TB Written Report

8/7/2019 TB Written Report

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TuberculosisI. Introduction

Tuberculosis (TB) is at least as old as mankind and the history of thisdisease is intertwined with the history of civilization. Like no otherillness, Tuberculosis has taken its toll of human life over the millenniaand has spread worldwide. Due to its worldwide incidence andprevalence, it has been referred to as "White Plague".

Robert Koch first described the tubercle bacillus, Mycobacteriumtuberculosis, in 1882.They are slender, rod-shaped, aerobic, non-spore forming and non-motile bacteria. One of the most strikingfeature of these bacilli is the acid-fastness i.e: difficult to stain. Butonce stained, they strongly retain the dye, which is not removed evenby acid alcohol. These can also be stained with fluorescent dyes. These are 2 - 4micrometer long and 0.2 -0.5 micrometer wide in size.

Tuberculosis is contagious. Tuberculosis is spread through the air by a person sufferingfrom tuberculosis. A single patient can infect 10 or more people in a year.

M. tuberculosis infection occurs due to inhalation of droplet nuclei infectious particlesaerosolized by coughing, sneezing or talking. These are sufficiently small to dry whileairborne, 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 dropletnuclei. Accordingly, the air in a room occupied by him may remain infectious even during histemporary absence.

II. Pathophysiology

Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosisbacteria. 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, thestain remains, or stays fast. M. tuberculosis can live in dark places in dried sputum formonths, but a few hours in direct sunlight kills it. It is spread by inhalation of the tuberculosisbacilli from respiratory droplets (droplet nuclei) of an infected person.Once the bacilli enter the lungs, they multiply and begin to disseminate to the lymph nodesand then to other parts of the body. The patient is then infected but may or may not go on todevelop clinical (active) disease. During this time the body develops immunity, which keepsthe infection under control. The immune system surrounds the infected lung area withneutrophils 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 orbecome dormant, and the patient is no longer infectious.If the patients immune system becomes compromised, however, some of the dormantbacteria can become active again, causing reinfection and active disease.


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Tubercle bacilli

Inhaled droplet nuclei

Enter bronchiole & alveoli

Surrounded & engulfed by

macrophages

Bacilli no known endotoxin

and exotoxin

No early Ig response toinfection

Growth of tuberculosis bacilliin the macrophages

Degradation of some

mycobacterium &

presentation of it to T-

lymphocytes

Cell-mediated immune

response

Ghons focus(primary lesion)

Caseous necrosisBacilli drain to

lymph channels

Caseous granuloma formation

(Ghons complex)

Post primary progressive progression of TB


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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 notinitiated, a downhill course occurs, with pulmonary fibrosis, hemoptysis, and progressiveweight loss.

Spread of the tuberculosis bacilli throughout the body can result in pleurisy, pericarditis,peritonitis, meningitis, bone and joint infection, genitourinary or gastrointestinal infection, orinfection 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 infectedwith tuberculosis. It has remained more or less unchanged for the last 60 years and hasbeen in existence for more than 100 years. There are three types of tuberculin skin test butthe most common is the Mantoux test.

The skin test works by injecting PurifiedProtein Derivative (PPD) into the skin. PPD isa collection of mixed proteins and other

materials filtered from killed M. tuberculosiscultures. The test works on the basis that if thebody has been exposed to infection with TB itwill recognise the proteins and mount animmune response to it. This response wouldtake the form of a lump, swelling or blister atthe site of injection. If there is a lump (calledan induration) then this may mean that theperson is infected. Unfortunately, the skin test

Post primary progressive progression of TB

Granulomatous lesions

erodes into bronchus

Bronchogenic spread

Bacilli enter

sputum

Infection occurs

Bacilli enter

blood stream

Hematogenicspread

(milliary TB)


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has a poor sensitivity (the ability to detect infection if it is present). This sensitivity fallsfurther if the person being tested has had the BCG vaccination earlier in life or if they have adepressed 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 gradeddoses 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, Siebertmade a simple protein precipitate of the old tuberculin (one prepared by Koch) and named itas 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 byaddition 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 youngchildren, to measure the prevalence of infection in a community and to select susceptible orhigh risk patients for BCG vaccination. All persons with prior infection with tubercle bacilli willexhibit a positive response.

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

False positives

As the active ingredient used in the skin test contains a whole series of proteins that areshared with the BCG vaccine and other mycobacterium common in the environment, theskin test is commonly falsely positive in people who have had no exposure to TB. Commoncauses of false positive results are prior BCG vaccination and infection with other types ofbacteria that are similar to TB. As a large percentage of the world's population is BCGvaccinated this causes considerable problems; it is currently estimated that almost one thirdof 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 aslow as 30% in the immunocompromised (which means the error rate can climb to 70% inthese people). This makes it very difficult for a doctor to be able to make the right medicaldecisions 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 varythe amount of PPD delivered into the skin and thus the resulting size of the reaction.


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Furthermore, the measurement of the reaction is highly subjective; the variations indiagnosis based on different clinicians reading the same bump in different ways is welldocumented.

Boosting

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

Convenience & Resources

The skin test is not patient friendly as it can result in painful blistering at the injection siteand result in a scar. It also requires two patient visits - one to inject the tuberculin and one toread the induration (although it is estimated that a third of people never return to have thetest 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. Thistest is based on the principle of Ziehl Neelsen diagnostic technique of direct smearmicroscopy of sputum. The unique properties of bacterial cell wall of Mycobacteriumtuberculosis allows it to retain the primary stain even after exposure to strongacid solutions, they are called acid-fast. In the Ziehl Neelsen stainingprocedure, using carbol fuschsin and methylene blue, the acid-fastorganisms 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 indetecting non-pulmonary TB. This test will also identify certain types ofbacteria that are not M. tuberculosis and so it cannot always distinguish between TB andother infections. Despite these shortcomings, it is still the front line tool for active TBdiagnosis, partly because the more definitive culture techniques take longer and partlybecause it can help determine if a person is infectious. It is argued that as long as bacteriaare 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'sresponse to treatment.

c. Chest X-ray

Chest x-rays are used to check for lung abnormalities in people whohave symptoms of TB disease, but the chest X-ray cannot confirm thata person has active TB, especially if the infection is not in the lungs asin 40% of all cases of active TB. The chest X-ray also has a poor abilityto detect infection in the early stages of disease, the damage to thelungs may not yet have become sufficiently marked to be detectable bychest X-ray and thus people who have active TB can be missed.Further, scarring in the lungs remains after a previous TB disease


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(even if the patient is completely cured) and therefore it is difficult to distinguish past curedTB 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 arelatively new development in active TB testing. Even though PCR techniques can magnifyeven the smallest amounts of genetic material, the sample used still has to contain a certainnumber of TB bacteria and this is not always possible, particularly with non-pulmonary TBwhere sensitivity can be as low as 60%. To increase the number of bacteria, and henceimprove the sensitivity of the test, the laboratory will often culture the sample, to allow thebacteria 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 crosscontamination and can be expensive.

The main use of PCR is not to diagnose TB per se , but to rule out other types of infection ina 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 stillseen as the gold standard for active TB as they are extremely sensitive if live mycobacteriacan be obtained in the sample. M. tuberculosis can be cultured (grown) from a variety ofspecimens and can be used to detect pulmonary as well as extra-pulmonary disease. Byassessing the effect of antibiotics on the cultured bacteria, this technique can also providedata on likely effectiveness of certain antibiotics. However, it is not always possible to obtainbacteria in the sample, especially in non-pulmonary TB and the test is therefore not alwaysreliable. A drawback of this test is the time to result, which can be anything from two to sixweeks.

V. Multidrug-Resistant Tuberculosis

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

Definition

Strains of M.tuberculosis resistant to both isoniazidand rifampicin with or without resistance to otherdrugs have been termed multidrug-resistant strains.

Multidrug-resistant tuberculosis (MDR-TB) is amongthe most worrisome elements of the pandemic ofantibiotic resistance because TB patients that failtreatment have a high risk of death.While resistance to either isoniazid or rifampicin maybe managed with other first-line drugs, resistance toboth isoniazid and rifampicin (MDR-TB) demands

treatment with second-line drugs. These drugs have limited sterilising capacity and are notsuitable for short course treatment. Thus, patients with MDR-TB require prolonged treatment


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with drugs that are less effective and more toxic1. Therefore, it is necessary to distinguishMDR-TB from mere drug-resistant tuberculosis by performing mycobacterial culture andsensitivity 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 theworld. Certainly, MDR-TB is present in five continents, a third of the countries surveyedhaving levels above 2% among new patients. In Latvia 30% of all patients presenting fortreatment 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 hasalso 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 TBpatients 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 outin industrialized economies. During the late 1980s and early 1990s outbreaks of MDR-TB inNorth America and Europe killed over 80% of those who contracted it. The major TBoutbreak in New York in the early 1990s was primarily a MDR-TB epidemic, with one in tencases 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 caseso In old cases

* Designing an appropriate regimeno Essential Drugso Second line Drugso Cross resistanceo 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 andrifampicin). This differentiation is important in order to decide the treatment regimens for thepatient.

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-linedrugs .


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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 effectiveand more toxic. Therefore, it is necessary to distinguish MDR-TB from mere drug-resistanttuberculosis by performing mycobacterial culture and sensitivity testing because thetherapeutic 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 TB5. Counsel the Patient and family members6. 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 Prothionamide4. Any one of the following: Cycloserine, PAS, Clofazimine or Moxifloxacin

The treatment of MDR TB has been increasingly successful over the last decade, withreported 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 sometimesconfused with non-respiratory disease. Disease of the larynx for example, which is part ofthe respiratory system, is respiratory but extra-pulmonary.

Extra-pulmonary TB may be characterized by swelling of the particular site infected (lymphnode), mobility impairment (spine),or severe headache and neurological dysfunction (TBmeningitis) etc. Extra-pulmonary TB is not accompanied by a cough because it does notoccur 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 ofthe body outside the lung may occur. In the fully immunocompetent host these bacteria areprobably destroyed. If some immune deficit is present some may concentrate at a particularsite where they may lie dormant for months or years before causing disease.


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Bacteria may be coughed from the lungs and swallowed. By this route they may enter thelymph 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 oftuberculosis could pass disease to humans who drank infected milk. Transmission by thisroute 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 orbladder 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 ofthe facial skin was supposed to give patients a wolf-like appearance

Clinical presentation

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

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

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

Abdominal disease characteristically causes pain and constipation. If advanced it maycause complete obstruction of the bowel.

Tuberculous meningitis (TBM)

Tuberculous meningitis (TBM) may cause a wide variety of symptoms. A single cranial nervemay be affected resulting in double vision. There may be mental confusion developing overdays 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. TBMhas the highest mortality of all complications of tuberculosis.

Diagnosis

The diagnosis at any site should be confirmed by obtaining specimens for bacteriologywherever possible. This means that fluid aspirated or biopsies taken should be placed in amedium such as saline which will not kill the bacteria. Too often still biopsy specimens are


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placed in formalin so that bacteriological confirmation including sensitivity testing cannot bedone.

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 forCNS disease when treatment should be continued for a full year. Steroids may be used inpericardial and meningeal disease. Surgery is usually unnecessary especially where lymphglands and abscess are pesent as long term discharging sinuses may result. Surgery issometimes necessary in spinal TB where there is instability and may be needed toovercome strictures in GU or GI disease. Occasionally pericardectomy may be requiredwhen pericardial disease causes tamponade. It is surprising how the most destructive lesioncan 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 moredifficult, 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 TBthe source ofmost TB infection in childrenbut does not address children and adolescents as vulnerablesub-groups. Furthermore, vaccination of infants with BCG is no longer believed to preventactive TB in adulthood, although it can protect children from the disseminated forms of thedisease, for example, tuberculosis meningitis.

Children are exposed to TB primarily through contact with infectious adultswith special riskin high TB-HIV settingsand 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 importantstrategy 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 noteffective in preventing the development of pulmonary TB in adulthood.

Children are also vulnerable to the direct and indirect impacts of other family membershaving TB. Already marginal households that lose income or incur debt due to TB willexperience even greater poverty as budgets are cut and assets sold. If their primary caregiver is ill or is preoccupied with caring for other ill family members, the childs care and

education may be neglected. If the principal family provider is ill and cannot work, childrenrisk malnutrition, which increases susceptibility to TB and brings with it lifelong deleteriouseffects on both health and education. Children are especially vulnerable if their motherbecomes sick and dies. There is a strong correlation between maternal survival and childsurvival to age 10. One study in Bangladesh revealed that whereas a fathers deathincreased child mortality rates by 6 per 100 000 for both boys and girls, a mothers deathwas associated with increases of 50 per 100 000 in sons and 144 per 100 000 in daughters.


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Children in households with TB may also be taken out of school or sent to work. Bothscenarios deprive them of their right to education and put them in situations that mayexpose them to more prolonged contact with persons with active TB. In rural Uganda, forexample, 32 patients were interviewed about the economic costs of TB. Five of their childrenhad had to be withdrawn from school because fees could not be paid. Even if not removedfrom 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 withaccess to health services, and the neglect of the right to education on childrens current andfuture 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 ofdeveloping active TB disease is therefore higher in young children. The chance ofdeveloping TB disease is greatest shortly after infection. When children present with activetuberculosis disease their family members and other close contacts should be investigatedfor 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 ofadults 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 devastatingresults for the child like deafness, blindness, paralysis and mental retardation as some ofthe consequences.

Tuberculosis and malnutrition often go together, and a child with TB disease may present asfailure 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 mortalityworldwide. Young children are more likely to develop severe disease from the causativeagent Mycobacterium tuberculosis. These clinical observations likely reflect fundamentaldifferences in the immune systems of young children and adults. Essential to effective TBimmunity are functioning macrophages, dendritic cells, strong Th1-type T-cell immunity anda relative absence of Th2-type T-cell immunity. Critical differences between adults andchildren relevant to TB immunity include deficiencies in macrophage and dendritic cellfunction, deficiencies in the development of Th1-type T-cells in response to pathogens, andthe propensity for infants and young children to develop Th2-type CD4+ T-cells in responseto immunogens. In this article, knowledge about the requisite components of protective

immunity, differences between the immune systems of children and adults relevant topediatric tuberculosis, M. tuberculosis-specific T-cell immunity in children, and potentialapplication 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 themost widely used vaccine in the world. Although it is relatively ineffective in preventinginfectious forms of TB, it does prevent more serious forms of TB disease in children.


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Nevertheless, a quarter of a million children still develop TB every year: Particularlyvulnerable to infection from household contacts, many of them have been infected in theirown homes, by parents or other relatives with active, infectious TB. Diagnosis of TB inchildren is notoriously difficult, as the early symptoms and signs are easily missed. Mostnational TB control programmes have little in the way of services for children. TB in thefamily 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 thereare 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 whoare at high risk for having the illness. Risk factors include being exposed to an infectedadult, contact with someone who has been in prison, contact with the homeless, and travelto 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. Evenwith a negative test, some younger children may need a chest x-ray and treatment if theywere recently exposed to someone with tuberculosis and that person was thought to becontagious. 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 5units of purified protein derivative (PPD). Other forms of testing are not recommended. Afterbeing placed on a child's forearm, the tuberculin skin test should be read 48-72 hours laterby experienced personnel. Interpretation depends not only on the type of reaction after thetest, 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 tuberculosisinfection, while a child who has had close contact with someone with tuberculosis will beconsidered infected even with a very small reaction (greater than or equal to 5mminduration). 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 skintest about 2-12 weeks later. Some children, especially with immune system problems, canhave 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 normalchest x-ray and no signs or symptoms of tuberculosis and are said to have a tuberculosisinfection 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 theinfection 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 positivechest x-ray are said to have tuberculosis disease. This is more serious than just have atuberculosis infection. If untreated, children with a tuberculosis infection can developtuberculosis disease (usually within six months to two years), with symptoms including acough, fever, night sweats, swollen glands, decreased appetite and activity, weight loss anddifficulty breathing.


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In addition to the tuberculin skin test, children with tuberculosis disease should haveadditional testing to try and culture the tuberculosis bacteria so that it can be determinedwhich 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 childhas 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 diseaseshould also be tested for HIV.

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

Treatment of tuberculosis is with long-term use of a combination of antibiotics, depending onwhether or not it is resistant to commonly used drugs. Treatment should be coordinated withthe local health department and/or a pediatric infectious disease specialist.

Treatments for tuberculosis disease involving the lungs consists of 6 or 9 months regimensincluding isoniazid, rifampin and pyrazinamide. Another drug, either ethambutol orstreptomycin 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 regimenof three or four drugs, depending on resistance.

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

Adults with tuberculosis disease are contagious for at least a few weeks after beginningproper 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 tuberculosis2. Children living in a household with an adult who is at high risk for contracting TB3. Children infected with HIV or another immunocompromising condition4. Children born in a country that has a high prevalence of tuberculosis5. Children from communities that are medically underserved

VIII. National Tuberculosis Program (NTP)

The National TB Program (NTP) is the Governments commitment to address the TBproblem in the country. The NTP is being implemented nationwide in all government healthcenters and government hospitals. Its objectives are to detect active TB cases (at least70%) and cure them (at least 85%). Achieving and sustaining targets will eventually result tothe decline of the TB problem in the Philippines.

Classification


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Category Type of TB PatientTreatment Regimen

IntensivePhase

ContinuationPhase

I

o New smear (+) PTBo New smear (-) PTB w/ extensive

parenchymal lesions on CXRo EPTBo Severe noncomitant HIV disease

2HRZE 4HR

II

o Treatment failureo Relapseo Return after defaulto Other

2HRZES /1HRZE

5HRE

IIIo New smear (-) PTB with minimal

parenchymal lesions on CXR2HRZE 4HR

IVo Chronic (still smear (+) after

supervised re-treatment)Refer to specialized facility

by DOH.

IX. DOTS

DOTS (Directly Observed Treatment, Short-course) has been identified by the World Bankas 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 toschool, work and their families.

DOTS strategy combines appropriate diagnosis of TB and registration of each patientdetected, followed by standardized multi-drug treatment, with a secure supply of high qualityanti-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 TBepidemic today.

DOTS is an inexpensive and highly effective means of treating patients already infected withTB and preventing new infections and the development of drug resistance. Between 1995and 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, and77% of the world's population was living in regions where DOTS was in place. DOTSprograms reported 1.8 million new TB cases through lab testing in 2003, a case detectionrate 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 prevalenceand death rates by 2015.

DOTS uses sound technologythe successful components of TB controland packages itwith good management practices for widespread use through the existing primary healthcare network.


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The technical, logistical, operational and political aspects of DOTS work together to ensureits 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 controlof tuberculosis (TB) every year since 1997. The main purpose of the report is to providea comprehensive and up-to-date assessment of the TB epidemic and progress made inTB care and control at global, regional and country levels. Progress towards globaltargets set for 2015 is given particular attention. The target included in the MillenniumDevelopment Goals (MDGs) is that TB incidence should be falling by 2015. The Stop TBPartnership has set two additional targets, which are to halve rates of prevalence andmortality by 2015 compared with their levels in1990. Collectively, the WHOs Stop TB Strategy and the Stop TB Partnerships GlobalPlan to Stop TB have set out how the 2015 targets can be achieved. This fifteenthannual report1 contains more up-todate information than any previous report in the

series, following earlier data collection and the completion of the production cycle withina calendar year. The estimates of the global burden of disease caused by TB in 2009are as follows: 9.4 million incident cases (range, 8.9 million9.9 million), 14 millionprevalent cases (range, 12 million16 million), 1.3 million deaths among HIV-negativepeople (range, 1.2 million1.5 million) and 0.38 million deaths among HIV-positivepeople (range, 0.32 million0.45 million). Most cases were in the South-East Asia,African and Western Pacific regions (35%, 30% and 20%, respectively). An estimated1113% of incident cases were HIV-positive; the African Region accounted forapproximately 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 casesthat were notified) of 63% (range, 6067%), up from 61% in 2008. Of the 2.6 millionpatients with sputum smear-positive pulmonary TB in the 2008 cohort, 86% were

successfully treated. New and compelling data from 15 countries show that efforts bynational TB programmes (NTPs) to engage all care providers in TB control (termedpublic-private mix, or PPM) can be a particularly effective way to increase the CDR. Inareas where PPM was implemented, non- NTP providers accounted for around one-fifthto onethird of total notifications in 2009. In 2009, 26% of TB patients knew their HIVstatus (up from 22% in 2008), including 53% of patients in the African Region. A total of300 000 HIV-positive TB patients were enrolled on co-trimoxazole preventive therapy,and almost 140 000 were enrolled on antiretroviral therapy (75% and 37% respectivelyof those who tested HIV-positive). To prevent TB, almost 80 000 people living with HIVwere 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 HIVworldwide. 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-TBneed to be rapidly expanded. Funding for TB control continues to increase and will reachalmost US$ 5 billion in 2011. There is considerable variation in what countries spend ona per patient basis (US$ 1000), and the extent to which countries rely ondomestic or external sources of funds. Compared with the funding requirementsestimated 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$ 3billion by 2015 without intensified efforts to mobilize more resources. Incidence rates are


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falling globally and in five of WHOs six regions (the exception is the South-East AsiaRegion, where the incidence rate is stable). If these trends are sustained, the MDGtarget will be achieved. Mortality rates at global level fell by around 35% between 1990and 2009, and the target of a 50% reduction by 2015 could be achieved if the currentrate of decline is sustained. At the regional level, the mortality target could be achievedin five of WHOs 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 targetof halving the 1990 prevalence rate by 2015 appears out of reach at global level, butcould be achieved in three of six regions: the Region of the Americas, the EasternMediterranean Region and the Western Pacific Region. Reductions in the burden ofdisease achieved to date follow 15 years of intensive efforts to improve TB care andcontrol. Between 1995 and 2009, a total of 41 million TB patients were successfullytreated in DOTS programmes, and up to 6 million lives were saved including 2 millionamong women and children. Looking forwards, the Stop TB Partnership launched anupdated version of the Global Plan to Stop TB in October 2010, for the years 20112015. In the five years that remain until the target year of 2015, intensified efforts areneeded to plan, finance and implement the Stop TB Strategy, according to the updatedtargets 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 costsAchievementsDOTS expanded rapidly in the South-East Asian Region over the period of thePartnerships first Global Plan (20012005), and 100% geographical coverage wasachieved in 2005. All the Regions TB high-burden countries (Bangladesh, India,Indonesia, Myanmar and Thailand) have made impressive progress in improvingcoverage and quality. Case detection increased from a mere 18% in 2000 to 45% in2003 and is expected to reach about 65% by the end of 2005, against the World HealthAssembly and Stop TB Partnerships 2005 target of 70%. The treatment success rate inthe region is already 85.3%, meeting the 2005 target of 85%. This progress has beenmade possible through strong political commitment and large investments in improved

infrastructure, reliable drug supply, increased staffing, improved laboratory services, andintensified training and supervision.Increasingly, TB programmes in the Region have reached out to a wide range of publicand private health care providers in order to increase access to quality services.Community involvement is already a prominent feature in several TB programmes in theRegion. NGOs with roots in the local community are playing leading roles in severalplaces. Community volunteers are widely used to supervise treatment. The WHOsRegional Strategic Plan on HIV/TB recommends key strategies and interventions forreducing HIV/TB-associated morbidity and mortality through enhanced collaborationbetween national TB and AIDS programmes. Thailand has established comprehensive

joint TB/HIV services throughout the country. India, Indonesia, and Myanmar haveestablished 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 HIVsurveillance among TB patients. DOTS-Plus pilot projects are being implemented inIndia and Nepal. India has a national plan for drug resistance surveillance as well as aplan for pilot-testing and implementing DOTS-Plus. Currently, the capacity for cultureand drug susceptibility testing is very limited in the Region, though Bangladesh,Indonesia and Myanmar are also planning to scale up quality-assured culture, DST andDOTS-Plus with resources from the GFATM.Challenges


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Over the Plan period of 20062015, strong political commitment needs to be maintainedand the current level of funding increased in order to continue to improve access toquality TB services. With an estimated 35% of cases still not being reached throughexisting DOTS services, significant and sustained efforts will be needed to continue thecurrent positive trends. Most countries in the Region have a very diversified health caresystem, 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 theseproviders in extending qualityassured DOTS services in both urban and rural areas. TheSouth-East Asian Region is the Region second-hardest hit by the HIV-epidemic, aftersub-Saharan Africa. More than 6 million people were estimated to be living with HIV inDecember 2004. The extent of the epidemic of TB/HIV coinfection in the Region willdepend 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, through4.6% in India, to 8.7% in Thailand. Data from a region of Thailand with low HIVprevalence illustrate that the uptake of HIV counseling and testing is low among TBpatients, a challenge that will need to be addressed as HIV counselling and testingfacilities become more readily accessible. Coverage of drug resistance surveillance islow 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%, thelarge numbers of TB cases translate into a significant burden of MDRTB in South-EastAsia. It is estimated that 25% of all MDR-TB cases worldwide are in India alone. Mostnational TB programmes in the Region do not at present diagnose and treat MDR-TBpatients, though many other public and private providers do, using second-line drugs,which are widely available.Priority activities 20062015First and foremost, attention will need to be focused on sustaining commitment andresources for TB control, particularly sustaining adequate human resource capabilities todeliver quality DOTS services. Second, to increase the reach of DOTS, scaling up theparticipation 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 especiallyimportant in the rapidly growing urban areas, where TB control struggles to cope with acomplex range of health providers as well as a diverse mix of TB patients, includingslum-dwellers and migrants. Community outreach activities, as well as education,information and communications campaigns empowering communities to develop theirown strategies, will be important if quality services are to be provided for the poor andthe marginalized in remote rural and cross-border areas, and among displacedcommunities. Decentralizing services and involving all health and social workers at thegrass-roots level should help reduce barriers to access for women and children. TheRegion also needs to focus on the growing problem of drug resistance. Improving thequality of DOTS services made available by all health care providers will halt andreverse 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-Pluspopulation coverage should expand to 50% by 2010 and 100% by 2015. Surveillance ofHIV 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 highburden of HIV-related TB by the end of 2009. PAL initiatives will be scaled up, with amain focus on urban areas.Expected effects and costsThrough the intensified efforts outlined above, case detection is expected to increase to79% by 2010 and 84% by 2015. Treatment success rate is already at the 2005 target


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level of 85% and is expected to increase to between 85%-90% by 2010 and then remainat this level (noting that 87% is used as the treatment success rate in the scenariocalculations). As a consequence, the expected decline in incidence, prevalence anddeath rates would mean that the Partnerships targets would be met ahead of the targetdate of 2015 in the South-East Asian Region. The projected rapid decline in incidenceand 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 tomaintain or surpass the 70% case detection and 85% treatment success rates. Theserates 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 counterbalancethe effect of HIV and the emergence of MDR-TB in countries in the Region. During theperiod of the Plan (20062015), it is estimated that at least 16 million people will betreated in DOTS programmes and more than 145 000 in DOTS-Plus. In addition, 306000 TB patients will be enrolled on antiretroviral therapy. The combined effect of allinterventions will be to prevent about 5 million deaths, in comparison with a situation inwhich no DOTS programmes are implemented, or about 460 000 deaths in comparisonwith a situation in which TB control efforts are sustained at 2005 levels. With theimplementation 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 inthe South-East Asian region from 2006 to 2015 is US$5.5 billion.

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

Todays TB vaccine, BCG, was developed almost 90 years ago and is routinely givento infants in much of the world. While it provides some protection against severe formsof paediatric TB, it is unreliable against pulmonary TB. In addition, BCG is notrecommended for use in infants infected with HIV, due to the risk of disseminated BCGdisease. There is an urgent need for modern, safe and effective vaccines that preventall forms of TB, in all

age groups and among people with HIV. A great deal of progress has been made inTB vaccine research over the past five years that has strengthened the pipeline of TBvaccine candidates and provided valuable information on TB vaccine development.According to recent modelling studies, the introduction of new effective TB vaccinesand vaccination strategies will make a crucial contribution to achieving thePartnerships goal to reduce the global incidence of TB disease to less than one caseper million population by 2050, and development of new vaccines to protect against TBis gaining substantial momentum.Historic opportunities arose in 2000 for development of new TB vaccines, resultingfrom the availability of techniques for the genetic manipulation of mycobacteria, andcompletion of the genome sequence of M. tuberculosis. These advances have beencritical for the construction of new live genetically altered mycobacterial vaccines, viral-

vectored vaccines and sub-unit vaccines composed of recombinant antigens. Inparallel, advances were being made in understanding of the cellular and molecularmechanisms underlying protective immunity in humans, as well as the development ofanimal models and immunoassays for TB.In the past decade, progress in TB vaccine development has included advancingcandidates into clinical trials, maintaining a robust TB vaccine candidate pipeline,developing capacity for large-scale trials and for vaccine production, as well as raisingawareness and support for new TB vaccines. The main target for vaccine developmentin the Global Plan to Stop TB 20062015 was that two vaccines would be in proof-of-


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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 stillbeing tested: five are in Phase I (safety) clinical trials, two are in Phase II trials, andtwo are in Phase IIb proof-of-concept trials. One vaccine has produced estimates ofsafety and effectiveness in a targeted HIV-infected population (Figure 7). At least sixTB 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 thedevelopment of new TB vaccine candidates, research is also underway to evaluatenew delivery platforms that would be affordable and suitable for resource-limitedsettings, including needle-free delivery. Next generation candidates are defined as TBvaccine candidates that are in the research and development stage with somepreclinical testing performed to show that they may confer protection. Capacity andinfrastructure for large-scale clinical trials are being developed at various sites inseveral endemic countries. The most advanced of these sites, located in South Africa

and operated by the South African Tuberculosis Vaccine Initiative is conductingclinical 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, epidemiologicalcohort studies in infants and adolescents are underway in several countries that will

provide important baseline TB incidence data and help determine the suitability of sitesfor large-scale efficacy trials. In order to ensure an ample supply of quality candidatevaccines for clinical trials and to minimize the lag time between licensure andworldwide distribution, it is imperative to invest in vaccine manufacturing capacity.Currently, some capacity exists in both the private and non-profit sectors, butadditional investment will be needed in order to meet future demands for new TBvaccines. Emerging economies will play an important role in vaccine manufacture anddelivery, and negotiations are taking place with several manufacturers in countries withemerging economies for production and distribution of new TB vaccines. Efforts arealso underway to implement delivery, regulatory and access strategies for TBvaccines, including the development of effective regulatory pathways that shortenreview timelines without compromising the ultimate quality of vaccines. A Task Force

on Economics and Product Profiles has been established to support the rapiddevelopment and deployment of newTB vaccines once they are licensed, by developing clear guidance on desired productcharacteristics and the likely economic impact in the context of large-scale TBprogrammes. A market research project is underway to provide information onpotential TB vaccine markets in target countries, as well as increase understanding ofin-country decision-makers views on procurement and integration of new TB vaccines.Strategies to harmonize regulatory review of TB vaccines in multi-country clinical trialsare also under development. The main goal of the new vaccines component of theGlobal Plan to Stop TB 20112015 is to prevent all forms of tuberculosis in all agegroups through the development of safe, effective and accessible vaccines that arealso 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 vaccinepipeline. Although development of new TB vaccines has not been as rapid as wasanticipated in 2006, due to the inherent complexity in developing biological products,current development timelines now indicate that three new vaccines will havecompleted Phase IIb proof of concept trials by 2015, and if successful, will enter largePhase III safety and efficacy trials. We can then anticipate that one or more new TBvaccines could be available by 2020. It is therefore expected that with the fundingsupport outlined below, the full implementation of research and development activitiespresented here will result in a safe and effective TB vaccine that can be distributed at


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reasonable cost to endemic countries. Towards that end, the Stop TB PartnershipWorking 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 safetyand efficacy; Assays to determine biomarkers and correlates of immune protection will beincorporated into clinical trials;

*Sufficient manufacturing capacity and licensing agreements will be in place to ensureample 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 endemiccountries with high TB incidence, and in different regions of the world to conductlarge-scale clinical trials that adhere to international standards; Regulatory pathways and access/delivery strategies will be developed to minimizelag time between licensure and distribution of new vaccines; Increased public support for and increased investment in TB vaccine developmentwill be ensured.

Documents

TB Written Report