**4. Diagnosis and treatment: Current state of affairs**

#### **4.1. Classical diagnosis**

among children from South Africa showed a significant increase in resistance to INH or RIF from 6.9% to 15.1% and an increase in multidrug resistance from 2.3% to 6.7% (Schaaf et al., 2009). Drug resistance among children has been documented in clinical trials of both pulmo‐ nary and extrapulmonary TB (Rekha and Swaminathan, 2007). Management of MDR-TB is a challenge, because it requires prolonged treatment for 24 months with second-line drugs, which are more toxic and expensive than first-line drugs. According to the 2006 WHO guidelines for programmatic management of MDR-TB, an optimal regimen should include a fluoroquinolone, an injectable (capreomycin, kanamycin, or amikacin), and at least 2 of the following drugs: cycloserine, thiomides, para-amino salicylic acid, and first-line agents other than INH and RIF (WHO, 2008). Experience with second-line TB drugs in children is limited; 38 children in Peru were treated with supervised, individualized regimens consisting of 5 drugs in the national program. Despite half of these children being anemic and malnourished,

treatment was well tolerated and resulted in a 95% cure rate (Drobac et al., 2006).

with MDR-TB.

to improve the diagnosis (Marais and Pai, 2007).

388 Tuberculosis - Current Issues in Diagnosis and Management

**3.7. Improving bacteriological detection and rapid resistance analysis**

There is little published information on optimal treatment of latent TB infection in children in contact with patients with MDR-TB. In a 30-month follow-up of contacts of patients with MDR-TB, 5% of children who received appropriate chemoprophylaxis and 20% of those who did not receive prophylaxis developed disease (Schaaf et al., 2007). Regimens used included INH, PZA, and ethionamide or EMB. Currently, the best approach may be to perform a complete risk assessment and clinical evaluation and to individualize therapy, while keeping these children under close observation. Multicentric trials are urgently required to determine the most effective drug combinations and optimal duration of chemoprophylaxis for contacts of patients

TB is often not considered in the differential diagnosis in children, especially in low endemic settings. TB can mimic many common childhood diseases, including pneumonia, generalised bacterial and viral infections, malnutrition and HIV. However, the main impediment to the accurate diagnosis of active TB is the paucibacillary nature (containing just a few bacilli) of the disease in children. Younger children also produce smaller amounts of sputum, which is usually swallowed rather than expectorated. Bacteriological samples may be collected by conducting early morning gastric washings, a fairly unpleasant procedure that requires hospital admission and overnight-fast for up to three consecutive nights. Consequently bacteriological confirmation is the exception rather than the rule with only 10-15 % of sputum samples revealing acid fast bacilli (AFB) and culture remaining negative in around 70% of cases with probable TB (Zar et al., 2005). Without a definitive diagnosis treatment is therefore often initiated on clinical judgment, aided by algorithms based on exposure history, clinical features, chest x-ray (CXR) and TST (Marais et al., 2006). Several approaches have been taken

Recent advances in bacteriological and molecular methods for the detection of MTB in patient samples aim to identify drug-resistance in parallel with detection of MTB. These include the Microscopic Observation Drug Susceptibility assay (MODS) (Moore et al., 2006), more sensitive PCR techniques (Sarmiento et al., 2003) or phage-based tests such as FASTPlaque

#### *4.1.1. Clinical symptoms approach*

The use of well-defined symptoms improves diagnostic accuracy of pulmonry tuberculo‐ sis (PTB) (Imaz et al., 2001). With clinical symptoms approach only, the status can be classified in two; suspected TB or probable TB. Two situations lead the clinician to sus‐ pect that a child has tuberculosis. The first is a history of chronic illness with clear symp‐ toms: cough and/or fever, weight loss or failure to thrive, an inability to return to normal health after measles or whooping cough, fatigue, and wheezing; second, is when one or more of the following: malnutrition, lymphadenopathy, chest signs, hepatomegaly and/or splenomegaly, meningeal signs, and/or ascites is/are observed. For probable TB, in addi‐ tion to suspected TB, the child presents with a positive TST, a suggestive radiological chest appearing as pleural effusion, caseation of biopsy material, poor response to 2 weeks of antibiotic treatment, and/or favourable response to antituberculous treatment (weight gain and loss of signs) (Hesseling et al., 2002).

In pediatric TB, the most common symptoms are pulmonary parenchymal disease and intrathoracic adenopathy accounting for 60–80% of all cases. Among extrapulmonary mani‐ festations, lymphadenopathy is the most common (67%), followed by central nervous system involvement (13%), pleural (6%), miliary and/or disseminated TB (5%), and skeletal TB form (4%). Disseminated disease and TB meningitis are usually found in very young children who are below the age of 3 years, and/or HIV-infected children (Nelson et al., 2004). TB meningitis occurs when the child has contact with a suspected or confirmed case.

In general, there is a sense of skepticism regarding the potential diagnostic value of symptombased approaches but nevertheless, the natural history of childhood tuberculosis demonstrates that symptoms may have diagnostic value if appropriate risk stratification is applied. Marais et al., (2005), evaluated whether well-defined symptoms have a diagnosis value in children and a standard symptom-based questionnaire was completed and reported symptoms were individually characterized. A tuberculin skin test (TST) and chest radiograph (CXR) were performed in all children. In this study,well-defined symptoms had excellent diagnostic value.

Stage 4: Stage 4 is defined as TB with no current disease. This implies that the patient has a history of previous episodes of TB or abnormal, stable radiographic findings with a significant reaction to the TST and negative bacteriologic studies. No clinical findings suggesting current

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Stage 5: TB is suspected, and the diagnosis is pending. Any patient with pneumonia, pleural effusion, or a cavitary or mass lesion in the lung that does not improve with standard anti‐ bacterial therapy should be evaluated for tuberculosis (TB). Also, patients with fever of unknown origin, failure to thrive, significant weight loss, or unexplained lymphadenopathy

Microbiological confirmation of TB in young children is not routinely attempted in many high burden settings due to the difficulty in obtaining samples and the poor performance of smear microscopy (Nicol and Zar, 2011). Diagnosis of TB still relies primarily on examination of Acid-Fast Bacilli- (AFB-) stained smears from clinical specimens in adults, however, children with pulmonary TB usually do not cough up voluntarily, either because they do not produce sputum or because it produces discomfort. When sputum samples cannot be obtained, gastric aspirate samples are used for detection and isolation of M. Tuberculosis. Most of the current TB diagnostic methods were developed over a century ago. In 1898, Neunier became the first person to culture stomach contents for the evidence of tuberculosis in children (Marais and Pai, 2007; Lalvani and Millington, 2007), so even with this method, fewer than 20% of children

For many years, the collection of three consecutive early morning gastric lavages or gastric aspirate samples has been the accepted method for attempting microbiological confirmation even as the yield is very low and that in many populations cannot be performed due to the lack of infrastructure. In addition low pH is known to kill tuberculous bacilli, indicating that stomach pH may inhibit TB survival for subsequent culture (Marais. and Pai, 2007). More recently, a number of less invasive alternative methods have been proposed, including induced sputum (administration of an inhaled bronchodilator followed by nebulized hypertonic 3–5% saline and then collecting nasopharyngeal aspiration or expectoration of mucus from lower respiratory tract). In the nasopharyngeal aspiration, a cannula elicits a cough reflex and the sweet string test mentioned above (Nicol and Zar, 2011). One of the methods that can be used to collect samples for microbiological analysis is the string test. This is a non-invasive collection method and is reported to be well tolerated by children as young as 4 years (Chow et al., 2006). Inducing sputum after hypertonic saline nebulization has also been shown to be feasible for young children, although the most widely used procedure is still the early-morning gastric aspiration or lavage. However, all these procedures involve hospitalization, trained personnel,

All of these alternative ways of sampling have been made to increase yield because a positive culture is regarded as the "gold standard test" to establish a definitive diagnosis of TB in a symptomatic child (Hesseling et al., 2002). If culture is negative, diagnosis is made on the basis of a positive TST. With clinical and radiographic findings suggestive of TB, and history of

disease are present.

should be evaluated for TB (Marais et al., 2006).

with TB have a positive AFB smear of sputum or gastric aspirate.

*4.1.4. Mycobacterial detection and isolation*

and attention to infection control.

#### *4.1.2. Radiologic studies*

Radiography became available after the First World War, and since that time, PTB detection became easier (Marais et al., 2004). Evidence of pulmonary TB in chest radiographs varies, but usually radiographs show enlargement of hilar, mediastinal, or subcarinal lymph nodes and lung parenchymal changes with hilar lymphodenopathy with or without a focal parenchymal lesion. The most common findings are segmental hyperinflation then atelectasis, alveolar consolidation, interstitial densities, pleural effusion, and, rarely, a focal mass. Cavitation is rare in young children but is more common in adolescents, who may develop reactivation disease similar to that seen in adults (Marais. and Pai, 2007). High-resolution computed tomography is the most sensitive tool currently available to detect hilar adenopathy and/or early cavitation (Hesseling et al., 2002).

#### *4.1.3. Diagnostic algorithms*

These are point-scoring systems to make diagnostic classifications. Diagnostic algorithms were developed to deal with these diagnostic difficulties and provide the health care worker with a rational, stepwise tool to identify children in need of treatment. They are very helpful and very easy to use in countries with restricted technology, but only few of them are available especially in resource limited countries (Edwards et al., (2007). Although the natural history of tuberculosis (TB) in children follows a continuum, the American Thoracic Society (ATS) definition of stages is useful (Blumberg, et al., 2003). According to the ATS the stages are as follows:

Stage 1: Exposure has occurred, implying that the child has had recent contact with an adult who has contagious TB. The child has no physical signs or symptoms and has a negative tuberculin skin test (TST) result. Chest radiography does not reveal any changes at this stage. However, not all patients who are exposed become infected, and the TST result may not be positive for 3 months. Unfortunately, children younger than 5 years may develop disseminated TB in the form of miliary disease or TB meningitis before the TST result becomes positive. Thus, a very high index of suspicion is required when a young patient has a history of contact.

Stage 2: This second stage is heralded by a positive TST result. No signs and symptoms occur, although an incidental chest radiograph may reveal the primary complex.

Stage 3: In stage 3, TB disease occurs and is characterized by the appearance of signs and symptoms depending on the location of the disease. Radiographic abnormalities may al‐ so be seen.

Stage 4: Stage 4 is defined as TB with no current disease. This implies that the patient has a history of previous episodes of TB or abnormal, stable radiographic findings with a significant reaction to the TST and negative bacteriologic studies. No clinical findings suggesting current disease are present.

Stage 5: TB is suspected, and the diagnosis is pending. Any patient with pneumonia, pleural effusion, or a cavitary or mass lesion in the lung that does not improve with standard anti‐ bacterial therapy should be evaluated for tuberculosis (TB). Also, patients with fever of unknown origin, failure to thrive, significant weight loss, or unexplained lymphadenopathy should be evaluated for TB (Marais et al., 2006).

#### *4.1.4. Mycobacterial detection and isolation*

In general, there is a sense of skepticism regarding the potential diagnostic value of symptombased approaches but nevertheless, the natural history of childhood tuberculosis demonstrates that symptoms may have diagnostic value if appropriate risk stratification is applied. Marais et al., (2005), evaluated whether well-defined symptoms have a diagnosis value in children and a standard symptom-based questionnaire was completed and reported symptoms were individually characterized. A tuberculin skin test (TST) and chest radiograph (CXR) were performed in all children. In this study,well-defined symptoms had excellent diagnostic value.

Radiography became available after the First World War, and since that time, PTB detection became easier (Marais et al., 2004). Evidence of pulmonary TB in chest radiographs varies, but usually radiographs show enlargement of hilar, mediastinal, or subcarinal lymph nodes and lung parenchymal changes with hilar lymphodenopathy with or without a focal parenchymal lesion. The most common findings are segmental hyperinflation then atelectasis, alveolar consolidation, interstitial densities, pleural effusion, and, rarely, a focal mass. Cavitation is rare in young children but is more common in adolescents, who may develop reactivation disease similar to that seen in adults (Marais. and Pai, 2007). High-resolution computed tomography is the most sensitive tool currently available to detect hilar adenopathy and/or early cavitation

These are point-scoring systems to make diagnostic classifications. Diagnostic algorithms were developed to deal with these diagnostic difficulties and provide the health care worker with a rational, stepwise tool to identify children in need of treatment. They are very helpful and very easy to use in countries with restricted technology, but only few of them are available especially in resource limited countries (Edwards et al., (2007). Although the natural history of tuberculosis (TB) in children follows a continuum, the American Thoracic Society (ATS) definition of stages is useful (Blumberg, et al., 2003). According to the ATS the stages are as

Stage 1: Exposure has occurred, implying that the child has had recent contact with an adult who has contagious TB. The child has no physical signs or symptoms and has a negative tuberculin skin test (TST) result. Chest radiography does not reveal any changes at this stage. However, not all patients who are exposed become infected, and the TST result may not be positive for 3 months. Unfortunately, children younger than 5 years may develop disseminated TB in the form of miliary disease or TB meningitis before the TST result becomes positive. Thus, a very high index of suspicion is required when a young patient has a history of contact.

Stage 2: This second stage is heralded by a positive TST result. No signs and symptoms occur,

Stage 3: In stage 3, TB disease occurs and is characterized by the appearance of signs and symptoms depending on the location of the disease. Radiographic abnormalities may al‐

although an incidental chest radiograph may reveal the primary complex.

*4.1.2. Radiologic studies*

390 Tuberculosis - Current Issues in Diagnosis and Management

(Hesseling et al., 2002).

follows:

so be seen.

*4.1.3. Diagnostic algorithms*

Microbiological confirmation of TB in young children is not routinely attempted in many high burden settings due to the difficulty in obtaining samples and the poor performance of smear microscopy (Nicol and Zar, 2011). Diagnosis of TB still relies primarily on examination of Acid-Fast Bacilli- (AFB-) stained smears from clinical specimens in adults, however, children with pulmonary TB usually do not cough up voluntarily, either because they do not produce sputum or because it produces discomfort. When sputum samples cannot be obtained, gastric aspirate samples are used for detection and isolation of M. Tuberculosis. Most of the current TB diagnostic methods were developed over a century ago. In 1898, Neunier became the first person to culture stomach contents for the evidence of tuberculosis in children (Marais and Pai, 2007; Lalvani and Millington, 2007), so even with this method, fewer than 20% of children with TB have a positive AFB smear of sputum or gastric aspirate.

For many years, the collection of three consecutive early morning gastric lavages or gastric aspirate samples has been the accepted method for attempting microbiological confirmation even as the yield is very low and that in many populations cannot be performed due to the lack of infrastructure. In addition low pH is known to kill tuberculous bacilli, indicating that stomach pH may inhibit TB survival for subsequent culture (Marais. and Pai, 2007). More recently, a number of less invasive alternative methods have been proposed, including induced sputum (administration of an inhaled bronchodilator followed by nebulized hypertonic 3–5% saline and then collecting nasopharyngeal aspiration or expectoration of mucus from lower respiratory tract). In the nasopharyngeal aspiration, a cannula elicits a cough reflex and the sweet string test mentioned above (Nicol and Zar, 2011). One of the methods that can be used to collect samples for microbiological analysis is the string test. This is a non-invasive collection method and is reported to be well tolerated by children as young as 4 years (Chow et al., 2006). Inducing sputum after hypertonic saline nebulization has also been shown to be feasible for young children, although the most widely used procedure is still the early-morning gastric aspiration or lavage. However, all these procedures involve hospitalization, trained personnel, and attention to infection control.

All of these alternative ways of sampling have been made to increase yield because a positive culture is regarded as the "gold standard test" to establish a definitive diagnosis of TB in a symptomatic child (Hesseling et al., 2002). If culture is negative, diagnosis is made on the basis of a positive TST. With clinical and radiographic findings suggestive of TB, and history of contact with an adult source case, the child may be diagnosed with positive TB based on symptomatology. This measure was taken because the yields in children are less than 50%. Zar et al., (2000), investigated whether sputum induction could be successfully performed in infants and young children with and without HIV and determined the utility of salbutamolinduced sputum compared to gastric lavage (GL) for the diagnosis of pulmonary tuberculosis. They concluded that sputum induction can be effectively performed and is well tolerated and safe even in infants and this induction is better than GL for the isolation of M. tuberculosis in both HIV-infected and uninfected infants and children.

after 48 to 72 hours. This test was the only method available for the diagnosis of latent

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393

The Heaf test uses what is called a Heaf gun which uses disposable single-use heads, each head having six needles arranged in a circle. The device has standard heads and pediatric heads the standard head being used on all patients aged 2 years and older while the pediatric head is for infants under the age of 2. For the standard head, its needles protrude 2 mm when the gun is actuated while for the pediatric heads, the needles protrude only 1 mm. Before appli‐ cation, the skin is cleaned with alcohol, then 100,000 units/ml (equivalent to about 0.1 ml) of tuberculin is evenly smeared on the skin and the gun applied to the skin and fired. The excess of the solution is then wiped off and a waterproof ink mark is drawn around the injection site as an indicator of the site of administration and the test read 2 to 7 days later. The results of

Grade 0: no reaction, or induration of 3 or less puncture points;Grade 1: induration of four or more puncture points; Grade 2: induration of the six puncture points coalesce to form a circle; Grade 3: induration of 5 mm; or more and Grade 4: induration of 10 mm or more, or ulceration. There is not much difference between the Heaf and Mantoux test, but the two tests can be related as follows: Heaf grade 0 and 1 approximately equivalent Mantoux less than 5 mm; Heaf grade 2 approximatley equivalent to Mantoux 5–14 mm and Heaf grade 3 & 4 being approxi‐ mately equivalent to Mantoux 15 mm or greater, To avoid cases of false positives and false negatives, the tuberculin used for Heaf tests is 1000 times more concentrated than that used for Mantoux tests. In countries where both tests are used, use of the correct concentration

The recommended Tuberculin Skin Test (TST), which has now been standardised by the WHO to contain 0.1 ml of tuberculin (100 units/ ml), is the Mantoux test (CDC, 2010). The dosage of 0.1 ml containing 5 tuberculin units [TU] of purified protein derivative (PPD) should be injected intradermally into the volar aspect of the forearm using a 27-gauge needle. A detergent called Tween 80 to prevent loss of efficacy on contact and adsorption by glass stabilizes the PPD. A wheal should be raised and should measure approximately 6-10 mm in diameter. Skilled personnel should always read the test 48-72 hours after administration. Measure the amount of induration and not erythema. This should be measured transverse to the long axis of the forearm. Multiple puncture tests such as Tine test and Heaf test lack sensitivity and

Subcutaneous injection should be avoided because it results in false negative results. The site of administration is indicated by a water-proof ink mark drawn around the site of injection to serve as an indicator for the site. The reading, which is done two to seven days involves measuring area of induration transversely (left to right) across the forearm and recorded to the nearest millimetre. It should be borne in mind that the induration (dermal thickening causing the cutaneous surface to feel thicker and firmer) should not be confused with erythema (redness of the skin) caused by hyperemia of the capillaries in the lower layers of the skin. If a patient who has previously had a negative tuberculin skin test develops a positive tuberculin skin test at a later date, tuberculin conversion is said to have occurred. When such

specificity and hence are not recommended in this situation (Marais et al., 2006).

tuberculosis infection (LTBI) until very recently.

the test are interpreted as follows:

avoids false positive and false negative results.

Although culture on Lowenstein-Jensen medium is considered to be the gold standard, liquid culture systems (commercial and non commercial) offer the possibility of more rapid and more sensitive diagnosis of active TB and drug susceptibility but are not widely available in resource-poor settings (Brittle et al., 2009) compared mycobacterial yields and time to detection in pediatric clinical samples with use of mycobacterial growth-indicator tubes with those with use of solid Lowenstein-Jensen slants and found that the yield was substantially higher with use of mycobacterial growth-indicator tubes (11% compared to 1.6%). Furthermore, the mean time to detection could be reduced from 18.5 days to 12.4 days with use of a nutrient broth supplement; newer approaches, such as the colorimetric culture systems and phage-based tests are of interest, but limited data are available for children.

#### *4.1.5. Smear microscopy*

Advances have been done in the performance of smear microscopy for the rapid detection of MTB, for example, the concentration of specimens by centrifugation or the change of the staining of carbol fuchsin (Ziehl-Neelsen or Kinyoun) for a fluorescent dyes (auraminerhodamine), which both increases sensitivity and reduces the time for screening (Bakir et al., 2008). However, even under optimal circumstances, the sensitivity of smear microscopy for the diagnosis of childhood TB remains less than 15%, except in older children with adult-like disease (Nicol and Zar, 2011).

#### *4.1.6. Tuberculin skin test (TST)*

This is one of the major classes of tests that are currently used to detect Latent TB. Tuberculin which is also called purified protein derivative or PPD is a standardised killed extract of cultured TB, which is injected into the skin to estimate an individual's immune response to TB. There are three methods of testing: the Mantoux test, the Heaf test and the Tine test but not all of them are currently available for use and some countries prefer one over the other. The Heaf test is no loner available because its continued manufacture was not economically viable.

The Tuberculin skin test, or Mantoux TST, is based on the detection of a cutaneous delayedtype hypersensitivity response to purified protein derivative, a poorly defined mixture of antigens present in M. tuberculosis, Mycobacterium bovis Bacille Calmette-Guerin (BCG) and several nontuberculous mycobacteria (Nicol et al., 2011). TST is the standard method for detecting infection by M. tuberculosis. The reaction is measured as millimeters of induration after 48 to 72 hours. This test was the only method available for the diagnosis of latent tuberculosis infection (LTBI) until very recently.

contact with an adult source case, the child may be diagnosed with positive TB based on symptomatology. This measure was taken because the yields in children are less than 50%. Zar et al., (2000), investigated whether sputum induction could be successfully performed in infants and young children with and without HIV and determined the utility of salbutamolinduced sputum compared to gastric lavage (GL) for the diagnosis of pulmonary tuberculosis. They concluded that sputum induction can be effectively performed and is well tolerated and safe even in infants and this induction is better than GL for the isolation of M. tuberculosis in

Although culture on Lowenstein-Jensen medium is considered to be the gold standard, liquid culture systems (commercial and non commercial) offer the possibility of more rapid and more sensitive diagnosis of active TB and drug susceptibility but are not widely available in resource-poor settings (Brittle et al., 2009) compared mycobacterial yields and time to detection in pediatric clinical samples with use of mycobacterial growth-indicator tubes with those with use of solid Lowenstein-Jensen slants and found that the yield was substantially higher with use of mycobacterial growth-indicator tubes (11% compared to 1.6%). Furthermore, the mean time to detection could be reduced from 18.5 days to 12.4 days with use of a nutrient broth supplement; newer approaches, such as the colorimetric culture systems and phage-based tests

Advances have been done in the performance of smear microscopy for the rapid detection of MTB, for example, the concentration of specimens by centrifugation or the change of the staining of carbol fuchsin (Ziehl-Neelsen or Kinyoun) for a fluorescent dyes (auraminerhodamine), which both increases sensitivity and reduces the time for screening (Bakir et al., 2008). However, even under optimal circumstances, the sensitivity of smear microscopy for the diagnosis of childhood TB remains less than 15%, except in older children with adult-like

This is one of the major classes of tests that are currently used to detect Latent TB. Tuberculin which is also called purified protein derivative or PPD is a standardised killed extract of cultured TB, which is injected into the skin to estimate an individual's immune response to TB. There are three methods of testing: the Mantoux test, the Heaf test and the Tine test but not all of them are currently available for use and some countries prefer one over the other. The Heaf test is no loner available because its continued manufacture was not economically

The Tuberculin skin test, or Mantoux TST, is based on the detection of a cutaneous delayedtype hypersensitivity response to purified protein derivative, a poorly defined mixture of antigens present in M. tuberculosis, Mycobacterium bovis Bacille Calmette-Guerin (BCG) and several nontuberculous mycobacteria (Nicol et al., 2011). TST is the standard method for detecting infection by M. tuberculosis. The reaction is measured as millimeters of induration

both HIV-infected and uninfected infants and children.

392 Tuberculosis - Current Issues in Diagnosis and Management

are of interest, but limited data are available for children.

*4.1.5. Smear microscopy*

disease (Nicol and Zar, 2011).

*4.1.6. Tuberculin skin test (TST)*

viable.

The Heaf test uses what is called a Heaf gun which uses disposable single-use heads, each head having six needles arranged in a circle. The device has standard heads and pediatric heads the standard head being used on all patients aged 2 years and older while the pediatric head is for infants under the age of 2. For the standard head, its needles protrude 2 mm when the gun is actuated while for the pediatric heads, the needles protrude only 1 mm. Before appli‐ cation, the skin is cleaned with alcohol, then 100,000 units/ml (equivalent to about 0.1 ml) of tuberculin is evenly smeared on the skin and the gun applied to the skin and fired. The excess of the solution is then wiped off and a waterproof ink mark is drawn around the injection site as an indicator of the site of administration and the test read 2 to 7 days later. The results of the test are interpreted as follows:

Grade 0: no reaction, or induration of 3 or less puncture points;Grade 1: induration of four or more puncture points; Grade 2: induration of the six puncture points coalesce to form a circle; Grade 3: induration of 5 mm; or more and Grade 4: induration of 10 mm or more, or ulceration.

There is not much difference between the Heaf and Mantoux test, but the two tests can be related as follows: Heaf grade 0 and 1 approximately equivalent Mantoux less than 5 mm; Heaf grade 2 approximatley equivalent to Mantoux 5–14 mm and Heaf grade 3 & 4 being approxi‐ mately equivalent to Mantoux 15 mm or greater, To avoid cases of false positives and false negatives, the tuberculin used for Heaf tests is 1000 times more concentrated than that used for Mantoux tests. In countries where both tests are used, use of the correct concentration avoids false positive and false negative results.

The recommended Tuberculin Skin Test (TST), which has now been standardised by the WHO to contain 0.1 ml of tuberculin (100 units/ ml), is the Mantoux test (CDC, 2010). The dosage of 0.1 ml containing 5 tuberculin units [TU] of purified protein derivative (PPD) should be injected intradermally into the volar aspect of the forearm using a 27-gauge needle. A detergent called Tween 80 to prevent loss of efficacy on contact and adsorption by glass stabilizes the PPD. A wheal should be raised and should measure approximately 6-10 mm in diameter. Skilled personnel should always read the test 48-72 hours after administration. Measure the amount of induration and not erythema. This should be measured transverse to the long axis of the forearm. Multiple puncture tests such as Tine test and Heaf test lack sensitivity and specificity and hence are not recommended in this situation (Marais et al., 2006).

Subcutaneous injection should be avoided because it results in false negative results. The site of administration is indicated by a water-proof ink mark drawn around the site of injection to serve as an indicator for the site. The reading, which is done two to seven days involves measuring area of induration transversely (left to right) across the forearm and recorded to the nearest millimetre. It should be borne in mind that the induration (dermal thickening causing the cutaneous surface to feel thicker and firmer) should not be confused with erythema (redness of the skin) caused by hyperemia of the capillaries in the lower layers of the skin.

If a patient who has previously had a negative tuberculin skin test develops a positive tuberculin skin test at a later date, tuberculin conversion is said to have occurred. When such a reaction occurs, it provides strong evidence for significant exposure to TB. Different countries have different standards about the time interval between tests. The UK recommendation is that the two tests have to be done at least six weeks apart; while in the U.S. the recommendation is that the two tests can be done one week apart.

not affect interpretation of a TST result for a person who is symptomatic or in whom TB is

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For the UK the guidelines for interpreting tuberculin skin tests are formulated according to the Heaf test. For patients who have had BCG previously, latent TB is diagnosed if the Heaf test is grade 3 or 4 and have no signs or symptoms of active; if the Heaf test is grade 0 or 1, then the test is repeated and, in patients who have not had BCG previously, latent TB isiag‐ nosed if the Heaf test if grade 2, 3 or 4, and have no signs or symptoms of active TB. Repeat Heaf testing is not done in patients who have had BCG of the phenomenon of boosting.

The Centers for Disease Control and Prevention (CDC) and the AAP provided recommenda‐ tions regarding the size of the induration created by the TST that is considered a positive result and indicative of disease [http://www.cdc.gov/tb/]. The TST is interpreted on the basis of 3 "cut points": 5 mm, 10 mm, and 15 mm. Induration of 5 mm or more is considered a positive TST result in the following children: 1) Children having close contact with known or suspected contagious cases of the disease, including those with household contacts with active TB whose treatment cannot be verified before exposure; 2) Children with immunosuppressive conditions (such as HIV) or children who are on immunosuppressive medications; 3) Children who have an abnormal chest radiograph finding consistent with active TB, previously active TB, or

Induration of 10 mm or more is considered a positive TST result in the following children: 1) Children who are at a higher risk of dissemination of TB disease, including those younger than 5 years or those who are immunosuppressed because of conditions such as lymphoma, Hodgkin disease, diabetes mellitus, and malnutrition; 2) Children with increased exposure to the disease, including those who are exposed to adults in high-risk categories (such as homeless, HIV infected, users of illicit drugs, residents of nursing homes, incarcerated or institutionalized persons); 3) those who were born in or whose parents were born in highprevalence areas of the world; and those with travel histories to high-prevalence areas of the world. Induration of 15 mm or more is considered a positive TST result in children aged 5

False-positive reactions and false-negative results are common and can be due to various causes. False-positive reactions are often attributed to asymptomatic infection by environ‐ mental non-TB mycobacteria (due to cross-reactivity). False-negative results, on the other hand, may be due to vaccination with live-attenuated virus, anergy, immunosuppression, immune deficiency, or malnutrition. In cases of anergy, a lack of reaction by the body's defence mechanisms when it comes into contact with foreign substances, the tuberculin reaction will occur weakly, thus compromising the value of Mantoux testing. For example, anergy is present in AIDS, a disease which strongly depresses the immune system. Therefore, anergy testing is advised in cases where suspicion is warranted that it is present. However, routine anergy skin testing is not recommended. Other factors that may cause a false-negative result include improper administration (such as subcutaneous injection, injection of too little antigen), improper storage, and contamination. PPD has been recognized to have an initial false-

strongly suspected (Marais et al., 2006).

clinical evidence of the disease.

years or older without any risk factors for the disease.

negative rate of 29% (Marais et al., 2006).

Another phenomenon associated with tuberculin skin test is what is called boosting, which occurs when people who have had some traces of infection with M. tuberculosis and/or previous exposure to BCG vaccination against tuberculosis, are given repeated tuberculin skin tests. In these cases, the first test revives or primes the immune response so that on repeat testing, the response is much stronger and the patient now appears to have a positive reaction. The second tuberculin skin test result is what is taken to be the correct one. Again, the guidelines on how to approach the phenomenon of boosting are different in different countries with the U.S. guidelines emphasising that, ignoring previous immunisation with BCG would lead to a person showing the phenomenon of boosting, being falsely described as a tuberculin converter. On the other hand, UK guidelines advocate two tuberculin skin tests one week apart, if boosting is suspected, taking the result of the second test as being the true result. The phenomenon of boosting can occur up to two years after the first Mantoux test.

According to the American Academy of Pediatrics (AAP) immediate skin testing is indicated for the following children: 1)Those who have been in contact with persons with active or suspected TB; 2) Immigrants from TB-endemic countries or children with travel histories to these countries; 3) Those who have radiographic or clinical findings suggestive of TB. 4) Children who are infected with human immunodeficiency virus (HIV) or those living in a household with persons infected with HIV and; 5) Incarcerated adolescents.

Testing at 2-year to 3-year intervals is indicated if the child has been exposed to high-risk individuals including those who are homeless, institutionalized adults who are infected with HIV, users of illicit drugs, residents of nursing homes, and incarcerated adolescents or adults. Testing when children are aged 4-6 years and 11-16 years is indicated for the following children:1) Children without risk factors residing in high-prevalence areas; 2) Children whose parents emigrated from regions of the world with a high prevalence of TB or who have continued potential exposure by travel to the endemic areas and/or household contact. Performing an initial TST before the initiation of immunosuppressive therapy is recommended in any patient (AAP, 1996).

Wit regard to administering the TST to previous recipients of the Bacille Calmette-Guérin (BCG) several problems are encountered when it comes to interpreting the results of the test. Immunization with BCG is not a contraindication to the TST but differentiating tuberculin reactions caused by vaccination with BCG versus reactions caused by infection with M tuberculosis is difficult. History of contact with a person with contagious TB or emigration from a country with a high prevalence of TB suggests that the positive results are due to infection with M tuberculosis. However, multiple BCG vaccinations may increase the likeli‐ hood that the positive TST result is due to the BCG vaccination. The positive reactivity caused by BCG vaccination generally wanes with the passage of time. With the administration of TST, this positive tuberculin reactivity may be boosted. However, previous BCG vaccination does not affect interpretation of a TST result for a person who is symptomatic or in whom TB is strongly suspected (Marais et al., 2006).

a reaction occurs, it provides strong evidence for significant exposure to TB. Different countries have different standards about the time interval between tests. The UK recommendation is that the two tests have to be done at least six weeks apart; while in the U.S. the recommendation

Another phenomenon associated with tuberculin skin test is what is called boosting, which occurs when people who have had some traces of infection with M. tuberculosis and/or previous exposure to BCG vaccination against tuberculosis, are given repeated tuberculin skin tests. In these cases, the first test revives or primes the immune response so that on repeat testing, the response is much stronger and the patient now appears to have a positive reaction. The second tuberculin skin test result is what is taken to be the correct one. Again, the guidelines on how to approach the phenomenon of boosting are different in different countries with the U.S. guidelines emphasising that, ignoring previous immunisation with BCG would lead to a person showing the phenomenon of boosting, being falsely described as a tuberculin converter. On the other hand, UK guidelines advocate two tuberculin skin tests one week apart, if boosting is suspected, taking the result of the second test as being the true result. The

phenomenon of boosting can occur up to two years after the first Mantoux test.

household with persons infected with HIV and; 5) Incarcerated adolescents.

According to the American Academy of Pediatrics (AAP) immediate skin testing is indicated for the following children: 1)Those who have been in contact with persons with active or suspected TB; 2) Immigrants from TB-endemic countries or children with travel histories to these countries; 3) Those who have radiographic or clinical findings suggestive of TB. 4) Children who are infected with human immunodeficiency virus (HIV) or those living in a

Testing at 2-year to 3-year intervals is indicated if the child has been exposed to high-risk individuals including those who are homeless, institutionalized adults who are infected with HIV, users of illicit drugs, residents of nursing homes, and incarcerated adolescents or adults. Testing when children are aged 4-6 years and 11-16 years is indicated for the following children:1) Children without risk factors residing in high-prevalence areas; 2) Children whose parents emigrated from regions of the world with a high prevalence of TB or who have continued potential exposure by travel to the endemic areas and/or household contact. Performing an initial TST before the initiation of immunosuppressive therapy is recommended

Wit regard to administering the TST to previous recipients of the Bacille Calmette-Guérin (BCG) several problems are encountered when it comes to interpreting the results of the test. Immunization with BCG is not a contraindication to the TST but differentiating tuberculin reactions caused by vaccination with BCG versus reactions caused by infection with M tuberculosis is difficult. History of contact with a person with contagious TB or emigration from a country with a high prevalence of TB suggests that the positive results are due to infection with M tuberculosis. However, multiple BCG vaccinations may increase the likeli‐ hood that the positive TST result is due to the BCG vaccination. The positive reactivity caused by BCG vaccination generally wanes with the passage of time. With the administration of TST, this positive tuberculin reactivity may be boosted. However, previous BCG vaccination does

is that the two tests can be done one week apart.

394 Tuberculosis - Current Issues in Diagnosis and Management

in any patient (AAP, 1996).

For the UK the guidelines for interpreting tuberculin skin tests are formulated according to the Heaf test. For patients who have had BCG previously, latent TB is diagnosed if the Heaf test is grade 3 or 4 and have no signs or symptoms of active; if the Heaf test is grade 0 or 1, then the test is repeated and, in patients who have not had BCG previously, latent TB isiag‐ nosed if the Heaf test if grade 2, 3 or 4, and have no signs or symptoms of active TB. Repeat Heaf testing is not done in patients who have had BCG of the phenomenon of boosting.

The Centers for Disease Control and Prevention (CDC) and the AAP provided recommenda‐ tions regarding the size of the induration created by the TST that is considered a positive result and indicative of disease [http://www.cdc.gov/tb/]. The TST is interpreted on the basis of 3 "cut points": 5 mm, 10 mm, and 15 mm. Induration of 5 mm or more is considered a positive TST result in the following children: 1) Children having close contact with known or suspected contagious cases of the disease, including those with household contacts with active TB whose treatment cannot be verified before exposure; 2) Children with immunosuppressive conditions (such as HIV) or children who are on immunosuppressive medications; 3) Children who have an abnormal chest radiograph finding consistent with active TB, previously active TB, or clinical evidence of the disease.

Induration of 10 mm or more is considered a positive TST result in the following children: 1) Children who are at a higher risk of dissemination of TB disease, including those younger than 5 years or those who are immunosuppressed because of conditions such as lymphoma, Hodgkin disease, diabetes mellitus, and malnutrition; 2) Children with increased exposure to the disease, including those who are exposed to adults in high-risk categories (such as homeless, HIV infected, users of illicit drugs, residents of nursing homes, incarcerated or institutionalized persons); 3) those who were born in or whose parents were born in highprevalence areas of the world; and those with travel histories to high-prevalence areas of the world. Induration of 15 mm or more is considered a positive TST result in children aged 5 years or older without any risk factors for the disease.

False-positive reactions and false-negative results are common and can be due to various causes. False-positive reactions are often attributed to asymptomatic infection by environ‐ mental non-TB mycobacteria (due to cross-reactivity). False-negative results, on the other hand, may be due to vaccination with live-attenuated virus, anergy, immunosuppression, immune deficiency, or malnutrition. In cases of anergy, a lack of reaction by the body's defence mechanisms when it comes into contact with foreign substances, the tuberculin reaction will occur weakly, thus compromising the value of Mantoux testing. For example, anergy is present in AIDS, a disease which strongly depresses the immune system. Therefore, anergy testing is advised in cases where suspicion is warranted that it is present. However, routine anergy skin testing is not recommended. Other factors that may cause a false-negative result include improper administration (such as subcutaneous injection, injection of too little antigen), improper storage, and contamination. PPD has been recognized to have an initial falsenegative rate of 29% (Marais et al., 2006).

With a TST, it is not possible to assert or deny the presence of TB, but it only indicates infection with a mycobacterium. In a child who has not been BCG-vaccinated, a TST has been defined as positive when the diameter of skin induration is greater than 10 mm, and in a BCGvaccinated child, when the diameter of induration is greater than 15 mm. A negative TST does not exclude TB and some induration (5–14 mm) could be supportive if the clinical features and contact history are suggestive (Lewinsohn et al., 2004). Furthermore, the utility of this con‐ ventional test is hampered by technical and logistical problems: potential for false-positive and false-negative results; problems in administration and interpretation; difficulty in separating true infection from the effects of prior BCG vaccination, infection due to nontuberculous mycobacteria (Dogra et al., 2007). In children with debilitating or immunosuppressive illnesses, malnutrition, or viral (as HIV) and certain bacterial infections, the yield is unknown, but it is certainly higher than 10%. Moreover, false-positive reactions to TST are often attributed to asymptomatic infection by environmental nontuberculous mycobacteria (Nicol et al., 2011).

However, these tests are not performed correctly in all clinical laboratories. The cost involved, the need for sophisticated equipment, the limitations in their specificity, the need to obtain multiple samples to optimize yield and scrupulous technique to avoid cross-contamination of specimens preclude the use of PCR techniques in many developing countries (Montenegro et al., 2003).The sensitivity of PCR of gastric lavage/bronchoalveolar lavage has been found to be 56.8% in children with clinically active disease. Authors conclude that nested PCR is a rapid and sensitive method for the early diagnosis of TB in children. Additionally, other unique sequences of M. tuberculosis have been suggested as diagnostic test for TB, because they are

Peadiatric Tuberculosis: Is the World Doing Enough?

http://dx.doi.org/10.5772/54953

397

absent in M. africanum, M. microti, M. bovis, and M. bovis BCG (Liang et al., 2008).

These assays are highly dependent on the operator's skills. Performance is also influenced by the choice of target sequence and DNA extraction method. Interpretation of the performance of these assays in pediatric TB suspects is hindered by the lack of a sensitive and specific reference standard. When compared with culture, the sensitivity of NAA for the diagnosis of childhood TB is typically low (40–83%). However, it appears, at least from some reports, that NAA identified a group of children who are clinically diagnosed with TB but in whom mycobacterial culture is negative. This means that with a proper technique it could be done

Adult studies have shown increased levels of adenosine deaminase (ADA) in pleural TB and TB-caused meningitis, both paucibacillary forms of TB, and have advocated for its use in diagnosis. Due to this evidence, a serum ADA has already been evaluated in a childhood population with a very high sensitivity (100%) and specificity (90.7%) for pul‐ monary TB. This study demonstrated the great potential of this technique because it has significant difference in serum ADA levels between children with disease and infection. However, there were several weaknesses in the study design, including unclear case defi‐ nition, exclusion of nontuberculous patients, and a relatively small TB patient population

In the case of extrapulmonary TB, ADA measurement can be helpful, but its sensitivity and specificity varies widely and has been lower than multiplex PCR using primers for IS6110, dnaJ, and hsp65. Specifically, a meta-analysis of 63 studies of ADA in tuberculous pleuritis reveals that the sensitivity of the test is of 0.92 (95% CI 0.90–0.93) and specificity of 0.90 (95%

In absence of good diagnostic method for tuberculosis, the interest in serodiagnosis has been increased (Marais et al., 2005). Serological tests vary in a number of features, including antigen composition (38 kDa, Ag 60, and lipoarabinomannan, LAM), antigen source (native or recombinant), chemical composition (protein or lipid), extent of antigen(s) purification, and

*4.2.2. In-house nucleic acid amplification (NAA) assays*

(20 with active disease) (Marais. and Pai, 2007).

CI 0.89–0.91) (Lawn and Nicol, 2011).

*4.2.4. Serology and antigen detection*

efficiently (Nicol and Zar, 2011 ).

*4.2.3. Adenosine deaminase*

Given that the US guidelines recommend that previous BCG vaccination be ignored in the interpretation of tuberculin skin tests, false positives are possible. People who have previously had BCG, will falsely appear to be tuberculin converters and this may lead to treating more people than necessary, with the possible risk of those patients suffering adverse drug reactions. However, considering the fact that BCG vaccine is not 100% effective, and that it is less protective in adults than pediatric patients, not treating these patients could lead to a possible infection which tennds to justify the current US policy. The U.S. guidelines also allow for tuberculin skin testing in immunosuppressed patients whereas the UK guidelines recommend that tuberculin skin tests should not be used for such patients because it is unreliable

#### **4.2. New approaches in TB diagnostics**

#### *4.2.1. Polymerase chain reaction (PCR)*

Diagnostic PCR is a technique of in vitro DNA amplification that uses specific DNA sequences (oligonucleotides) as effective fishhooks for the DNA/cDNA of microorganisms. In theory, this technique can detect a single organism in a lot of specimens such as sputum, gastric aspirate, pleural fluid, cerebrospinal fluid, blood, and urine. Various PCR assays, mostly using the mycobacterial insertion element IS6110 as the DNA marker for M. tuberculosis-complex organisms, have a sensitivity and specificity greater than 90% for detecting pulmonary TB in adults. This is a rapid, sensitive, specific, and reasonable-cost (Montenegro et al., 2003) method for the detection of M. tuberculosis in clinical samples. The PCR may be used to (a) diagnose tuberculosis in difficult samples with negative microscopic examination, negative culture, or with scarce sample; (b) determine if the organisms in the sample are M. tuberculosis or atypical mycobacteria; (c) identify the presence of genetic variations like a mutations or deletions known to be associated with resistance to some antimycobacterial agents (Marais et al., 2005).

Studies in children have obtained better sensitivity by PCR than by culture. In 2001, Gomez-Pastrana et al., (2001) reported a comparison between sensitivity of culture and PCR showing higher sensitivity for the latter. PCR may have a special role in the diagnosis of extrapulmonary TB and pulmonary TB in children since sputum smears are usually unrevealing in these cases. However, these tests are not performed correctly in all clinical laboratories. The cost involved, the need for sophisticated equipment, the limitations in their specificity, the need to obtain multiple samples to optimize yield and scrupulous technique to avoid cross-contamination of specimens preclude the use of PCR techniques in many developing countries (Montenegro et al., 2003).The sensitivity of PCR of gastric lavage/bronchoalveolar lavage has been found to be 56.8% in children with clinically active disease. Authors conclude that nested PCR is a rapid and sensitive method for the early diagnosis of TB in children. Additionally, other unique sequences of M. tuberculosis have been suggested as diagnostic test for TB, because they are absent in M. africanum, M. microti, M. bovis, and M. bovis BCG (Liang et al., 2008).

#### *4.2.2. In-house nucleic acid amplification (NAA) assays*

These assays are highly dependent on the operator's skills. Performance is also influenced by the choice of target sequence and DNA extraction method. Interpretation of the performance of these assays in pediatric TB suspects is hindered by the lack of a sensitive and specific reference standard. When compared with culture, the sensitivity of NAA for the diagnosis of childhood TB is typically low (40–83%). However, it appears, at least from some reports, that NAA identified a group of children who are clinically diagnosed with TB but in whom mycobacterial culture is negative. This means that with a proper technique it could be done efficiently (Nicol and Zar, 2011 ).

#### *4.2.3. Adenosine deaminase*

With a TST, it is not possible to assert or deny the presence of TB, but it only indicates infection with a mycobacterium. In a child who has not been BCG-vaccinated, a TST has been defined as positive when the diameter of skin induration is greater than 10 mm, and in a BCGvaccinated child, when the diameter of induration is greater than 15 mm. A negative TST does not exclude TB and some induration (5–14 mm) could be supportive if the clinical features and contact history are suggestive (Lewinsohn et al., 2004). Furthermore, the utility of this con‐ ventional test is hampered by technical and logistical problems: potential for false-positive and false-negative results; problems in administration and interpretation; difficulty in separating true infection from the effects of prior BCG vaccination, infection due to nontuberculous mycobacteria (Dogra et al., 2007). In children with debilitating or immunosuppressive illnesses, malnutrition, or viral (as HIV) and certain bacterial infections, the yield is unknown, but it is certainly higher than 10%. Moreover, false-positive reactions to TST are often attributed to asymptomatic infection by environmental nontuberculous mycobacteria (Nicol et al., 2011).

Given that the US guidelines recommend that previous BCG vaccination be ignored in the interpretation of tuberculin skin tests, false positives are possible. People who have previously had BCG, will falsely appear to be tuberculin converters and this may lead to treating more people than necessary, with the possible risk of those patients suffering adverse drug reactions. However, considering the fact that BCG vaccine is not 100% effective, and that it is less protective in adults than pediatric patients, not treating these patients could lead to a possible infection which tennds to justify the current US policy. The U.S. guidelines also allow for tuberculin skin testing in immunosuppressed patients whereas the UK guidelines recommend

that tuberculin skin tests should not be used for such patients because it is unreliable

Diagnostic PCR is a technique of in vitro DNA amplification that uses specific DNA sequences (oligonucleotides) as effective fishhooks for the DNA/cDNA of microorganisms. In theory, this technique can detect a single organism in a lot of specimens such as sputum, gastric aspirate, pleural fluid, cerebrospinal fluid, blood, and urine. Various PCR assays, mostly using the mycobacterial insertion element IS6110 as the DNA marker for M. tuberculosis-complex organisms, have a sensitivity and specificity greater than 90% for detecting pulmonary TB in adults. This is a rapid, sensitive, specific, and reasonable-cost (Montenegro et al., 2003) method for the detection of M. tuberculosis in clinical samples. The PCR may be used to (a) diagnose tuberculosis in difficult samples with negative microscopic examination, negative culture, or with scarce sample; (b) determine if the organisms in the sample are M. tuberculosis or atypical mycobacteria; (c) identify the presence of genetic variations like a mutations or deletions known to be associated with resistance to some antimycobacterial agents (Marais et al., 2005).

Studies in children have obtained better sensitivity by PCR than by culture. In 2001, Gomez-Pastrana et al., (2001) reported a comparison between sensitivity of culture and PCR showing higher sensitivity for the latter. PCR may have a special role in the diagnosis of extrapulmonary TB and pulmonary TB in children since sputum smears are usually unrevealing in these cases.

**4.2. New approaches in TB diagnostics**

396 Tuberculosis - Current Issues in Diagnosis and Management

*4.2.1. Polymerase chain reaction (PCR)*

Adult studies have shown increased levels of adenosine deaminase (ADA) in pleural TB and TB-caused meningitis, both paucibacillary forms of TB, and have advocated for its use in diagnosis. Due to this evidence, a serum ADA has already been evaluated in a childhood population with a very high sensitivity (100%) and specificity (90.7%) for pul‐ monary TB. This study demonstrated the great potential of this technique because it has significant difference in serum ADA levels between children with disease and infection. However, there were several weaknesses in the study design, including unclear case defi‐ nition, exclusion of nontuberculous patients, and a relatively small TB patient population (20 with active disease) (Marais. and Pai, 2007).

In the case of extrapulmonary TB, ADA measurement can be helpful, but its sensitivity and specificity varies widely and has been lower than multiplex PCR using primers for IS6110, dnaJ, and hsp65. Specifically, a meta-analysis of 63 studies of ADA in tuberculous pleuritis reveals that the sensitivity of the test is of 0.92 (95% CI 0.90–0.93) and specificity of 0.90 (95% CI 0.89–0.91) (Lawn and Nicol, 2011).

#### *4.2.4. Serology and antigen detection*

In absence of good diagnostic method for tuberculosis, the interest in serodiagnosis has been increased (Marais et al., 2005). Serological tests vary in a number of features, including antigen composition (38 kDa, Ag 60, and lipoarabinomannan, LAM), antigen source (native or recombinant), chemical composition (protein or lipid), extent of antigen(s) purification, and immunoglobulin detected. The majority are based on the enzyme-linked immunosorbent assay (ELISA) rapid versions and use various immunochromatographic formats, with lateral flow being the most popular.

Quanti FERON-TB Gold In-Tube and T-SPOT.TB. These tests are aimed at he body's response to specific TB antigens not present in other forms of mycobacteria and BCG (ESAT-6). The tests are not affected by prior BCG vaccination, and despite their being new, these are now becoming available globally and CDC recommends that QFT-G may be used in all circumstances in which the TST is currently used, including contact investigations, evaluation of recent immigrants, and sequential-testing surveillance programs for infection control such as those for health-care workers. Health Protection Agency (HPA) recommends the use of IGRA testing in health care workers, if available, in view of the importance of detecting latently infected staff that may go on to develop active disease and come into contact with immunocompromised patients and

Peadiatric Tuberculosis: Is the World Doing Enough?

http://dx.doi.org/10.5772/54953

399

GeneXpert includes the development of integrated DNA extraction and amplification systems. This requires minimal manipulation of sample and operator training. It utilizes real-time PCR (rt-PCR) technology to both diagnose TB and detect rifampicin resistance. The test amplifies a region of the rpoB gene of M. tuberculosis. Mutations of this region give rise to 95% of rifampicin resistance. Resistant strains contain mutations localized within the 81 bp core region of the bacterial RNA polymerase rpoB gene, which encodes the active site of the enzyme. In addition, the rpoB core region is flanked by Mycobacterium tuberculosis-specific DNA sequences. Thus, it is possible to test for M. tuberculosis and for rifampicin resistance simul‐ taneously. The simplicity for the user makes this an assay that could feasibly be widely implemented outside centralized laboratories and potentially impacts on TB control (Gordet‐ sov et al., (2008). The Xpert system has some advantages over the cultivation, mainly in

Recently, Nicol et al., (2011), reported the application of this method in 452 hospitalized children from South Africa, with or without HIV, with a median age of 19.4 months, and suspected of having TB. Two Xpert tests doubled the case detection rate compared with smear microscopy (76% versus 38%), identifying all smear-positive and 61% of smear-negative cases, the specificity was 98.8%. The sensitivities for smear-negative TB were 33.3% and 61.1% when testing one or two samples, respectively. The samplings were induced sputum and they detected three quarters of culture-confirmed tuberculosis with very high specificity; the yield of this method was twice that of smear microscopy. This could suggest the possibility of replacing the microscopy for this type of methodology which has greater sensitivity especially

The potential to detect different Mycobacterium species in the headspaces of cultures and sputum samples is another innovative approach that is currently in development. The array uses 14 sensors to profile a "smell" by assessing the change in each sensor's electrical properties when exposed to a specific odour mixture. In an initial study using sputum samples from patients with culture-confirmed tuberculosis and those without tuberculosis, the E-Nose correctly predicted 89% of culture-positive patients with a specificity of 91% (Imaz. et al.,

the logistical simplicity of IGRA testing.

specificity and a shorter time to get results (Imaz. et al., 2001).

with a second sample (Rachow et al., 2011).

*4.2.7. Gas sensor array electronic nose (electronic nose)*

*4.2.6. GeneXpert MTB/RIF system*

A recent review of serological tests concluded that commercial antibody detection tests for extrapulmonary TB have no role in clinical care or case detection (Steingart et al., 2007). The search for novel biomarkers in blood or urine that can reliably distinguish active from latent TB in children with and without other co-infections remains an important global goal. Welldefined cohorts of paediatric patients in TB-endemic and non-endemic settings will be essential for initial screening and future validation of such potential markers. In the meantime, the diagnosis of TB in children in resource-poor countries continues to rely on practical algorithms, which lack standard symptom definitions and adequate validation (Marais et al., 2006). This poses an increased challenge in the context of HIV infection

Imaz et al., (2001) reported the importance of the recombinant 16-kDa antigen (re-Ag16) of M. tuberculosis in the serodiagnosis of tuberculosis (TB) in children measuring the values of IgA, IgM, and IgG and an increased mean antibody response to reAg16 was observed in contact children compared with nonmycobacterial disease patient with a 95% of specificity. A combining result of the IgG and IgA assays led to 43% positivity in children with active TB (Trilling. et al., 2011).

Mycobacterial antigen detection has been evaluated in adults, but rarely in children. Serology has found little place in the routine diagnosis of tuberculosis in children, even though it is rapid and does not require specimen from the site of disease. Sensitivity and specificity depend on the antigen used, gold standard for the diagnosis of tuberculosis, and the type of tubercular infection. Though most of these tests have high specificity, their sensitivity is poor because several factors can alter the results such as age, exposure to other mycobacteria, and BCG vaccination (Marais et al., 2005).

#### *4.2.5. In vitro interferon-γ (IFN-γ) release assays (IGRAs) and antigen-testing*

In addition to the traditional TST, which is known to lack both sensitivity and specificity, blood based assays have recently become available. These T-cell assays rely on stimulation of host blood cells with MTB specific antigens and measure production of IFN-γ. Numerous published studies compare the two available commercial assays, T Spot TB (Oxford Immunotec) and Quantiferon-Gold IT (Cellestis), with the TST for both detection of active disease and LTBI (Ferrara et al., 2006). T-cell assays have proven to be more specific than the TST, (Arend et al., 2007) but they are still unable to distinguish between active disease and LTBI. Interpretation therefore remains dependent on the clinical context. Some few studies have presented paediatric data but none have provided an assessment of age-related performance of these assays, and reservations remain regarding their performance in very young children and in immunocompromised populations, such as those with HIV (Clark et al., 2007).

There is still a lot of on going research aimed at establishing the proper role of gamma interferon tests and the guidelines ar still under constant review. The interferon-γ release assays (IGRAs) currently commercially available include QuantiFERON-TB Gold (QFT-G), Quanti FERON-TB Gold In-Tube and T-SPOT.TB. These tests are aimed at he body's response to specific TB antigens not present in other forms of mycobacteria and BCG (ESAT-6). The tests are not affected by prior BCG vaccination, and despite their being new, these are now becoming available globally and CDC recommends that QFT-G may be used in all circumstances in which the TST is currently used, including contact investigations, evaluation of recent immigrants, and sequential-testing surveillance programs for infection control such as those for health-care workers. Health Protection Agency (HPA) recommends the use of IGRA testing in health care workers, if available, in view of the importance of detecting latently infected staff that may go on to develop active disease and come into contact with immunocompromised patients and the logistical simplicity of IGRA testing.

### *4.2.6. GeneXpert MTB/RIF system*

immunoglobulin detected. The majority are based on the enzyme-linked immunosorbent assay (ELISA) rapid versions and use various immunochromatographic formats, with lateral

A recent review of serological tests concluded that commercial antibody detection tests for extrapulmonary TB have no role in clinical care or case detection (Steingart et al., 2007). The search for novel biomarkers in blood or urine that can reliably distinguish active from latent TB in children with and without other co-infections remains an important global goal. Welldefined cohorts of paediatric patients in TB-endemic and non-endemic settings will be essential for initial screening and future validation of such potential markers. In the meantime, the diagnosis of TB in children in resource-poor countries continues to rely on practical algorithms, which lack standard symptom definitions and adequate validation (Marais et al., 2006). This

Imaz et al., (2001) reported the importance of the recombinant 16-kDa antigen (re-Ag16) of M. tuberculosis in the serodiagnosis of tuberculosis (TB) in children measuring the values of IgA, IgM, and IgG and an increased mean antibody response to reAg16 was observed in contact children compared with nonmycobacterial disease patient with a 95% of specificity. A combining result of the IgG and IgA assays led to 43% positivity in children with active TB

Mycobacterial antigen detection has been evaluated in adults, but rarely in children. Serology has found little place in the routine diagnosis of tuberculosis in children, even though it is rapid and does not require specimen from the site of disease. Sensitivity and specificity depend on the antigen used, gold standard for the diagnosis of tuberculosis, and the type of tubercular infection. Though most of these tests have high specificity, their sensitivity is poor because several factors can alter the results such as age, exposure to other mycobacteria, and BCG

In addition to the traditional TST, which is known to lack both sensitivity and specificity, blood based assays have recently become available. These T-cell assays rely on stimulation of host blood cells with MTB specific antigens and measure production of IFN-γ. Numerous published studies compare the two available commercial assays, T Spot TB (Oxford Immunotec) and Quantiferon-Gold IT (Cellestis), with the TST for both detection of active disease and LTBI (Ferrara et al., 2006). T-cell assays have proven to be more specific than the TST, (Arend et al., 2007) but they are still unable to distinguish between active disease and LTBI. Interpretation therefore remains dependent on the clinical context. Some few studies have presented paediatric data but none have provided an assessment of age-related performance of these assays, and reservations remain regarding their performance in very young children and in

There is still a lot of on going research aimed at establishing the proper role of gamma interferon tests and the guidelines ar still under constant review. The interferon-γ release assays (IGRAs) currently commercially available include QuantiFERON-TB Gold (QFT-G),

*4.2.5. In vitro interferon-γ (IFN-γ) release assays (IGRAs) and antigen-testing*

immunocompromised populations, such as those with HIV (Clark et al., 2007).

flow being the most popular.

398 Tuberculosis - Current Issues in Diagnosis and Management

(Trilling. et al., 2011).

vaccination (Marais et al., 2005).

poses an increased challenge in the context of HIV infection

GeneXpert includes the development of integrated DNA extraction and amplification systems. This requires minimal manipulation of sample and operator training. It utilizes real-time PCR (rt-PCR) technology to both diagnose TB and detect rifampicin resistance. The test amplifies a region of the rpoB gene of M. tuberculosis. Mutations of this region give rise to 95% of rifampicin resistance. Resistant strains contain mutations localized within the 81 bp core region of the bacterial RNA polymerase rpoB gene, which encodes the active site of the enzyme. In addition, the rpoB core region is flanked by Mycobacterium tuberculosis-specific DNA sequences. Thus, it is possible to test for M. tuberculosis and for rifampicin resistance simul‐ taneously. The simplicity for the user makes this an assay that could feasibly be widely implemented outside centralized laboratories and potentially impacts on TB control (Gordet‐ sov et al., (2008). The Xpert system has some advantages over the cultivation, mainly in specificity and a shorter time to get results (Imaz. et al., 2001).

Recently, Nicol et al., (2011), reported the application of this method in 452 hospitalized children from South Africa, with or without HIV, with a median age of 19.4 months, and suspected of having TB. Two Xpert tests doubled the case detection rate compared with smear microscopy (76% versus 38%), identifying all smear-positive and 61% of smear-negative cases, the specificity was 98.8%. The sensitivities for smear-negative TB were 33.3% and 61.1% when testing one or two samples, respectively. The samplings were induced sputum and they detected three quarters of culture-confirmed tuberculosis with very high specificity; the yield of this method was twice that of smear microscopy. This could suggest the possibility of replacing the microscopy for this type of methodology which has greater sensitivity especially with a second sample (Rachow et al., 2011).

#### *4.2.7. Gas sensor array electronic nose (electronic nose)*

The potential to detect different Mycobacterium species in the headspaces of cultures and sputum samples is another innovative approach that is currently in development. The array uses 14 sensors to profile a "smell" by assessing the change in each sensor's electrical properties when exposed to a specific odour mixture. In an initial study using sputum samples from patients with culture-confirmed tuberculosis and those without tuberculosis, the E-Nose correctly predicted 89% of culture-positive patients with a specificity of 91% (Imaz. et al., 2001). In a further development applying advanced data extraction and linear discriminant function analysis, obtained sensitivities were of 68% and 75%, and specificities of 75% and 67% for Rob and Walter electronic noses, respectively (Imaz. et al., 2001). Further applications of this test, including its potential value in the diagnosis of child tuberculosis, are needed.

weight loss. This condition presents with classic signs of pneumonia, including tachypnea, nasal flaring, grunting, dullness to percussion, egophony or egobronchophony (increased resonance of voice sounds, with a high-pitched bleating quality, heard especially over lung tissue compressed by pleural effusion); decreased breath sounds, and crackles (Marais et al., 2006). Reactivation of TB disease usually has a sub-acute presentation with weight loss, fever, cough, and, rarely, hemoptysis (coughing up of blood or bloody sputum from the lungs or airway). This condition typically occurs in older children and adolescent and is more common in patients who acquire TB at age 7 years and older. Physical examination results may be

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In this case the clinical picture is used to get an indication of the 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. Miliary TB may manifest sub acutely with low-grade fever, malaise, weight loss, and fatigue. A rapid onset of fever and associated symptoms may also be observed. History of cough and respiratory distress may be obtained. Physical examination findings include lymphadenopathy, hepatos‐ plenomegaly, and systemic signs including fever. Respiratory signs may evolve to include tachypnea, cyanosis, and respiratory distress. Other signs, which are subtle and should be carefully sought in the physical examination, include papular, necrotic, or purpuric lesions on

Patients with lymphadenopathy (scrofula or deposits in subcutaneous lymphatic ganglia) may have a history of enlarged nodes. Fever, weight loss, fatigue, and malaise are usually absent or minimal. One of the most severe complications of TB is TB meningitis, which develops in 5-10% of children younger than 2 years; thereafter, the frequency drops to less than 1%. A very high index of suspicion is required to make a timely diagnosis because of the insidious onset of the disease. A sub-acute presentation usually occurs within 3-6 months after the initial infection. Nonspecific symptoms such as anorexia, weight loss, and fever may be present. After 1-2 weeks, patients may experience vomiting and seizures or alteration in the sensorium (the part of the cerebral cortex that receives and coordinates all the impulses sent to individual nerve centers which includes auditory, gustatory, olfactory, somatosensory and visual centers). Deterioration of mental status, coma, and death may occur despite prompt diagnosis

Three stages of TB meningitis have been identified. Stage 1 is defined by the absence of focal or generalized neurologic signs. Possibly, only nonspecific behavioral abnormalities are found. Stage 2 is characterized by the presence of nuchal rigidity (inability or discomfort during neck flexion), altered deep tendon reflexes, lethargy (abnormal lack of energy), and/or cranial nerve palsies. TB meningitis most often affects the sixth cranial nerve due to the pressure of the thick basilar inflammatory exudates on the cranial nerves or to hydrocephalus; this results in lateral rectus palsy. The third, fourth, and seventh cranial nerves may also be affected. Funduscopic

normal or may reveal post-tussive crackles (Marais et al., 2006).

the skin or choroidal tubercles in the retina (Marais et al., 2006).

**4.4. Diagnosis of extrapulmonary TB**

and early intervention.

### **4.3. Diagnosing congenital TB**

Congenital TB is rare but symptoms typically develop during the second or third week of life and include poor feeding, poor weight gain, cough, lethargy, and irritability. Other symptoms include fever, ear discharge, and skin lesions. The principles in place are that for one to make a definitive diagnosis of congenital TB, the infant should have proven TB lesions and that it should have at least one of the following: 1) skin lesions during the first week of life, including papular lesions (ulcerated areas of the skin) or petechiae (bleeding into the skin); 2) documen‐ tation of TB infection of the placenta or the maternal genital tract; 3) presence of a primary complex in the liver and 4) the possibility of postnatal transmission should be ruled out. Signs of congenital TB include failure to thrive, icterus (jaundice or yellow skin), hepatosplenome‐ galy (enlargement of both the liver and spleen), tachypnea (rapid breathing), and lympha‐ denopathy (involving inflammation of lymphnodes) (Marais et al., 2006). Patients with asymptomatic infection have a positive tuberculin skin test (TST) result, but they do not have any clinical or radiographic manifestations. Children with asymptomatic infection may be identified on a routine healthy-child physical examination, or they may be identified subse‐ quent to TB diagnosis in household or other contacts ( for example, children who recently have immigrated or adopted children). Primary TB is characterized by the absence of any signs on clinical evaluation. As discussed above, these patients are identified by a positive TST result. Tuberculin hypersensitivity may be associated with erythema nodosum and phlyctenular conjunctivitis (Marais et al., 2006).

Endobronchial TB with lymphadenopathy, which is the disease with enlargement of lymph nodes, is the most common variety of pulmonary TB. Symptoms are the result of impingement on various structures by the enlarged lymph nodes. Enlargement of lymph nodes and persistent cough may result in signs suggestive of bronchial obstruction or hemi-diaphrag‐ matic paralysis, whereas difficulty in swallowing may result from esophageal compression. Vocal cord paralysis may be suggested by hoarseness or difficulty breathing and may occur as a result of local nerve compression. Dysphagia (swallowing problems) due to esophageal compression may also be observed. Pleural effusions due to TB may also occur and usually occur in older children and are rarely associated with miliary disease. The typical history reveals an acute onset of fever, chest pain that increases in intensity on deep inspiration, and shortness of breath. Fever usually persists for 14-21 days. Signs include: tachypnea, respiratory distress, decreased breath sounds, and, occasionally, features of mediastinal shift (moving of the tissues and organs that comprise the mediastinum) (Marais et al., 2006).

Progression of the pulmonary parenchymal component of TB leads to enlargement of the caseous area (caseated = cheese-like necrotised tissue) and may lead to pneumonia, atelectasis (collapse of lung tissue), and air trapping. This is more likely to occur in young children than in adolescents. The child usually appears ill with symptoms of fever, cough, malaise, and weight loss. This condition presents with classic signs of pneumonia, including tachypnea, nasal flaring, grunting, dullness to percussion, egophony or egobronchophony (increased resonance of voice sounds, with a high-pitched bleating quality, heard especially over lung tissue compressed by pleural effusion); decreased breath sounds, and crackles (Marais et al., 2006). Reactivation of TB disease usually has a sub-acute presentation with weight loss, fever, cough, and, rarely, hemoptysis (coughing up of blood or bloody sputum from the lungs or airway). This condition typically occurs in older children and adolescent and is more common in patients who acquire TB at age 7 years and older. Physical examination results may be normal or may reveal post-tussive crackles (Marais et al., 2006).

## **4.4. Diagnosis of extrapulmonary TB**

2001). In a further development applying advanced data extraction and linear discriminant function analysis, obtained sensitivities were of 68% and 75%, and specificities of 75% and 67% for Rob and Walter electronic noses, respectively (Imaz. et al., 2001). Further applications of this test, including its potential value in the diagnosis of child tuberculosis, are needed.

Congenital TB is rare but symptoms typically develop during the second or third week of life and include poor feeding, poor weight gain, cough, lethargy, and irritability. Other symptoms include fever, ear discharge, and skin lesions. The principles in place are that for one to make a definitive diagnosis of congenital TB, the infant should have proven TB lesions and that it should have at least one of the following: 1) skin lesions during the first week of life, including papular lesions (ulcerated areas of the skin) or petechiae (bleeding into the skin); 2) documen‐ tation of TB infection of the placenta or the maternal genital tract; 3) presence of a primary complex in the liver and 4) the possibility of postnatal transmission should be ruled out. Signs of congenital TB include failure to thrive, icterus (jaundice or yellow skin), hepatosplenome‐ galy (enlargement of both the liver and spleen), tachypnea (rapid breathing), and lympha‐ denopathy (involving inflammation of lymphnodes) (Marais et al., 2006). Patients with asymptomatic infection have a positive tuberculin skin test (TST) result, but they do not have any clinical or radiographic manifestations. Children with asymptomatic infection may be identified on a routine healthy-child physical examination, or they may be identified subse‐ quent to TB diagnosis in household or other contacts ( for example, children who recently have immigrated or adopted children). Primary TB is characterized by the absence of any signs on clinical evaluation. As discussed above, these patients are identified by a positive TST result. Tuberculin hypersensitivity may be associated with erythema nodosum and phlyctenular

Endobronchial TB with lymphadenopathy, which is the disease with enlargement of lymph nodes, is the most common variety of pulmonary TB. Symptoms are the result of impingement on various structures by the enlarged lymph nodes. Enlargement of lymph nodes and persistent cough may result in signs suggestive of bronchial obstruction or hemi-diaphrag‐ matic paralysis, whereas difficulty in swallowing may result from esophageal compression. Vocal cord paralysis may be suggested by hoarseness or difficulty breathing and may occur as a result of local nerve compression. Dysphagia (swallowing problems) due to esophageal compression may also be observed. Pleural effusions due to TB may also occur and usually occur in older children and are rarely associated with miliary disease. The typical history reveals an acute onset of fever, chest pain that increases in intensity on deep inspiration, and shortness of breath. Fever usually persists for 14-21 days. Signs include: tachypnea, respiratory distress, decreased breath sounds, and, occasionally, features of mediastinal shift (moving of

Progression of the pulmonary parenchymal component of TB leads to enlargement of the caseous area (caseated = cheese-like necrotised tissue) and may lead to pneumonia, atelectasis (collapse of lung tissue), and air trapping. This is more likely to occur in young children than in adolescents. The child usually appears ill with symptoms of fever, cough, malaise, and

the tissues and organs that comprise the mediastinum) (Marais et al., 2006).

**4.3. Diagnosing congenital TB**

400 Tuberculosis - Current Issues in Diagnosis and Management

conjunctivitis (Marais et al., 2006).

In this case the clinical picture is used to get an indication of the 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. Miliary TB may manifest sub acutely with low-grade fever, malaise, weight loss, and fatigue. A rapid onset of fever and associated symptoms may also be observed. History of cough and respiratory distress may be obtained. Physical examination findings include lymphadenopathy, hepatos‐ plenomegaly, and systemic signs including fever. Respiratory signs may evolve to include tachypnea, cyanosis, and respiratory distress. Other signs, which are subtle and should be carefully sought in the physical examination, include papular, necrotic, or purpuric lesions on the skin or choroidal tubercles in the retina (Marais et al., 2006).

Patients with lymphadenopathy (scrofula or deposits in subcutaneous lymphatic ganglia) may have a history of enlarged nodes. Fever, weight loss, fatigue, and malaise are usually absent or minimal. One of the most severe complications of TB is TB meningitis, which develops in 5-10% of children younger than 2 years; thereafter, the frequency drops to less than 1%. A very high index of suspicion is required to make a timely diagnosis because of the insidious onset of the disease. A sub-acute presentation usually occurs within 3-6 months after the initial infection. Nonspecific symptoms such as anorexia, weight loss, and fever may be present. After 1-2 weeks, patients may experience vomiting and seizures or alteration in the sensorium (the part of the cerebral cortex that receives and coordinates all the impulses sent to individual nerve centers which includes auditory, gustatory, olfactory, somatosensory and visual centers). Deterioration of mental status, coma, and death may occur despite prompt diagnosis and early intervention.

Three stages of TB meningitis have been identified. Stage 1 is defined by the absence of focal or generalized neurologic signs. Possibly, only nonspecific behavioral abnormalities are found. Stage 2 is characterized by the presence of nuchal rigidity (inability or discomfort during neck flexion), altered deep tendon reflexes, lethargy (abnormal lack of energy), and/or cranial nerve palsies. TB meningitis most often affects the sixth cranial nerve due to the pressure of the thick basilar inflammatory exudates on the cranial nerves or to hydrocephalus; this results in lateral rectus palsy. The third, fourth, and seventh cranial nerves may also be affected. Funduscopic changes may include papilledema (swelling of the optic disc from increased intracranial pressure) and the presence of choroid tubercles (chroid plexus = vascular proliferation of the cerebral ventricles that serves to regulate intraventricular pressure by secretion or absorption of cerebrospinal fluid).which should be carefully sought. Stage 3, the final stage, comprises major neurologic defects, including coma, seizures, and abnormal movements such as choreoathetosis (irregular involuntary movements that may involve the face, neck, trunk, extremities, or respiratory muscles, giving an appearance of restlessness), paresis (slight or incomplete paralysis), paralysis of one or more extremities. In the terminal phase, decerebrate (elimination of cerebral brain function) or decorticate posturing, opisthotonus (a type of spasm in which the head and heels arch backward in extreme hyperextension and the body forms a reverse bow), and/or death may occur. Patients with tuberculomas or TB brain abscesses may present with focal neurologic signs. Spinal cord disease may result in the acute development of spinal block or a transverse myelitis–like syndrome (an abnormal condition characterized by inflammation of the spinal cord with associated motor or sensory dysfunction). A slowly ascending paralysis may develop over several months to years.

important operational issues. However, the predominant emphasis of the DOTS strategy on sputum smear–positive disease excludes the vast majority of children. There is a desperate need to improve service delivery to children with tuberculosis, particularly in endemic areas

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Chemoprophylaxis refers to preventive treatment given after exposure (without proof of infection), whereas treatment of latent infection implies that infection (indicated by a positive TST) was documented. The term preventive chemotherapy is preferred because it is more inclusive and incorporates both chemoprophylaxis and treatment of latent infection. The TST is a fairly accurate measure of infection after exposure in immune-competent children, although TST conversion, which reflects a sufficiently strong delayed-type hypersensitivity response, may be delayed for up to 3 months (Marais et al., 2004). Therefore, household exposure, particularly involving high-risk children, should be treated as infection until the absence of infection can be convincingly demonstrated. In immune-competent children this can be done by repeating the TST 3 months after exposure ended (American Thoracic Society, 2000). In immunocompromised children the TST is not a sufficiently reliable test to exclude M. tuberculosis infection and children with documented exposure should receive preventive

The reality on the ground is that most endemic areas do not have the capacity to follow current World Health Organization guidelines regarding the use of preventive chemotherapy in children, which advise active tracing and screening of all children less than 5 years old in household contact with a sputum smear–positive adult source case. This results mainly from the huge burden of adult tuberculosis and resource constraints that limit the ability to perform TST and chest X-ray screening tests. Because the TST and chest X-ray are regarded as prereq‐ uisite screening tests, screening of exposed children and the provision of preventive chemo‐ therapy are not even attempted in most resource-constrained areas. Access to preventive chemotherapy in these settings may be improved by employing symptom-based screening, although the benefits and risks of such a simplified approach require further evaluation. A study from an endemic area indicated that symptom-based screening may identify those children who require further investigation to exclude active tuberculosis (Marais et al., 2006), thus allowing asymptomatic household contacts, especially those who are at high risk to progress to disease, immediate access to preventive therapy despite the inability to perform

Another consideration is that in some endemic areas the majority of disease transmission, particularly in children greater than 2 to 3 years of age, occurs outside the household (Verver et al., 2004). In endemic areas, narrowing the focus of contact tracing to those children who are at highest risk to progress to disease after exposure or infection (less than 3 years of age and/or immune compromised) will decrease the burden placed on already overstretched health care systems, while still ensuring access to preventive chemotherapy for the children who need it most (Van Zyl et al., 2006). In older (greater than 3 years of age), immunecompetent children the risk of tuberculosis after exposure is low and disease progression is

with limited resources (Starke, 2002).

chemotherapy as if they are infected (Marais et al., 2006).

TST and chest X-ray–based screening (Marais et al., 2006).

*4.5.2. Preventive chemotherapy*

#### **4.5. Treatment**

#### *4.5.1. General treatment overview*

Each of the first-line drugs makes a specific contribution during different periods of drug action (assuming complete drug susceptibility and the absence of significant immune compromise). Period 1 lasts 2 to 3 days (van der Weert et al., 2006), during which time fast-growing extrac‐ ellular bacilli, comprising the vast majority of the organism load, are killed, mainly by the excellent bactericidal activity of isoniazid (INH) (Kampmann et al., 2005). Period 2 lasts 4 to 8 weeks. Slower growing extracellular bacilli are killed (van der Weert et al., 2006) and the rate of killing is determined more by the physiological state of the bacilli and less by the bactericidal activity of the drug. During this period, the bactericidal activity of rifampin (RIF) is important and pyrazinamide (PZA) contributes by killing extracellular bacilli that persist in acidic areas of inflammation (van der Weert et al., 2006). Period 3 lasts 4 to 6 months. Persistent intracellular bacilli are eradicated mainly by RIF, although INH will continue to offer protection against the development of resistance and may assist with organism eradication, especially in fibrocaseous tissue with poor drug penetration. Host immunity plays an important role throughout, but is of particular importance to effect organism eradication and prevent disease relapse, as indicated by the high relapse rate in HIV-infected children.

Practical operational issues are extremely important for effective public health intervention. Operational issues include access to early and accurate diagnosis, the uninterrupted provision of quality-assured drugs and appropriate treatment regimens, as well as the establishment of systems to ensure good treatment adherence. Fixed-dose combinations should be used whenever possible to reduce the risk of drug resistance and to improve simplicity and adherence, but quality assurance is essential to ensure optimal bioavailability of all the constituent drugs (Dekker and Lotter, 2003). With proper implementation, the World Health Organization's directly observed therapy, short-course (DOTS) strategy addresses most of the important operational issues. However, the predominant emphasis of the DOTS strategy on sputum smear–positive disease excludes the vast majority of children. There is a desperate need to improve service delivery to children with tuberculosis, particularly in endemic areas with limited resources (Starke, 2002).

#### *4.5.2. Preventive chemotherapy*

changes may include papilledema (swelling of the optic disc from increased intracranial pressure) and the presence of choroid tubercles (chroid plexus = vascular proliferation of the cerebral ventricles that serves to regulate intraventricular pressure by secretion or absorption of cerebrospinal fluid).which should be carefully sought. Stage 3, the final stage, comprises major neurologic defects, including coma, seizures, and abnormal movements such as choreoathetosis (irregular involuntary movements that may involve the face, neck, trunk, extremities, or respiratory muscles, giving an appearance of restlessness), paresis (slight or incomplete paralysis), paralysis of one or more extremities. In the terminal phase, decerebrate (elimination of cerebral brain function) or decorticate posturing, opisthotonus (a type of spasm in which the head and heels arch backward in extreme hyperextension and the body forms a reverse bow), and/or death may occur. Patients with tuberculomas or TB brain abscesses may present with focal neurologic signs. Spinal cord disease may result in the acute development of spinal block or a transverse myelitis–like syndrome (an abnormal condition characterized by inflammation of the spinal cord with associated motor or sensory dysfunction). A slowly

Each of the first-line drugs makes a specific contribution during different periods of drug action (assuming complete drug susceptibility and the absence of significant immune compromise). Period 1 lasts 2 to 3 days (van der Weert et al., 2006), during which time fast-growing extrac‐ ellular bacilli, comprising the vast majority of the organism load, are killed, mainly by the excellent bactericidal activity of isoniazid (INH) (Kampmann et al., 2005). Period 2 lasts 4 to 8 weeks. Slower growing extracellular bacilli are killed (van der Weert et al., 2006) and the rate of killing is determined more by the physiological state of the bacilli and less by the bactericidal activity of the drug. During this period, the bactericidal activity of rifampin (RIF) is important and pyrazinamide (PZA) contributes by killing extracellular bacilli that persist in acidic areas of inflammation (van der Weert et al., 2006). Period 3 lasts 4 to 6 months. Persistent intracellular bacilli are eradicated mainly by RIF, although INH will continue to offer protection against the development of resistance and may assist with organism eradication, especially in fibrocaseous tissue with poor drug penetration. Host immunity plays an important role throughout, but is of particular importance to effect organism eradication and prevent disease

Practical operational issues are extremely important for effective public health intervention. Operational issues include access to early and accurate diagnosis, the uninterrupted provision of quality-assured drugs and appropriate treatment regimens, as well as the establishment of systems to ensure good treatment adherence. Fixed-dose combinations should be used whenever possible to reduce the risk of drug resistance and to improve simplicity and adherence, but quality assurance is essential to ensure optimal bioavailability of all the constituent drugs (Dekker and Lotter, 2003). With proper implementation, the World Health Organization's directly observed therapy, short-course (DOTS) strategy addresses most of the

ascending paralysis may develop over several months to years.

relapse, as indicated by the high relapse rate in HIV-infected children.

**4.5. Treatment**

*4.5.1. General treatment overview*

402 Tuberculosis - Current Issues in Diagnosis and Management

Chemoprophylaxis refers to preventive treatment given after exposure (without proof of infection), whereas treatment of latent infection implies that infection (indicated by a positive TST) was documented. The term preventive chemotherapy is preferred because it is more inclusive and incorporates both chemoprophylaxis and treatment of latent infection. The TST is a fairly accurate measure of infection after exposure in immune-competent children, although TST conversion, which reflects a sufficiently strong delayed-type hypersensitivity response, may be delayed for up to 3 months (Marais et al., 2004). Therefore, household exposure, particularly involving high-risk children, should be treated as infection until the absence of infection can be convincingly demonstrated. In immune-competent children this can be done by repeating the TST 3 months after exposure ended (American Thoracic Society, 2000). In immunocompromised children the TST is not a sufficiently reliable test to exclude M. tuberculosis infection and children with documented exposure should receive preventive chemotherapy as if they are infected (Marais et al., 2006).

The reality on the ground is that most endemic areas do not have the capacity to follow current World Health Organization guidelines regarding the use of preventive chemotherapy in children, which advise active tracing and screening of all children less than 5 years old in household contact with a sputum smear–positive adult source case. This results mainly from the huge burden of adult tuberculosis and resource constraints that limit the ability to perform TST and chest X-ray screening tests. Because the TST and chest X-ray are regarded as prereq‐ uisite screening tests, screening of exposed children and the provision of preventive chemo‐ therapy are not even attempted in most resource-constrained areas. Access to preventive chemotherapy in these settings may be improved by employing symptom-based screening, although the benefits and risks of such a simplified approach require further evaluation. A study from an endemic area indicated that symptom-based screening may identify those children who require further investigation to exclude active tuberculosis (Marais et al., 2006), thus allowing asymptomatic household contacts, especially those who are at high risk to progress to disease, immediate access to preventive therapy despite the inability to perform TST and chest X-ray–based screening (Marais et al., 2006).

Another consideration is that in some endemic areas the majority of disease transmission, particularly in children greater than 2 to 3 years of age, occurs outside the household (Verver et al., 2004). In endemic areas, narrowing the focus of contact tracing to those children who are at highest risk to progress to disease after exposure or infection (less than 3 years of age and/or immune compromised) will decrease the burden placed on already overstretched health care systems, while still ensuring access to preventive chemotherapy for the children who need it most (Van Zyl et al., 2006). In older (greater than 3 years of age), immunecompetent children the risk of tuberculosis after exposure is low and disease progression is usually indicated by the presence of persistent, slowly progressive symptoms. Therefore, passive case finding together with adequate diagnostic vigilance seems appropriate in this low-risk group.

However, reports have documented significant protection against the development of adulttype tuberculosis when BCG was administered to TST-negative adolescents in locations with

Peadiatric Tuberculosis: Is the World Doing Enough?

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405

In addition, a report from Turkey indicated that contrary to the prevailing theory, BCG may also protect against M. tuberculosis infection as based on a positive enzyme-linked immuno‐ spot result. An even more controversial area is the risk versus benefit that BCG provides to HIV-infected children. There is a definite risk for HIV-infected infants to develop severe forms of BCG disease after neonatal BCG vaccination (Hesseling et al., 2006), but it remains poorly quantified. As the risk:benefit ratio has not been determined, the World Health Organization still advises BCG vaccination of asymptomatic HIV-exposed infants in tuberculosis endemic areas. Establishing the risk: benefit ratio of BCG vaccination in HIV-infected infants and the development of novel vaccines with improved efficacy and safety, remain major research

The main variables that influence the success of chemotherapy, apart from primary drug resistance, are the bacterial load and the anatomic distribution of bacilli. Cavitary disease indicates a high bacterial load, as demonstrated by the frequency with which these patients are sputum smear–positive, which implies an increased risk for random drug resistance against individual drugs. Disseminated disease may signify penetration of bacilli into the central nervous system (CNS) (Van den Bosch et al., 2004) implying that adequate drug penetration across the blood–brain barrier is an important requirement for the treatment of

From a public health perspective the challenge is to develop a pragmatic classification of childhood tuberculosis that incorporates the diverse spectrum of disease, but focuses pri‐ marily on treatment relevance. The main variables that influence the success of chemo‐ therapy identify three groups of children with tuberculosis: (1) those with sputum smear–negative disease, (2) those with sputum smear–positive (often cavitary) disease and (3) those with disseminated disease. The discussion reflects current treatment guide‐ lines for these three groups as well as the new regimens to consider on the basis of es‐

As a guide for individual patient classification and management five simple questions have been formulated: (1) Is the child exposed to or infected with M. tuberculosis? (2) Does the child have active tuberculosis? (3) If the child is exposed or infected, but does not have active tuberculosis, is preventive chemotherapy indicated? (4) If the child has active tuberculosis, what is the appropriate treatment regimen? (5) Are there any special circumstances such as HIV infection, retreatment, or exposure to a drug-resistant source case to consider? The underlying rationale is universally applicable irrespective of diagnostic or resource con‐ straints; although areas with access to advanced technology may achieve improved levels of

a low prevalence of environmental mycobacterial exposure (Bjarveit et al., 2003).

challenges (Marais et al., 2006).

disseminated disease (Marais et al., 2006).

tablished treatment principles (Marais et al., 2006).

*4.5.3. Curative treatment*

diagnostic certainty.

In non endemic areas where resources permit and where the risk of future reinfection is low, it seems warranted to extend preventive chemotherapy to low-risk children as well, to eliminate the reservoir of latent infection within the community. INH monotherapy for 6 to 9 months is the best-studied chemoprophylactic regimen and it reduces the tubercu‐ losis risk in exposed children by at least two-thirds; probably by more than 90% with good adherence. However, poor adherence is a major concern, particularly in endemic areas (Van Zyl et al., 2006).

In real life the effectiveness of a preventive chemotherapy regimen is determined first by its efficacy and second by adherence to the prescribed regimen. Because of documented poor adherence to 6–9 months of unsupervised INH monotherapy, consideration should be given to alternative preventive strategies with comparable efficacy but with improved adherence. Theoretically the addition of RIF has important advantages; RIF has strong sterilizing activity to eradicate latent bacilli and its addition will shorten the duration of treatment required (Mitchison, 2005). It will also improve efficacy in settings where INH mono-resistance is prevalent. The use of a 3-month INH and RIF regimen for preventive chemotherapy is well established and trials have shown equivalence to 6 to 9 months of INH alone, although the evidence is not as comprehensive as that for INH monotherapy (Ena and Valls, 2005).

PZA is another important sterilizing drug and in theory the combination of RIF and PZA represents the treatment of choice for latent infection. This combination has proven efficacy in animal but adverse reactions in adults have limited the initial enthusiasm (Priest, 2004). However, these adverse reactions have not been observed in children, in whom the three-drug combination of INH, RIF, and PZA is generally well tolerated (Marais et al., 2006). Adherence may be improved by shortening the duration of treatment, but consideration may also be given to the provision of supervised preventive therapy. Creative approaches will be required to achieve this, particularly in places where health care services are already overburdened. With curative treatment, intermittent (two or three times weekly) therapy during the continuation phase is as effective as daily therapy to achieve organism eradication, once the organism load has been sufficiently reduced (Al-Dossary et al., 2002). The same principle would apply to the treatment of latent infection, where the organism load is low. Targeting high-risk children for short-course, supervised intermittent preventive therapy seems achievable, but defining optimal preventive therapy regimens remains a fertile and important area for future research (Marais et al., 2006).

Vaccination with BCG is the most widely used preventive strategy, although its efficacy remains controversial and studies have shown that it contributes to this variable protection: variations in strain-specific immunogenicity, timing and technique of vaccine administration, genetic factors, the presence or absence of environmental mycobacteria, and the effect of multiple re-infection events as may occur in highly endemic areas. It is generally accepted that BCG vaccination offers significant protection against disseminated disease in young children (below 2 years), but that it offers little or no protection against adult-type tuberculosis. However, reports have documented significant protection against the development of adulttype tuberculosis when BCG was administered to TST-negative adolescents in locations with a low prevalence of environmental mycobacterial exposure (Bjarveit et al., 2003).

In addition, a report from Turkey indicated that contrary to the prevailing theory, BCG may also protect against M. tuberculosis infection as based on a positive enzyme-linked immuno‐ spot result. An even more controversial area is the risk versus benefit that BCG provides to HIV-infected children. There is a definite risk for HIV-infected infants to develop severe forms of BCG disease after neonatal BCG vaccination (Hesseling et al., 2006), but it remains poorly quantified. As the risk:benefit ratio has not been determined, the World Health Organization still advises BCG vaccination of asymptomatic HIV-exposed infants in tuberculosis endemic areas. Establishing the risk: benefit ratio of BCG vaccination in HIV-infected infants and the development of novel vaccines with improved efficacy and safety, remain major research challenges (Marais et al., 2006).

### *4.5.3. Curative treatment*

usually indicated by the presence of persistent, slowly progressive symptoms. Therefore, passive case finding together with adequate diagnostic vigilance seems appropriate in this

In non endemic areas where resources permit and where the risk of future reinfection is low, it seems warranted to extend preventive chemotherapy to low-risk children as well, to eliminate the reservoir of latent infection within the community. INH monotherapy for 6 to 9 months is the best-studied chemoprophylactic regimen and it reduces the tubercu‐ losis risk in exposed children by at least two-thirds; probably by more than 90% with good adherence. However, poor adherence is a major concern, particularly in endemic

In real life the effectiveness of a preventive chemotherapy regimen is determined first by its efficacy and second by adherence to the prescribed regimen. Because of documented poor adherence to 6–9 months of unsupervised INH monotherapy, consideration should be given to alternative preventive strategies with comparable efficacy but with improved adherence. Theoretically the addition of RIF has important advantages; RIF has strong sterilizing activity to eradicate latent bacilli and its addition will shorten the duration of treatment required (Mitchison, 2005). It will also improve efficacy in settings where INH mono-resistance is prevalent. The use of a 3-month INH and RIF regimen for preventive chemotherapy is well established and trials have shown equivalence to 6 to 9 months of INH alone, although the

evidence is not as comprehensive as that for INH monotherapy (Ena and Valls, 2005).

PZA is another important sterilizing drug and in theory the combination of RIF and PZA represents the treatment of choice for latent infection. This combination has proven efficacy in animal but adverse reactions in adults have limited the initial enthusiasm (Priest, 2004). However, these adverse reactions have not been observed in children, in whom the three-drug combination of INH, RIF, and PZA is generally well tolerated (Marais et al., 2006). Adherence may be improved by shortening the duration of treatment, but consideration may also be given to the provision of supervised preventive therapy. Creative approaches will be required to achieve this, particularly in places where health care services are already overburdened. With curative treatment, intermittent (two or three times weekly) therapy during the continuation phase is as effective as daily therapy to achieve organism eradication, once the organism load has been sufficiently reduced (Al-Dossary et al., 2002). The same principle would apply to the treatment of latent infection, where the organism load is low. Targeting high-risk children for short-course, supervised intermittent preventive therapy seems achievable, but defining optimal preventive therapy regimens remains a fertile and important area for future research

Vaccination with BCG is the most widely used preventive strategy, although its efficacy remains controversial and studies have shown that it contributes to this variable protection: variations in strain-specific immunogenicity, timing and technique of vaccine administration, genetic factors, the presence or absence of environmental mycobacteria, and the effect of multiple re-infection events as may occur in highly endemic areas. It is generally accepted that BCG vaccination offers significant protection against disseminated disease in young children (below 2 years), but that it offers little or no protection against adult-type tuberculosis.

low-risk group.

areas (Van Zyl et al., 2006).

404 Tuberculosis - Current Issues in Diagnosis and Management

(Marais et al., 2006).

The main variables that influence the success of chemotherapy, apart from primary drug resistance, are the bacterial load and the anatomic distribution of bacilli. Cavitary disease indicates a high bacterial load, as demonstrated by the frequency with which these patients are sputum smear–positive, which implies an increased risk for random drug resistance against individual drugs. Disseminated disease may signify penetration of bacilli into the central nervous system (CNS) (Van den Bosch et al., 2004) implying that adequate drug penetration across the blood–brain barrier is an important requirement for the treatment of disseminated disease (Marais et al., 2006).

From a public health perspective the challenge is to develop a pragmatic classification of childhood tuberculosis that incorporates the diverse spectrum of disease, but focuses pri‐ marily on treatment relevance. The main variables that influence the success of chemo‐ therapy identify three groups of children with tuberculosis: (1) those with sputum smear–negative disease, (2) those with sputum smear–positive (often cavitary) disease and (3) those with disseminated disease. The discussion reflects current treatment guide‐ lines for these three groups as well as the new regimens to consider on the basis of es‐ tablished treatment principles (Marais et al., 2006).

As a guide for individual patient classification and management five simple questions have been formulated: (1) Is the child exposed to or infected with M. tuberculosis? (2) Does the child have active tuberculosis? (3) If the child is exposed or infected, but does not have active tuberculosis, is preventive chemotherapy indicated? (4) If the child has active tuberculosis, what is the appropriate treatment regimen? (5) Are there any special circumstances such as HIV infection, retreatment, or exposure to a drug-resistant source case to consider? The underlying rationale is universally applicable irrespective of diagnostic or resource con‐ straints; although areas with access to advanced technology may achieve improved levels of diagnostic certainty.

Sputum smear–negative disease is usually paucibacillary and therefore the risk of acquired drug resistance is low. Drug penetration into the anatomic sites involved is good and the success of three drugs (INH, RIF, and PZA) during the 2-month intensive phase, and of two drugs (INH and RIF) during the 4-month continuation phase, is well established. In the presence of extensive radiographic disease with or without cavitation, and/or suspicion of INH resistance, the use of ethambutol (EMB) in addition to the three drugs during the intensive phase should be contemplated. After completion of the intensive phase, successful organism eradication may be achieved with intermittent (two or three times weekly) therapy during the continuation phase (Al-Dossary et al., 2002). The efficacy of shorter treatment durations for HIV-uninfected immune-competent children with sputum smear–negative disease requires further evaluation, as a 4-month regimen of INH and RIF may be an acceptable therapy for some adults with sputum smear– and culture-negative tuberculosis.

larly in settings where the majority of the bacterial population rapidly acetylates INH (Schaaf et al., 2005). In addition, the serum level achieved with a similar dose of INH per kilogram is lower in children than in adults, increasing the risk for suboptimal dosing in children (Schaaf et al., 2005). The majority of new INH resistance encountered in endemic areas is of an intermediate or low level, which underscores the importance of optimal INH dosing (Donald et al., 2004). A standard INH dose of 10 mg/kg seems appropriate in children, as even doses up to 20 mg/kg are well tolerated (Schaaf et al., 2005); children are less susceptible to the toxic

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In general, adverse events are less common in children than in adults. The most severe adverse event is the development of hepatotoxicity, which can be caused by INH, RIF, PZA, or ethionamide. An elevation of liver enzymes (less than five times normal values) is not an indication to stop treatment, but the occurrence of liver tenderness, hepatomegaly, or jaundice should prompt the immediate stopping of all potentially hepatotoxic drugs. Jaundice is often preceded by a period of days or weeks of malaise and nausea. Hepatic reactions usually occur in the first weeks of therapy, but may happen at any time during the treatment period. Drugrelated hepatic toxicity is usually caused by a single drug, but rarely a combination of drugs, which individually cause no problem, may cause hepatic toxicity. Children should be screened for other causes of hepatitis, as in many cases the anti-tuberculosis drugs are not the cause of liver function derangement. In South Africa, hepatitis A infection is frequently responsible for non–drug-related liver function derangement in children receiving anti-tuberculosis treat‐ ment. Potentially hepatotoxic drugs should be reintroduced only after liver functions have normalized. Non-hepatotoxic drugs should be used in the interim and expert opinion should

Ethambutol is usually not advised in children less than 7 years as visual acuity cannot be evaluated. However, its use may be warranted in children with hepatotoxicity, cavitary disease, or resistance to first-line drugs; it seems safe at recommended dosages. Ethionamide frequently causes vomiting, but this can usually be overcome by dividing the daily dose and by a slow increase up to the full dose during the first week or two of therapy. Recommended dosages for the various first- and second-line drugs are reflected in the publication by Marais

Despite significant symptomatic improvement radiographic disease resolution may take many months; persistent radiographic signs are not an indication to change treatment if there is clinical improvement. Paradoxical exacerbation of symptoms or signs may also occur after anti-tuberculosis therapy is initiated. This results from immune reconstitution with increased inflammation, particularly surrounding diseased lymph nodes or tuberculomas, that may follow nutritional rehabilitation (Marais et al., 2004), and/or antiretroviral therapy. The release

Treatment should be continued unaltered, although the temporary addition of corticosteroids may be considered. Such adjunctive therapy may be helpful in a number of disease manifes‐ tations where the host inflammatory response contributes to disease pathology such as CNS involvement, severe lymph node compression of the airways, and pericardial effusion. There

of bacterial toxins after successful anti-tuberculosis treatment may also contribute.

effects of INH than are adults.

et al., (2006) as indicated in the Table 1 below:

be sought.

Sputum smear–positive disease implies a high organism load and an increased risk for random drug resistance against individual drugs. Selecting drug-resistant mutants is a particular concern where INH mono-resistance is prevalent, as this increases the likelihood of selecting multidrug-resistant (MDR) organisms. The use of four drugs (INH, RIF, PZA, and EMB) during the 2-month intensive phase should reduce this risk. Once the organism load is sufficiently reduced, intermittent (two or three times weekly) therapy with INH and RIF during the 4 month continuation phase is sufficient to ensure organism eradication (Al-Dossary et al., 2002). However, caution should be exercised when initial treatment response has not been optimal and in HIV-infected patients. The use of long-acting rifamycins together with INH is discouraged (Rieder et al., 2001).

Disseminated disease is frequently associated with CNS involvement (Donald et al., 2005). It is therefore essential to consider the cerebrospinal fluid (CSF) penetration of drugs used in the treatment of disseminated disease. INH and PZA penetrate the CSF well. RIF and streptomycin penetrate the CSF poorly, but may achieve therapeutic levels in the presence of meningeal inflammation. The value of streptomycin is limited by poor CSF penetration and intramuscular administration. EMB hardly penetrates the CSF, even in the presence of meningeal inflamma‐ tion, and has no demonstrated efficacy in the treatment of TBM. Ethionamide shows good CSF penetration and has been used successfully as a fourth drug in the treatment of TBM. The fact that RIF penetrates the CSF poorly in the absence of meningeal inflammation reduces its sterilization value and may warrant the inclusion of PZA during the continuation phase, to assist with CNS sterilization.

Several reports have illustrated the efficacy of short-course regimens in the treatment of TB meningitis, but the risk of CNS relapse is rarely reported. In two of these studies a relapse was documented despite the completion of 6 months of treatment with INH and RIF with an initial 2 months of PZA. Therefore, it seems prudent to include a fourth drug with good CNS penetration (such as ethionamide) for the treatment of disseminated disease, at least during the intensive phase, and to consider PZA for the full 6 months of treatment to reduce the risk of CNS relapse. CNS relapse is rare in the United States, where PZA is routinely discontinued after 2 months, but the total treatment duration is 9 to 12 months. Current fixed-dose combi‐ nation tablets provide 4 to 6 mg of INH per kilogram. This dose may be suboptimal, particu‐ larly in settings where the majority of the bacterial population rapidly acetylates INH (Schaaf et al., 2005). In addition, the serum level achieved with a similar dose of INH per kilogram is lower in children than in adults, increasing the risk for suboptimal dosing in children (Schaaf et al., 2005). The majority of new INH resistance encountered in endemic areas is of an intermediate or low level, which underscores the importance of optimal INH dosing (Donald et al., 2004). A standard INH dose of 10 mg/kg seems appropriate in children, as even doses up to 20 mg/kg are well tolerated (Schaaf et al., 2005); children are less susceptible to the toxic effects of INH than are adults.

Sputum smear–negative disease is usually paucibacillary and therefore the risk of acquired drug resistance is low. Drug penetration into the anatomic sites involved is good and the success of three drugs (INH, RIF, and PZA) during the 2-month intensive phase, and of two drugs (INH and RIF) during the 4-month continuation phase, is well established. In the presence of extensive radiographic disease with or without cavitation, and/or suspicion of INH resistance, the use of ethambutol (EMB) in addition to the three drugs during the intensive phase should be contemplated. After completion of the intensive phase, successful organism eradication may be achieved with intermittent (two or three times weekly) therapy during the continuation phase (Al-Dossary et al., 2002). The efficacy of shorter treatment durations for HIV-uninfected immune-competent children with sputum smear–negative disease requires further evaluation, as a 4-month regimen of INH and RIF may be an acceptable therapy for

Sputum smear–positive disease implies a high organism load and an increased risk for random drug resistance against individual drugs. Selecting drug-resistant mutants is a particular concern where INH mono-resistance is prevalent, as this increases the likelihood of selecting multidrug-resistant (MDR) organisms. The use of four drugs (INH, RIF, PZA, and EMB) during the 2-month intensive phase should reduce this risk. Once the organism load is sufficiently reduced, intermittent (two or three times weekly) therapy with INH and RIF during the 4 month continuation phase is sufficient to ensure organism eradication (Al-Dossary et al., 2002). However, caution should be exercised when initial treatment response has not been optimal and in HIV-infected patients. The use of long-acting rifamycins together with INH is

Disseminated disease is frequently associated with CNS involvement (Donald et al., 2005). It is therefore essential to consider the cerebrospinal fluid (CSF) penetration of drugs used in the treatment of disseminated disease. INH and PZA penetrate the CSF well. RIF and streptomycin penetrate the CSF poorly, but may achieve therapeutic levels in the presence of meningeal inflammation. The value of streptomycin is limited by poor CSF penetration and intramuscular administration. EMB hardly penetrates the CSF, even in the presence of meningeal inflamma‐ tion, and has no demonstrated efficacy in the treatment of TBM. Ethionamide shows good CSF penetration and has been used successfully as a fourth drug in the treatment of TBM. The fact that RIF penetrates the CSF poorly in the absence of meningeal inflammation reduces its sterilization value and may warrant the inclusion of PZA during the continuation phase, to

Several reports have illustrated the efficacy of short-course regimens in the treatment of TB meningitis, but the risk of CNS relapse is rarely reported. In two of these studies a relapse was documented despite the completion of 6 months of treatment with INH and RIF with an initial 2 months of PZA. Therefore, it seems prudent to include a fourth drug with good CNS penetration (such as ethionamide) for the treatment of disseminated disease, at least during the intensive phase, and to consider PZA for the full 6 months of treatment to reduce the risk of CNS relapse. CNS relapse is rare in the United States, where PZA is routinely discontinued after 2 months, but the total treatment duration is 9 to 12 months. Current fixed-dose combi‐ nation tablets provide 4 to 6 mg of INH per kilogram. This dose may be suboptimal, particu‐

some adults with sputum smear– and culture-negative tuberculosis.

discouraged (Rieder et al., 2001).

406 Tuberculosis - Current Issues in Diagnosis and Management

assist with CNS sterilization.

In general, adverse events are less common in children than in adults. The most severe adverse event is the development of hepatotoxicity, which can be caused by INH, RIF, PZA, or ethionamide. An elevation of liver enzymes (less than five times normal values) is not an indication to stop treatment, but the occurrence of liver tenderness, hepatomegaly, or jaundice should prompt the immediate stopping of all potentially hepatotoxic drugs. Jaundice is often preceded by a period of days or weeks of malaise and nausea. Hepatic reactions usually occur in the first weeks of therapy, but may happen at any time during the treatment period. Drugrelated hepatic toxicity is usually caused by a single drug, but rarely a combination of drugs, which individually cause no problem, may cause hepatic toxicity. Children should be screened for other causes of hepatitis, as in many cases the anti-tuberculosis drugs are not the cause of liver function derangement. In South Africa, hepatitis A infection is frequently responsible for non–drug-related liver function derangement in children receiving anti-tuberculosis treat‐ ment. Potentially hepatotoxic drugs should be reintroduced only after liver functions have normalized. Non-hepatotoxic drugs should be used in the interim and expert opinion should be sought.

Ethambutol is usually not advised in children less than 7 years as visual acuity cannot be evaluated. However, its use may be warranted in children with hepatotoxicity, cavitary disease, or resistance to first-line drugs; it seems safe at recommended dosages. Ethionamide frequently causes vomiting, but this can usually be overcome by dividing the daily dose and by a slow increase up to the full dose during the first week or two of therapy. Recommended dosages for the various first- and second-line drugs are reflected in the publication by Marais et al., (2006) as indicated in the Table 1 below:

Despite significant symptomatic improvement radiographic disease resolution may take many months; persistent radiographic signs are not an indication to change treatment if there is clinical improvement. Paradoxical exacerbation of symptoms or signs may also occur after anti-tuberculosis therapy is initiated. This results from immune reconstitution with increased inflammation, particularly surrounding diseased lymph nodes or tuberculomas, that may follow nutritional rehabilitation (Marais et al., 2004), and/or antiretroviral therapy. The release of bacterial toxins after successful anti-tuberculosis treatment may also contribute.

Treatment should be continued unaltered, although the temporary addition of corticosteroids may be considered. Such adjunctive therapy may be helpful in a number of disease manifes‐ tations where the host inflammatory response contributes to disease pathology such as CNS involvement, severe lymph node compression of the airways, and pericardial effusion. There


for a previous episode, then it most likely represents re-infection disease and standard firstline treatment is appropriate. In the case of genuine treatment failure (absence of clinical response to supervised treatment) drug susceptibility testing is of paramount importance. If an adult source case is identified with drug-resistant tuberculosis, the child should be treated according to the drug susceptibility pattern of the source case's strain (Marais et al., 2006).

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The high risk of HIV-infected children to progress to disease after infection justifies the use of preventive chemotherapy in children who are latently infected. However, the difficult issue in endemic areas is how to deal with the ever-present risk of undocumented re-infection within the community. The prevention or reversal of severe immune compromise by using highly active antiretroviral therapy (HAART) should preclude the need for repeated or continuous preventive chemotherapy, although the risk for tuberculosis probably remains higher than in HIV-uninfected children. The cellular immune response assists with organism eradication and therefore it is not unexpected that disease relapse has been documented in HIV-infected children. The value of prolonging the treatment duration from 6 to 9 months, to ensure organism eradication in HIV-infected children, is under investigation. During a repeat episode both relapse and reinfection should be considered and every effort should be made to establish a culture-confirmed diagnosis and to do drug susceptibility testing (Marais et al., 2006).

When initiating treatment (curative treatment or RIF-containing preventive therapy) in HIVinfected children already receiving HAART or for whom HAART is contemplated, it should be appreciated that the rifamycins, especially RIF, and some of the nonnucleoside reverse transcriptase inhibitors and/or protease inhibitors may cause significant drug interactions. HIV-infected children may also develop particularly pronounced paradoxical reactions after the institution of HAART, because of immune reconstitution inflammatory syndrome. Recommendations on optimal drug combinations are frequently revised. The most recent recommendations can be obtained from the Centers for Disease Control and Prevention

Latest WHO recommendations advise starting antiretroviral therapy (ART) once anti-TB therapy (ATT) is established (after a period of 2-8 weeks) for all WHO clinical Stage Four HIVinfected children and Stage Three children with advanced or severe immunosuppression. For children in WHO clinical stage with mild or no immunosuppression, ART may be deferred until 6 months of ATT are completed (WHO, 2006). On-going prospective trials involving adults and children in TB/HIV endemic countries might provide future guidelines for the ideal timing of the initiation of anti-retroviral therapy (ART) in patients with HIV receiving TB therapy. There is already evidence from prospective trials that shows that high mortality is associated with TB in advanced stages of HIV-disease in children who do not receive ART promptly. Further research is required to improve our understanding of immune reconstitu‐ tion disease (IRD) in children (Walters et al., 2006). Also, therapeutic drug monitoring (TDM), where available, should be undertaken when children are receiving concomitant ART and ATT. TDM data from ethnically similar children in resource-rich countries may in the future inform dosing recommendations in resource-poor settings where TDM is not available.

*4.5.5. Treatment of paediatric TB/HIV co-infection*

website, at [http://www.cdc.gov/nchstp/tb/].

**Table 1.** First- And Second-Line Antituberculosis Drugs And Recommended Dosages In Children

is insufficient evidence to demonstrate whether steroids are effective in tuberculous pleural effusion.

#### *4.5.4. Retreatment*

Anti-tuberculosis treatment rarely fails in children and, if it does, every effort should be made to find the most likely cause. In settings where the prevalence of drug resistance is low the commonest cause is failure to properly take the medications, which can occur even during DOT, if supervision is not complete. It is important to remember that non-adherence has a differential diagnosis; there are psychologic, sociologic, religious, economic, and practical reasons why people are non-adherent and one must deal with all these issues for chemotherapy to be successful. With treatment interruption the child may be restarted on the original treatment regimen while ensuring adequate supervision, as the risk of developing drug resistance is small in children with paucibacillary disease. If an immune-competent child presents with a new episode of tuberculosis more than 6 months after completing treatment for a previous episode, then it most likely represents re-infection disease and standard firstline treatment is appropriate. In the case of genuine treatment failure (absence of clinical response to supervised treatment) drug susceptibility testing is of paramount importance. If an adult source case is identified with drug-resistant tuberculosis, the child should be treated according to the drug susceptibility pattern of the source case's strain (Marais et al., 2006).
