- Email: [email protected]
Tuberculosis and HIV – dual epidemics
Oral Presentations / Paediatric Respiratory Reviews 11S1 (2010) S1–S78
The most common extrathoracic manifestation of TB in children is cervical lymphadenitis. A simple clinical algorithm that identified children with a persistent (longer than 4 weeks) cervical mass of 2×2 cm or more, without a visible local cause or response to firstline antibiotics, showed excellent diagnostic accuracy in an area with endemic TB. However, this approach would be less accurate in non-endemic areas and also is fraught with a risk of missing serious disease like lymphoma. Thus, establishing a definitive tissue and/or culture diagnosis is preferable, and this can be done in a minimally invasive fashion using fine needle aspiration. In the absences of the services of a qualified or skilled cytopathologist, mycobacteriological staining and examination of the smears made from the aspirates may be useful. A positive Tuberculin Skin test or PPD test is often used as an adjunct tool for diagnosing TB in children in appropriate clinical settings. Positive PPD test is merely an evidence of TB infection but in children it is often used for making a diagnosis of active TB, when used in addition to symptoms, radiological abnormalities, history of exposure, and microbiological investigations. Despite reservations about the specificity of the TST response after bacillus CalmetteGuerin ´ (BCG) vaccination, a positive TST reaction remains a fairly accurate measure of M. tuberculosis infection in immune-competent children. In endemic areas, a positive TST is not uncommon in randomly selected healthy children, which limits its diagnostic value somewhat. A recent meta-analysis suggested that a PPD reaction of 15 mm or more is highly unlikely due to BCG interference. The standarised PPD (RT23) manufactured over 5 decades back is no more available in many high burden countries like India. Use of standardized preparations and correct strengths of PPD, appropriate cutoffs is needed for optimal utilisaton of this test. Newer skin test which use specific antigens like MPB64 or antigens in the RD1 area of the mycobacterium (namely, ESAT6 and CFP 10) may make a future skin test more reliable and helpful. Interferon-gamma release assays (IGRAs) have been evolved as an in vitro method of identifying TB infection. Currently they are being largely used in the countries and communities with low prevalence of TB to identify the people with latent bacterial infection. The role of the IGRAs as an alternative to PPD as a diagnostic tool in childhood TB has not been as well understood. Intra-individual and inter-laboratory variations in these tests needs to be understood well before they can replace the PPD tests. In the absence of symptoms or radiologic signs indicative of disease, qualitative T-cell-based IGRAs, like the TST, also fail to make the crucial distinction between latent M. tuberculosis infection and active disease. The application of these new diagnostic tools is a priority for future research in endemic areas mainly to assess their ability to detect M. tuberculosis infection in HIV-infected individuals where TST often fails. Given the limitations of the tests discussed so far, the diagnosis of tuberculosis in children from endemic areas depends mainly on clinical features and the subjective interpretation of the chest radiograph. But even chest skiagram have their well-known limitations that may result in both under- and overdiagnosis of disease and do not necessarily help in clearing the diagnostic dilemma – TB or not TB. Despite all the handicaps, it still can provide a fairly accurate diagnosis in the majority of symptomatic children with tuberculosis if appropriate and adequate skill is used and therefore the interpretation of the chest radiograph remains the most widely used diagnostic criterion in clinical practice. Serologic tests for measuring various antibodies to different mycobacterial antigens or their combinations are commercially available and often used. None of these currently are able to diagnose childhood tuberculosis with accuracy. Their poor positive as well as negative predictive value precludes their use as a diagnostic tool for both pulmonary as well as extra-pulmonary form of the disease. Similarly, the polymerase chain reaction (PCR) tests using various body fluids have also shown variable results and limited utility. The inability of PCR-based tests to differentiate latent infection from
S57
active disease is an important issue and raises concerns regarding the specificity of PCR-based tests as a diagnostic tool. The diagnostic dilemma is even more pronounced in HIV infected children. The specificity of symptom-based diagnostic approaches is reduced by the presence of chronic HIV-related symptoms, while the potential window for symptom-based diagnosis is limited by the rapidity with which disease progression may occur. The common non-TB respiratory infections complicating HIV and the involvement of lungs in HIV further limits the interpretation of chest skiagrams for the diagnosis of TB co-infection. It is further complicated by atypical disease pattern in co-infected children. These difficulties increase the potential diagnostic value of sensitive bacteriology-based approaches, to identify HIV-infected children with tuberculosis. The traditional TST has poor sensitivity to detect M. tuberculosis infection in HIV-infected children; 50% or less of HIVinfected children with bacteriologicaly confirmed tuberculosis are TST positive, despite using an induration size of at least 5 mm. This is a major limitation and a more reliable measure of infection will be valuable to identify HIV-infected children who may benefit from preventive chemotherapy; it may also provide supportive evidence to establish a diagnosis of active tuberculosis. Given the shortcomings of the existing diagnostic tools for childhood TB, the quest for new TB diagnostics should focus on high specificity, affordability and sensitivity for cases missed by existing diagnostic standards. Reference(s) [1] Marais Ben J, Pai M. New approaches and emerging technologies in the diagnosis of childhood tuberculosis. Paediatric Respiratory Reviews (2007) 8, 124–133. [2] Marais Ben J. Tuberculosis in Children Pediatric Pulmonology 2008; 43:322–329. [3] Pai M, Minion J, Sohn H, Zwerling A, Perkins MD. Novel and improved technologies for tuberculosis diagnosis: progress and challenges. Clin Chest Med. 2009;30(4):701–16, [4] Lewinsohn DA, Lobato MN, Jereb JA. Interferon-gamma release assays: new diagnostic tests for Mycobacterium tuberculosis infection, and their use in children. Curr Opin Pediatr. 2010;22(1):71–6. [5] Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skin tests: what is the absolute effect of BCG and non-tuberculous mycobacteria? Int J Tuberc Lung Dis. 2006 10(11):1192–204.
O.22.2 Tuberculosis and HIV – dual epidemics H.J. Zar. Department of Paediatrics and Child Health, Red Cross War Memorial Childrens Hospital, University of Cape Town, South Africa TB is a major cause of morbidity and mortality in HIV-infected children. The HIV pandemic has been associated with a dramatic increase in the number of new cases of TB, has destabilised TB control efforts and led to unprecedented difficulties in confirming the diagnosis of TB. HIV-infected children have higher rates of TB infection and progression to disease compared to immunocompetent children. Therefore, it is important to know the HIV status of a child with suspected or confirmed TB. Diagnosing paediatric TB in the context of HIV is particularly challenging due to non-specific clinical and radiological signs and anergy to the tuberculin skin test (TST). In high HIV prevalence areas, scoring systems have been especially variable, lacking sensitivity and specificity. Microbiological confirmation is rarely achieved. Co-existing malnutrition, the paucibacillary nature of childhood TB, difficulty in obtaining adequate clinical specimens for culture and variable interpretation of chest radiographs further compound the difficulty of making a definitive diagnosis. However, the consequences of undiagnosed TB in HIV-infected children are serious. HIV-infected children are at high risk of developing severe, disseminated disease. Co-infection with M. tuberculosis and HIV results in deterioration of immune dysfunction, enhanced viral replication, HIV progression and frequent, severe opportunistic infections. HIV-infected children who
S58
Oral Presentations / Paediatric Respiratory Reviews 11S1 (2010) S1–S78
commence HAART are also at risk of developing an immune reconstitution inflammatory syndrome in the context of untreated TB. Conversely, reliance on clinical and radiological findings may lead to over diagnosis and inappropriate treatment. Empiric therapy for pulmonary TB in HIV-infected children includes 3–4 drugs daily for a 2 month induction period; the fourth drug should be added if drug resistance is suspected or if there is extensive pulmonary disease or severe immunosuppression. Thereafter 2 drugs for at least 4 months are recommended as maintenance therapy. For children on HAART, the antiretroviral regimen should provide optimal TB and HIV therapy and minimize potential toxicity and drug interactions. Rifampicin induces hepatic cytochrome P450 enzymes and may therefore reduce levels of antiretroviral agents, particularly the protease inhibitors (PI) and to a lesser extent the non nucleoside reverse transcriptase inhibitors (NNRTI). Therefore rifampicin should preferably be used with an NNRTI-based regimen. If a PI is used, a ritonavir-boosted PI such as lopinavir/ritonavir is required. BCG vaccination, isoniazid (INH) prophylaxis or HAART are possible strategies to prevent TB in HIV-infected children. BCG is ineffective for primary prevention of pulmonary TB and provides little protection in HIV infected infants. Moreover, World Health Organization (WHO) guidelines have recently been revised to recommend against BCG vaccination in HIV-infected infants due to the high risk of disseminated BCG and associated mortality. The risk of TB in HIV-infected children is greatly reduced by the use of HAART or by the use of isoniazid (INH) preventive treatment, although the risk remains higher than that of HIV-uninfected children. Use of INH prophylaxis together with HAART offers greater protection than each individually.
The action of anti-TB drugs on these different populations may be bactericidal or sterilizing (or both). Bactericidal activity refers to the agent’s ability to rapidly kill the actively metabolizing organisms in the sputum of patients with pulmonary TB. Agents can be compared by determining their “Early bactericidal activity” (EBA), defined as the fall in viable colony-forming units (cfu) of Mycobacterium tuberculosis per ml of sputum per day during the first 2 days of treatment [3].There are five “first line” anti-TB agents that have been in use for over 30 years: Isoniazid (INH, H); Rifampicin (RMP, R); Pyrazinamide (Z); Ethambutol (EMB, E) and Streptomycin (S). Regimens: Most children are not smear-positive and do not require four drugs in the initial intensive phase; those who are smearpositive or have a visible cavity on chest radiograph have a high bacillus count and should be treated with four drugs. Also those with severe disease such as extensive lung disease, meningitis or disseminated and Spinal TB with neurological signs, are managed with four drugs in the intensive phase. There is a standard code for TB treatment regimens [4] (Table 1). Table 1. Recommended treatment regimens for each diagnostic category based on WHO recommendations: TB diagnostic TB cases category
Daily regimen Intensive phase
III I
I
II IV
New smear – negative PTB. Less severe forms of EPTB 2HRZ New smear – positive PTB 2HRZS (or E) New smear – negative PTB with extensive parenchymal involvement Severe forms of EPTB Severe concomitant HIV disease TB meningitis 2RHZS Disseminated TB Spinal TB Previously treated smear-positive PTB 2RHZS Chronic and MDR-TB Specially designed
Three times a week regimen Continuation phase 4HR or 6HE 4HR or 6HE
7RH
4RH Specially designed
O.22.3 Therapies for childhood tuberculosis – current and future approaches
TB: tuberculosis; PTB: pulmonary tuberculosis; EPTB: extra-pulmonary tuberculosis; H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambutol; S: streptomycin; HIV: human immunodeficiency virus; MDR-TB: multidrug resistant TB. The number in front of each phase represents the duration of that phase in months.
C. Pierry. Division of Pediatric Pulmonology, Clinica Alemana de Santiago, Santiago, Chile
Doses: The need for better data on anti-TB drug pharmacokinetics in children is highlighted by the variations in national recommendations for drug doses, particularly those related to INH. Based on several studies it appears that dosage calculations of RPM and EMB are more valid based on body surface area rather than body weight, the latter may be leading to higher doses. Most of the guidelines worldwide recommend the same doses [5] (Table 2).
Correspondence: C. Pierry. E-mail: [email protected]
Tuberculosis (TB) in children is an important cause of morbidity and mortality. Multiple therapeutic regimens for different clinical manifestations are in use. The World Health Organization (WHO) has suggested a category-based treatment that has its focus on adult type of TB [1]. DOTS (directly observed therapy, short-course) has become the cornerstone for TB control across the world. There are five key elements for treatment: 1. Government commitment to sustained TB control 2. Case detection by sputum smear microscopy 3. Standardized treatment regimens for all confirmed smearpositive cases 4. Regular uninterrupted supply of essential anti-TB drugs 5. A standardized recording and reporting system DOTS has been adopted by 148 of 210 countries around the world [2]. The main objectives in TB treatment are: 1. To cure the patient of TB (by rapidly eliminating most of the bacilli) 2. To prevent death from active TB or its late effects 3. To prevent relapse of TB (by eliminating the dormant bacilli) 4. To prevent development of drug resistance (by using a combination of drugs) 5. To reduce transmission of TB [1]. Anti-tuberculosis drugs: TB treatment is divided into two phases: • An intensive initial multidrug phase that aims at killing of the majority of viable bacilli and preventing the emergence of drug resistance. • A continuation phase: aims at sterilization of TB lesions and prevention of relapse by eradicating the dormant organisms. Fewer drugs are generally used.
Table 2. Doses of first line anti-TB drugs in children in mg/kg body weight (range) and varying regimens [1]. Drug
Daily regimen
Three time/week regimen
Isoniazid Rifampicin Pyrazinamide Ethambutol Streptomycin
5 (4–6) max 300 mg 10 (8–12) max 600 mg 25 (20–30) 20 (15–25) 15 (12–18)
10 (8–12) 10 (8–12) 35 (30–40) 30 (25–35) 15 (12–18)
• Isoniazid: remains the most important agent, because of its high EBA, outstanding pharmacokinetics and relatively low toxicity. It is rapidly absorbed and has excellent penetration into most body compartments. It is the first agent against which resistance develops. Recent pediatric studies suggest higher doses of INH per kilogram of body weight to achieve similar concentration to those in adults [6]. • Rifampicin: is a key drug in chemotherapy because it rapidly kills the majority of bacilli in TB lesions and prevents relapse, it has moderate EBA. Absorption is influenced by gastric pH. Pharmacokinetic studies of higher dosages in children are urgently needed [7]. • Pyrazinamide: has favorable pharmacokinetics and penetrates most tissues, including cerebrospinal fluid; serum levels are related to body weight. Resistance is uncommon but
The most common extrathoracic manifestation of TB in children is cervical lymphadenitis. A simple clinical algorithm that identified children with a persistent (longer than 4 weeks) cervical mass of 2×2 cm or more, without a visible local cause or response to firstline antibiotics, showed excellent diagnostic accuracy in an area with endemic TB. However, this approach would be less accurate in non-endemic areas and also is fraught with a risk of missing serious disease like lymphoma. Thus, establishing a definitive tissue and/or culture diagnosis is preferable, and this can be done in a minimally invasive fashion using fine needle aspiration. In the absences of the services of a qualified or skilled cytopathologist, mycobacteriological staining and examination of the smears made from the aspirates may be useful. A positive Tuberculin Skin test or PPD test is often used as an adjunct tool for diagnosing TB in children in appropriate clinical settings. Positive PPD test is merely an evidence of TB infection but in children it is often used for making a diagnosis of active TB, when used in addition to symptoms, radiological abnormalities, history of exposure, and microbiological investigations. Despite reservations about the specificity of the TST response after bacillus CalmetteGuerin ´ (BCG) vaccination, a positive TST reaction remains a fairly accurate measure of M. tuberculosis infection in immune-competent children. In endemic areas, a positive TST is not uncommon in randomly selected healthy children, which limits its diagnostic value somewhat. A recent meta-analysis suggested that a PPD reaction of 15 mm or more is highly unlikely due to BCG interference. The standarised PPD (RT23) manufactured over 5 decades back is no more available in many high burden countries like India. Use of standardized preparations and correct strengths of PPD, appropriate cutoffs is needed for optimal utilisaton of this test. Newer skin test which use specific antigens like MPB64 or antigens in the RD1 area of the mycobacterium (namely, ESAT6 and CFP 10) may make a future skin test more reliable and helpful. Interferon-gamma release assays (IGRAs) have been evolved as an in vitro method of identifying TB infection. Currently they are being largely used in the countries and communities with low prevalence of TB to identify the people with latent bacterial infection. The role of the IGRAs as an alternative to PPD as a diagnostic tool in childhood TB has not been as well understood. Intra-individual and inter-laboratory variations in these tests needs to be understood well before they can replace the PPD tests. In the absence of symptoms or radiologic signs indicative of disease, qualitative T-cell-based IGRAs, like the TST, also fail to make the crucial distinction between latent M. tuberculosis infection and active disease. The application of these new diagnostic tools is a priority for future research in endemic areas mainly to assess their ability to detect M. tuberculosis infection in HIV-infected individuals where TST often fails. Given the limitations of the tests discussed so far, the diagnosis of tuberculosis in children from endemic areas depends mainly on clinical features and the subjective interpretation of the chest radiograph. But even chest skiagram have their well-known limitations that may result in both under- and overdiagnosis of disease and do not necessarily help in clearing the diagnostic dilemma – TB or not TB. Despite all the handicaps, it still can provide a fairly accurate diagnosis in the majority of symptomatic children with tuberculosis if appropriate and adequate skill is used and therefore the interpretation of the chest radiograph remains the most widely used diagnostic criterion in clinical practice. Serologic tests for measuring various antibodies to different mycobacterial antigens or their combinations are commercially available and often used. None of these currently are able to diagnose childhood tuberculosis with accuracy. Their poor positive as well as negative predictive value precludes their use as a diagnostic tool for both pulmonary as well as extra-pulmonary form of the disease. Similarly, the polymerase chain reaction (PCR) tests using various body fluids have also shown variable results and limited utility. The inability of PCR-based tests to differentiate latent infection from
S57
active disease is an important issue and raises concerns regarding the specificity of PCR-based tests as a diagnostic tool. The diagnostic dilemma is even more pronounced in HIV infected children. The specificity of symptom-based diagnostic approaches is reduced by the presence of chronic HIV-related symptoms, while the potential window for symptom-based diagnosis is limited by the rapidity with which disease progression may occur. The common non-TB respiratory infections complicating HIV and the involvement of lungs in HIV further limits the interpretation of chest skiagrams for the diagnosis of TB co-infection. It is further complicated by atypical disease pattern in co-infected children. These difficulties increase the potential diagnostic value of sensitive bacteriology-based approaches, to identify HIV-infected children with tuberculosis. The traditional TST has poor sensitivity to detect M. tuberculosis infection in HIV-infected children; 50% or less of HIVinfected children with bacteriologicaly confirmed tuberculosis are TST positive, despite using an induration size of at least 5 mm. This is a major limitation and a more reliable measure of infection will be valuable to identify HIV-infected children who may benefit from preventive chemotherapy; it may also provide supportive evidence to establish a diagnosis of active tuberculosis. Given the shortcomings of the existing diagnostic tools for childhood TB, the quest for new TB diagnostics should focus on high specificity, affordability and sensitivity for cases missed by existing diagnostic standards. Reference(s) [1] Marais Ben J, Pai M. New approaches and emerging technologies in the diagnosis of childhood tuberculosis. Paediatric Respiratory Reviews (2007) 8, 124–133. [2] Marais Ben J. Tuberculosis in Children Pediatric Pulmonology 2008; 43:322–329. [3] Pai M, Minion J, Sohn H, Zwerling A, Perkins MD. Novel and improved technologies for tuberculosis diagnosis: progress and challenges. Clin Chest Med. 2009;30(4):701–16, [4] Lewinsohn DA, Lobato MN, Jereb JA. Interferon-gamma release assays: new diagnostic tests for Mycobacterium tuberculosis infection, and their use in children. Curr Opin Pediatr. 2010;22(1):71–6. [5] Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skin tests: what is the absolute effect of BCG and non-tuberculous mycobacteria? Int J Tuberc Lung Dis. 2006 10(11):1192–204.
O.22.2 Tuberculosis and HIV – dual epidemics H.J. Zar. Department of Paediatrics and Child Health, Red Cross War Memorial Childrens Hospital, University of Cape Town, South Africa TB is a major cause of morbidity and mortality in HIV-infected children. The HIV pandemic has been associated with a dramatic increase in the number of new cases of TB, has destabilised TB control efforts and led to unprecedented difficulties in confirming the diagnosis of TB. HIV-infected children have higher rates of TB infection and progression to disease compared to immunocompetent children. Therefore, it is important to know the HIV status of a child with suspected or confirmed TB. Diagnosing paediatric TB in the context of HIV is particularly challenging due to non-specific clinical and radiological signs and anergy to the tuberculin skin test (TST). In high HIV prevalence areas, scoring systems have been especially variable, lacking sensitivity and specificity. Microbiological confirmation is rarely achieved. Co-existing malnutrition, the paucibacillary nature of childhood TB, difficulty in obtaining adequate clinical specimens for culture and variable interpretation of chest radiographs further compound the difficulty of making a definitive diagnosis. However, the consequences of undiagnosed TB in HIV-infected children are serious. HIV-infected children are at high risk of developing severe, disseminated disease. Co-infection with M. tuberculosis and HIV results in deterioration of immune dysfunction, enhanced viral replication, HIV progression and frequent, severe opportunistic infections. HIV-infected children who
S58
Oral Presentations / Paediatric Respiratory Reviews 11S1 (2010) S1–S78
commence HAART are also at risk of developing an immune reconstitution inflammatory syndrome in the context of untreated TB. Conversely, reliance on clinical and radiological findings may lead to over diagnosis and inappropriate treatment. Empiric therapy for pulmonary TB in HIV-infected children includes 3–4 drugs daily for a 2 month induction period; the fourth drug should be added if drug resistance is suspected or if there is extensive pulmonary disease or severe immunosuppression. Thereafter 2 drugs for at least 4 months are recommended as maintenance therapy. For children on HAART, the antiretroviral regimen should provide optimal TB and HIV therapy and minimize potential toxicity and drug interactions. Rifampicin induces hepatic cytochrome P450 enzymes and may therefore reduce levels of antiretroviral agents, particularly the protease inhibitors (PI) and to a lesser extent the non nucleoside reverse transcriptase inhibitors (NNRTI). Therefore rifampicin should preferably be used with an NNRTI-based regimen. If a PI is used, a ritonavir-boosted PI such as lopinavir/ritonavir is required. BCG vaccination, isoniazid (INH) prophylaxis or HAART are possible strategies to prevent TB in HIV-infected children. BCG is ineffective for primary prevention of pulmonary TB and provides little protection in HIV infected infants. Moreover, World Health Organization (WHO) guidelines have recently been revised to recommend against BCG vaccination in HIV-infected infants due to the high risk of disseminated BCG and associated mortality. The risk of TB in HIV-infected children is greatly reduced by the use of HAART or by the use of isoniazid (INH) preventive treatment, although the risk remains higher than that of HIV-uninfected children. Use of INH prophylaxis together with HAART offers greater protection than each individually.
The action of anti-TB drugs on these different populations may be bactericidal or sterilizing (or both). Bactericidal activity refers to the agent’s ability to rapidly kill the actively metabolizing organisms in the sputum of patients with pulmonary TB. Agents can be compared by determining their “Early bactericidal activity” (EBA), defined as the fall in viable colony-forming units (cfu) of Mycobacterium tuberculosis per ml of sputum per day during the first 2 days of treatment [3].There are five “first line” anti-TB agents that have been in use for over 30 years: Isoniazid (INH, H); Rifampicin (RMP, R); Pyrazinamide (Z); Ethambutol (EMB, E) and Streptomycin (S). Regimens: Most children are not smear-positive and do not require four drugs in the initial intensive phase; those who are smearpositive or have a visible cavity on chest radiograph have a high bacillus count and should be treated with four drugs. Also those with severe disease such as extensive lung disease, meningitis or disseminated and Spinal TB with neurological signs, are managed with four drugs in the intensive phase. There is a standard code for TB treatment regimens [4] (Table 1). Table 1. Recommended treatment regimens for each diagnostic category based on WHO recommendations: TB diagnostic TB cases category
Daily regimen Intensive phase
III I
I
II IV
New smear – negative PTB. Less severe forms of EPTB 2HRZ New smear – positive PTB 2HRZS (or E) New smear – negative PTB with extensive parenchymal involvement Severe forms of EPTB Severe concomitant HIV disease TB meningitis 2RHZS Disseminated TB Spinal TB Previously treated smear-positive PTB 2RHZS Chronic and MDR-TB Specially designed
Three times a week regimen Continuation phase 4HR or 6HE 4HR or 6HE
7RH
4RH Specially designed
O.22.3 Therapies for childhood tuberculosis – current and future approaches
TB: tuberculosis; PTB: pulmonary tuberculosis; EPTB: extra-pulmonary tuberculosis; H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambutol; S: streptomycin; HIV: human immunodeficiency virus; MDR-TB: multidrug resistant TB. The number in front of each phase represents the duration of that phase in months.
C. Pierry. Division of Pediatric Pulmonology, Clinica Alemana de Santiago, Santiago, Chile
Doses: The need for better data on anti-TB drug pharmacokinetics in children is highlighted by the variations in national recommendations for drug doses, particularly those related to INH. Based on several studies it appears that dosage calculations of RPM and EMB are more valid based on body surface area rather than body weight, the latter may be leading to higher doses. Most of the guidelines worldwide recommend the same doses [5] (Table 2).
Correspondence: C. Pierry. E-mail: [email protected]
Tuberculosis (TB) in children is an important cause of morbidity and mortality. Multiple therapeutic regimens for different clinical manifestations are in use. The World Health Organization (WHO) has suggested a category-based treatment that has its focus on adult type of TB [1]. DOTS (directly observed therapy, short-course) has become the cornerstone for TB control across the world. There are five key elements for treatment: 1. Government commitment to sustained TB control 2. Case detection by sputum smear microscopy 3. Standardized treatment regimens for all confirmed smearpositive cases 4. Regular uninterrupted supply of essential anti-TB drugs 5. A standardized recording and reporting system DOTS has been adopted by 148 of 210 countries around the world [2]. The main objectives in TB treatment are: 1. To cure the patient of TB (by rapidly eliminating most of the bacilli) 2. To prevent death from active TB or its late effects 3. To prevent relapse of TB (by eliminating the dormant bacilli) 4. To prevent development of drug resistance (by using a combination of drugs) 5. To reduce transmission of TB [1]. Anti-tuberculosis drugs: TB treatment is divided into two phases: • An intensive initial multidrug phase that aims at killing of the majority of viable bacilli and preventing the emergence of drug resistance. • A continuation phase: aims at sterilization of TB lesions and prevention of relapse by eradicating the dormant organisms. Fewer drugs are generally used.
Table 2. Doses of first line anti-TB drugs in children in mg/kg body weight (range) and varying regimens [1]. Drug
Daily regimen
Three time/week regimen
Isoniazid Rifampicin Pyrazinamide Ethambutol Streptomycin
5 (4–6) max 300 mg 10 (8–12) max 600 mg 25 (20–30) 20 (15–25) 15 (12–18)
10 (8–12) 10 (8–12) 35 (30–40) 30 (25–35) 15 (12–18)
• Isoniazid: remains the most important agent, because of its high EBA, outstanding pharmacokinetics and relatively low toxicity. It is rapidly absorbed and has excellent penetration into most body compartments. It is the first agent against which resistance develops. Recent pediatric studies suggest higher doses of INH per kilogram of body weight to achieve similar concentration to those in adults [6]. • Rifampicin: is a key drug in chemotherapy because it rapidly kills the majority of bacilli in TB lesions and prevents relapse, it has moderate EBA. Absorption is influenced by gastric pH. Pharmacokinetic studies of higher dosages in children are urgently needed [7]. • Pyrazinamide: has favorable pharmacokinetics and penetrates most tissues, including cerebrospinal fluid; serum levels are related to body weight. Resistance is uncommon but