Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.

BACKGROUND: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. METHODS: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC0-24) and peak plasma concentration (C max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0-24 and C max were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L-1), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L-1), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L-1) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L-1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC0-24. CONCLUSIONS: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

Comparison of awareness and perception of menstrual hygiene between pre and postmenarchal adolescents of North India: A cross-sectional study.

CONTEXT: Menstruation is a normal physiologic phenomenon. Due to lack of awareness regarding menstrual hygiene among adolescent girls in India, majority have unhygienic practices which make them vulnerable to various adverse health and social outcomes. AIMS AND OBJECTIVE: The aim of this study was to compare the awareness and perception of pre- and postmenarchal adolescent girls regarding menstrual hygiene. SETTINGS AND DESIGN: A hospital-based cross-sectional study was conducted by the Department of Obstetrics and Gynaecology and Paediatrics of a Government tertiary care center, Lucknow, Uttar Pradesh for 6 months from 1 July 2019 to 31 December 2019. MATERIAL AND METHODS: The study was undertaken among 120 adolescent girls between 09 and 19 years of age. Premenarchal age group was from 9 to 12 years and postmenarchal was 13-19 years. All the adolescent girls who fulfilled the inclusion criteria were subjected to a pretested prevalidated semi-structured questionnaire assessing their awareness and perceptions regarding menstrual hygiene. RESULT: Of 120 respondents, 43 girls were aware of menstruation prior to attainment of menarche. Mother was the first informant regarding menstruation in the case of 49 (49.65%) girls. A total of 57 girls believed it as a physiological process. 32 (53.3%) girls knew the use of sanitary pads during menstruation. Regarding restrictions practiced, 136 (85%) girls practiced different restrictions during menstruation. CONCLUSION: Adolescent girls, being vulnerable, need to have adequate and correct awareness regarding menstrual hygiene. This will protect them from risk of developing reproductive or sexually transmitted infections (RTI/STI) which is a burden on our society and render many females infertile and cause other adverse health outcomes.

Comparison of Diagnostic Yield of Tuberculosis Loop-Mediated Isothermal Amplification Assay With Cartridge-Based Nucleic Acid Amplification Test, Acid-Fast Bacilli Microscopy, and Mycobacteria Growth Indicator Tube Culture in Children With Pulmonary Tuberculosis.

BACKGROUND: Cartridge-based nucleic acid amplification test (CB-NAAT) has been recommended for diagnosis of tuberculosis (TB) in children, but its wide use is limited by high cost and the need for well-equipped laboratories. This study was conducted in children with pulmonary TB to compare the diagnostic yield of TB-LAMP (loop-mediated isothermal amplification test) with CB-NAAT and other conventional methods. METHODS: Patients ≤ 14 years of age diagnosed with probable pulmonary TB were included in the study. Induced sputum/gastric aspirate was obtained and subjected to acid-fast bacilli (AFB) microscopy, mycobacteria growth indicator tube (MGIT) culture, CB-NAAT, and TB-LAMP. The TB-LAMP assay was performed using 2 different primers, IS6110 and mpb64, for detection of Mycobacterium tuberculosis (MTB). TB-LAMP assays were compared to other assays using appropriate statistical tests. RESULTS: One hundred fourteen subjects were recruited in the study. AFB microscopy, MGIT culture, CB-NAAT, TB-LAMP IS6110, and TB-LAMP mpb64 showed positivity of 32 (28.1%), 59 (51.7%), 66 (57.9%), 75 (65.8%), and 81 (71%), respectively. TB-LAMP IS6110 showed significantly higher MTB detection in comparison to AFB microscopy and MGIT culture (P = .0001 and P = .03, respectively), and showed no significant difference in MTB detection in comparison with CB-NAAT (P = .219). TB-LAMP mpb64 showed significantly higher MTB detection as compared to AFB microscopy, MGIT culture, and CB-NAAT (P = .0001, P = .003, and P = .037, respectively). TB-LAMP mpb64 and IS6110 showed sensitivity of 94.9% (95% confidence interval [CI], 85.9%-98.9%) and 89.8% (95% CI, 79.7%-96.2%), respectively, in reference to MGIT culture. The degree of agreement between TB-LAMP (mpb64 and IS6110) with CB-NAAT showed κ values of 0.718 and 0.834, respectively. CONCLUSIONS: TB-LAMP assay can be a useful alternative test in diagnosis of pulmonary TB in children.

Recurrent Peumonia in an Infant With an Esophageal Lung.

Esophageal lung is a rare variety of communicating bronchopulmonary foregut malformation with anomaolous communication between an isolated portion of respiratory tissue and esophagus. Children present in early life with recurrent cough and pneumonia. Majority of the reported cases are associated with other anomalies like tracheoesophageal fistula. We report a case of a 7-month-old girl with right sided esophageal lung who was misdiagnosed as dextrocardia with right sided pneumonitis.

Characterization of a Newly Isolated Probiotic Strain from Oecophylla smaragdina, an Edible Insect Popular Among the Indigenous Communities of Northeast India.

Northeast India is amongst the 34 Biodiversity Hot Spots of the world with large number of unexplored flora and fauna. A total of 74 potential isolates with probiotic properties were isolated from Oecophylla smaragdina, an edible insect used by local tribes as a nutritious medicinal food source out of which, the most potential probiotic candidate was identified as Bacillus sp. PD6 by 16S rRNA sequencing. Cell surface trait analysis shows hydrophobicity and auto-aggregation percentage of 46.2 ± 0.32% and 61.41 ± 0.28% respectively. The cell free extract (CFE) of the isolate shows the presence of essential amino acids viz, lysine, valine, leucine, isoleucine, and threonine indicating its nutritional value. It survives significantly at pH range from 1 to 10 and capable of hydrolyzing bile salt. The CFE shows antagonistic effect against B. cereus ATCC 11778, E. coli ATCC 25922 and L. monocytogenes ATCC BAA751. FTIR spectra of bacterial exo-polysaccharide shows the presence of νC=C-H stretch, νN-H stretch, νC-H stretch, νC-H bending and νC=O stretch bonds. It was found to be non-cytotoxic against primary mouse liver cell line and sheep erythrocytes and also, sensitive against wide range of broad and narrow spectrum antibiotics making it recommendable for human consumption.

Pharmacokinetic study of isoniazid and pyrazinamide in children: impact of age and nutritional status.

OBJECTIVES: To evaluate pharmacokinetics of first-line antitubercular drugs, isoniazid (INH) and pyrazinamide (PZA), with revised WHO dosages and to assess its adequacy in relation to age and nutritional status. DESIGN: Observational study. SETTING: This study was conducted at Sarojini Naidu Medical College, Agra, and National Institute for Research in Tuberculosis, Chennai. PATIENTS: 40 subjects diagnosed with tuberculosis were registered in the study and started on daily first-line antitubercular regimen based on the revised WHO guidelines. INTERVENTIONS: Blood samples were collected at 0, 2, 4, 6 and 8 hours from these subjects after 15 days of treatment for drug estimations. MAIN OUTCOME MEASURE: The measurement of drug concentrations (maximum peak concentration (Cmax) and area under the time -concentration curve (AUC0-8 hours)) for INH and PZA. Appropriate statistical methods were used to evaluate the impact of age and nutritional status on pharmacokinetic variables. RESULTS: For INH, the difference in drug exposures in children <3 years (Cmax 3.18 µg/mL and AUC0-8 hours15.76 µg/mL hour) and children >3 years (Cmax3.05 µg/mL and AUC0-8 hours 14.37 µg/mL hour) was not significant (P=0.94, P=0.81, respectively). The drug levels in children with low body mass index (BMI) (Cmax3.08 µg/mL; AUC0-8 hours14.81 µg/mL hour) were also comparable with their normal counterparts (Cmax3.09 µg/mL, P=0.99; AUC0-8 hours 14.69 µg/mL hour, P=0.82). PZA drug exposures obtained in children less than 3 years (Cmax29.22 µg/mL, AUC0-8 hours 155.45 µg/mL hour) were significantly lower compared with drug levels in children above 3 years (Cmax 37.12 µg/mL, P=0.03; AUC 202.63 µg/mL hour, P value=0.01). Children with low BMI had significantly lower drug concentrations (Cmax 31.90 µg/mL, AUC0-8 hours167.64 µg/mL hour) when compared with normal counterparts (Cmax 37.60 µg/mL, P=0.02; AUC0-8 hours 208.77 µg/mL hour, P=0.01). CONCLUSIONS: The revised WHO drug dosages were found to be adequate for INH with respect to age and nutritional status, whereas PZA showed significantly lower drug levels in children <3 years and in malnourished children.

Tuberculosis Burden among Household Pediatric Contacts of Adult Tuberculosis Patients.

OBJECTIVES: To find out the prevalence of latent tuberculosis (TB) infection and TB disease among pediatric household contacts of adult drug resistant (MDR) and drug susceptible (DS) TB patients and to identify the risk factors for occurrence of TB infection in the contacts. METHODS: Pediatric household contacts (less than 15 y age) of adult TB patients (both MDR and DS) were included in the study. They were categorized as latent TB infection (LTBI), TB disease and TB exposed based on the results of tuberculin skin testing (TST), clinical examination and chest X-ray. Various factors (age, gender, socioeconomic status, BCG immunization etc.) were evaluated to assess their association with TB transmission. RESULTS: A total of 271 household contacts were included in the study. Prevalence of LTBI was 20.3% (31% in MDR TB group and 14% in DS TB group); difference was significant (p value = 0.0018). TB disease was seen in 3 subjects in DS group while none in MDR group developed TB disease. Lower socioeconomic status was significantly associated with risk of TB infection in MDR group (p value =0.0027). In DS TB group, male gender, BCG non-immunization was significantly associated with risk of developing TB (p value 0.0068 and 0.0167 respectively). CONCLUSIONS: Prevalence of latent TB infection was found to be high in household pediatric contacts especially in contacts of MDR TB patients. Risk factors identified for occurrence of TB included lower socioeconomic status, BCG non-immunization and male gender. The study focuses on the importance of contact screening and the need for its implementation in TB control programs.

Pharmacokinetics of Second-Line Antituberculosis Drugs in Children with Multidrug-Resistant Tuberculosis in India.

We studied the pharmacokinetics of levofloxacin (LFX), pyrazinamide (PZA), ethionamide (ETH), and cycloserine (CS) in children with multidrug-resistant tuberculosis (MDR-TB) who were being treated according to the Revised National TB Control Programme (RNTCP) guidelines in India. This observational, pharmacokinetic study was conducted in 25 children with MDR-TB at the Sarojini Naidu Medical College, Agra, India, who were being treated with a 24-month daily regimen. Serial blood samples were collected after directly observed administration of drugs. Estimations of plasma LFX, PZA, ETH, and CS were undertaken according to validated methods by high-performance liquid chromatography. Adverse events were noted at 6 months of treatment. The peak concentration (Cmax) of LFX was significantly higher in female than male children (11.5 µg/ml versus 7.3 µg/ml; P = 0.017). Children below 12 years of age had significantly higher ETH exposure (area under the concentration-time curve from 0 to 8 h [AUC0-8]) than those above 12 years of age (17.5 µg/ml · h versus 9.4 µg/ml; P = 0.030). Multiple linear regression analysis showed significant influence of gender on Cmax of ETH and age on Cmax and AUC0-8 of CS. This is the first and only study from India reporting on the pharmacokinetics of LFX, ETH, PZA, and CS in children with MDR-TB treated in the Government of India program. More studies on the safety and pharmacokinetics of second-line anti-TB drugs in children with MDR-TB from different settings are required.

Clinical and pulmonary functions profiling of patients with chronic obstructive pulmonary disease experiencing frequent acute exacerbations.

PURPOSE: The present study aimed at clinical and pulmonary functions profiling of patients with chronic obstructive pulmonary disease (COPD) to anticipate future exacerbations. METHODS: The study included 80 COPD patients; 40 patients had ≥2 acute exacerbations during preceding 1 year (frequent exacerbation [FECOPD] group) and 40 patients had <2 acute exacerbations during preceding 1 year (infrequent exacerbation [I-FECOPD] group). Clinical profile, sputum microbiology, blood gas analysis, spirometric indices, and diffusion capacity (transfer test) variables were assessed. Groups' comparison was performed using an independent t-test for numeric scale parameters and Chi-square test for nominal parameters. Pearson's and Spearman's correlation coefficients were derived for numeric scale parameters and numeric nominal parameters, respectively. Multinomial logistic regression analysis was done using SPSS software. RESULTS: FECOPD group contained younger patients than in I-FECOPD group although the difference was not statistically significant. There was no significant difference between two groups regarding smoking pack-years and duration of illness. FECOPD group had significantly more expectoration score and Modified Medical Research Council dyspnea scores. Cough score and wheeze score did not differ significantly between two groups. More patients in FECOPD group (12/40 vs. 4/40) had lower airway bacterial colonization. Arterial blood gas parameters were more deranged in FECOPD group. Spirometric indices (forced expiratory volume during 1st s) as well as transfer test (both diffusing capacity for carbon monoxide and transfer coefficient of the lung values) were significantly reduced in FECOPD group. CONCLUSIONS: The patients in FECOPD group had clinical, spirometric, and transfer test profiling suggestive of a severe COPD phenotype, the recognition will help in predicting future exacerbations and a better management.

Epidemiological Profile of Acute Viral Encephalitis.

OBJECTIVE: To study the etiology and clinico-epidemiological profile of acute viral encephalitis in children with acute encephalitis syndrome (AES). METHODS: An observational study including 100 patients fulfilling the criteria for AES was conducted in children of age group 1 mo - 16 y. Viral isolation was done on RD cells, HEp-2 cells and Vero cells from the cerebrospinal fluid samples of suspected viral encephalitis (VE) cases. An enzyme immunoassay for IgM antibodies was performed for measles, mumps, Varicella zoster virus (VZV), Herpes simplex virus 1 (HSV1) and Japanese encephalitis virus (JEV). Multiplex polymerase chain reaction (PCR) was done for Cytomegalovirus, Epstein Barr virus (EBV), HSV1 & 2, VZV, Enterovirus, Parecho virus, Human Herpes virus (HHV 6, 7) and Parvovirus B19. A micro neutralization test was performed for Enterovirus 71. RESULTS: Out of enrolled 100 patients, 73 were of probable viral encephalitis. HSV1 (31.50%) was the commonest virus followed by Adenovirus (10.95%), Parvovirus (2.73%), JE virus (1.36%), Enterovirus (1.36%), EBV (1.36%), and mixed infection with HSV & EBV (1.36%). HSV 1 caused significant morbidity in children. The common computed tomography (CT) findings were hypodensities in the fronto- parietal lobe followed by cerebral edema. CONCLUSIONS: The landscape of AES in India has changed in the previous decade, and both outbreak investigations and surveillance studies have increasingly reported non-JEV etiologies; because of these findings there is a need to explore additional strategies to prevent AES beyond vector control and JEV vaccination.

Visceral Leishmaniasis-Optimum Treatment Options in Children.

Visceral leishmaniasis affects 200-400 thousands people annually worldwide. For last few decades, there has been a steady decline in the response to pentavalent antimonial (Sb), the drug that has been used for treating visceral leishmaniasis for almost a century. Oral miltefosine and amphotericin B are alternative drugs being been used in the treatment of leishmaniasis in children. Liposomal amphotericin B has the advantage over conventional amphotericin B is that higher doses can be given with fewer adverse effects. Liposomal amphotericin B in combination with other drugs is the preferred treatment option globally especially in Indian subcontinent. Combination therapy with multiple drugs should undergo larger clinical trials in children as these will shorten the duration of therapy, improve compliance and decrease both toxicity and drug resistance.

The Bedside Index for Severity in Acute Pancreatitis: a systematic review of prospective studies to determine predictive performance.

Background: predicting the development of severe disease has remained a major challenge in management of acute pancreatitis. The Bedside Index for Severity in Acute Pancreatitis (BISAP) is easy to calculate from the data available in the first 24 hours. Here, we performed a systematic review to determine the prognostic accuracy of the BISAP for severe acute pancreatitis (SAP). Methods: major databases of biomedical publications were searched during the first week of October 2015. Two independent reviewers searched records in two phases. Studies that reported prognostic accuracy of the BISAP for SAP from prospective cohorts were included. The pooled area under the receiver operating curve (AUC) was calculated. Results: Twelve studies were included for data-synthesis and methodology quality assessment was performed for 10. All the studies had enrolled consecutive patients, had a broad spectrum of the disease severity, reported explicit interpretation of the predictor, outcome of interest was well defined and had adequate follow-up. Blinded outcome assessment was reported in only one study. The pooled AUC was 0.85 (95% CI 0.80-0.90). There was significant heterogeneity, I2 86.6%. Studies using revised Atlanta classification in defining SAP had a pooled AUC of 0.92 (95% CI, 0.90-0.95), but heterogeneity persisted, I2 67%. Subgroup analysis based on rate of SAP (>20% vs <20%) did not eliminate the heterogeneity. Conclusion: the BISAP has very good predictive performance for SAP across different patient population and etiologies. Studies to evaluate the impact of incorporating the BISAP into clinical practice to improve outcome in acute pancreatitis are needed before adoption could be advocated with confidence.

Assessment for Efficacy of Additional Breathing Exercises Over Improvement in Health Impairment Due to Asthma Assessed using St. George's Respiratory Questionnaire.

BACKGROUND: Breathing exercises have been described to be useful in asthma management by few researchers in the past. OBJECTIVE: To assess the efficacy of breathing exercises (Pranayamas) added to regular optimal medications in asthma patients in improving health impairment using St. George's Respiratory Questionnaire (SGRQ). METHODS: Sixty stable asthma patients (34 females) receiving optimal treatment at our institute for 3 months or more as per the Global Initiative for Asthma guidelines were included in the study. They performed seven breathing exercises under supervision at yoga center of our institute for 3 months in addition to their regular medications. SGRQ (1 month symptoms version) was used to assess the quality of life before and after breathing exercises intervention for following subsets: Symptom score, activity score, impact score, and total score to assess the efficacy of breathing exercises. RESULTS: Of 60 asthma patients, 34 were females and 26 were males, and their mean age was 25.45 ± 5.41 years. Their baseline spirometric values were as follow: Forced expiratory volume in 1 s (FEV1) - 2.492 ± 0.358 L and peak expiratory flow rate (PEFR) - 283.82 ± 51.12 L/min. The SGRQ scores after breathing exercises intervention decreased from 45.98 ± 5.61 to 38.78 ± 4.92 for symptom subset, from 15.45 ± 3.33 to 12.34 ± 2.39 for activity subset, from 17.95 ± 4.22 to 12.12 ± 3.82 for impact subset, and from 25.83 ± 8.31 to 19.20 ± 7.09 for total scores. All these reductions were statistically highly significant (P < 0.001). Decrease in symptoms, activity, and total SGRQ scores each was significantly correlated with FEV1, FEV1/forced vital capacity (FVC) ratio, and PEFR; decrease in impact score was significantly related only with FEV1/FVC ratio. CONCLUSIONS: Breathing exercises significantly decreased all component scores of SGRQ, signifying a global improvement in health impairment due to asthma; this improvement was in addition to that was achieved with optimal asthma therapy alone.

PCR targeting IS6110 in diagnosing tuberculosis in children in comparison to MGIT culture.

BACKGROUND: Diagnosis of tuberculosis (TB) in children is difficult in children especially in extrapulmonary tuberculosis (EPTB). This study was conducted to evaluate the use of polymerase chain reaction (PCR) targeting IS6110 in the diagnosis of TB in children with pulmonary TB and EPTB and also to compare its performance with MGIT 960 culture and conventional microscopy. METHODS: A total of 142 cases (50 pulmonary, 92 extrapulmonary) of suspected TB patients <15 years of age were included in the study. The clinical specimens obtained from these cases were subjected to Ziehl-Neelsen staining (ZN), MGIT 960 TB culture and PCR targeting insertion sequence IS6110. Sensitivity and specificity of PCR were calculated in pulmonary and extrapulmonary specimens. The results were compared to MGIT culture. RESULTS: PCR targeting IS6110 sequence had sensitivity of 69.01% in various clinical specimens which was significantly more than MGIT culture showing a sensitivity of 47.41% (p<0.05). Sensitivity of PCR IS6110 in extrapulmonary specimens was 65.21% which was lower than sensitivity in pulmonary specimens (76%) but was not statistically significant (p>0.05). CONCLUSIONS: Diagnostic efficacy of PCR IS6110 in pulmonary and extrapulmonary TB cases was similar. PCR using IS6110 primer had significantly better efficiency than MGIT culture in diagnosing TB in children.

GeneXpert for Diagnosis of Tubercular Meningitis.

Diagnosis of tubercular meningitis (TBM) is difficult in children. The GeneXpert MTB/RIF assay has been recommended by WHO in 2013 to be used in children and in extra pulmonary clinical specimens. The present study was designed to assess the diagnostic utility of GeneXpert in detecting Mycobacterium tuberculosis in cerebrospinal fluid (CSF) in TBM cases and to compare the results with liquid culture BACTEC 460. Thirty four subjects <15 y were diagnosed as TBM based on clinical, CSF and imaging details. Sensitivity of GeneXpert in CSF was 38.24 % as compared to Bactec culture which was only 14.71 % (p 0.0279). To conclude, GeneXpert MTB/RIF test is able to rapidly confirm diagnosis of TBM with higher sensitivity as compared to conventional methods and liquid culture.

Low Serum Concentrations of Rifampicin and Pyrazinamide Associated with Poor Treatment Outcomes in Children with Tuberculosis Related to HIV Status.

OBJECTIVES: To compare the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) between HIV-infected and HIV-uninfected children with tuberculosis (TB) and correlate it with TB treatment outcome. METHODS: HIV-uninfected (n = 84) and HIV-infected (n = 77) children with TB receiving standard thrice weekly treatment were recruited from 6 hospitals in India. Semi-intensive pharmacokinetic sampling was performed during intensive phase of TB treatment after directly observed administration of drugs. Drug concentrations were measured by high performance liquid chromatography. INH acetylator status was determined, and nutritional assessment was done. Children were followed-up and treatment outcomes noted. RESULTS: Children with HIV and TB had significantly lower RMP peak concentration (Cmax) (2.6 vs. 5.1 µg/mL; P < 0.001) and exposure [area under the time-concentration curve (AUC0-8); 10.4 vs. 23.4 µg/mL h; P < 0.001] than those with TB. Among HIV-infected children, a significantly higher proportion had stunting (77% vs. 29%; P < 0.001) and underweight (73% vs. 38%; P < 0.001) compared with children with TB. Combining both groups, RMP Cmax (P = 0.001; adjusted odds ratio = 1.437; 95% confidence interval: 1.157-1.784) and PZA Cmax (P = 0.027; adjusted odds ratio = 1.041; 95% confidence interval: 1.005-1.079) significantly influenced treatment outcome. CONCLUSIONS: HIV infection was associated with lower Cmax of RMP and INH and AUC0-8 of RMP. Over 90% of children in both groups had subtherapeutic RMP Cmax. Cmax of RMP and PZA significantly influenced TB treatment outcome in children with TB. The findings have important clinical implications and suggest the need to increase anti-TB drug doses in children with HIV and TB.

Fever in Children and Fever of Unknown Origin.

Fever is the most common symptom in children and can be classified as fever with or without focus. Fever without focus can be less than 7 d and is subclassified as fever without localizing signs and fever of unknown origin (FUO). FUO is defined as a temperature greater than 38.3 °C, for more than 3 wk or failure to reach a diagnosis after 1 wk of inpatient investigations. The most common causes of FUO in children are infections, connective tissue disorders and neoplasms. Infectious diseases most commonly implicated in children with FUO are salmonellosis, tuberculosis, malaria and rickettsial diseases. Juvenile rheumatic arthritis is the connective tissue disease frequently associated with FUO. Malignancy is the third largest group responsible for FUO in children. Diagnostic approach of FUO includes detailed history and examination supported with investigations. Age, history of contact, exposure to wild animals and medications should be noted. Examination should include, apart from general appearance, presence of sweating, rashes, tonsillitis, sinusitis and lymph node enlargement. Other signs such as abdominal tenderness and hepatosplenomegly should be looked for. The muscles and bones should be carefully examined for connective tissue disorders. Complete blood count, blood smear examination and level of acute phase reactants should be part of initial investigations. Radiological imaging is useful aid in diagnosing FUO. Trials of antimicrobial agents should not be given as they can obscure the diagnosis of the disease in FUO.