during reactivation of a latent site; it is thought to
occur during haematological spread.

The classic acute form is mostly found in children, young adults and HIV patients. The presentation can
be either abrupt or insidious, marked by a progressive deterioration of the patient’s physical condition.
The clinical picture is often completed within one to two weeks and is characterized by a profoundly
altered physical condition, marked wasting, headaches and constant high fever. Discrete dyspnoea and
coughing suggest a pulmonary focus; however, lungs can often be clear on auscultation. A moderate
hepatosplenomegaly is occasionally found. Certain forms of miliary TB evolve in a subacute fashion over
several months. Given this non-specific clinical picture, typhoid fever and septicaemia should be
considered in a differential diagnosis.

Diagnosis of miliary TB is confirmed by chest X-ray. When feasible, fundoscopy would reveal choroidal
tubercles. Generally, sputum smear examination is negative. When there is no possibility of obtaining
chest X-rays, the lack of response to broad-spectrum antibiotics is an argument in favour of miliary TB.
In children, the risk of meningeal involvement is high (60-70%). Lumbar puncture should be routinely
performed if miliary TB is suspected. The tuberculin skin test is more likely to be falsely negative than in
any other form of TB. Miliary TB is a medical emergency.

Clinical presentation in HIV-infected patients

TB is a leading cause of HIV-related morbidity and mortality, and it is one of the main opportunistic
diseases. According to the WHO clinical staging of HIV/AIDS, HIV patients with pulmonary TB are in
clinical stage III and HIV patients with extrapulmonary TB are in clinical stage IV.

In the early stages of HIV infection, when the immune system is functioning relatively normally, the
clinical signs of TB are similar to those in HIV-negative individuals. As the immune system deteriorates
in later stages of the disease, the patterns of TB presentation become increasingly atypical, with
pulmonary smear-negative, disseminated, and extrapulmonary TB forms becoming more common. These
cases are more difficult to diagnose and have a higher fatality rate than smear-positive cases.

HIV patients with PTB tend to experience more fever and weight loss compared to those who are HIV-
negative. Yet, these patients suffer with less coughing and haemoptysis due to lesser inflammation and
cavity formation. Smear microscopy is more often negative.

In HIV adult patients, the most common non-pulmonary forms of TB are lymphadenopathy, pleural
effusion, pericarditis, meningitis, as well as, miliary (disseminated) TB. In HIV infected children, miliary
TB, TB meningitis and diffuse lymphadenopathy are the most common non-pulmonary forms. PTB is
also present in patients with EPTB. Immune reconstitution inflammatory syndrome (IRIS) is a clinical
presentation of TB in patients starting antiretroviral therapy.
Tuberculosis in Children

The diagnosis of TB in children relies on careful and thorough assessment of all the evidence derived
from a careful history, clinical examination and relevant investigations, e.g. Tuberculin Skin Testing,
Chest X-ray (CXR) and Sputum smear microscopy. Most children with TB have pulmonary TB.
Although bacteriological confirmation of TB is not always possible, it should, nevertheless, be sought
whenever possible, e.g. by sputum microscopy for children with suspected pulmonary TB who are old
enough to produce a sputum sample. Newer diagnostics techniques like PCR and IGRA have an emerging
role in diagnosis. A trial of treatment with anti-TB medications is not recommended as a method to
diagnose TB in children. Treatment is same as for adults with parental supervision in DOTS programme.
Regimens including Ethambutal are best avoided in children younger than five years.

When should Tuberculosis be suspected?

The most common symptom of pulmonary tuberculosis is persistent cough usually productive of two
weeks or more for which no cause has been found. The other associated symptoms may be fever, loss of
appetite, weight loss, tiredness, night sweats, chest pain, shortness of breath and hemoptysis. The
suspicion of tuberculosis is much more likely to be correct in patients with the above-mentioned
symptoms and history of close contact with a smear-positive tuberculosis patient. For extra-pulmonary
tuberculosis, symptoms depend on the organ involved. Tuberculosis should be suspected in the
differential diagnosis of any patients with the following symptoms for example:

 Cough and shortness of breath with pleural or pericardial effusions.

 Swelling, occasionally with pus discharge when lymph nodes are affected.
 Joints pain and swelling.
 Headache, fever, neck stiffness and confusion in possible tuberculous men
 Backache with or without loss of function in lower limbs when there is Gibbu and spinal
involvement.
 Abdominal pain, diarrhoea or ascites with abdominal involvement.
 Infertility when genital organs are affected.
DEFINITIONS

Tuberculosis should be defined accurately for registration and programmatic management.

Presumptive Tuberculosis: Any person who presents with symptoms or signs suggestive of
Tuberculosis (previously known as TB suspect). The most common symptom of pulmonary TB is a
productive cough for more than 2 weeks, which may be accompanied by other respiratory symptoms
(shortness of breath, chest pains, hemoptysis) and/or constitutional symptoms (loss of appetite, weight
loss, fever, night sweats, and fatigue).

Case of tuberculosis: A definite case of TB (defined below) or one in which a health worker (clinician or
other medical practitioner) has diagnosed TB and has decided to treat the patient with a full course of
anti-TB treatment.

Note. Any person given treatment for TB should be recorded as a case. Incomplete “trial” TB treatment
should not be given as a method for diagnosis.

Bacteriologically confirmed TB case: is one from whom a biological specimen is positive by smear
microscopy, culture or by a newer method such as Xpert MTB/RIF assays (GeneXpert) or molecular line
probe assay. All such cases should be notified, regardless of whether TB treatment has started.

Clinically diagnosed TB case: is one who does not fulfill the criteria for bacteriological confirmation but
has been diagnosed with active TB by a clinician or other medical practitioner who has decided to give
the patient a full course of TB treatment. This definition includes cases diagnosed on the basis of X-ray
abnormalities or suggestive histology and extra pulmonary cases without laboratory confirmation.

Clinically diagnosed cases subsequently found to be bacteriologically positive (before or after starting
treatment) should be reclassified as bacteriologically confirmed.

Bacteriologically confirmed or clinically diagnosed cases of TB are also classified according to: −

 Anatomical site of disease

 History of previous treatment
 Drug resistance
 HIV status.
Classification based on anatomical site of disease

Pulmonary tuberculosis (PTB): This refers to any bacteriologically confirmed or clinically diagnosed
case of TB involving the lung parenchyma or the tracheobronchial tree.

Miliary TB is classified as PTB because there are lesions in the lungs. Tuberculous intra-thoracic
lymphadenopathy (mediastinal and/or hilar) or tuberculous pleural effusion, without radiographic
abnormalities in the lungs, constitutes a case of extrapulmonary TB.

A patient with both pulmonary and extrapulmonary TB should be classified as a case of PTB.
Extrapulmonary tuberculosis (EPTB): This refers to any bacteriologically confirmed or clinically
diagnosed case of TB involving organs other than the lungs, e.g. pleura, lymph nodes, abdomen,
genitourinary tract, skin, joints and bones, meninges

Classification based on history of previous TB treatment (patient registration group)

Classifications based on history of previous TB treatment are slightly different from those previously
published.

They focus only on history of previous treatment and are independent of bacteriological confirmation or
site of disease

New patients: who have never been treated for TB or have taken anti-TB drugs for less than 1 month.

Previously treated patients: who have received 1 month or more of anti-TB drugs in the past. They are
further classified by the outcome of their most recent course of treatment.

Relapse patients: who have previously been treated for TB, were declared cured or treatment completed
at the end of their most recent course of treatment, and are now diagnosed with a recurrent episode of TB
(either a true relapse or a new episode of TB caused by reinfection).

Treatment after failure patients: are those who have previously been treated for TB and whose
treatment failed at the end of their most recent course of treatment.

Treatment after loss to follow-up patients: have previously been treated for TB and were declared lost
to follow-up at the end of their most recent course of treatment. (These were previously known as
treatment after default patients.) Other previously treated patients are those who have previously been
treated for TB but whose outcome after their most recent course of treatment is unknown or
undocumented.

Patients with unknown previous TB treatment history: do not fit into any of the categories listed
above.

New and relapse cases of TB are incident TB cases.

Classification based on HIV status

HIV-positive TB patient refers to any bacteriologically confirmed or clinically diagnosed case of TB

who has a positive result from HIV testing conducted at the time of TB diagnosis or other documented
evidence of enrolment in HIV care, such as enrolment in the pre-ART register or in the ART register once
ART has been started.

HIV-negative TB patient refers to any bacteriologically confirmed or clinically diagnosed case of TB

who has a negative result from HIV testing conducted at the time of TB diagnosis. Any HIV-negative TB
patient subsequently found to be HIV-positive should be reclassified accordingly.

HIV status unknown TB patient refers to any bacteriologically confirmed or clinically diagnosed case
of TB who has no result of HIV testing and no other documented evidence of enrolment in HIV care. If
the patient’s HIV status is subsequently determined, he or she should be reclassified accordingly.
Treatment outcome definitions

The new treatment outcome definitions make a clear distinction between two types of patients

 Patients treated for drug-susceptible TB

 Patients treated for drug-resistant TB using second-line treatment (defined as combination
chemotherapy for drug-resistant tuberculosis which includes drugs other than those in Group 1).
The two groups are mutually exclusive. Any patient found to have drug-resistant TB and placed on
second line treatment is removed from the drug-susceptible TB outcome cohort. This means that
management of the standard TB register and of the second-line TB treatment register needs to be
coordinated to ensure proper accounting of the outcomes of treatment.

Treatment outcomes for TB patients (excluding patients treated for RR-TB or MDR-TB)

All bacteriologically confirmed and clinically diagnosed TB cases should be assigned an outcome from
this list except those with RR-TB or MDR-TB, who are placed on a second-line drug regimen.

Outcome Definition
Cured A pulmonary TB patient with bacteriologically confirmed TB at the beginning
of treatment who was smear- or culture-negative in the last month of treatment
and on at least one previous occasion.
Treatment completed A TB patient who completed treatment without evidence of failure BUT with
no record to show that sputum smear or culture results in the last month of
treatment and on at least one previous occasion were negative, either because
tests were not done or because results are unavailable.
Treatment failed A TB patient whose sputum smear or culture is positive at month 5 or later
during treatment.
Died A TB patient who dies for any reason before starting or during the course of
treatment.
Lost to follow-up A TB patient who did not start treatment or whose treatment was interrupted
for 2 consecutive months or more.
Not evaluated A TB patient for whom no treatment outcome is assigned. This includes cases
“transferred out” to another treatment unit as well as cases for whom the
treatment outcome is unknown to the reporting unit.
Treatment success The sum of cured and treatment completed.

Patients found to have an RR-TB or MDR-TB TB strain at any point in time should be started on an
adequate second-line drug regimen. These cases are excluded from the main TB cohort when calculating
treatment outcomes1 and included only in the second-line TB treatment cohort analysis. If treatment with
a second-line drug regimen is not possible, the patient is kept in the main TB cohort and assigned an
outcome from among those in table above
 Classification based on drug resistance (adopted from WHO 2014 DR TB companion handbook)
Cases are classified in different types based on drug susceptibility testing (DST) of clinical isolates
confirmed to be M. tuberculosis:

Mono-resistance: resistance to one first-line anti-TB drug only.

Poly-resistance: resistance to more than one first-line anti-TB drug, other than both isoniazid and
rifampicin together

Multidrug resistance (MDR): resistance to at least both isoniazid and rifampicin.

Extensive drug resistance (XDR): resistance to any fluoroquinolone, and at least one of three second-
line injectable drugs (capreomycin, kanamycin and amikacin), in addition to multidrug resistance.

Rifampicin resistance (RR): resistance to rifampicin detected using phenotypic or genotypic methods,
with or without resistance to other anti-TB drugs. It includes any resistance to rifampicin, in the form of
mono-resistance, poly-resistance, MDR or XDR.

• Poly-/mono-resistant TB without rifampicin resistance. Some of these cases may have second-line anti-
TB drugs added to their treatment. These patients should be treated in the program registered in separate
ENRS as per program protocols.

• XDR-TB (confirmed or presumptive). Patients maybe started on XDR-TB treatment on the basis of a
laboratory diagnosis or, in its absence, because of significant risk.

 Patient based on previous H/O treatment (registration group): New, previously treated, Relapse
patients, Treatment after failure, Treatment after lost to follow up, other previously treated, patients with
unknown previous TB treatment history.

Definitions of Conversion & Reversion:

The terms “conversion” and “reversion” of culture as used here are defined as follows

 Conversion (to negative): culture is considered to have converted to negative when two consecutive
cultures, taken at least 30 days apart, are found to be negative. In such a case, the specimen collection
date of the first negative culture is used as the date of conversion.

 Reversion (to positive): culture is considered to have reverted to positive when, after an initial
conversion, two consecutive cultures, taken at least 30 days apart, are found to be positive. For the
purpose of defining Treatment failed, reversion is considered only when it occurs in the continuation
phase.

Treatment Outcomes for RR-TB/MDR-TB/XDR-TB patients treated using second-line treatment

Cured:

• Treatment completed as recommended by the national policy (minimum 20 months with 18 months
past culture conversion) without evidence of failure AND 3(three) or more consecutive cultures taken at
least 30 days apart are negative after the intensive phase
 • For the purpose of declaring cure, the patient should have three consecutive negative cultures reported
by the end of treatment, ensuring that cultures are done as per national policy.

• If there is one positive culture by the end of treatments, this positive culture should be followed by 3
negative cultures Treatment completed.

Treatment completed as recommended by the national policy (minimum 20 months 18 months past
culture conversion) without evidence of failure BUT no record that three consecutive cultures taken at
least 30 days apart are negative after the intensive phase.

Treatment failed Treatment terminated or need for permanent regimen change of at least two anti-TB
drugs because of:

 Lack of conversion by the end of the intensive phase, or

 Bacteriological reversion in the continuation phase after conversion to negative, or

 Evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs, or

 Adverse drug reactions (ADRs).

NOTE:

 If an MDR TB patient has 4 positive cultures and is on month 6 of treatment, it is suggested to repeat
DST to SLDs and act accordingly as per result. Please note that there may be a delayed response to
treatment in XDR-TB patients.

 In case of reversion in continuation phase repeat DST to SLDs, continue with treatment and decide as
per further response to treatment and in the light of result of DST.

 On the basis of baseline DST results there is only adjustment in treatment as per DST pattern and not to
be declared failure.

Died: A patient who dies for any reason during the course of treatment

Lost to follow-up: A patient whose treatment was interrupted for 2 consecutive months or more.

Not evaluated: A patient for whom no treatment outcome is assigned. (This includes cases “transferred
out” to another treatment unit and whose treatment outcome is unknown)

Treatment success: The sum of cured and treatment completed

• For Treatment failed, lack of conversion by the end of the intensive phase implies that the patient does
not convert within the duration of intensive phase applied by the program.

• If no specific duration is defined, an 8-month cut-off is proposed.

• For regimens without a clear distinction between intensive and continuation phases, a cut-off 8 months
after the start of treatment is suggested to determine when the criteria for Cured, Treatment completed
and Treatment failed start to apply provided that the patient had at least 18 months of treatment past
culture conversion.

The sum total of Cured and Treatment completed is commonly used as an indicator of favorable
outcome, or Treatment success. The outcome Cured is restricted to pulmonary bacteriologically
confirmed TB cases only.

Latent Tuberculosis Infection (LTBI)

Latent Tuberculosis Infection (LTBI) is defined as exposure and infection of an individual by

Mycobacterium Tuberculosis without clinical signs of disease. LTBI is associated with less than 10%
chances of developing overt Tuberculosis over a period of 10 years. It is diagnosed best by Interferon
Gamma Release Assays (IGRA) and less accurately by Tuberculin Skin Testing (TST).
 DIAGNOSIS OF TUBERCULOSIS

TB CASE FINDING APPROACHES

Currently the case detection rate CDR in Pakistan is about 64 %. This means that more than 200,000 TB
cases are missed annually in Pakistan against estimated 600,000 incident cases. About 74% of the "missed
cases" exist in 10 countries and Pakistan stands third among these countries and contribute 7% of the
globally missed TB cases.

To improve tuberculosis control, patient with active TB disease must be diagnosed quickly and treated
immediately. Passive case finding approaches were used mostly for TB case finding in the past however
now NTP recommends using active case finding approaches in certain population to enhance case
finding. Main difference between two approaches is described below.

PASSIVE TUBERCULOSIS CASE FINDING

Relies on patients seeking medical help because they feel unwell, Examination is recommended of:

 Presumptive TB cases (cough >two weeks or with relevant symptoms) who present themselves at
health facilities

 Patient with radiological examination of the chest showing an abnormality consistent with
Tuberculosis.

Passive case finding is likely to delay the diagnosis and treatment of tuberculosis and increases M
tuberculosis transmission

ACTIVE TUBERCULOSIS CASE FINDING

Where health workers seek out and diagnose individuals with TB mainly in the communities who have
not sought care on their own initiative- The ultimate goal of active TB case finding is to reduce TB
transmission in the community through improved case detection and reduction in diagnostic delays.
Active tuberculosis case finding is recommended among

 Household contacts of all pulmonary TB patients

 Marginalized population e.g. Urban slums

 High vulnerable population prisons and institutes

 Internally displaced population

 Patients with positive HIV status

 DIAGNOSTIC TOOLS FOR TUBERCULOSIS

AFB SMEAR MICROSCOPY

Mycobacteria are distinguished from other micro-organisms by thick lipid-containing cell-walls that
retain biochemical stains despite decolourisation by acid-containing reagents (so-called 'acid-fastness').
Sputum smear microscopy allows a rapid, inexpensive and reliable identification of patients with
pulmonary tuberculosis (PTB) where there are more than 5000 bacilli/ml of sputum.

Shortcomings of smear microscopy are that it cannot distinguish Mycobacterium tuberculosis from NTM,
nor viable from non-viable organisms, or drug-susceptible from drug-resistant strains. Also smear
sensitivity is further reduced in patients with extra-pulmonary TB, those with HW-co-infection, and those
with disease due to non-tuberculous mycobacteria (NTM). However, in areas of high TB prevalence,
positive smears have a very high probability of being M. tuberculosis.

The reliability of sputum microscopy depends on the quality of sputum collection. Sputum produced on
early morning often shows a higher concentration of M. tuberculosis. Importantly, the reliability of
sputum microscopy depends on the proper preparation and interpretation of slides. Thus, laboratory
technicians must be properly trained and quality control checks must be regularly carried out in a
supervising laboratory.

It is recommended that all patients presumptive of PTB should submit at least two sputum specimens.
Studies have shown that, when collection and examination techniques are correctly conducted, about 80%
of sputum smear-positive patients are found during the first sputum examination and over 15% more
during the second. Successive, repeated examinations yield fewer positives. Usually, a first sample is
collected at the time of the consultation when the patient is identified as a suspected TB case. A second
sample is collected in the early morning the day after the initial consultation (and the patient brings the
sample to the health facility if it is collected at home).

In order to limit the number of visits to the health facility, “frontloaded microscopy” (also referred to as
'same day' or 'spot-spot' microscopy) can be performed. Two sputum specimens are collected one hour
apart. This strategy has shown similar results to the standard strategy over two days (spot-morning-spot)
in terms of diagnostic yield.

Conventional light microscopy

Ziehl-Neelsen (ZN) light microscopy performed directly on sputum specimens is suitable for all
laboratory service levels, including peripheral laboratories at primary health care centers or districts
hospitals. In general, one ZN microscopy centre per 100,000 populations is sufficient; however,
expansion of ZN microscopy services should also take into account the location and utilization of existing
services, urban/rural population distribution, and specimen transport mechanisms.
Conventional fluorescent microscopy

Fluorescence microscopy is on average 10% more sensitive than ZN microscope. Conventional

fluorescent microscopes require technical expertise and capital and running costs is considerably higher.
Conventional fluorescent microscopy is therefore recommended at intermediate laboratory level where
more than 100 smears are examined per day.

Light-emitting diode (LED) fluorescent microscopy: LED microscopes are cost effective as require
less power, are able to run on batteries, the bulbs have a very long half-life. WHO evaluation (2007)
confirmed the diagnostic accuracy of LED microscopy compared to conventional fluorescent
microscopy, and superior efficiency of LED over conventional ZN microscopy. It is therefore
recommended that conventional fluorescence microscopy be replaced by LED microscopy and that LED
microscopy be phased in as an alternative for conventional ZN light microscopy in both high and low-
volume laboratories.

Culture and species identification

Mycobacterial culture and identification of M. tuberculosis provide a definitive diagnosis of TB and is the
gold standard for diagnosis. It can detect far lower numbers of AFB, the detection limit being around 10-
100 organisms per ml and thus and can detect cases earlier (often before they become infectious). Culture
also provides the necessary isolates for conventional DST. Moreover, culture makes it possible to identify
the mycobacterial species. It therefore seems that, for the diagnosis of tuberculosis, both the sensitivity
and the specificity of culture methods are better than those of smear microscopy as well as X-pert
MTB/Rif assay. However, it is not considered for use as an initial diagnostic test because it demands more
resources, is technically complex and requires infrastructure of biosafety laboratory for processing and
requires a much longer wait of 2-6 weeks for results (1-2 weeks on liquid culture media and 4-8 weeks on
solid culture media) than both the X-pert MTB/Rif test and sputum-smear microscopy, both of which can
provide final test results in less than 1 day.

Solid and liquid culture methods are suitable for Regional /Provincial and National reference laboratories
(or regional laboratories in large countries). Usually, one culture laboratory is adequate to cover 500,000 -
1 million populations. Solid culture methods are less expensive than liquid culture systems, but results are
invariably delayed due to the slow growth of mycobacteria. Liquid culture increases the case yield by
10% over solid media, and automated systems reduce the diagnostic delay to days rather than weeks.
Liquid systems are, however, more prone to contamination and the manipulation of large volumes of
infectious material mandates appropriate and adequate biosafety measures.

Culture should play a bigger role in diagnosis and patient follow-up due to the limited value of direct
microscopy for:

 Confirmation of failure cases;

 To obtain Culture isolates for conventional DST.
 Diagnosis of EPTB;
 Confirmation of smear negative TB when the diagnosis is in doubt;
  Distinction between M. tuberculosis complex and NTM;
 Monitoring treatment and outcome evaluation for patients on second-line anti-TB drugs.

Once there is growth on either a solid or liquid media, the organism must be identified. There are a
number of ways to identify M. tuberculosis. The tests can be phenotypic (the most common being the
niacin test) or genotypic (which use DNA analysis, Section 3.4). Given the complexities associated with
phenotypic identification, genetic tests are preferred. The drawback is their cost. Nonetheless, laboratories
performing cultures, at a minimum, should be able to conduct identification tests for M. tuberculosis that
follow international guidelines.

Phenotypic drug susceptibility tests (DST)

Phenotypic DST determines if a strain is resistant to an anti-TB drug by evaluating the growth (or
metabolic activity) in the presence of the drug. The laboratory performing phenotypic DST should be
specialised in mycobacterial cultures, reliable and subject to external quality assessment, often by a
supranational laboratory or national reference laboratory. The reliability of DST varies from one drug to
another. For Group 1 anti-TB drugs, DST is very reliable for rifampicin and isoniazid but less so for
pyrazinamide and much less for ethambutol. DST for aminoglycosides, polypeptides and
fluoroquinolones have been tested in different laboratories and shown to have relatively good reliability
and reproducibility. DST to other second-line drugs (para aminosalicylic acid, ethionamide and
cycloserine) is much less reliable and reproducible.

Molecular techniques

• Automated real time PCR (Xpert MTB/RIF)

• Line probe assays (LPA)

Molecular (or genotypic) tests can be used to diagnose TB through the amplification of nucleic acids
(DNA or RNA). They are also used to detect drug resistance through identifying genetic mutations (drug-
resistant alleles) in the bacterium responsible (genotypic DST). So far two types of assays and platforms
have been developed.

1 Automated real time PCR (Xpert MTB/RIF)

The Xpert MTB/RIF assay is a new test that is revolutionizing tuberculosis (TB) control by contributing
to the rapid diagnosis of TB disease and drug resistance. The test is based on real-time PCR, targeting
specific nucleic acid sequences in the M. tuberculosis complex genome, while also simultaneously
providing information about the most common mutations related to rifampicin resistance. Thus this test
simultaneously detects Mycobacterium tuberculosis complex (MTBC) and resistance to rifampin (RIF) in
less than 2 hours. In comparison, standard cultures can take 2 to 6 weeks for MTBC to grow and
conventional drug resistance tests can add 3 more weeks. The information provided by the Xpert
MTB/RIF assay aids in selecting treatment regimens and reaching infection control decisions quickly. In
contrast to other techniques (in vitro culture, DST and conventional molecular techniques) the Xpert
MTB/RIF can be used in peripheral laboratories and does not require sophisticated equipment or highly-
skilled personnel. It is a highly automated test (only 3 manual steps required), which is run in a closed
system with one cartridge per sample. Thus, it is less prone to contamination than other PCR-based tests.
Each instrument can process 4 samples at one time, with a processing time of just under 2 hours. Higher
capacity machines processing 16 samples at one time are also made available. The performances of this
test are almost similar to that of the culture. Published results have shown that for PTB detection, the
assay has sensitivities of 98% for smear-positive, culture-positive samples, and 72% for smear-negative,
culture-positive samples (sensitivity can reach 90% if the test is repeated 3 times).
The test Xpert MTB/RIF also has good sensitivity (80%) and excellent specificity (> 98%) when
performed on cerebrospinal fluid, lymph node material and gastric fluid. Because of its excellent
performance, its quick turn around time and its ease of use, this test should be used as an initial diagnostic
test in HIV-infected patients and when multidrug-resistant TB (MDR-TB) or TB meningitis are
suspected, in both adults and children. It can also be used for diagnosis of lymph node TB. As the
sensitivity of the Xpert test in pleural fluid is low, its use is not recommended.
The sensitivity for the detection of rifampicin resistance compared with conventional DST on culture is
97.6%. The test has a high negative predictive value, therefore, non rifampicin resistant results can be
considered to be true susceptible. However Xpert MTB/RIF does not eliminate the need for conventional
microscopy, culture and DST, which are required to monitor treatment progress and to detect resistance to
drugs other than rifampicin.
2 Line probe assays (LPA) (this topic need expert review to include or exclude)
To date no fully automated LPA exist. These molecular tests can only be performed by specialized
laboratories with strict quality assurance procedures in place.
There are a number of different molecular assays available:
– Conventional Nucleic Acid Amplification (NAA) amplifies M. tuberculosis-specific nucleic acid
sequences with a nucleic acid probe, enabling direct detection of the bacillus. The current NAA tests
available show a lower sensitivity than culture and therefore, are not recommended for the diagnosis of
TB. They are also too labour intensive to be implemented for routine diagnosis in most laboratories.
– Two molecular techniques are commercially available:
1 Hain assays: GenoType® MTBDRplus assay and GenoType®MTBDRsl (Hain Lifescience GmbH,
Nehren, Germany).
The GenoType® MTBDRplus assay has been shown to be good at detecting rifampicin resistance but less
so for isoniazid resistance among smear positive patients. The GenoType®MTBDRsl assay can detect
resistance to fluoroquinolones and injectables drugs with a reasonable specificity.
2 The INNO-LiPA Rif. TB® line probe assay (Innogenetics, Belgium).
The GenoType® MTBDRplus assay can identify mutations on the KatG or on the InhA genes:
– Mutation on KatG gene corresponds to resistance to high-dose isoniazid;
– Mutation on InhA gene corresponds to resistance to both isoniazid and ethionamide, but not necessarily
to high-dose isoniazid. The GenoType®MTBDRsl assay can be used as a triage test on smear-positive
patients to guide the initial treatment in extensively drug-resistant TB (XDR-TB) suspects while awaiting
confirmatory results from conventional phenotypic testing. However, LPA assays cannot be used as
replacement tests for conventional phenotypic second-line anti-TB DST.
These molecular methods have the advantage of giving fast results, within a few hours, for smear-positive
patients (referred to as direct testing, because the sputum can be directly tested). For smear negative
patients, a primary culture is needed prior to testing (referred to as indirect testing because a culture first
has to be grown from the patient’s sputum).
In order to benefit from the short turn around time of these tests, good logistical support is required for
sample transportation to the reference laboratory with timely return of results. The main constraints
remain the high cost, high infrastructure requirements, high level of technical training and the risk of
cross-contamination.

Radiological Methods:
 X ray chest
 Ultrasound
X ray chest
Chest X-ray is a non-specific investigation for TB. In national programmes, it is not routinely indicated in
sputum smear-positive patients because of limited resources. Chest X-ray is considered as an additional
diagnostic tool given its limitations of nonspecificity. It is often difficult to detect the difference between
old healed lesions of fibrosis and active TB. They are rarely conclusive and can only complete the clinical
presentation and history to constitute a body of arguments suggestive of TB. Chest X-ray is however
recommended when the smear microscopy results are negative and still TB is suspected. It is particularly
useful where the proportion of bacteriologically unconfirmed TB (i.e. smear microscopy or Xpert
MTB/RIF negative) is likely to be high; for example, in populations with a high incidence of TB.
However chest X-rays are valuable tools for the diagnosis of pleural and pericardial effusions, especially
at the early stages of the disease when the clinical signs are minimal. The X-ray showing an enlarged
heart is a key element for diagnosis of pericardial TB. Chest X-ray is essential in the diagnosis of miliary
TB. It shows small characteristic nodulary infiltrations disseminated in both pulmonary fields. Another
use of radiography includes examination of the joints and bones when TB is suspected. Special
Radiography, including the use of computerized tomography scans (CT scans) and MRI can be useful
only in specific clinical conditions like Pott’s disease CNS TB.
Ultrasound
Ultrasound is useful in confirming pleural effusions. Ultrasound is extremely useful in pericardial TB as it
can document that an effusion is the cause of an enlarged heart seen on chest X-ray. It is moderately
useful in diagnosing abdominal TB, whereby documenting multiple enlarged lymph nodes on an
abdominal ultrasound is consistent with TB, however, multiple enlarged lymph nodes can be seen in other
diseases, especially in lymphoma, leukemia, and HIV. Bowel wall thickening (ileocaecal region) is also
suggestive of abdominal TB.
Interferon gamma release assays (IGRAs)
These in vitro tests of cellular immunity detect interferon. Individuals who were once exposed to M.
tuberculosis complex have lymphocytes in their blood that maintain memory for the priming TB antigen.
Addition of TB antigen to blood in vitro results in rapid stimulation of memory T lymphocytes and
release of interferon gamma, which is a specific marker of activation of the immune response. IGRAs
have the advantage that there is no cross reactivity with prior BCG vaccination and with most
environmental mycobacteria. However, overall, they offer little advantage over conventional skin testing
and may be a less sensitive test in HIV co-infected. In addition, IGRAs remain expensive and are not
routinely used in resource-constrained settings.
Tuberculin Skin Test (TST)
TST e.g Mantoux Test has limited value in the diagnosis of TB, especially in high prevalence countries. A
“ Positive” tuberculin test does not in itself confirm the diagnosis of TB. At the same time a “Negative”
tuberculin test does not exclude active tuberculosis. TST is, however, important in non-GCG vaccinated
children under 5 years of age where a positive test is more likely to reflect recent infection with
tuberculosis and a much higher risk of developing disease.
Invasive Investigations
Fasting gastric lavage: Useful technique for microscopy of AFB especially in children.
Bronchoscopy (BAL / Safe Brush microscopy): for culture, histopathology, PCR, IGRA), where
relevant and available. Therefore not recommended for routine use.
Pleural fluid examination: (microscopy, chemistry, culture, histopathology, PCR, IGRA, ADA) is
mainstay of diagnosis in suspected Tuberculous Pleural disease.
Tissue FNAC/ Biopsy: Fine needle aspiration for microscopy for AFB and Cytology and tissue biopsy
for culture and histopathology have diagnostic role in special conditions.

Other nonspecific tests

ESR
Sedimentation rate is almost always higher but this examination is very non-specific. A normal
sedimentation rate makes TB less likely but still possible. Therefore ESR has no role in the diagnosis and
in monitoring a patient with tuberculosis.
C-reactive protein
C-reactive protein is also generally increased but this test also is very non-specific.
Serological diagnosis of TB
Commercially available rapid blood tests for “serological diagnosis of TB” like e.g Mycodot assay, ICT
TB, are unreliable and ineffective methods and are not recommended for clinical use.
 Management of Drug Sensitive TB

Health education

Public awareness programs for early detection and effective treatment of TB plays important role in
control of disease in any country.

Following measures are recommended for practice at all levels of health care delivery.

General public should be taught the importance of early attendance at a health facility for those with chest
symptoms, especially cough persisting for two weeks or more.

Patients with these symptoms should present themselves for an examination to the nearest doctor or chest
clinic/hospital.

Efforts should be made to make people aware of the nature of tuberculosis, so as to know that it is a
curable disease with adequate treatment, but if not treated properly it may result in infection of other
people, or disability and death of the individual.

Tuberculosis is considered as stigma in many communities in our country. Social support services,
poverty eradication programmes should have component of health education for hygienic and healthy
living. Psychological support in the form of counselling sessions or peer-group support must should be
atrated.

School health examinations and Tuberculosis awareness programmes should be started.

Public private partnership has shown tremendous overall benefit and it should be encouraged at all levels.
Good communication between a tuberculosis patient and the health care provider who treats him is also
very important.

Supervised treatment by the health care workers or trained volunteers is an essential component of
Tuberculosis control and the health care provider should make utmost efforts to ensure completion of
treatment by the patient till the cure has been achieved.

Printed material for guidance of patients and their social contacts should be used in all communities.

Print and electronic media should be used for advocacy and education.

Modern communication sources including mobile telephone communication such as SMS or telephone
(voice) call. Digital medication monitor is a device that can measure the time between openings of the pill
box can be used. The medication monitor can give audio reminders or send SMS to remind patient to take
medications, along with recording when the pill box is opened.
Principles of Chemotherapy

Basis of Treatment

The basis of treatment of tuberculosis is chemotherapy. It is also one of the most efficient means of
preventing the spread of tuberculosis microorganisms. The requirements for adequate chemotherapy are;

 An appropriate combination of anti-tuberculosis medications to prevent the development of

resistance to those medications;
 A correct Weight Based dosage, Regular administration and swallowing of each dose under DOT.
Directly observed therapy (DOT) may be ensured by a daily visit to the health facility by the
patient or through a treatment supporter (a respected member of the community e.g. Imam, school
teacher, community leader) who would visit the patient at his house daily for administering the
drugs.
 In educating the patients and their relatives on the importance of regular drug intake, DOT and
treatment completion must be emphasized.
 A Full course of treatment regimen to prevent relapse of the disease after the completion of
treatment.

DOSAGE AND DURATION OF ANTI-TB DRUGS:

It is very important to treat TB with the correct dosage of recommended drugs for a specified period (6
months for new case and 8 months for re-treatment case of TB). Anti-TB drugs are not effective if they
are not given in the correct dose and according to the weight group of the patient. If the dose prescribed is
less than the recommended dose, the TB bacteria will not be killed and they may become resistant to the
drugs. If the dose is higher than recommended, the drugs may cause severe toxic effects. To simplify the
drug prescription process, the following three pretreatment weight groups have been suggested in adults: •
30 –39 kg • 40-54kg • 55 kg or more The number of tablets differs only if patients fall in different
weight categories otherwise it remains same for all the patients within the same range of any given weight
category.

Patient weight should be monitored each month, and dosages should be adjusted if weight changes from
one weight band to another. The number of drugs prescribed is determined by the category of the TB
patient and phase of the treatment (intensive or continuation). The dosage (number of tablets) of each
drug is determined by weight of the patient at the time of diagnosis. Anti-TB drugs may need to be
temporarily suspended or stopped in case of severe drug intolerance or toxicity. :

Directly Observed Treatment Short Course (DOTS)

WHO recommends a strategy for TB control called DOTS (Directly Observed Treatment, Short-course).
DOTS is a comprehensive strategy which ensures cure to a majority of patients presenting to health
services. The DOTS strategy for TB control is based on the widespread use of simple technology and
good management practices integrated into an existing network of health services. Its integration into
existing services allows the DOTS strategy to reach a majority of the population in any country. DOTS
has been determined to be the most cost-effective strategy for TB control. The success of the DOTS
strategy depends on the implementation of a five-point package which consists of:
 1. Government commitment to a National Tuberculosis Programme (NTP).
2. Case detection through case finding by sputum smear microscopy examination of TB suspects in
general health services, with priority given to detecting infectious cases.
3. Standardized short-course chemotherapy (SCC) for at least all smear-positive TB cases under
proper case management conditions – health personnel or trained volunteer “directly observed
treatment” (DOT) by watching patient ingest anti-TB drugs
4. A regular, uninterrupted supply of all essential anti-TB drugs
5. A monitoring system for programme supervision and evaluation

Categorization of Patients for treatment

In order to ensure appropriate treatment to a TB patients, it is of paramount important to categorize them

in light of the history of previous anti TB treatment. It is mandatory to ask the patient about history of anti
TB in the past before starting treatment. The guidelines recommend 3 categories of patients;

1. New cases

2. Retreatment cases

3. Retreatment failures

Duration of Chemotherapy

The modern strategy of TB treatment is based on standardized short-course chemotherapy regimens of;

6 months duration for New cases and

8 months for Re-treatment cases.

Duration & regimen of treatment for patients who have failed the retreatment regimen depends on the
culture & sensitivity report. Such patients should be referred to a Drug Resistant TB centre (PMDT site).
In special circumstances like TB Meningitis longer duration for up to 9 to 12 months treatment regimens
are recommended. Chemotherapy should Not be stopped or interrupted unless severe drug intolerance or
toxicity occurs necessitating a special management by a specialist to ensure a proper completion of ATT
treatment.

Drugs and Regimens

Tuberculosis treatment should be started after a firm diagnosis has been made. TB patients should receive
a full course of treatment according to their weight, specific regimens and specified duration and no ATT
drugs should be given on a trial basis. TB patients can be categorized into 3 major groups:

1. New Cases

2. Re-Treatment Cases

3. Re-Treatment failures
1. New Cases

Patients who have never received treatment for tuberculosis or taken it for less than one month. This
group includes the following:

• Smear positive pulmonary tuberculosis.

• Smear negative pulmonary tuberculosis.

• Extra-pulmonary tuberculosis.

The treatment for this group of patients should be 6 months short course chemotherapy (SCC).

Initial Intensive Phase:

2HRZE, i.e. Isoniazid, Rifampicin, Pyrazinamide and Ethambutol administered under direct observation
(DOT) daily for 2 months.

Continuation Phase:

4HRE i.e. Isoniazid, Rifampacin and Ethambutol daily for 4 months.

Thus this regimen is 2HRZE/4HRE and administered on daily basis for 4 months.

This regime is in compliance with WHO recommendation and has been implemented based on country
expert opinion.

WHO recommends that in populations with known or suspected high levels of isoniazid resistance new
TB patients should receive HRE as therapy in the continuation phase as an acceptable alternative to HR.

SPUTUM EXAMINATION

Sputum smear examination is the key follow-up examination, and treatment decisions are based on
sputum smear results of the patient. At least one sputum sample, preferably a morning sample should be
examined on each follow-up visit.

Monitoring during Treatment

Perform Sputum Exam Treatment regimen 6 months

At the end of the initial phase The end of 2nd month

During the continuation phase The start of 5h month

At the end of treatment The end of the 6th month

 Monitoring Timeline for New patients

Treatment monitoring calendar

Month 1st 2nd 3rd 4th 5th 6th
Start X
End X X

When the patient has completed the initial intensive phase of two months, first follow up sputum test is
done, and continuation phase will start irrespective of sputum smear result. Similarly for smear negative
cases initial intensive phase (HRZE) is administered for two months. Sputum smear is done at the end of
2 month, if smear is negative, the continuation phase will start. However if sputum smear is positive, this
does not necessarily mean failure or emergence of resistance and will be tested on X-pert and if test result
is Mycobacterium detected but RR not detected patient, continuation phase will start. Additionally,
patient’s management plan should be reviewed and supervision and support should be enhanced. Proper
dosage should be recalculated. Sputum positive at this stage does not necessarily mean failure or
emergence of resistance. During the continuation phase, isoniazid, rifampicin and ethambutol (HRE) are
administered daily for four months.

Note: Rifampicin-containing regimens should be taken under direct observation.

In all patients with drug-susceptible pulmonary TB, the use of thrice-weekly dosing is not recommended
in both the intensive and continuation phases of therapy and daily dosing remains the recommended
dosing frequency.

(In patients with drug-susceptible pulmonary TB, 4-month luoroquinolone-containing regimens

(4MfxHRZ, 4MfxRZE, or 2MfxRZE + 2(Mfx+RFP), 2MfxRZE/4(Mfx+RFP) should not be used and the
6-month rifampicin-based regimen 2HRZE/4HR remains the recommended regimen.)

Table: when to end intensive phase & start continuation phase of treatment

If Next Step
At the end of the 2nd month patients Start & Continue with the continuation phase treatment as planned
sputum smear-negative (true for until the end of regimen
vast majority)
At the end of the 2nd month patient Do Xpert/MTB Rif assay .
is sputum smear-positive If RR not detected. START continuation phase treatment.
If RR detected then refer to PMDT site for Management of DR
TB.
At the start of the 5th month patient Declare treatment outcome as New Case- CAT –I treatment
is sputum smear-positive failure
Do drug susceptibility test
Re-register patient as treatment failure
Start retreatment regimen as treatment failure
Obtain result of sensitivity test For further management refer
protocol for Previously treated case- CAT II
At the start of the 5th month patient
is sputum smear-negative Continue with the treatment as planned until the end of regimen
At the end of the 6th month patient Patient is considered cured, If last sputum not done, declare
is sputum smear-negative treatment completed
At the end of the 6th month patient Follow the same steps as at the
is sputum smear-positive start of 5th month if sputum
smear – positive

2. Re-Treatment Cases

In patients who require TB retreatment, the current category II regimen (2HRZES/1HRZE/5HRE) should
no longer be prescribed and drug-susceptibility testing should be conducted to inform the choice of
treatment. Therefore after registration as re-treatment case & before starting treatment, all TB cases
eligible for re-treatment regimen will be tested on X-pert to exclude RR, it is preferable also to
determine isoniazid resistance status. Standard first-line treatment regimen (2HRZE/4HR) is to be
repeated if no resistance is documented. If rifampicin resistance is present then these patients are referred
to PMDT unit for further drug susceptibility testing and treated as MDR cases.

All smear-positive cases identified as “failures”, “treatment after lost to follow up” and “relapses” should
be classified as “retreatment” cases. In patients who have had treatment interruption, the reason for the
interruption, such as medication stock-outs, adverse effects from medicines or need for greater
patient/provider education should be addressed.

The recommended treatment for this group of patients is 8 months as follows:

Initial Intensive Phase:

3HREZ: i.e. Rifampicin, Isoniazid, Pyrazinamide and Ethambutol for 3 months.

Continuation Phase:

5HRE: i.e Rifampicin, Isoniazid and Ethambutal for a period of 5 months

In settings where rapid molecular-based drug-susceptibility testing results are not routinely available to
guide the management of individual patients, these patients may receive the retreatment regimen
containing first-line drugs 2HRZES/1HRZE/5HRE if data show low or medium levels of MDR in the
area or if such data are unavailable.

Monitoring during Treatment:

SPUTUM EXAMINATION

Sputum smear examination is the key follow-up examination, and treatment decisions are based on
sputum smear results of the patient. At least one sputum sample, preferably a morning sample should be
examined on each follow-up visit.

Perform Sputum Exam Treatment regimen 8 months

At the end of the initial phase The end of 3rd month
During the continuation phase The end of 5th month
At the end of treatment The end of 8thmonth
Monitoring Timeline for CAT II patients

Treatment monitoring calendar

Month 1st 2nd 3rd 4th 5th 6th 7th 8th

End of X X X

Table: when to end intensive phase & start continuation phase of treatment in Retreatment TB
cases

If Next Step
At the star of first month patient is Register patient for Previously treated case- CAT II
sputum smear-positive Do Xpert/MTB Rif assay before start of treatment
If R resistant refer to the DR TB management unit
If R sensitive, Start intensive Phase (2RHZE+5RHE).
At the end of the 3rd month patients Start continuation phase treatment until the end of regimen
sputum smear-negative (true for
vast majority)
At the end of the 3rd month patient Repeat Xpert/MTB Rif assay / X-pert test- if DST available send
is sputum smear-positive specimen for DST also. If X-pert report as RR, refer patient to
PMDT site for management
If RR not detected start continuation phase of re-treatment.
At the end of the 5th month patient Continue continuation phase until the end of regimen
is sputum smear-Negative
At the end of the 5th month patient Declare Treatment outcome Previously treated case- CAT-II
is sputum smear-positive TREATMENT FAILURE
Declare DR presumptive case and refer patient to PMDT site for
management
At the end of the 8th month patient Declare treatment outcome “ CURE”, If last sputum not done,
is sputum smear-negative declare treatment completed
At the end of the 8th month patient Declare Treatment outcome Previously treated case- CAT-II
is sputum smear-positive TREATMENT FAILURE
Declare DR presumptive case and refer patient to PMDT site for
management

Remember: Never add a single drug if the patient is not responding well to treatment.

Follow-up: Subsequent relapse is rare when patients complete the prescribed course of chemotherapy.
They should be told to report for re-examination if symptoms recur.

3. Re-treatment Failure:
This is a group of patient who during the re-treatment regimen are found to be smear positive in the fifth
month of the treatment regimen or a case of relapse of having completed the full course of re-treatment
regimen. This group is considered as DR TB suspect and their sputum should be collected for culture and
drug sensitivity testing at the outset and a special treatment regimen is designed and instituted with
combination of second line anti TB drugs pending the receipt of bacteriological results. All patients have
to be referred to DR TB management centers and registered with NTP DR Registry as suspects. All close
contacts are to be traced and evaluated for tuberculosis.

Treatment of extrapulmonary TB

Pulmonary and extrapulmonary disease should be treated with the same regimens. Note that some experts
recommend 9–12 months of treatment for TB meningitis given the serious risk of disability and mortality,
and 9 months of treatment for TB of bones or joints because of the difficulties of assessing treatment
response. Unless drug resistance is suspected, adjuvant corticosteroid treatment is recommended for TB
meningitis and pericarditis.

In Tuberculous meningitis, Ethambutol should be replaced by Streptomycin. Although sometimes

required for diagnosis, surgery plays little role in the treatment of extrapulmonary TB. It is reserved for
management of late complications of disease such as hydrocephalus, obstructive uropathy, constrictive
pericarditis and neurological involvement from Pott’s disease (spinal TB). For large, fluctuant lymph
nodes that appear to be about to drain spontaneously, aspiration or incision and drainage appear
beneficial.

COUNSELING AND EDUCATION OF TB PATIENTS

Proper counseling and education of TB patients along with chemotherapy is of utmost importance.
Patients should be counseled that tuberculosis (> 95%) is curable if the right drugs are taken for the right
duration. The patients should be explained that incomplete treatment may lead to drug resistance, which is
an extremely difficult form of tuberculosis to treat.

Most TB patients (about three in four) are poor and illiterate, so numerical explanation of six/eight month
treatment should be supplemented by sign-posting the treatment duration in terms of the month when the
patient is expected to complete the treatment.

Some patients may develop symptoms related to the side effects of TB drugs. These symptoms may range
from mild nausea to severe jaundice. The education of patients helps them to detect and take action
concerning these side effects promptly. Patients should be advised to consult staff at the health facility if
itching of the skin, jaundice, vomiting, impaired vision etc. is noticed.

Patients should cover their mouths when they cough. This will reduce the chances of spreading the spread
of disease through droplet infection. Patients do not need to cover their mouth when they are not
coughing.

Patients should not spit close to other people. Spit into a container and then bury it or put it into the drain.
TB bacteria are not spread by sharing dishes, plates, clothes, or through sexual contact. This is an
important message, because it helps to prevent social exclusion of TB patients by avoiding unnecessary
separation of his/her household belongings and activities.
Patients are required to visit the health Care Facility at the end of the 2nd, /5th and 6th for new case while
3rd,5th & 8th month for previously treated case of treatment.

It is important to verify that patients have clearly understood the messages provided by asking specific
questions. The patient should be given an opportunity to share his/her concerns with the care provided
and the care provided should also do everything possible to deal with these concerns.

MANAGING CONTACTS

Contacts are people who have been sharing the same living premises and the daily life activities with the
patient. It is important to identify contacts, of a patient with sputum smear positive pulmonary
tuberculosis, and manage them in order to reduce the risk of missing cases and continued transmission of
TB to other family members. Priority is assigned in screening contacts that had frequent, prolonged and
close contact with the patient during the infectious period, in an enclosed environment. This may include
all people living in the same household or dwelling, close relatives and friends, and close work colleagues
who share the same indoor small work area on daily basis.

All child contacts till 5 years must be examined for symptoms and BCG scar. The management of
contacts consists of the following two steps.

1. Identifying and Retrieving Contacts All the household members should be considered to be Contacts.
All household members irrespective of age and gender need be assessed and those who need further
screening at the health Care Facility should be identified.

- All children less than 5 years of age should be brought to the BMU /TB Care Facility for further
assessment and management. The children below 5 year of age found not suffering from any symptoms
are put on INH prophylaxis therapy (IPT). The INH is prescribed in a dosage of 5mg/kg and is given for a
period of 6 months. Child breast- fed by sputum smear-positive mother would continue breast feed and is
protected by prescribing INH in same dosage for six months and is given BCG, if not already given.

Adults and children (older than 5 years of age) with symptoms suggestive of tuberculosis i.e. cough > two
weeks, weight loss, fever etc. should be asked to visit the BMU/ TB Care Facility at their earliest
convenient date. The significance of screening all Contacts should be explained to the patient and the
patient should be given a list of the household members who need to visit the BMU /TB Care Facility.
The patient should also be requested to encourage the household members to get screened.

DIRECTLY OBSERVED TREATMENT

It is very important to explain the importance of “direct observation” to the patient and help the patient to
identify an acceptable and affordable means of supervising his/her treatment. Direct observation of all
patients taking Rifampicin (throughout whole period of treatment of new and previously treated cases)
IDENTIFYING & MANAGING SIDE EFFECTS

Screening for side effects of anti-tuberculosis drugs is essential part of follow-up at Health Care Facility.
There are two main types of side effects of anti-tuberculosis drugs, major and minor side effects.

Major Side Effects: are those that give rise to serious health hazards. In this case, discontinuation of anti-
tuberculosis drugs is mandatory and the patient should be referred to a hospital specialist. TB drugs can
cause the following major side effects:

MAJOR SIDE EFFECTS LIKELY CAUSATIVE DRUGS

Major side effects Likely causative drugs

Skin rash Thiacetazone, Streptomycin
Deafness Streptomycin
Dizziness Streptomycin
Jaundice Isoniazid, Rifampicin, Pyrazinamide
Visual Impairment Ethambutal
Shock Rifampicin
Purpura Rifampicin

Minor Side Effects: Minor side effects cause only relatively little discomfort. They often respond
to symptomatic or simple treatment but occasionally persist for the duration of drug treatment. In
this case, anti-tuberculosis treatment should be continued and symptomatic treatment added. TB
drugs can cause the following minor side effects:

Minor side effects Likely causative drugs

Anorexia, nausea, abdominal pain Rifampicin
Joint pain Pyrazinamide
eddish change in urine colour Rifampicin
Burning sensation in feet Isoniazid,
Itching of skin Isoniazid, Rifampicin, Pyrazinamide,

ANTI TUBERCULOSIS DRUGS

The first line anti TB drugs ( FLD) used in the treatment of tuberculosis consists of Isoniazid (H),
Rifampcicin(R), Pyrazinamide (Z), Streptomycin (S) and Ethambutol (E). Most of the above drugs are
available in combined preparations. Only fixed drug combination (FDC) of proven bioavailability
according to WHO recommended strengths should be used. The bioavailability should be assessed for all
2, 3 or 4 drugs in the FDC, according to the WHO protocol at a WHO recommended site. The quality
should be the prime consideration in selecting the Anti-TB drugs. Drugs should be manufactured to GMP
(Good Manufacturing Practice) standards. The use of Rifampicin or Streptomycin, for disease other than
mycobacterium disease should be carefully evaluated and used only for very specific indications.
ANTI-TB DRUGS – MECHANISMS OF ACTION

Rifampicin A bactericidal drug active against all populations of TB bacilli

Semi-synthetic, macrocyclic antibiotic inhibiting nucleic acid
Synthesis
Potent bactericidal action andpotent sterilizing effect against
tubercle bacilli
Isoniazid A bactericidal drug active against all p o p u l a t i o n s of TB
bacilli
Highly bactericidal against r e p l i ca t i n g t u b e r c l e bacilli
Kills 90% during first few days of treatment

Pyrazinamide A bactericidal drug active against certain populations of TB

bacilli
Particularly active in acid intra c e l l u l a r e n v i r o n m e n t a n d in
a r e a s of a c u t e inflammation
Active in acid environment against b a c i l l i i n s i d e
macrophages
Synthetic analogue of nicotinamide with weak bactericidal, but
potent sterilizing activity against M.tuberculosis
A bactericidal drug active against certain populations of TB
Streptomycin
bacilli
Active against rapidly multiplying extra -cellular TB bacilli

A synthetic, bacteriostatic drug active a g a i n s t M.

Ethambutol
t u b e r c u l o s i s and o t h e r mycobacteria.
Used in combination with other more powerful drugs to
prevent e me r ge n c e of r e s i s t a n t bacilli

CLINICAL INFORMATION ABOUT ESSENTIAL ANTI-TB DRUGS

Rifampicin (R)

Forms 150 mg and 300 mg capsule

Administration Remarks • Must always be administered in

combination with other anti -

mycobacterial agents

• Should be given at least 30 minutes

before meals, since absorption is

r e d u c e d when taken with food

Dosage
• 10 mg/kg ( 8 – 1 2 mg/kg) daily •Maximum 600 mg daily

Adverse Reaction • Gastrointestinal intolerance

• Hepatitis/ Chole stasis • Hepatic enzyme induction/ drug

interactions

Contraindication • Hepatic dysfunction

• Known hypersensitivity to Rifamycins

Isoniazid (H)

Forms • 50 mg, 100 mg, 300 mg tablets

• 50 mg in 2 ml injection
• Taken orally
Administration Remarks
• Injections reserved for critically
ill patients

Dosage • 5 mg/kg (4–6 mg/kg) daily

• Maximal dose is 300 mg when
given daily

Adverse Reaction • Hepatic dysfunction

• Skin rashes
• Neurotoxicity

Contraindication • Hepatic dysfunction

• Known hypersensitivity

Pyrazinamide (Z)

Forms 500 mg tablet

Administration Remarks • Highly effective during the first 2
months of therapy

Dosage • 25 mg/kg (20–30 mg/kg) daily

• Hepatitis
Adverse Reaction
• Hyperuricaemia
• Rash
 Contraindication • Hepatic dysfunction, Known
hypersensitivity

Streptomycin (S)
Forms • 1.0 g ampoule injections
Administration Remarks • Given by intramuscular
• injection
Streptomycin is an
aminoglicoside
antibiotic with bactericidal
activity
against TB bacilli
Dosage • 15 mg/kg (12–18 mg/kg) daily
• In patients over age 60, 500-
mg daily
750

Adverse Reaction • Vestibular damage

• Hypersensitivity
• Nephrotoxicity
Contraindication • Pre-existing auditory nerve
impairment
• Renal impairment
• Myasthenia gravis
• Pregnancy

• Known hypersensitivity

Ethambutol (E)
Forms • 100 mg, 250 mg, 400 mg
tablets
Administration Remarks • Used in combination with other
anti-TB drugs to prevent the
emergence of resistant strains
Dosage • 15 mg/kg (15-25 mg/kg) daily
 Adverse Reaction • Ocular toxicity

Contraindication • Pre-existing optic neuritis from

any cause
• Renal impairment
• Inability (young children,
Unconscious patients) to report
visual disturbances
• Known hypersensitivity

Treatment regimens in special situations

WHO recommends testing for HIV testing for all TB patients in all settings including low
prevalence countries. Where possible and clinically warranted it should be considered. If
HIV positive when available, CD4 cell counts should be a factor in the decisi on on ART
initiation in TB patients as follows:

• ART is recommended for all people infected with HIV and diagnosed with TB
whose CD4 counts are 350 cells/mm3 or less.

• ART should be deferred in pulmonary TB patients whose CD4 cell count exceeds

350 cells/mm3 provided that there is no other stage 3 or 4 event. Patients whose CD4
count at TB diagnosis exceeds 350 cells/mm3 should be re -evaluated 8 weeks after
starting TB therapy and again when TB treatment is completed.

• ART is recommended for all people living with HIV diagnosed with
extrapulmonary TB, regardless of the CD4 count.

• Co trimoxazole is recommended to be added to all cases through out the treatment

period. Only specialized centers should undertake treatment of such cases.

Pregnancy and breastfeeding

Women of childbearing age should be asked about current or planned pregnancy before
starting TB treatment. A pregnant woman should be advised that successful treatment of
TB with the standard regimen is important for successful outcome of pregnancy. With the
exception of streptomycin, the first line anti -TB drugs are safe for use in pregnancy:
streptomycin is ototoxic to the fetus and should not be used during pregnancy.

A lactating female who has TB should receiv e a full course of TB treatment. Timely and
properly applied chemotherapy is the best way to prevent transmission of tubercle bacilli
to the baby. Mother and baby should stay together and the baby should continue to
breastfeed and she should cover her face with mask/veil to avoid breathing over the
infant. After active TB in the baby is ruled out, the baby should be given 6 months of
isoniazid preventive therapy, followed by BCG vaccination. Pyridoxine supplementation
is recommended for all pregnant or brea stfeeding women taking isoniazid.

Liver disorders

Patients with the following conditions can receive the usual TB regimens provided that
there is no clinical evidence of chronic liver disease: hepatitis virus carriage, a past
history of acute hepatitis, current excessive alcohol consumption. However, hepatotoxic
reactions to anti-TB drugs may be more common among these patients and should
therefore be anticipated.

In patients with unstable or advanced liver disease, liver function tests should be done at
the start of treatment, if possible. If the serum alanine aminotransferase level is more
than 3 times normal before the initiation of treatment, the following regimens should be
considered. More unstable or severe the liver disease is, the fewer hepatotoxic drugs
should be used.

Possible regimens include:

• Two hepatotoxic drugs (rather than the three in the standard regimen):

_ 9 months of isoniazid and rifampicin, plus ethambutol (until or unless isoniazid

susceptibility is documented);

_ 2 months of isoniazid, rifampicin, streptomycin and ethambutol, followed by 6 months

of isoniazid and rifampicin;

_ 6–9 months of rifampicin, pyrazinamide and ethambutol.

• One hepatotoxic drug:

_ 2 months of isoniazid, ethambutol and streptomycin, followed by 10 months o f

isoniazid and ethambutol.

• No hepatotoxic drugs:

_ 18–24 months of streptomycin, ethambutol and a fluoroquinolone.

Expert consultation is advisable in treating patients with advanced or unstable liver

disease. Clinical monitoring (and liver function te sts, if possible) of all patients with pre -
existing liver disease should be performed during treatment.

“In tuberculous patients with drug induced hepatitis, the treatment should be stopped if
the ALT is more than 5 times normal in the absence of symptom s and 3 times normal in
the presence of symptoms suggestive of hepatitis. If the TBsituation is serious enough to
continue ATT (like in TBM, tuberculous pericarditisor tuberculous spine) then any one of
the above mentioned regimens (with twoor one hepatoto xic drugs) should be continued.
In less serious situations,treatment can be halted till hepatic functions have returned to
normal and theneither the treatment is reinstituted or any of the two above mentioned
regimens(with two or one hepat otoxic drugs)can be started”.

Renal failure and severe renal insufficiency

The recommended initial TB treatment regimen for patients with renal failure or severe
renal insufficiency is 2 months of isoniazid, rifampicin, pyrazinamide and ethambutol ,
followed by 4 months of isoniazid and rifampicin. Isoniazid and rifampicin are eliminated
by biliary excretion, so no change in dosing is necessary. There is significant renal
excretion of ethambutol and metabolites of pyrazinamide and doses should there fore be
adjusted. Three times per week administration of these two drugs at the following doses
is recommended: pyrazinamide (25 mg/kg), and ethambutol (15 mg/kg).While receiving
isoniazid, patients with severe renal insufficiency or failure should also be given
pyridoxine in order to prevent peripheral neuropathy. Because of an increased risk of
nephrotoxicity and ototoxicity, streptomycin should be avoided in patients with renal
failure. If streptomycin must be used, the dosage is 15 mg/kg, two or three t imes per
week, to a maximum of 1 gram per dose, and serum levels of the drug should be
monitored.

TUBERCULOSIS & TOBACCO

Both tobacco smoking and tuberculosis are major global public health problems. Globally, nearly
6.4 million people died from tobacco use in 2015 and tobacco use is estimated to be responsible for
16% of deaths among men and 7% of deaths among women each year. In 2012, there were an
estimated 8.6 million new tuberculosis cases and 1.3 million tuberculosis-related deaths worldwide.
Smoking is common in the 22 countries categorized by the World Health Organization (WHO) as
high-burden countries for tuberculosis – which together account for more than 80% of all tuberculosis
cases. The burden of smoking among patients with tuberculosis is poorly defined in most countries.
An understanding of the epidemiological relationship between smoking and tuberculosis is important
because both smoking and tuberculosis cause extensive morbidity and mortality worldwide.
Furthermore, tobacco smoking amplifies the negative impact of TB. Compared with those who have
never smoked, it is estimated that people who smoke have approximately twice the risk of
both Mycobacterium tuberculosis infection and active tuberculosis. There is now a growing body of
evidence on the impact of smoking on treatment outcomes among patients with active tuberculosis.

In short there is a strong association between smoking and TB as

• Smoking substantially increases the risk of tuberculosis (TB) and death from TB
• More than 20% of global TB-related burden may be attributable to smoking

• Controlling the tobacco epidemic will help control the TB epidemic

• Smoking is a risk factor for TB, independent of alcohol use and other socioeconomic risk factors

• Smoking increases the risk of TB disease by more than two-and-a-half times

• Smoking increases severity of disease with more cavity lesions and greater likelihood of
hospitalization.

• Smoking is associated with poorer adherence to anti-TB medicines

• Smoking leads to a higher risk of relapse after the initial treatment and the development of multi-
drug resistance TB

• Smokers have a higher treatment default rate, and are also more likely to transmit TB to others

Recommended Policies to Combat Tobacco and TB

Control tobacco everywhere, but especially where people are at risk of TB infection

Coordinate national TB and tobacco control programmes

Train TB healthcare workers in delivering behavioural support (counseling) to TB patients who smoke

Register TB patients' tobacco use in TB surveillance tools (e.g. TB03 forms) and offer them behavioural
support (counseling) and treatment for tobacco addiction

Promote and enforce smoke-free policies, particularly where TB services are delivered

Offer tobacco cessation support to those health workers who smoke themselves

Integrate brief tobacco interventions (5 'A's and the 5 'R's) into TB control programme activities

Implement smoking cessation procedures through PAL (the Practical Approach to Lung Health)

Public Health-Oriented Actions to Combat Tobacco and TB

TB control programmes can support tobacco control by promoting policies to:

• Apply price and tax increases

• Provide protection from exposure to tobacco smoke

• Ban tobacco advertising, promotion and sponsorship

• Regulate the packaging and labelling of tobacco products

• Raise public awareness of tobacco risks

• Treat tobacco dependence

(These and other recommendations are featured in the WHO Framework Convention on Tobacco
Control)

Patient-Oriented Actions to Combat Tobacco and TB

The 5 'A's The 5 'R's

ASK TB patients about their tobacco use RELEVANCE ensure TB patients know their treatment
will be more effective if they quit smoking

ADVISE them to quit RISKS – point out all the risks of continuing to smoke
including the risk of TB relapses

ASSESS their willingness to attempt to quit REWARDS – educate the TB patient about the many
other benefits of quitting smoking

ASSIST in their attempt to quit ROADBLOCKS – ask the TB patient to identify obstacles
to quitting smoking

ARRANGE follow up with them REPETITION – continue to encourage the TB patient to

quit smoking

Drug resistant Tuberculosis

DR-TB is confirmed through laboratory tests that show that the infecting isolates of Mycobacterium
tuberculosis grow in vitro in the presence of one or more anti-tuberculosis drugs. Four different categories
of drug resistance have been established:

• Mono-resistance: resistance to one antituberculosis drug.

• Poly-resistance: resistance to more than one first line antituberculosis drug other than both isoniazid
and rifampicin.

• Multidrug-resistance: resistance to at least isoniazid and rifampicin.

• Extensive drug-resistance: resistance to any fluoroquinolone, and at least one of three injectable
second-line drugs (capreomycin, kanamycin and amikacin), in addition to multidrug-resistance.
Culture and DST guide the therapy in DR TB cases. Where DST facilities are not readily available
empiric DR TB regimen should be started. An empiric regimen for MDR TB should be started in cases
where DST results are not available on the basis of moderate or high level of suspicion (clinical
assessment levels). An empiric regimen is to be designed using the following classes of anti tuberculosis
drugs.

Treatment of DR TB is under taken essentially under the Programmatic Management of Drug resistance
TB (PMDT) sites theses are specialized centers and having facilities of management of this serious
disease with highly specific treatment regimen which is not only prolonged and very expensive but also
has high rate of drug adverse reactions.

SCREENING OF DRUG RESISTANT TB: PRESUMPTIVE CASES:

The use of X-pert / MTB Rif has been recommended as a first diagnostic testing for screening to the
following high risk groups (DR-TB presumptive cases.

1. ALL PREVIOUSLY TREATED TB CASES:

All TB cases (AFB SS +ve or clinically diagnosed) with history of previous ATT should be tested for X-
pert at month zero of enrolment. This includes:

• Treatment Failure New Case (Cat-I)

• Treatment Failure Previously Treated Case (Cat-II)

• Relapse after New Case (Cat-I)

• Relapse after Previously Treated Case (Cat-II)

• Treatment after loss to follow up New Case (Cat-I)

• Treatment after loss to follow up Previously Treated Case (Cat-II)

• Other Previously treated Case

2. SYMPTOMATIC CONTACTS OF DR-TB PATIENT:

All household and workplace symptomatic contacts of DR-TB patients should be screed for drug
resistance. Specimen from these individuals should be processed for AFB smear and then the specimen is
referred for X-pert MTB/RIF assay irrespective of smear results.

C. TB PATIENTS UNDER TREATMENT WHO FAIL TO CONVERT AT THE END OF

INTENSIVE PHASE

• B+ive patient on New Case (Cat-1 who fail to convert at the end of month #2 of treatment.

• B+ive patient on Previously Treated Case (Cat- II who fail to convert at the end of 3 months.
• B-ive Patient who is reported AFB smear positive at the end of intensive phase

Comprehensive First and second line DST: All patient who are reported rifampicin resistant on
Xpert/MTB Rif assay should be referred to DR treatment site and specimen should be referred to quality
assured DST laboratory for comprehensive first and second line DST before start of treatment .

If patient is reported rifampicin sensitive on X-pert MTB/Rif assay but is clinically considered at high risk
of DR (e.g. Cat-II-failure), patient may be referred for phenotypic drug susceptibility testing as small
number of rifampicin resistant are not detected by X-pertMTB/RIF assay Reporting pattern and
interpretation of results of X-pert MTB Rif

REPORT DR-TB RISK ASSESSMENT, INTERPRETATION and ACTION based on

Xpert / MTB Rif assay

REPORT DR-TB RISK INTERPRETATION ACTION

ASSESSMENT
1 MTB Detected No previous Definite TB case NO Start New
Rif resistance history of ATT Rifampicin resistance Case treatment Cat-I
NOT detected

History of Definite TB case NO Start Previously

previous ATT Rifampicin resistance Treated Case
Treatment Cat- II

History of Cat- Definite TB case No Start Previously

II Failure Rifampicin resistance Treated Case
Treatment Cat- II
And transport
sample/Refer patient
for pheno DST
2 MTB Detected No previous Definite TB case Repeat X-pert
history with MTB/Rif assay –
Rifampicin of ATT Rifampicin resistance If
Resistance -RR Not detected -
Detected start on FLD- New
Case treatment Cat-I
-RR detected
Reg and start on SLD
History of Definite TB case Refer patient to DR
previous with Treatment site enroll
ATT Rifampicin resistance Patient on SLD and
send specimen for FL
and SL DST.
3 MTB NOT MTB Not detected Culture / clinical
detected but TB not excluded evaluation diagnosis
INTERPRET CULTURE AND DST (R/H) RESULTS

Results, if Interpretation Further action

♦ DST – resistance to R and H, with DR-TB patient ♦ Register, further assess,

smear positive or negative and culture and put patient on DR-

positive (or result awaited, if rapid DST TB treatment

in-use)

♦ DST – susceptible to R and/or H, with TB but not DR- ♦ Manage as non-DR TB

smear positive or negative & culture TB (e.g. re-treatment or

positive (or result awaited, if rapid DST mono-drug resistant TB)

in-use)

CONCLUSIONT

The above guidelines are to be followed under a programmatic approach with DOTS protocol. Failure and
default cases are to be dealt with under the specific guidelines detailed in National Drug Resistance
Tuberculosis Guidelines. All cases must be registered and followed.
 ANNEXURES

TREATMENT TABLETS

Fixed Dose Combinations (FDCS)

FDCs have the advantage of improving patient compliance. With FDC the prescription errors are likely to
be less frequent because dosage recommendations are straight forward and adjustment of dose according
to patient’s weight is easier. The number of tablets to ingest is smaller, which makes patients more
adherent to treatment. Fixed dose combination drugs have also some disadvantages. If prescription error
occurs and excess dose is prescribed, toxicity of all drugs will increase. Similarly under dose prescription
will lead to sub inhibitory concentrations of all drugs favoring development of drug resistance. FDC
drugs also cannot be continued once there is side effects to anyone companion drug, which justify.
Always calculate dosage according to weight of the patient. Use of separate drugs is advised in case of
weight-dosage discrepancy with FDCs. Any FDCs with Rifampicin must have a certificate of
bioavailability by a WHO recommended reference laboratory.

NEW CASES: (FDCS)

PATIENT BODY Initial Phase Continuation

Phase
WEIGHT (KG) 02 Months 04 Months

R H Z E H R
30-39 02 tablets 1
40-54 03 Tablets 1.5 Tablets

55 & above 04 Tablets 02 Tablets

(RHZE) R= 150 mg+ H= 75mg+ Z= 400mg+ E= 275. (HR) H= 150mg+ R= 300mg

R= Rifampicin H= Isoniazid Z= Pyrazinamide E= Ethambutol

NEW CASES: 2 FDC and Separate Drugs

INITIAL INTENSIVE PHASE Continuation Phase

Weight of patient Daily During First 2 Daily During next

4 months

HR Z HR

30-39 1 2 1.5 1.5

40-54 1.5 3 2 2

55 & above 2 4 3 2

(HR) H= 150mg+ R 300 mg, (Z) = 400mg Tab. (E) = 400mg Tab. R= Rifampicin H= Isoniazid Z=
Pyrazinamide E= Ethambutol

RE-TREATMENT CASES: (FDCS)

Patient body Initial Phase Continuation

Weight (kg) for 3 months Phase

2 Months 1 Months 05 Months

S RHZE RHZE HRE

30-39 500mg 02 tablets 02 tablets 02 tablets

40-54 750mg 03 Tablets 03 Tablets 03 Tablets

55 & above 750mg 04 Tablets 04 Tablets 04 Tablets

(RHZE) R= 150 mg, H= 75mg, Z= 400mg, E= 275. (RHE) R=150mg+H=75mg+E=275mg

R= Rifampicin H= Isoniazid Z= Pyrazinamide E= Ethambutol S= Streptomycin

Re-TREATMENT CASES: 2 FDC and Separate Drugs

INITIAL INTENSIVE PHASE Continuation Phase

Daily during first 3 months Daily During next

5 months

Weight of patient S (first 2 months HR Z E H E

only) R
(pretreatment weight)

30-39 500mg 1 2 1.5 1 1.5

40-54 750mg 1.5 3 2 1.5 2

55 & above 750mg 2 4 3 2 3

(HR) = H 150mg, R 300mg (Z) = 400mg Tab. (E) = 400mg Tab.

R= Rifampicin H= Isoniazid Z= Pyrazinamide E= Ethambutol S= Streptomycin