Tuberculosis (TB) has re-emerged as a major worldwide public health hazard with increasing incidence among adults and children. Although cases among children represent a small percentage of all TB cases, they are a reservoir from which many adult cases will arise. Estimates indicate that 9 million people develop TB annually, out of which 1 million (11 percent) occur in children less than 15 years old. Childhood tuberculosis is on the increase worldwide because of persisting inability to conform the diagnosis, leading to a large number of children dying of undiagnosed tuberculosis. Diagnosis of pulmonary tuberculosis has depended on bacteriological examination of sputum. In most of the developing countries sputum smear microscopy has been used as it has been found to be cheap and relative efficient. As a result of the high TB burden, there is an urgent need for improved methods of laboratory diagnosis of TB. This is especially needed in children were diagnosis is more challenging as mycobacteria is being detected in fewer than 50 percent of the cases. Children cannot produce adequate sputum samples for examination. Their sputum samples, if produced, has a low bacterial yield and making detection of mycobacteria by using the smear microscopy difficult. Therefore, gastric lavages from children are being recommended as the best specimen for culture. In this study, gastric lavages from 408 children suspected of having tuberculosis were examined for the recovery of mycobacteria. Recovery was optimized by the use of the relatively new non-radiometric fully automated BACTEC MGIT 960. BACTEC MGIT 960 produced a positivity rate of 27.2 percent against 17.2 percent that of Lowenstein-Jensen (L-J) media, which is a conventional culture method used widely. The direct microscopy which is the cheapest traditional method used in diagnosis of tuberculosis (TB) yielded a 5.6 percent positive rate. The BACTEC MGIT 960 had also a very high isolate detection rate of 98.2 percent compared to that of L-J media of 61.9 percent, and only 20.4 percent were detected with the direct microscopy. On time taken to detection or mean time to detection (TTD) of v isolates, the BACTEC MGIT 960 technique had a shorter mean time to detection, 12.5 days as compared to 34.3 days shown by the L-J media technique. The study showed that children normally get tuberculosis from adult members of the household. A positive TB case was found in the households of 55.4 percent of the suspects. The study has found that 46.4 percent of the children below the age of 4 years developed the disease, compared to 10.5 percent the older children in the age group 10 to 14 years. The study found that tuberculosis in children is mainly caused by Mycobacterium tuberculosis. Out of the 113 isolates detected, 110 (97.3 percent) were M. tuberculosis. The remaining 2.7 percent were the non-tuberculous M. avium complex and M. kansasii. It was inconclusive whether the 2.7 percent of other species were causing tuberculosis and this need to be studied further.

Dissertation (PhD)--University of Stellenbosch, 2006. / ENGLISH ABSTRACT: Children contribute little to disease transmission and the maintenance of the tuberculosis epidemic, but they constitute a significant proportion of the total tuberculosis (TB) caseload and experience considerable morbidity and mortality in endemic areas, despite the availability of cheap and effective treatment. The difficulty of diagnosing childhood tuberculosis is one of the major obstacles that hinder the provision of antituberculosis treatment to children in endemic areas. The diagnosis of childhood tuberculosis is complicated by the lack of a practical gold standard, as bacteriologic specimens are difficult to collect and the yield is low. In non-endemic countries the diagnosis of childhood tuberculosis is based on the triad of: 1) exposure to an adult index case, 2) a positive tuberculin skin test, and 3) suggestive radiographic signs. However, the triad has limited value in endemic areas where exposure to and/or infection with Mycobacterium tuberculosis is common, and chest radiography is rarely available. The objective of this dissertation was to address the diagnostic dilemma faced by health professionals in endemic areas with limited resources, where children currently have poor access to chemoprophylaxis and antituberculosis treatment. We first clarified basic disease concepts, through a critical review of the pre-chemotherapy literature that documented the natural history of childhood tuberculosis. Three central concepts were identified; 1) the importance of accurate case definition, 2) the relevance of risk stratification, and 3) the diverse spectrum of disease, which necessitates accurate disease classification. The importance of accurate case definition is illustrated by the fact that isolated hilar adenopathy, considered the principal radiographic sign of primary tuberculosis, becomes transiently visible in the majority of children following recent primary infection. Our analysis of the natural history of childhood tuberculosis allowed accurate quantification of the risk to progress to disease following primary infection with M.tuberculosis. This demonstrated that the risk depends mainly on the age and/or immune-status of the child, the time since primary infection occurred and the presence or absence of symptoms. After analysing these historic studies, we proceeded to document the burden of childhood tuberculosis in an endemic area. We first conducted a retrospective study to describe current diagnostic practices and demonstrated almost exclusive reliance on chest radiography. We then calculated the burden of childhood tuberculosis in a prospective descriptive study. The corrected tuberculosis incidence rate in children was 407/100 000/year and children with severe forms of disease, such as disseminated (miliary) tuberculosis and/or tuberculous meningitis, were rarely recorded in the TB treatment register used for routine community-based surveillance. An additional obstacle to progress in the field of childhood tuberculosis has been the lack of standard descriptive terminology. Following a careful review of the literature, we proposed a radiological classification of childhood intra-thoracic tuberculosis and explored the different pathologic mechanisms that underlie these diverse disease manifestations. We then conducted a prospective descriptive study to document the disease spectrum in children treated for tuberculosis in an endemic area. The disease patterns observed were consistent with those described in the pre-chemotherapy literature. In addition, we demonstrated that bacteriologic confirmation may be achieved in the majority of children with intra-thoracic tuberculosis, in highly endemic settings. Finally we developed a novel symptom-based approach to diagnose pulmonary tuberculosis in children from endemic areas with limited resources. We followed a step-wise approach by first conducting a community-based survey to document the prevalence of symptoms traditionally associated with tuberculosis in a random selection of children from an endemic area. The survey demonstrated that poorly defined symptoms offer poor diagnostic value. The second step was to evaluate the diagnostic value of well-defined (persistent, non-remitting) symptoms in a small prospective study. Well-defined symptoms demonstrated good diagnostic value, but these promising results required further validation. As a final step, we validated the diagnostic value of a novel symptom-based approach in a large prospective, community-based study. In this study, a simple symptom-based approach diagnosed childhood pulmonary tuberculosis with a remarkable degree of accuracy, particularly in HIV-uninfected children older than 3 years of age. This novel diagnostic approach offers the exciting prospect of extending antituberculosis treatment to children in endemic areas with limited resources, where current treatment access is poor. / AFRIKAANSE OPSOMMING: Tuberkulose beheer programme plaas feitlik geen klem op die behandeling van kinders nie, omdat kindertuberkulose selde aansteeklik is en die persepsie bestaan dat kinders slegs in raar gevalle ernstig siek word. Tuberkulose lewer egter ‘n betekenisvole bydrae tot kindermorbiditeit en mortaliteit in endemiese areas, terwyl dit ‘n maklik behandelbare siekte is. Kindertuberkulose is moeilik om te diagnoseer en dit is ‘n belangrike faktor wat daartoe bydra dat kinders dikwels nie antituberkulose behandeling ontvang wanneer hulle dit benodig nie. Die diagnose van kindertuberkulose is moeilik, omdat die organisme selde aangetoon kan word. In nie endemiese areas word kindertuberkulose dikwels gediagnoseer na aanleiding van: 1) blootstelling aan ‘n volwasse indeks geval, 2) ‘n positiewe tuberkulien veltoets, en 3) die teenwoordigheid van radiologiese tekens suggestief van tuberkulose. Hierdie benadering het defnitiewe tekortkominge in endemiese areas, waar blootstelling aan en infeksie met Mycobacterium tuberculosis algemeen is. Gevolglik berus die diagnose van kindertuberkulose hoofsaaklik op die subjektiewe interpretasie van die borskasplaat, wat welbekende tekortkominge het en verder is radiologiese toetse dikwels nie beskikbaar in hierdie areas nie. Die doel van die navorsingsprojek was om die dilemma rondom die diagnose van kindertuberkulose in endemiese areas aan te spreek. Eerstens is basiese siektekonsepte uitsorteer deur ‘n kritiese oorsig van studies uit die pre-chemoterapie era. Hierdie kosbare studies het die natuurlike verloop van tuberkulose in kinders beskryf, nog voordat antituberkulose middels beskikbaar was. Drie sentrale konsepte is geidentifiseer; 1) die belang van akkurate siekte definisie, 2) die relevansie van risiko stratifikasie en 3) die diverse spektrum van patologie wat akkurate siekte klassifikasie noodsaak. Die belang van akkurate siekte definisie word geïllustreer deur die feit dat geïsoleerde hilêre adenopatie ‘n verbygaande verskynsel is in die meerderheid van kinders kort na primêre infeksie. Ons analise het daarop gefokus om die risiko om siekte te ontwikkel nadat primêre infeksie met M.tuberculosis plaasgevind het, te kwantifiseer. Die hoof risiko faktore was; 1) die ouderdom en/of immuunstatus van die kind, 2) die tydsverloop sedert infeksie, en 3) die teenwoordigheid van simptome al dan nie. Hierna het ons die siektelas wat tuberkulose vandag op kinders in endemiese areas plaas gedokumenteer. Ons het eers die huidige diagnostiese praktyke geëvaluaeer in ‘n retrospektiewe studie en toe ‘n prospektiewe beskrywende studie gedoen om die siektelas so akkuraat as moontlik te meet. Die insidensie van kindertuberkulose was hoog (>400/100 000/jaar), selfs na korreksie vir kinders wat ontoepaslik behandeling ontvang het. Verder is gevind dat die meerderheid van kinders met ernstige siekte toestande soos miliêre tuberkulose en/of meningitis, nie in roetine moniterings data reflekteer word nie. ‘n Bykomende struikelblok in kindertuberkulose is die gebrek aan standaard beskrywende terminologie. Om dit te bevorder ontwikkel ons ‘n nuwe radiologiese klassifikasie van intra-torakale kindertuberkulose en beskryf ons die verskillende patologiese meganismes onderliggend tot hierdie uiteenlopende siektebeelde. Daarna dokumenteer ons die volledige spektum van kindertuberkulose in ‘n endemiese area en demonstreer dat die siektepatrone wat ons vandag observeer soortgelyk is aan die wat in die pre-chemoterapie literatuur beskryf is. Ons toon ook dat bakteriologiese bevestiging moontlik blyk te wees in die meerderheid van kinders wat vir intra-torakale tuberkulose behandel word in endemiese areas. Nadat ons duidelikheid verkry het oor die basiese siektekonsepte, siekte klassifikasie en die siektelading in ons omgewing, kon ons op die ontwikkeling van ‘n simptoom-gebaseerde benadering tot die diagnose van kindertuberkulose fokus. Ons het ‘n stapsgewyse benadering gevolg. Die eerste stap was om die voorkoms van simptome wat gebruiklik met tuberkulose vereenselwig word te dokumenteer in ‘n ewekansige groep kinders. Die gemeenskapsopname het getoon dat swak gedefiniëerde simptome swak diagnostiese waarde bied. Die tweede stap was om vas te stel of verbeterde simptoom definisie die diagnostiese waarde kan verbeter. ‘n Klein prospektiewe studie het getoon dat goed gedefiniëerde simptome (persisterende simptome van onlangse aankoms) goeie diagnostiese waarde bied. Die finale stap was om hierdie belowende benadering formeel te toets in ‘n groot prospektiewe, gemeenskapsgebaseerde studie. Hierdie studie het getoon dat ‘n eenvoudige simptoom-gebaseerde benadering pulmonale tuberkulose met goeie akkuraatheid kan diagnoseer, veral in HIV-ongeïnfekteerde kinders wat ouer is as 3 jaar. Hierdie nuwe diagnostiese benadering bied die moontlikheid om antituberkulose behandeling te voorsien aan kinders in endemiese areas wat tans feitlik geen behandeling ontvang nie.

Tuberculosis (TB) has re-emerged as a major worldwide public health challenge in the last decade with an increasing incidence amongst children. The diagnosis of TB in children is difficult as the presentation is not always classical and available diagnostic modalities are imperfect. Diagnosis is, especially complex in developing countries where resources and access to sophisticated diagnostic facilities are limited. Thus practical score charts combining a number of complementary clinical characteristics with affordable special investigations have been developed to aid diagnosis. The new South African primary health care (PHC) nurse-driven system demands that first line nurses be equipped to suspect, diagnose, confirm the diagnosis and treat children with TB. Very little is known about the ability of PHC nurses to diagnose TB in children. In Mpumalanga province relatively low rates of notified paediatric TB prompted an investigation to determine the ability of local PHC nurses to diagnose TB in children and explore whether the PHC setting allowed this. Within method triangulation was used in this quantitative descriptive study by combining a self-completed knowledge survey with clinic visits to audit records and assess access to diagnostic aids and tests. Important deficiencies in knowledge and limited access to certain diagnostic modalities found in this study must be addressed if appropriate management of TB in children is to be assured. / Health Studies / M. A. (Public Health)

Thesis (MScMedSc)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: BACKGROUND: The emergence of mycobacterium tuberculosis resistance to first line drugs has renewed interest in second-line anti-tuberculosis drugs. Generally, Paraaminosalicylic acid (PAS) is less potent and frequently more toxic than the first line drugs. Furthermore, the pharmacokinetics of PAS in children has not been well characterized. AIMS: The aims of the present study were (1) to determine the pharmacokinetics of PAS in pediatric patients, (2) to describe the discrepancy between children and adult pharmacokinetics and the appropriate dosing regimen of PAS and (3) to investigate the potential of the second-line anti-tuberculosis drugs PAS, terizidone and ethionamide (often used as first-line drug in children) to inhibit the catalytic activities of CYP450 1A2 and 2C9. PATIENTS: Twenty two patients with drug resistant tuberculosis were included in the study. Ten patients were children with mean age of 4.2 years (range: 1 to 12 years). Twelve patients were adults with mean age of 31.3 years (range: 18 to 53). 4 children (40%) and 4 adults (33.3%) were HIV positive and were on ART. METHODS: Children received 75 mg/kg twice daily on the first visit and after two weeks they received 150 mg/kg once. Adults received a standard 4 g twice daily. Blood samples were taken at different time points after the dose. In the additional study, the inhibitory effects of PAS, ethionamide and terizidone on phenacetin O-deethylation, a marker substrate of CYP1A2 and diclofenac 4’-hydroxylation, a marker substrate of CYP2C9, were studied using human liver microsomes. RESULTS: For the 75 mg/kg dose, the mean AUC was 233.3 =g•h/ml and the mean CL was 10.4 l/h/kg. The mean of the observed Cmax of the drug was 45.4 =g/ml and the mean Tmax was 4.8 hrs. For the 150 mg/kg dose, the mean AUC of PAS was 277.9 =g•h/ml and the mean CL was 47.1 l/h/kg. The mean of the observed Cmax of the drug was 56.5 =g/ml and the mean Tmax was 4.8 hrs. On the first visit the mean AUC was 368 =g•h/ml and the mean CL was 13.2 l/h/kg. The mean of the observed Cmax of PAS was 51.3 =g/ml and the mean Tmax was 5.2 hrs. On the second visit the mean AUC was 230 =g•h/ml and the mean CL was 23.9 l/h/kg. The mean of the observed Cmax of PAS was 37.6 =g/ml and the mean Tmax was 5.2 hrs. The comparisons between pharmacokinetics profile of PAS and patients characteristics e.g. age, indicated no statistically significant differences between children (both treatment regimens) and adult patients as well as HIV positive and negative patients. In the in vitro study, all drugs demonstrated no inhibition potency towards the investigated CYP450 enzymes. CONCLUSIONS:The dose of 75 mg/kg twice daily in children appears to be appropriate to achieve serum concentration above the PAS minimum inhibitory concentration of approximately 1 =g/ml. PAS, ethionamide and terizidone are unlikely to affect the metabolism of concomitantly administered medications that are metabolized by either CYP450 1A2 and/or 2C9 isoenzymes. / AFRIKAANSE OPSOMMING: AGTERGROND: Die opkoming van eersteliniemiddel-weerstandige mycobacterium tuberculosis het opnuut belangstelling in tweedelinie-antituberkulosemiddels aangewakker. Oor die algemeen is para-aminosalisielsuur (PAS) minder kragtig en dikwels ook meer toksies. Verder is die farmakokinetika van PAS in kinders nog nie goed vasgestel nie. DOELSTELLINGS: Die doelstellings van hierdie studie was (1) om die farmakokinetika van PAS in pediatriese pasiënte vas te stel, (2) om die diskrepansie tussen kinder- en volwasse-farmakokinetika, sowel as die toepaslike doseringskedule, van PAS te beskryf en (3) om die potensiaal van die tweedeline-antituberkulosemiddels PAS, terisidoon en etioonamied (gereeld gebruik as eerste linie middels in kinders) te ondersoek wat betref hul vermoë om die katalitiese werking van CYP450 1A2 en 2C9 te inhibeer. PASIËNTE: Twee-en-twintig pasiënte met middelweerstandige tuberkulose is in hierdie studie ingesluit. Tien pasiënte was kinders met ‘n gemiddelde ouderdom van 4.2 jaar (reeks: 1 tot 12 jaar). Twaalf pasiënte was volwassenes met ‘n gemiddelde ouderdom van 31.3 jaar (reeks: 18 tot 53 jaar). 4 kinders (40%) en 4 volwassenes (33.3%) was MIV positief en was op TRM’s. METODES: Kinders het 75 mg/kg twee maal daaliks gedurende die eerste besoek ontvang en 150 mg/kg een maal ná twee weke ontvang. Volwassenes het ‘n standaarddosis van 4 g twee maal daagliks ontvang. Bloedmonsters is op verskillende tye ná die dosering geneem. In die addisionele studie is in die inhiberende effekte van PAS, etioonamied en terisidoon op fenasetien-O-deëtilering, ‘n merkersubstraat van CYP1A2 en diklofenak-4’-hidroksilasie, ‘n merkersubstraat van CYP2C9, ondersoek deur gebruik te maak van menslike lewermikrosome. RESULTATE: Vir die 75 mg/kg dosis was die gemiddelde area-onder-die-kurwe (AOK) 233.3 =g•h/ml en die gemiddelde middelopruiming (CL) 10.4 l/h/kg. Die gemiddelde geobserveerde Cmaks van die middel was 45.4 =g/ml en die gemiddelde Tmaks was 4.8 h. Vir die 150 mg/kg dosering was die gemiddelde AOK van PAS 277.9 =g•h/ml en die gemiddelde CL 47.1 l/h/kg. Die gemiddelde geobserveerde Cmaks van die middel was 56.5 =g/ml en die gemiddelde Tmaks was 4.8 h. Gedurende die eerste besoek was die AOK 368 =g•h/ml en die gemiddelde CL was 13.2 l/h/kg. Die gemiddelde geobserveerde Cmaks van PAS was 51.3 =g/ml en die gemiddelde Tmaks was 5.2 h. Gedurende die tweede besoek was die gemiddelde AOK 230 =g•h/ml en die gemiddelde CL 23.9 l/h/kg. Die gemiddelde geobserveerde Cmaks van PAS was 37.6 =g/ml en die gemiddelde Tmaks was 5.2 h. Die vergelyking van PAS-farmakokinetika en eienskappe van die pasiënte het geen statisties beduidende verskille in die gemiddelde AOK tussen kinders (op albei doserings) en volwassenes getoon nie. Met die in vitrostudie het geen van die middels inhibisie-werking teenoor die CYP450-ensieme wat ondersoek is, getoon nie. GEVOLGTREKKINGS: Die gevolgtrekking kan gemaak word dat die dosering van 75 mg/kg twee maal daagliks voldoende is om serumkonsentrasies wat bo PAS se minimum inhiberende konsentrasie van 1 =g/ml te bereik. Dit is onwaarskynlik dat PAS, etioonamied en terisidoon die metabolisme van gelyktydig-toegediende medikasies, wat op hul beurt deur die CYP240-isoënsieme 1A2 en/of 2C9 gemetaboliseer word, sal affekteer. / Division of Pharmacology, Stellenbosch University / National Research Foundation (NRF) grant generously offered by Professor Donald Grant

Tuberculosis (TB) has re-emerged as a major worldwide public health challenge in the last decade with an increasing incidence amongst children. The diagnosis of TB in children is difficult as the presentation is not always classical and available diagnostic modalities are imperfect. Diagnosis is, especially complex in developing countries where resources and access to sophisticated diagnostic facilities are limited. Thus practical score charts combining a number of complementary clinical characteristics with affordable special investigations have been developed to aid diagnosis. The new South African primary health care (PHC) nurse-driven system demands that first line nurses be equipped to suspect, diagnose, confirm the diagnosis and treat children with TB. Very little is known about the ability of PHC nurses to diagnose TB in children. In Mpumalanga province relatively low rates of notified paediatric TB prompted an investigation to determine the ability of local PHC nurses to diagnose TB in children and explore whether the PHC setting allowed this. Within method triangulation was used in this quantitative descriptive study by combining a self-completed knowledge survey with clinic visits to audit records and assess access to diagnostic aids and tests. Important deficiencies in knowledge and limited access to certain diagnostic modalities found in this study must be addressed if appropriate management of TB in children is to be assured. / Health Studies / M. A. (Public Health)