Tuberculosis

I. Introduction

Tuberculosis (TB) is at least as old as mankind and the history of this

disease is intertwined with the history of civilization. Like no other
illness, Tuberculosis has taken its toll of human life over the millennia
and has spread worldwide. Due to its worldwide incidence and
prevalence, it has been referred to as "White Plague".

Robert Koch first described the tubercle bacillus, Mycobacterium

tuberculosis, in 1882.They are slender, rod-shaped, aerobic, non-
spore forming and non-motile bacteria. One of the most striking
feature of these bacilli is the acid-fastness i.e: difficult to stain. But
once stained, they strongly retain the dye, which is not removed even
by acid alcohol. These can also be stained with fluorescent dyes. These are 2 - 4
micrometer long and 0.2 -0.5 micrometer wide in size.

Tuberculosis is contagious. Tuberculosis is spread through the air by a person suffering

from tuberculosis. A single patient can infect 10 or more people in a year.

M. tuberculosis infection occurs due to inhalation of droplet nuclei – infectious particles

aerosolized by coughing, sneezing or talking. These are sufficiently small to dry while
airborne, remain suspended for long periods and reach terminal air passages of the lungs.

It has been observed that a cough from an infected person produces 3000 infectious droplet
nuclei. Accordingly, the air in a room occupied by him may remain infectious even during his
temporary absence.

II. Pathophysiology

Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis

bacteria. TB primarily affects the lungs, although other areas, such as the kidneys, liver,
brain, and bone, may be affected as well. M. tuberculosis is an acid-fast bacillus (AFB),
which means that when it is stained in the laboratory and then washed with an acid, the
stain remains, or stays fast. M. tuberculosis can live in dark places in dried sputum for
months, but a few hours in direct sunlight kills it. It is spread by inhalation of the tuberculosis
bacilli from respiratory droplets (droplet nuclei) of an infected person.
Once the bacilli enter the lungs, they multiply and begin to disseminate to the lymph nodes
and then to other parts of the body. The patient is then infected but may or may not go on to
develop clinical (active) disease. During this time the body develops immunity, which keeps
the infection under control. The immune system surrounds the infected lung area with
neutrophils and alveolar macrophages. This process creates a lesion called a tubercle,
which seals off the bacteria and prevents spread. The bacteria within the tubercle die or
become dormant, and the patient is no longer infectious.
If the patient’s immune system becomes compromised, however, some of the dormant
bacteria can become active again, causing reinfection and active disease.
 Tubercle bacilli

Inhaled droplet nuclei

Enter bronchiole & alveoli

Surrounded & engulfed by Bacilli no known endotoxin

macrophages and exotoxin

Growth of tuberculosis bacilli No early Ig response to

in the macrophages infection

Degradation of some
mycobacterium &
presentation of it to T-
lymphocytes

Cell-mediated immune
response

Ghon’s focus
(primary lesion)

Bacilli drain to
Caseous necrosis
lymph channels

Caseous granuloma formation

(Ghon’s complex)

Post primary progressive progression of TB

 Post primary progressive progression of TB

Granulomatous lesions Bacilli enter Bacilli enter

erodes into bronchus sputum blood stream

Infection occurs
Hematogenic
Bronchogenic spread spread
(milliary TB)

III. Signs and Symptoms

Active tuberculosis is characterized by a chronic productive cough, blood-tinged sputum,

and drenching night sweats. A low-grade fever may be present. If effective treatment is not
initiated, a downhill course occurs, with pulmonary fibrosis, hemoptysis, and progressive
weight loss.

Spread of the tuberculosis bacilli throughout the body can result in pleurisy, pericarditis,
peritonitis, meningitis, bone and joint infection, genitourinary or gastrointestinal infection, or
infection of many other organs.

IV. Diagnosis

a. Tuberculin Skin Test (TST)

The TST is widely used as a supportive second line test to identify patients actively infected
with tuberculosis. It has remained more or less unchanged for the last 60 years and has
been in existence for more than 100 years. There are three types of tuberculin skin test but
the most common is the Mantoux test.

The skin test works by injecting Purified

Protein Derivative (PPD) into the skin. PPD is
a collection of mixed proteins and other
materials filtered from killed M. tuberculosis
cultures. The test works on the basis that if the
body has been exposed to infection with TB it
will recognise the proteins and mount an
immune response to it. This response would
take the form of a lump, swelling or blister at
the site of injection. If there is a lump (called
an induration) then this may mean that the
person is infected. Unfortunately, the skin test
has a poor sensitivity (the ability to detect infection if it is present). This sensitivity falls
further if the person being tested has had the BCG vaccination earlier in life or if they have a
depressed immune system (immunocompromised) due to other illness or medical treatment.

TB skin test is also known as Mantoux test. It is the most widely used test in which graded
doses of tuberculin are injected intradermally on the forearm using a tuberculin syringe.

Koch's tuberculin was an impure extract of boiled culture of tubercle bacilli. In 1934, Siebert
made a simple protein precipitate of the old tuberculin (one prepared by Koch) and named it
as purified protein derivative (PPD).

During 1970, it was recognized that PPD in solution adheres to glass to the extent that 20%
of its potency can be lost in 30 minutes and 80% in 24 hours. This can be prevented by
addition of Tween 80.

Procedure:

0.1 ml of the 5 TU of PPD is injected intradermally on the forearm. On examination after 48-
72 hours a positive reaction is indicated by erythema and in duration of > 10 mm size.
Erythema(Redness) alone is not taken as positive reaction.

Tuberculin skin testing is used as an aid in diagnosing active infection in infants and young
children, to measure the prevalence of infection in a community and to select susceptible or
high risk patients for BCG vaccination. All persons with prior infection with tubercle bacilli will
exhibit a positive response.

Some of the common problems doctors and nurses encounter with the skin test are
described below:

False positives

As the active ingredient used in the skin test contains a whole series of proteins that are
shared with the BCG vaccine and other mycobacterium common in the environment, the
skin test is commonly falsely positive in people who have had no exposure to TB. Common
causes of false positive results are prior BCG vaccination and infection with other types of
bacteria that are similar to TB. As a large percentage of the world's population is BCG
vaccinated this causes considerable problems; it is currently estimated that almost one third
of people positive to the TST do not actually have TB infection.

False negatives

The sensitivity of the skin test is estimated to be only around 70% in known active TB cases;
so the test misses up to 30% of the people who are infected. This sensitivity decreases to as
low as 30% in the immunocompromised (which means the error rate can climb to 70% in
these people). This makes it very difficult for a doctor to be able to make the right medical
decisions because the reliability of the result is so poor.

Subjectivity and variability

The skin test is difficult to administer correctly as small variations in the way it is done vary
the amount of PPD delivered into the skin and thus the resulting size of the reaction.
Furthermore, the measurement of the reaction is highly subjective; the variations in
diagnosis based on different clinicians reading the same bump in different ways is well
documented.

Boosting

A common problem in those people who are regularly screened for TB infection using the
skin test (e.g. Healthcare Workers) is that they start to become immunised to PPD by the
repeated administrations of it. This is called 'boosting' and results in a false positive reaction
to the skin test.

Convenience & Resources

The skin test is not patient friendly as it can result in painful blistering at the injection site
and result in a scar. It also requires two patient visits - one to inject the tuberculin and one to
read the induration (although it is estimated that a third of people never return to have the
test read). This is inconvenient for the clinician and patient alike

b. Sputum Smear Microscopy (SSM)

The simplest laboratory test is the examination of sputum (matter thrown up from the lungs)
for the detection of a certain type of bacteria. It is cheap and is performed in minutes. This
test is based on the principle of Ziehl Neelsen diagnostic technique of direct smear
microscopy of sputum. The unique properties of bacterial cell wall of Mycobacterium
tuberculosis allows it to retain the primary stain even after exposure to strong
acid solutions, they are called acid-fast. In the Ziehl Neelsen staining
procedure, using carbol fuschsin and methylene blue, the acid-fast
organisms appear red.

However, the WHO estimates that it only identifies 35% of patients with
active TB. As the test is based on sputum, it has particular difficulty in
detecting non-pulmonary TB. This test will also identify certain types of
bacteria that are not M. tuberculosis and so it cannot always distinguish between TB and
other infections. Despite these shortcomings, it is still the front line tool for active TB
diagnosis, partly because the more definitive culture techniques take longer and partly
because it can help determine if a person is infectious. It is argued that as long as bacteria
are found in the sputum the patient can continue to pass on the disease to other people.
Sputum smear is therefore one method that can be used to monitor an active TB patient's
response to treatment.

c. Chest X-ray

Chest x-rays are used to check for lung abnormalities in people who
have symptoms of TB disease, but the chest X-ray cannot confirm that
a person has active TB, especially if the infection is not in the lungs as
in 40% of all cases of active TB. The chest X-ray also has a poor ability
to detect infection in the early stages of disease, the damage to the
lungs may not yet have become sufficiently marked to be detectable by
chest X-ray and thus people who have active TB can be missed.
Further, scarring in the lungs remains after a previous TB disease
(even if the patient is completely cured) and therefore it is difficult to distinguish past cured
TB from current active disease.

d. Polymerase Chain Reaction (PCR)

This technique detects the presence of DNA-type (genetic) material from bacteria by
effectively amplifying the measurable amount. Polymerase chain reaction (PCR), is a
relatively new development in active TB testing. Even though PCR techniques can magnify
even the smallest amounts of genetic material, the sample used still has to contain a certain
number of TB bacteria and this is not always possible, particularly with non-pulmonary TB
where sensitivity can be as low as 60%. To increase the number of bacteria, and hence
improve the sensitivity of the test, the laboratory will often culture the sample, to allow the
bacteria to multiply, before carrying out the PCR test. This can take several days or weeks.
The test is also relatively complicated to run in the laboratory, is prone to cross
contamination and can be expensive.

The main use of PCR is not to diagnose TB per se , but to rule out other types of infection in
a sputum smear positive patient, before culture results are known.

e. Culture

Cell culture techniques (where live bacteria are grown on a plate in the laboratory) are still
seen as the gold standard for active TB as they are extremely sensitive if live mycobacteria
can be obtained in the sample. M. tuberculosis can be cultured (grown) from a variety of
specimens and can be used to detect pulmonary as well as extra-pulmonary disease. By
assessing the effect of antibiotics on the cultured bacteria, this technique can also provide
data on likely effectiveness of certain antibiotics. However, it is not always possible to obtain
bacteria in the sample, especially in non-pulmonary TB and the test is therefore not always
reliable. A drawback of this test is the time to result, which can be anything from two to six
weeks.

V. Multidrug-Resistant Tuberculosis

TB remains one of the world’s leading infectious causes of adult deaths; furthermore,
multidrug-resistant strains of the disease are emerging as a considerable threat to human
health and a danger to TB control in numerous “hot spots” throughout the world.

Definition

Strains of M.tuberculosis resistant to both isoniazid

and rifampicin with or without resistance to other
drugs have been termed multidrug-resistant strains.
Multidrug-resistant tuberculosis (MDR-TB) is among
the most worrisome elements of the pandemic of
antibiotic resistance because TB patients that fail
treatment have a high risk of death.
While resistance to either isoniazid or rifampicin may
be managed with other first-line drugs, resistance to
both isoniazid and rifampicin (MDR-TB) demands
treatment with second-line drugs. These drugs have limited sterilising capacity and are not
suitable for short course treatment. Thus, patients with MDR-TB require prolonged treatment
with drugs that are less effective and more toxic1. Therefore, it is necessary to distinguish
MDR-TB from mere drug-resistant tuberculosis by performing mycobacterial culture and
sensitivity testing because the therapeutic implications are different.

Overview of the global situation of MDR TB

According to WHO, resistance to tuberculosis drugs is probably present everywhere in the

world. Certainly, MDR-TB is present in five continents, a third of the countries surveyed
having levels above 2% among new patients. In Latvia 30% of all patients presenting for
treatment had MDR-TB. The region of Russia surveyed had 5% of TB patients with MDR-
TB. In the Dominican Republic, 10% of TB patients had MDR-TB. In Africa, Ivory Coast has
also witnessed the emergence of MDR-TB. Preliminary reports from Asia (India and China)
show high levels of drug resistance as well. In the State of Delhi, India, 13% of all TB
patients had MDR-TB.

Data from Makati Medical Centre DOTS Clinic (2003) indicates high incidence of MDR TB.
Approximately 30% of isolates tested were resistant to all five first line drugs, 39.4% to four,
16.8% to three, 12.1% to two. Fluroquinolone resistance was noted in 40.9% isolates.

While MDR-TB afflicts countries with poor health infrastructure, it is just as likely to break out
in industrialized economies. During the late 1980s and early 1990s outbreaks of MDR-TB in
North America and Europe killed over 80% of those who contracted it. The major TB
outbreak in New York in the early 1990s was primarily a MDR-TB epidemic, with one in ten
cases being drug-resistant.

Key factors for the management of MDR TB are as follows:

* Diagnosis of MDR TB
* Reliable susceptibility testing
* Prevention of MDR TB
o In new cases
o In old cases
* Designing an appropriate regimen
o Essential Drugs
o Second line Drugs
o Cross resistance
o Ranking with respect to Efficacy, Cost, Tolerance
* Reliable drug supply of second line drugs

Treatment of MDR TB

It is important for the clinician to identify whether the patient is suffering from Drug resistant
TB ( resistance to either INH or rifampicin ) or from MDR TB( resistance to both INH and
rifampicin). This differentiation is important in order to decide the treatment regimens for the
patient.

While resistance to either isoniazid or rifampicin may be managed with other first-line drugs,
resistance to both isoniazid and rifampicin (MDR-TB) demands treatment with second-line
drugs .
These drugs have limited sterilising capacity and are not suitable for short course treatment.
Thus, patients with MDR-TB require prolonged treatment with drugs that are less effective
and more toxic. Therefore, it is necessary to distinguish MDR-TB from mere drug-resistant
tuberculosis by performing mycobacterial culture and sensitivity testing because the
therapeutic implications are different.

Principles to be followed while treating MDR-TB patients:

Starting MDR-TB drug regimen:

1. Check the history of the patient carefully for previous treatment regimens.
2. Check whether all drugs in the previous regimens have been taken and for how
long.
3. Determine the status of sputum smears at all junctures (in terms of positivity,
conversions and sensitivities – if available).
4. Confirmed/ Strongly suspect MDR TB
5. Counsel the Patient and family members
6. Send Tissue / sputum for culture and sensitivity testing (if available)
7. Start MDR Regimen

Choice of drugs

Add at least 3 new drugs.

1. Preferably have an aminoglycoside (Streptomycin / Kanamycin / Amikacin/
Capreomycin).
2. One fluoroquinolone (Ofloxacin / Ciprofloxacin / Levofloxacin).
3. Ethionamide or Prothionamide
4. Any one of the following: Cycloserine, PAS, Clofazimine or Moxifloxacin

The treatment of MDR TB has been increasingly successful over the last decade, with
reported cure rates over 80% in many settings. This is especially true when fluoroquinolones
and adjuvant surgical therapy are used.

VI. Extra-pulmonary Tuberculosis

Extra-pulmonary tuberculosis (EPTB) refers to disease outside the lungs. It is sometimes

confused with non-respiratory disease. Disease of the larynx for example, which is part of
the respiratory system, is respiratory but extra-pulmonary.

Extra-pulmonary TB may be characterized by swelling of the particular site infected (lymph

node), mobility impairment (spine),or severe headache and neurological dysfunction (TB
meningitis) etc. Extra-pulmonary TB is not accompanied by a cough because it does not
occur in the lungs. It is equally important that both the infectious and non-infectious forms of
TB are diagnosed and treated as both can be fatal.

Development of extra-pulmonary disease

At the time primary infection occurs blood or lymphatic spread of tubercle bacilli to parts of
the body outside the lung may occur. In the fully immunocompetent host these bacteria are
probably destroyed. If some immune deficit is present some may concentrate at a particular
site where they may lie dormant for months or years before causing disease.
Bacteria may be coughed from the lungs and swallowed. By this route they may enter the
lymph nodes of the neck or parts of the gastro-intestinal (GI) tract.

Before milk was routinely pasteurised cattle infected with M. bovis, the bovine variant of
tuberculosis could pass disease to humans who drank infected milk. Transmission by this
route would also give rise to GI diseases.

The commonest sites of infection are:

* Lymph glands and abscesses particularly around the neck.

* Orthopaedic sites such as bones and joints. The spine is affected in about half such
cases.
* GU tract - In women uterine disease is probably the most common while in men the
epididymis is the site most frequently affected. Both sexes are affected by renal , ureteric or
bladder disease equally.
* Abdomen - This may affect the bowel and or peritoneum.
* Meningitis - which may be rapidly fatal if not, treated in time
* Pericardium- which causes constriction to the heart
* Skin - which can take a number of forms, most notably Lupus vulgaris where changes of
the facial skin was supposed to give patients a wolf-like appearance

Clinical presentation

Clinical presentation is characteristically chronic with pain and swelling being the principal
features.

Lymph glands of the neck may develop singly or in chains. They become swollen painful
and may have a rubbery texture. They may break down to give abscess formation. These
may discharge onto the skin giving a very unsightly combination of swelling a pus around
the neck.

Bony disease causes pain and swelling of the affected part. Spinal disease may cause
paraplegia if enough of the vertebrae are destroyed to cause instability of the spine.

Abdominal disease characteristically causes pain and constipation. If advanced it may

cause complete obstruction of the bowel.

Tuberculous meningitis (TBM)

Tuberculous meningitis (TBM) may cause a wide variety of symptoms. A single cranial nerve
may be affected resulting in double vision. There may be mental confusion developing over
days or weeks. If not detected and treated coma may develop. If treated soon enough
recovery may be complete but long term sequelae are likely if the treatment is delayed. TBM
has the highest mortality of all complications of tuberculosis.

Diagnosis

The diagnosis at any site should be confirmed by obtaining specimens for bacteriology
wherever possible. This means that fluid aspirated or biopsies taken should be placed in a
medium such as saline which will not kill the bacteria. Too often still biopsy specimens are
placed in formalin so that bacteriological confirmation including sensitivity testing cannot be
done.

Treatment

Treatment is as for pulmonary disease with isoniazid, rifampicin, pyrazinamide and

ethambutol for two months followed by isoniazid and rifampicin for four months, except for
CNS disease when treatment should be continued for a full year. Steroids may be used in
pericardial and meningeal disease. Surgery is usually unnecessary especially where lymph
glands and abscess are pesent as long term discharging sinuses may result. Surgery is
sometimes necessary in spinal TB where there is instability and may be needed to
overcome strictures in GU or GI disease. Occasionally pericardectomy may be required
when pericardial disease causes tamponade. It is surprising how the most destructive lesion
can be healed with drug treatment alone.

VII. Pediatric Tuberculosis

TB is difficult to diagnose in children because it is hard to confirm the diagnosis by culture

even where laboratory facilities are good. The presence of HIV makes the task even more
difficult, resulting in some children being misdiagnosed as having TB and given treatment,
while others with TB may be falsely negative and not receive treatment.

The current international TB control strategy focuses on active pulmonary TB—the source of
most TB infection in children—but does not address children and adolescents as vulnerable
sub-groups. Furthermore, vaccination of infants with BCG is no longer believed to prevent
active TB in adulthood, although it can protect children from the disseminated forms of the
disease, for example, tuberculosis meningitis.

Children are exposed to TB primarily through contact with infectious adults—with special risk
in high TB-HIV settings—and will continue to be at risk for TB as long as those adults remain
untreated. Curing TB and preventing its spread in the wider community is thus one important
strategy to reducing children s vulnerability to TB.

No vaccine yet exists that is truly effective against pulmonary disease. BCG vaccine
(Bacillus Camille Guerin) was invented in 1921. It is useful in preventing certain types of TB,
namely miliary and meningeal tuberculosis occurring in the first year of life, but is not
effective in preventing the development of pulmonary TB in adulthood.

Children are also vulnerable to the direct and indirect impacts of other family members
having TB. Already marginal households that lose income or incur debt due to TB will
experience even greater poverty as budgets are cut and assets sold. If their primary care
giver is ill or is preoccupied with caring for other ill family members, the child’s care and
education may be neglected. If the principal family provider is ill and cannot work, children
risk malnutrition, which increases susceptibility to TB and brings with it lifelong deleterious
effects on both health and education. Children are especially vulnerable if their mother
becomes sick and dies. There is a strong correlation between maternal survival and child
survival to age 10. One study in Bangladesh revealed that whereas a father’s death
increased child mortality rates by 6 per 100 000 for both boys and girls, a mother’s death
was associated with increases of 50 per 100 000 in sons and 144 per 100 000 in daughters.
Children in households with TB may also be taken out of school or sent to work. Both
scenarios deprive them of their right to education and put them in situations that may
expose them to more prolonged contact with persons with active TB. In rural Uganda, for
example, 32 patients were interviewed about the economic costs of TB. Five of their children
had had to be withdrawn from school because fees could not be paid. Even if not removed
from school, children from poor or marginalized communities where poor nutrition and ill-
health prevail have a below-average school enrolment and attendance rate and, as a result,
lower-than-average educational attainment. Lack of education correlated negatively with
access to health services, and the neglect of the right to education on children’s current and
future health can be profound.

Reasons why children have a high risk of developing active TB disease

The immune system of young children is less developed than that of an adult and the risk of
developing active TB disease is therefore higher in young children. The chance of
developing TB disease is greatest shortly after infection. When children present with active
tuberculosis disease their family members and other close contacts should be investigated
for TB to find the source of the disease and treat them as necessary.

Therefore a good TB control programme, which will ensure early diagnosis and treatment of
adults with infectious form of TB is the best way to prevent TB in children.

In HIV infected children the risk is very high to develop TB meningitis with often devastating
results for the child like deafness, blindness, paralysis and mental retardation as some of
the consequences.

Tuberculosis and malnutrition often go together, and a child with TB disease may present as
failure to gain weight with loss of energy and a cough lasting for more than three weeks.

Tuberculosis immunology in children: Diagnostic and Therapeutic challenges and

opportunities

Tuberculosis (TB) is one of the most important causes of infectious morbidity and mortality
worldwide. Young children are more likely to develop severe disease from the causative
agent Mycobacterium tuberculosis. These clinical observations likely reflect fundamental
differences in the immune systems of young children and adults. Essential to effective TB
immunity are functioning macrophages, dendritic cells, strong Th1-type T-cell immunity and
a relative absence of Th2-type T-cell immunity. Critical differences between adults and
children relevant to TB immunity include deficiencies in macrophage and dendritic cell
function, deficiencies in the development of Th1-type T-cells in response to pathogens, and
the propensity for infants and young children to develop Th2-type CD4+ T-cells in response
to immunogens. In this article, knowledge about the requisite components of protective
immunity, differences between the immune systems of children and adults relevant to
pediatric tuberculosis, M. tuberculosis-specific T-cell immunity in children, and potential
application to immunodiagnostics and vaccine development will be reviewed.

Identifying TB in Children

Vaccination has been the primary TB prevention method in children. In fact, BCG is the
most widely used vaccine in the world. Although it is relatively ineffective in preventing
infectious forms of TB, it does prevent more serious forms of TB disease in children.
Nevertheless, a quarter of a million children still develop TB every year: Particularly
vulnerable to infection from household contacts, many of them have been infected in their
own homes, by parents or other relatives with active, infectious TB. Diagnosis of TB in
children is notoriously difficult, as the early symptoms and signs are easily missed. Most
national TB control programmes have little in the way of services for children. TB in the
family also has a serious impact on children. In India alone, 300,000 children are taken out
of school every year to care for a parent sick with TB.

Tuberculosis (TB) is a serious infection caused by the bacteria Mycobacterium tuberculosis.

Unfortunately, the incidence of tuberculosis has been increasing in recent years and there
are an increasing number of cases of multi-drug resistance tuberculosis.

Routine testing for TB with a tuberculin skin test is now only recommended in children who
are at high risk for having the illness. Risk factors include being exposed to an infected
adult, contact with someone who has been in prison, contact with the homeless, and travel
to countries with a high rate of tuberculosis, including Mexico, India, Vietnam, China,
Philippines, and many countries in Latin America, Asia, the Middle East and Africa. Adopted
children from any high risk area should also be tested, including Romania and Russia.

Also, all contacts of a person with a positive tuberculin skin test should also be tested. Even
with a negative test, some younger children may need a chest x-ray and treatment if they
were recently exposed to someone with tuberculosis and that person was thought to be
contagious. Negative skin tests may need to be repeated in three months.

Testing for tuberculosis is by the tuberculin skin test, which is usually a Mantoux test with 5
units of purified protein derivative (PPD). Other forms of testing are not recommended. After
being placed on a child's forearm, the tuberculin skin test should be read 48-72 hours later
by experienced personnel. Interpretation depends not only on the type of reaction after the
test, but also the child's risk of having tuberculosis. A child over 4 years of age with no risk
factors may have a small reaction (5-14mm of induration) and not have a tuberculosis
infection, while a child who has had close contact with someone with tuberculosis will be
considered infected even with a very small reaction (greater than or equal to 5mm
induration). Even children who have received the BCG vaccine can have skin testing done.

Children exposed to someone with tuberculosis will likely develop a positive tuberculin skin
test about 2-12 weeks later. Some children, especially with immune system problems, can
have a negative tuberculin skin test and still be infected with tuberculosis.

Most children with tuberculosis do not have symptoms. They have a positive PPD, a normal
chest x-ray and no signs or symptoms of tuberculosis and are said to have a tuberculosis
infection or a latent tuberculosis infection. Even though they do not have symptoms, people
with a positive PPD need treatment, which usually consists of 9 months of isoniazid. If the
infection is thought to be resistant to isoniazid, then rifampicin may be used for 6 months.

Children with symptoms of tuberculosis, a positive tuberculin skin test and/or a positive
chest x-ray are said to have tuberculosis disease. This is more serious than just have a
tuberculosis infection. If untreated, children with a tuberculosis infection can develop
tuberculosis disease (usually within six months to two years), with symptoms including a
cough, fever, night sweats, swollen glands, decreased appetite and activity, weight loss and
difficulty breathing.
In addition to the tuberculin skin test, children with tuberculosis disease should have
additional testing to try and culture the tuberculosis bacteria so that it can be determined
which drugs the infection is sensitive to. Because tuberculosis is a slow growing bacteria,
culture can take as long as ten weeks for a final result. To obtain a culture, unless the child
has a productive cough and can produce a sputum sample, cultures may need to be
obtained from a gastric aspirate in the early morning. Children with tuberculosis disease
should also be tested for HIV.

In the lungs, tuberculosis causes the formation of cavitary lesions, pleural effusions and
enlarged lymph nodes. These can usually be seen on a chest x-ray. In addition to the
pulmonary symptoms described above, tuberculosis can also cause meningitis and
infections of the ear, kidney, bones and joints.

Treatment of tuberculosis is with long-term use of a combination of antibiotics, depending on

whether or not it is resistant to commonly used drugs. Treatment should be coordinated with
the local health department and/or a pediatric infectious disease specialist.

Treatments for tuberculosis disease involving the lungs consists of 6 or 9 months regimens
including isoniazid, rifampin and pyrazinamide. Another drug, either ethambutol or
streptomycin may be needed for multi-drug resistant TB. Extrapulmonary tuberculosis
(either meningitis or infections of the bones or joints) usually includes a 9-12 month regimen
of three or four drugs, depending on resistance.

Most people with tuberculosis disease need to undergo directly observed therapy (DOT) in
which treatment is observed by a health care worker, either in person or sometimes by
video.

Adults with tuberculosis disease are contagious for at least a few weeks after beginning
proper treatment. Children with tuberculosis disease are not as contagious, because they
usually have smaller lung lesions and do not cough as much.

Children at greater risk for Tuberculosis

Some groups of children are at greater risk for tuberculosis than others. These include:

1. Children living in a household with an adult who has active tuberculosis

2. Children living in a household with an adult who is at high risk for contracting TB
3. Children infected with HIV or another immunocompromising condition
4. Children born in a country that has a high prevalence of tuberculosis
5. Children from communities that are medically underserved

VIII. National Tuberculosis Program (NTP)

The National TB Program (NTP) is the Government’s commitment to address the TB

problem in the country. The NTP is being implemented nationwide in all government health
centers and government hospitals. Its objectives are to detect active TB cases (at least
70%) and cure them (at least 85%). Achieving and sustaining targets will eventually result to
the decline of the TB problem in the Philippines.

Classification
 Treatment Regimen
Category Type of TB Patient Intensive Continuation
Phase Phase
o New smear (+) PTB
o New smear (-) PTB w/ extensive
I parenchymal lesions on CXR 2HRZE 4HR
o EPTB
o Severe noncomitant HIV disease
o Treatment failure
o Relapse 2HRZES /
II 5HRE
o Return after default 1HRZE
o Other
o New smear (-) PTB with minimal
III 2HRZE 4HR
parenchymal lesions on CXR
o Chronic (still smear (+) after Refer to specialized facility
IV
supervised re-treatment) by DOH.

IX. DOTS

DOTS (Directly Observed Treatment, Short-course) has been identified by the World Bank
as one of the most cost-effective health strategies available.

DOTS costs only US $3 - $7 for every healthy year of life gained. DOTS get people back to
school, work and their families.

DOTS strategy combines appropriate diagnosis of TB and registration of each patient

detected, followed by standardized multi-drug treatment, with a secure supply of high quality
anti-TB drugs for all patients in treatment, individual patient outcome evaluation to ensure
cure and cohort evaluation to monitor overall programme performance.

DOTS is THE MOST EFFECTIVE STRATEGY available for controlling the worldwide TB
epidemic today.

DOTS is an inexpensive and highly effective means of treating patients already infected with
TB and preventing new infections and the development of drug resistance. Between 1995
and 2003, more than 17.1 million patients were treated under the DOTS strategy.
Worldwide, 182 countries were implementing the DOTS strategy by the end of 2003, and
77% of the world's population was living in regions where DOTS was in place. DOTS
programs reported 1.8 million new TB cases through lab testing in 2003, a case detection
rate of 45%, and the average success rate for DOTS treatment was 82%. WHO aims to
achieve a 70% case detection rate of TB cases and cure 85% of those detected by 2005.
The U.N. Millennium Development Goals include targets to halve the 1990 TB prevalence
and death rates by 2015.

DOTS uses sound technology—the successful components of TB control—and packages it

with good management practices for widespread use through the existing primary health
care network.
The technical, logistical, operational and political aspects of DOTS work together to ensure
its success and applicability in a wide variety of contexts.

X. Updates

I. Summary of WHO Report 2010 Global Tuberculosis Control

The World Health Organization (WHO) has published an annual report on global control
of tuberculosis (TB) every year since 1997. The main purpose of the report is to provide
a comprehensive and up-to-date assessment of the TB epidemic and progress made in
TB care and control at global, regional and country levels. Progress towards global
targets set for 2015 is given particular attention. The target included in the Millennium
Development Goals (MDGs) is that TB incidence should be falling by 2015. The Stop TB
Partnership has set two additional targets, which are to halve rates of prevalence and
mortality by 2015 compared with their levels in
1990. Collectively, the WHO’s Stop TB Strategy and the Stop TB Partnership’s Global
Plan to Stop TB have set out how the 2015 targets can be achieved. This fifteenth
annual report1 contains more up-todate information than any previous report in the
series, following earlier data collection and the completion of the production cycle within
a calendar year. The estimates of the global burden of disease caused by TB in 2009
are as follows: 9.4 million incident cases (range, 8.9 million–9.9 million), 14 million
prevalent cases (range, 12 million–16 million), 1.3 million deaths among HIV-negative
people (range, 1.2 million–1.5 million) and 0.38 million deaths among HIV-positive
people (range, 0.32 million–0.45 million). Most cases were in the South-East Asia,
African and Western Pacific regions (35%, 30% and 20%, respectively). An estimated
11–13% of incident cases were HIV-positive; the African Region accounted for
approximately 80% of these cases. There were 5.8 million notified cases of TB in 2009,
equivalent to a case detection rate (CDR, defined as the proportion of incident cases
that were notified) of 63% (range, 60–67%), up from 61% in 2008. Of the 2.6 million
patients with sputum smear-positive pulmonary TB in the 2008 cohort, 86% were
successfully treated. New and compelling data from 15 countries show that efforts by
national TB programmes (NTPs) to engage all care providers in TB control (termed
public-private mix, or PPM) can be a particularly effective way to increase the CDR. In
areas where PPM was implemented, non- NTP providers accounted for around one-fifth
to onethird of total notifications in 2009. In 2009, 26% of TB patients knew their HIV
status (up from 22% in 2008), including 53% of patients in the African Region. A total of
300 000 HIV-positive TB patients were enrolled on co-trimoxazole preventive therapy,
and almost 140 000 were enrolled on antiretroviral therapy (75% and 37% respectively
of those who tested HIV-positive). To prevent TB, almost 80 000 people living with HIV
were provided with isoniazid preventive therapy. This is an increase from previous years,
but still represents less than 1% of the estimated number of people living with HIV
worldwide. Among TB patients notified in 2009, an estimated 250 000 (range, 230 000–
270 000) had multidrugresistant TB (MDR-TB). Of these, slightly more than 30 000
(12%) were diagnosed with MDR-TB and notified. Diagnosis and treatment of MDR-TB
need to be rapidly expanded. Funding for TB control continues to increase and will reach
almost US$ 5 billion in 2011. There is considerable variation in what countries spend on
a per patient basis (<US$ 100 to >US$ 1000), and the extent to which countries rely on
domestic or external sources of funds. Compared with the funding requirements
estimated in the Global Plan, the funding gap is approximately US$ 1 billion in 2011.
Given the scale-up of interventions set out in the plan, this could increase to US$ 3
billion by 2015 without intensified efforts to mobilize more resources. Incidence rates are
 falling globally and in five of WHO’s six regions (the exception is the South-East Asia
Region, where the incidence rate is stable). If these trends are sustained, the MDG
target will be achieved. Mortality rates at global level fell by around 35% between 1990
and 2009, and the target of a 50% reduction by 2015 could be achieved if the current
rate of decline is sustained. At the regional level, the mortality target could be achieved
in five of WHO’s six regions; the exception is the African Region (although rates of
mortality are falling). Prevalence is falling globally and in all six WHO regions. The target
of halving the 1990 prevalence rate by 2015 appears out of reach at global level, but
could be achieved in three of six regions: the Region of the Americas, the Eastern
Mediterranean Region and the Western Pacific Region. Reductions in the burden of
disease achieved to date follow 15 years of intensive efforts to improve TB care and
control. Between 1995 and 2009, a total of 41 million TB patients were successfully
treated in DOTS programmes, and up to 6 million lives were saved including 2 million
among women and children. Looking forwards, the Stop TB Partnership launched an
updated version of the Global Plan to Stop TB in October 2010, for the years 2011–
2015. In the five years that remain until the target year of 2015, intensified efforts are
needed to plan, finance and implement the Stop TB Strategy, according to the updated
targets included in this plan. This could save at least one million lives per year.

II. WHO South-East Asian Region: summary of planned activities, impact and costs
Achievements
DOTS expanded rapidly in the South-East Asian Region over the period of the
Partnership’s first Global Plan (2001–2005), and 100% geographical coverage was
achieved in 2005. All the Region’s TB high-burden countries (Bangladesh, India,
Indonesia, Myanmar and Thailand) have made impressive progress in improving
coverage and quality. Case detection increased from a mere 18% in 2000 to 45% in
2003 and is expected to reach about 65% by the end of 2005, against the World Health
Assembly and Stop TB Partnership’s 2005 target of 70%. The treatment success rate in
the region is already 85.3%, meeting the 2005 target of 85%. This progress has been
made possible through strong political commitment and large investments in improved
infrastructure, reliable drug supply, increased staffing, improved laboratory services, and
intensified training and supervision.
Increasingly, TB programmes in the Region have reached out to a wide range of public
and private health care providers in order to increase access to quality services.
Community involvement is already a prominent feature in several TB programmes in the
Region. NGOs with roots in the local community are playing leading roles in several
places. Community volunteers are widely used to supervise treatment. The WHO’s
Regional Strategic Plan on HIV/TB recommends key strategies and interventions for
reducing HIV/TB-associated morbidity and mortality through enhanced collaboration
between national TB and AIDS programmes. Thailand has established comprehensive
joint TB/HIV services throughout the country. India, Indonesia, and Myanmar have
established formal collaboration between their national TB programmes and national
AIDS programmes and have identified collaborative TB/HIV interventions and activities,
while three countries (India, Myanmar and Thailand) are planning to carry out HIV
surveillance among TB patients. DOTS-Plus pilot projects are being implemented in
India and Nepal. India has a national plan for drug resistance surveillance as well as a
plan for pilot-testing and implementing DOTS-Plus. Currently, the capacity for culture
and drug susceptibility testing is very limited in the Region, though Bangladesh,
Indonesia and Myanmar are also planning to scale up quality-assured culture, DST and
DOTS-Plus with resources from the GFATM.
Challenges
Over the Plan period of 2006–2015, strong political commitment needs to be maintained
and the current level of funding increased in order to continue to improve access to
quality TB services. With an estimated 35% of cases still not being reached through
existing DOTS services, significant and sustained efforts will be needed to continue the
current positive trends. Most countries in the Region have a very diversified health care
system, with a number of public and private health care providers still not linked to the
DOTS programmes. A major challenge for the future is to involve a critical mass of these
providers in extending qualityassured DOTS services in both urban and rural areas. The
South-East Asian Region is the Region second-hardest hit by the HIV-epidemic, after
sub-Saharan Africa. More than 6 million people were estimated to be living with HIV in
December 2004. The extent of the epidemic of TB/HIV coinfection in the Region will
depend on the future course of the HIV epidemic, as well as on efforts to control TB.
Estimated HIV prevalence among TB patients ranges from 0.1% in Bangladesh, through
4.6% in India, to 8.7% in Thailand. Data from a region of Thailand with low HIV
prevalence illustrate that the uptake of HIV counseling and testing is low among TB
patients, a challenge that will need to be addressed as HIV counselling and testing
facilities become more readily accessible. Coverage of drug resistance surveillance is
low in the Region, mainly because of limited data from Bangladesh, India and Indonesia,
making it difficult to assess the regional MDR-TB situation. Available data show that,
while the levels of MDR-TB among previously untreated cases may be below 3%, the
large numbers of TB cases translate into a significant burden of MDRTB in South-East
Asia. It is estimated that 25% of all MDR-TB cases worldwide are in India alone. Most
national TB programmes in the Region do not at present diagnose and treat MDR-TB
patients, though many other public and private providers do, using second-line drugs,
which are widely available.
Priority activities 2006–2015
First and foremost, attention will need to be focused on sustaining commitment and
resources for TB control, particularly sustaining adequate human resource capabilities to
deliver quality DOTS services. Second, to increase the reach of DOTS, scaling up the
participation of other sectors – particularly the large and vibrant private sector in the
Region – will be critical. Expanding the public-private mix for DOTS will be especially
important in the rapidly growing urban areas, where TB control struggles to cope with a
complex range of health providers as well as a diverse mix of TB patients, including
slum-dwellers and migrants. Community outreach activities, as well as education,
information and communications campaigns empowering communities to develop their
own strategies, will be important if quality services are to be provided for the poor and
the marginalized in remote rural and cross-border areas, and among displaced
communities. Decentralizing services and involving all health and social workers at the
grass-roots level should help reduce barriers to access for women and children. The
Region also needs to focus on the growing problem of drug resistance. Improving the
quality of DOTS services made available by all health care providers will halt and
reverse the development of drug resistance. DST should be scaled up to cover 20% of
new TB patients and 100% of previously treated TB patients in 2015. DOTS-Plus
population coverage should expand to 50% by 2010 and 100% by 2015. Surveillance of
HIV among TB patients needs to be established in countries with a high burden of HIV-
related TB. Collaborative TB/HIV activities will be expanded to all populations with a high
burden of HIV-related TB by the end of 2009. PAL initiatives will be scaled up, with a
main focus on urban areas.
Expected effects and costs
Through the intensified efforts outlined above, case detection is expected to increase to
79% by 2010 and 84% by 2015. Treatment success rate is already at the 2005 target
 level of 85% and is expected to increase to between 85%-90% by 2010 and then remain
at this level (noting that 87% is used as the treatment success rate in the scenario
calculations). As a consequence, the expected decline in incidence, prevalence and
death rates would mean that the Partnership’s targets would be met ahead of the target
date of 2015 in the South-East Asian Region. The projected rapid decline in incidence
and new cases under the scenario shown in the figures is based on the assumption that
all countries and particularly the five high-burden countries in the Region will continue to
maintain or surpass the 70% case detection and 85% treatment success rates. These
rates of decline will also depend on how effectively initiatives such as DOTS-Plus, PPM-
DOTS and interventions for TB-HIV among others, are implemented to counterbalance
the effect of HIV and the emergence of MDR-TB in countries in the Region. During the
period of the Plan (2006–2015), it is estimated that at least 16 million people will be
treated in DOTS programmes and more than 145 000 in DOTS-Plus. In addition, 306
000 TB patients will be enrolled on antiretroviral therapy. The combined effect of all
interventions will be to prevent about 5 million deaths, in comparison with a situation in
which no DOTS programmes are implemented, or about 460 000 deaths in comparison
with a situation in which TB control efforts are sustained at 2005 levels. With the
implementation of sound TB control, the estimated proportion of re-treatment cases
should decrease from 25% in 2005 to 12% in 2015.
The total estimated cost of DOTS expansion, DOTS-Plus and TB/HIV control activities in
the South-East Asian region from 2006 to 2015 is US$5.5 billion.

III. The Global Plan to Stop TB: Developing New Vaccines

Today’s TB vaccine, BCG, was developed almost 90 years ago and is routinely given
to infants in much of the world. While it provides some protection against severe forms
of paediatric TB, it is unreliable against pulmonary TB. In addition, BCG is not
recommended for use in infants infected with HIV, due to the risk of disseminated BCG
disease. There is an urgent need for modern, safe and effective vaccines that prevent
all forms of TB, in all
age groups and among people with HIV. A great deal of progress has been made in
TB vaccine research over the past five years that has strengthened the pipeline of TB
vaccine candidates and provided valuable information on TB vaccine development.
According to recent modelling studies, the introduction of new effective TB vaccines
and vaccination strategies will make a crucial contribution to achieving the
Partnership’s goal to reduce the global incidence of TB disease to less than one case
per million population by 2050, and development of new vaccines to protect against TB
is gaining substantial momentum.
Historic opportunities arose in 2000 for development of new TB vaccines, resulting
from the availability of techniques for the genetic manipulation of mycobacteria, and
completion of the genome sequence of M. tuberculosis. These advances have been
critical for the construction of new live genetically altered mycobacterial vaccines, viral-
vectored vaccines and sub-unit vaccines composed of recombinant antigens. In
parallel, advances were being made in understanding of the cellular and molecular
mechanisms underlying protective immunity in humans, as well as the development of
animal models and immunoassays for TB.
In the past decade, progress in TB vaccine development has included advancing
candidates into clinical trials, maintaining a robust TB vaccine candidate pipeline,
developing capacity for large-scale trials and for vaccine production, as well as raising
awareness and support for new TB vaccines. The main target for vaccine development
in the Global Plan to Stop TB 2006–2015 was that two vaccines would be in proof-of-
concept trials by 2010 and that one new and safe vaccine would be available by 2015.
As of 2009, 12 TB vaccine candidates had entered clinical trials. Of these, nine are still
being tested: five are in Phase I (safety) clinical trials, two are in Phase II trials, and
two are in Phase IIb ‘proof-of-concept’ trials. One vaccine has produced estimates of
safety and effectiveness in a targeted HIV-infected population (Figure 7). At least six
TB vaccine candidates are in preclinical development,6 and at least 21 additional next
generation candidates are in the vaccine discovery phase.7 In addition to the
development of new TB vaccine candidates, research is also underway to evaluate
new delivery platforms that would be affordable and suitable for resource-limited
settings, including needle-free delivery. Next generation candidates are defined as TB
vaccine candidates that are in the research and development stage with some
preclinical testing performed to show that they may confer protection. Capacity and
infrastructure for large-scale clinical trials are being developed at various sites in
several endemic countries. The most advanced of these sites, located in South Africa
– and operated by the South African Tuberculosis Vaccine Initiative – is conducting
clinical trials of several vaccine candidates, and initiated the first Phase IIb ‘proof-of-
concept’ trial of a preventive vaccine in infants in July 2009. In parallel, epidemiological
cohort studies in infants and adolescents are underway in several countries that will
provide important baseline TB incidence data and help determine the suitability of sites
for large-scale efficacy trials. In order to ensure an ample supply of quality candidate
vaccines for clinical trials and to minimize the lag time between licensure and
worldwide distribution, it is imperative to invest in vaccine manufacturing capacity.
Currently, some capacity exists in both the private and non-profit sectors, but
additional investment will be needed in order to meet future demands for new TB
vaccines. Emerging economies will play an important role in vaccine manufacture and
delivery, and negotiations are taking place with several manufacturers in countries with
emerging economies for production and distribution of new TB vaccines. Efforts are
also underway to implement delivery, regulatory and access strategies for TB
vaccines, including the development of effective regulatory pathways that shorten
review timelines without compromising the ultimate quality of vaccines. A Task Force
on Economics and Product Profiles has been established to support the rapid
development and deployment of new
TB vaccines once they are licensed, by developing clear guidance on desired product
characteristics and the likely economic impact in the context of large-scale TB
programmes. A market research project is underway to provide information on
potential TB vaccine markets in target countries, as well as increase understanding of
in-country decision-makers’ views on procurement and integration of new TB vaccines.
Strategies to harmonize regulatory review of TB vaccines in multi-country clinical trials
are also under development. The main goal of the new vaccines component of the
Global Plan to Stop TB 2011–2015 is to prevent all forms of tuberculosis in all age
groups through the development of safe, effective and accessible vaccines that are
also safe for people with HIV. Progress in TB vaccine research over the last five years
has informed novel TB vaccine development and strengthened the TB vaccine
pipeline. Although development of new TB vaccines has not been as rapid as was
anticipated in 2006, due to the inherent complexity in developing biological products,
current development timelines now indicate that three new vaccines will have
completed Phase IIb ‘proof of concept’ trials by 2015, and if successful, will enter large
Phase III safety and efficacy trials. We can then anticipate that one or more new TB
vaccines could be available by 2020. It is therefore expected that with the funding
support outlined below, the full implementation of research and development activities
presented here will result in a safe and effective TB vaccine that can be distributed at
reasonable cost to endemic countries. Towards that end, the Stop TB Partnership
Working Group on New Vaccines expects that, by 2015, the following will be achieved:
• Four new TB vaccine candidates will have entered Phase III clinical trials for safety
and efficacy;
• Assays to determine biomarkers and correlates of immune protection will be
incorporated into clinical trials;
*Sufficient manufacturing capacity and licensing agreements will be in place to ensure
ample supply of new TB vaccines for large-scale trials and uptake of new vaccines,
once licensed, at reasonable cost;
• Appropriate infrastructure and capacity will be in place at multiple sites – in endemic
countries with high TB incidence, and in different regions of the world – to conduct
large-scale clinical trials that adhere to international standards;
• Regulatory pathways and access/delivery strategies will be developed to minimize
lag time between licensure and distribution of new vaccines;
• Increased public support for and increased investment in TB vaccine development
will be ensured.