Journal Article > ResearchFull Text
BMC Infect Dis. 22 March 2025; Volume 25 (Issue 1); 396.; DOI:10.1186/s12879-025-10732-w
Rasti R, Kumbakumba E, Nanjebe D, Mlotshwa P, Nassejje M, et al.
BMC Infect Dis. 22 March 2025; Volume 25 (Issue 1); 396.; DOI:10.1186/s12879-025-10732-w
BACKGROUND
In low-resource settings, limited laboratory capacity adds to the burden of central nervous system (CNS) infections in children and spurs overuse of antibiotics. The commercially available BioFire® FilmArray® Meningitis/Encephalitis Panel (FA-ME) with its capability to simultaneously detect 14 pathogens in cerebrospinal fluid (CSF), could potentially narrow such a diagnostic gap.
METHODS
In Mbarara, Uganda, we compared clinical utility (clinical turnaround time [cTAT], microbial yield, and influence on patient outcome and antibiotic exposure) of FA-ME with bacterial culture, in children 0–12 years with suspected CNS infection.
RESULTS
Of 212 enrolled children, CSF was sampled from 194. All samples underwent bacterial culture, of which 193 also underwent FA-ME analyses. FA-ME analyses prospectively influenced care for 169 of the 193 patients, and they constituted an ‘Index group’. The remaining 43/212 patients constituted a ‘Reference group’. Of all 194 CSF-sampled patients, 87% (168) had received antibiotics before lumbar puncture. Median cTAT for FA-ME was 4.2 h, vs. two days for culture. Bacterial yield was 12% (24/193) and 1.5% (3/194) for FA-ME and culture, respectively. FA-ME viral yield was 12% (23/193). Fatality rate was 14% in the Index group vs. 19% in the Reference group (P = 0.20). From clinician receival of FA-ME results, median antibiotic exposure was 6 days for bacteria-negative vs. 13 days for bacteria-positive patients (P = 0.03). Median hospitalization duration was 7 vs. 12 days for FA-ME negative and positive patients, respectively (P < 0.01).
CONCLUSIONS
In this setting, clinical FA-ME utility was found in a higher and faster microbial yield and shortened hospitalization and antibiotic exposure of patients without CSF pathology. More epidemiologically customized pathogen panels may increase FA-ME utility locally, although its use in similar settings would require major cost reductions.
Journal Article > ResearchAbstract
Pediatr Infect Dis J. 2 August 2017; Volume 37 (Issue 2); 147-152.; DOI:10.1097/INF.0000000000001727
Bonnet MMB, Nansumba M, Bastard M, Orikiriza P, Kyomugasho N, et al.
Pediatr Infect Dis J. 2 August 2017; Volume 37 (Issue 2); 147-152.; DOI:10.1097/INF.0000000000001727
BACKGROUND
Mortality among children with presumptive tuberculosis (TB) empiric TB treatment can be high. We describe the predictors of death among children with presumptive TB, and the relation between treatment and mortality.
METHODS
A prospective cohort of children with presumptive TB who underwent clinical assessment, chest radiograph, tuberculin skin test and sputum bacterial tests for TB was followed up for 3 months. TB diagnosis was based on mycobacterial, clinical and radiologic findings. Predictors of deaths were determined using cox regression model.
RESULTS
Of 360 children included in the analysis, 31.4% were younger than 2 years; 31.6% were HIV infected and 11.3% were severely malnourished. One hundred forty (38.9%) were diagnosed with TB, 18 (13%) of whom were bacteriologically confirmed. At 3 months of follow up, 25 of 360 (6.9%) children had died: 15 of 140 (10.7%) were receiving TB treatment versus 10 of 220 (4.5%) were not receiving treatment (P = 0.025). Severely malnourished children [adjusted hazard ratio (aHR), 9.86; 95% confidence interval (CI): 3.11-31.23] and those with chest radiographs suggestive of TB (aHR, 4.20; 95% CI: 0.93-19.01) were more likely to die. Children receiving empiric TB treatment had an increased risk of death (aHR, 2.37; 95% CI: 1.01-5.55) compared with children without treatment after adjustment for age, sex, HIV status and Bacillus Calmette-Guérin (BCG) vaccination.
CONCLUSIONS
The high mortality in children receiving empirically TB treatment highlights the difficulty in diagnosing childhood TB, the increased likelihood of starting treatment in critically ill children and in children with chronic disease, and the possibility of misdiagnosis. It strengthens the need to invest further in early TB detection and diagnosing nonsevere illness.
Mortality among children with presumptive tuberculosis (TB) empiric TB treatment can be high. We describe the predictors of death among children with presumptive TB, and the relation between treatment and mortality.
METHODS
A prospective cohort of children with presumptive TB who underwent clinical assessment, chest radiograph, tuberculin skin test and sputum bacterial tests for TB was followed up for 3 months. TB diagnosis was based on mycobacterial, clinical and radiologic findings. Predictors of deaths were determined using cox regression model.
RESULTS
Of 360 children included in the analysis, 31.4% were younger than 2 years; 31.6% were HIV infected and 11.3% were severely malnourished. One hundred forty (38.9%) were diagnosed with TB, 18 (13%) of whom were bacteriologically confirmed. At 3 months of follow up, 25 of 360 (6.9%) children had died: 15 of 140 (10.7%) were receiving TB treatment versus 10 of 220 (4.5%) were not receiving treatment (P = 0.025). Severely malnourished children [adjusted hazard ratio (aHR), 9.86; 95% confidence interval (CI): 3.11-31.23] and those with chest radiographs suggestive of TB (aHR, 4.20; 95% CI: 0.93-19.01) were more likely to die. Children receiving empiric TB treatment had an increased risk of death (aHR, 2.37; 95% CI: 1.01-5.55) compared with children without treatment after adjustment for age, sex, HIV status and Bacillus Calmette-Guérin (BCG) vaccination.
CONCLUSIONS
The high mortality in children receiving empirically TB treatment highlights the difficulty in diagnosing childhood TB, the increased likelihood of starting treatment in critically ill children and in children with chronic disease, and the possibility of misdiagnosis. It strengthens the need to invest further in early TB detection and diagnosing nonsevere illness.
Journal Article > ResearchFull Text
Clin Microbiol Infect. 8 May 2018; Volume 37 (Issue 8); 1465-1473.; DOI:10.1007/s10096-018-3272-0
Orikiriza P, Nansumba M, Nyehangane D, Bastard M, Mugisha IT, et al.
Clin Microbiol Infect. 8 May 2018; Volume 37 (Issue 8); 1465-1473.; DOI:10.1007/s10096-018-3272-0
The Xpert MTB/RIF assay is a major advance for diagnosis of tuberculosis (TB) in high-burden countries but is limited in children by their difficulty to produce sputum. We investigated TB in sputum and stool from children with the aim of improving paediatric TB diagnosis. A prospective cohort of children with presumptive TB, provided two sputum or induced sputum at enrolment in a regional referral hospital in Uganda. Stool was collected from those started on TB treatment. All specimen were tested for Xpert MTB/RIF, mycobacteria growth indicator tube (MGIT), Lowenstein Jensen cultures and microscopy (except stool). We compared TB detection between age categories and assessed the performance of Xpert MTB/RIF in sputum and stool. Of the 392 children enrolled, 357 (91.1%) produced at least one sputum sample. Sputum culture yield was 13/357 (3.6%): 3/109 (2.6%), 3/89 (3.2%), 3/101 (2.6%) and 4/44 (8.2%) among children of < 2, 2-5, ≥ 5-10 and > 10 years, respectively (p = 0.599). Xpert MTB/RIF yield was 14/350 (4.0%): 3/104 (2.9%), 4/92 (4.3%), 3/88 (2.9%) and 4/50 (.0%), respectively (p = 0.283). Sensitivity and specificity of Xpert MTB/RIF in sputum against sputum culture were 90.9% (95% CI 58.7-99.8) and 99.1% (99.1-99.8). In stool, it was 55.6% (21.2-86.3) and 98.2% (98.2-100) against Xpert MTB/RIF and culture in sputum. Only a minority of children had microbiologically confirmed TB with a higher proportion in children above 10 years. Although sensitivity of Xpert MTB/RIF in stool was low, with good optimization, it might be a good alternative to sputum in children.
Protocol > Research Protocol
JMIR Res Protoc. 4 November 2020; Volume 9 (Issue 11); e21430.; DOI:10.2196/21430
Gaudenzi G, Kumbakumba E, Rasti R, Nanjebe D, Reu P, et al.
JMIR Res Protoc. 4 November 2020; Volume 9 (Issue 11); e21430.; DOI:10.2196/21430
BACKGROUND
A timely differential diagnostic is essential to identify the etiology of central nervous system (CNS) infections in children, in order to facilitate targeted treatment, manage patients, and improve clinical outcome.
OBJECTIVE
The Pediatric Infection-Point-of-Care (PI-POC) trial is investigating novel methods to improve and strengthen the differential diagnostics of suspected childhood CNS infections in low-income health systems such as those in Southwestern Uganda. This will be achieved by evaluating (1) a novel DNA-based diagnostic assay for CNS infections, (2) a commercially available multiplex PCR-based meningitis/encephalitis (ME) panel for clinical use in a facility-limited laboratory setting, (3) proteomics profiling of blood from children with severe CNS infection as compared to outpatient controls with fever yet not severely ill, and (4) Myxovirus resistance protein A (MxA) as a biomarker in blood for viral CNS infection. Further changes in the etiology of childhood CNS infections after the introduction of the pneumococcal conjugate vaccine against Streptococcus pneumoniae will be investigated. In addition, the carriage and invasive rate of Neisseria meningitidis will be recorded and serotyped, and the expression of its major virulence factor (polysaccharide capsule) will be investigated.
METHODS
The PI-POC trial is a prospective observational study of children including newborns up to 12 years of age with clinical features of CNS infection, and age-/sex-matched outpatient controls with fever yet not severely ill. Participants are recruited at 2 Pediatric clinics in Mbarara, Uganda. Cerebrospinal fluid (for cases only), blood, and nasopharyngeal (NP) swabs (for both cases and controls) sampled at both clinics are analyzed at the Epicentre Research Laboratory through gold-standard methods for CNS infection diagnosis (microscopy, biochemistry, and culture) and a commercially available ME panel for multiplex PCR analyses of the cerebrospinal fluid. An additional blood sample from cases is collected on day 3 after admission. After initial clinical analyses in Mbarara, samples will be transported to Stockholm, Sweden for (1) validation analyses of a novel nucleic acid–based POC test, (2) biomarker research, and (3) serotyping and molecular characterization of S. pneumoniae and N. meningitidis.
RESULTS
A pilot study was performed from January to April 2019. The PI-POC trial enrollment of patients begun in April 2019 and will continue until September 2020, to include up to 300 cases and controls. Preliminary results from the PI-POC study are expected by the end of 2020.
CONCLUSIONS
The findings from the PI-POC study can potentially facilitate rapid etiological diagnosis of CNS infections in low-resource settings and allow for novel methods for determination of the severity of CNS infection in such environment.
A timely differential diagnostic is essential to identify the etiology of central nervous system (CNS) infections in children, in order to facilitate targeted treatment, manage patients, and improve clinical outcome.
OBJECTIVE
The Pediatric Infection-Point-of-Care (PI-POC) trial is investigating novel methods to improve and strengthen the differential diagnostics of suspected childhood CNS infections in low-income health systems such as those in Southwestern Uganda. This will be achieved by evaluating (1) a novel DNA-based diagnostic assay for CNS infections, (2) a commercially available multiplex PCR-based meningitis/encephalitis (ME) panel for clinical use in a facility-limited laboratory setting, (3) proteomics profiling of blood from children with severe CNS infection as compared to outpatient controls with fever yet not severely ill, and (4) Myxovirus resistance protein A (MxA) as a biomarker in blood for viral CNS infection. Further changes in the etiology of childhood CNS infections after the introduction of the pneumococcal conjugate vaccine against Streptococcus pneumoniae will be investigated. In addition, the carriage and invasive rate of Neisseria meningitidis will be recorded and serotyped, and the expression of its major virulence factor (polysaccharide capsule) will be investigated.
METHODS
The PI-POC trial is a prospective observational study of children including newborns up to 12 years of age with clinical features of CNS infection, and age-/sex-matched outpatient controls with fever yet not severely ill. Participants are recruited at 2 Pediatric clinics in Mbarara, Uganda. Cerebrospinal fluid (for cases only), blood, and nasopharyngeal (NP) swabs (for both cases and controls) sampled at both clinics are analyzed at the Epicentre Research Laboratory through gold-standard methods for CNS infection diagnosis (microscopy, biochemistry, and culture) and a commercially available ME panel for multiplex PCR analyses of the cerebrospinal fluid. An additional blood sample from cases is collected on day 3 after admission. After initial clinical analyses in Mbarara, samples will be transported to Stockholm, Sweden for (1) validation analyses of a novel nucleic acid–based POC test, (2) biomarker research, and (3) serotyping and molecular characterization of S. pneumoniae and N. meningitidis.
RESULTS
A pilot study was performed from January to April 2019. The PI-POC trial enrollment of patients begun in April 2019 and will continue until September 2020, to include up to 300 cases and controls. Preliminary results from the PI-POC study are expected by the end of 2020.
CONCLUSIONS
The findings from the PI-POC study can potentially facilitate rapid etiological diagnosis of CNS infections in low-resource settings and allow for novel methods for determination of the severity of CNS infection in such environment.
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 1 February 2018; Volume 22 (Issue 2); 151-157.; DOI:10.5588/ijtld.17.0535
Nansumba M, Kumbakumba E, Orikiriza P, Bastard M, Mwanga JP, et al.
Int J Tuberc Lung Dis. 1 February 2018; Volume 22 (Issue 2); 151-157.; DOI:10.5588/ijtld.17.0535
BACKGROUND
In 2010, the World Health Organization (WHO) revised the paediatric dosages of anti-tuberculosis drugs, increasing rifampicin to 15 mg/kg, isoniazid to 10 mg/kg and pyrazinamide to 35 mg/kg. We assessed treatment outcomes, safety and adherence among children treated with the new recommended dosages.
METHODS
Prospective cohort of children started on anti-tuberculosis treatment in Uganda with 12 months of follow-up, including alanine aminotransferase (ALT) monitoring. Treatment intake was observed.
RESULTS
Of 144 treated children, 81 were male (56.3%), 106 (73.6%) were aged <5 years, 30 (22%) had moderate to severe malnutrition and 48 (33.3%) had human immunodeficiency virus infection. Treatment outcomes were as follows: 117 (81.3%) successes, 3 (2.1%) failures, 4 (2.8%) lost to follow-up, 19 (13.2%) deaths and 1 (0.7%) transferred out. There was no relapse. Severe malnutrition (adjusted hazard ratio 8.76, 95% confidence interval [CI] 1.59–48.25) was the only predictor of death. Two serious adverse events were attributed to treatment: one case of increased ALT and one with peripheral neuropathy. Median ALT values at baseline and at weeks 2, 4 and 8 were respectively 24 (interquartile range [IQR] 16–39), 26 (IQR 18–38), 28 (IQR 21–40) and 27 (IQR 19–38) international units/l. Treatment adherence was above 85% on all visits.
CONCLUSION
We confirm the good tolerability of and adherence to the new treatment recommendations. The increased risk of fatal outcome among severely malnourished children requires attention.
In 2010, the World Health Organization (WHO) revised the paediatric dosages of anti-tuberculosis drugs, increasing rifampicin to 15 mg/kg, isoniazid to 10 mg/kg and pyrazinamide to 35 mg/kg. We assessed treatment outcomes, safety and adherence among children treated with the new recommended dosages.
METHODS
Prospective cohort of children started on anti-tuberculosis treatment in Uganda with 12 months of follow-up, including alanine aminotransferase (ALT) monitoring. Treatment intake was observed.
RESULTS
Of 144 treated children, 81 were male (56.3%), 106 (73.6%) were aged <5 years, 30 (22%) had moderate to severe malnutrition and 48 (33.3%) had human immunodeficiency virus infection. Treatment outcomes were as follows: 117 (81.3%) successes, 3 (2.1%) failures, 4 (2.8%) lost to follow-up, 19 (13.2%) deaths and 1 (0.7%) transferred out. There was no relapse. Severe malnutrition (adjusted hazard ratio 8.76, 95% confidence interval [CI] 1.59–48.25) was the only predictor of death. Two serious adverse events were attributed to treatment: one case of increased ALT and one with peripheral neuropathy. Median ALT values at baseline and at weeks 2, 4 and 8 were respectively 24 (interquartile range [IQR] 16–39), 26 (IQR 18–38), 28 (IQR 21–40) and 27 (IQR 19–38) international units/l. Treatment adherence was above 85% on all visits.
CONCLUSION
We confirm the good tolerability of and adherence to the new treatment recommendations. The increased risk of fatal outcome among severely malnourished children requires attention.
Journal Article > ResearchFull Text
Pediatr Infect Dis J. 1 February 2016; Volume 35 (Issue 2); 146-151.; DOI:10.1097/INF.0000000000000956
Nansumba M, Kumbakumba E, Orikiriza P, Muller Y, Nackers F, et al.
Pediatr Infect Dis J. 1 February 2016; Volume 35 (Issue 2); 146-151.; DOI:10.1097/INF.0000000000000956
BACKGROUND
Difficulty to obtain sputum in children complicates diagnosis of intrathoracic tuberculosis (TB). The intragastric string test (ST) used for retrieval of enteric pathogens might be an alternative specimen collection method but requires further evaluation of its utility in TB diagnosis. We conducted a cross-sectional study comparing the TB detection yield and the tolerability of ST and sputum induction (SI) in children.
METHODS
Two ST and SI procedures were performed in children (3–14 years of age) who were clinically suspected of having TB. The string was removed after a 2-hour gastric downtime, and SI was done after a maximum of 20 minutes nebulization with 5% saline solution. LED-fluorescence microscopy and mycobacterial cultures were performed on all specimens, and XpertMTB/RIF assay was performed on stored specimen sediments. Tolerability questionnaires were administered to parents of children.
RESULTS
Of 137 included children (median age: 8.1 years; 33.3% with HIV infection), 14 (10.2%) were diagnosed with TB, 10 (71.4%) by ST and 12 (85.7%) by SI. Among 105 children with both ST and SI performed, 5 (4.8%) versus 4 (3.8%) were smear positive using ST and SI, respectively (McNemar P = 1.00). Nine (8.6%) in each group had positive cultures (P = 1.00). Of 64 children tested with XpertMTB/RIF, 3 (4.7%) of the ST group versus 4 (6.3%) of the SI group were TB positive (P = 1.00). No adverse serious events were reported. ST could not be performed in 22 of 137 (16.1%) children because they were unable to swallow the capsule.
CONCLUSIONS
TB detection yield was comparable between ST and SI. The tolerability of ST in young children might be improved by the reduction of the size of the capsule.
Difficulty to obtain sputum in children complicates diagnosis of intrathoracic tuberculosis (TB). The intragastric string test (ST) used for retrieval of enteric pathogens might be an alternative specimen collection method but requires further evaluation of its utility in TB diagnosis. We conducted a cross-sectional study comparing the TB detection yield and the tolerability of ST and sputum induction (SI) in children.
METHODS
Two ST and SI procedures were performed in children (3–14 years of age) who were clinically suspected of having TB. The string was removed after a 2-hour gastric downtime, and SI was done after a maximum of 20 minutes nebulization with 5% saline solution. LED-fluorescence microscopy and mycobacterial cultures were performed on all specimens, and XpertMTB/RIF assay was performed on stored specimen sediments. Tolerability questionnaires were administered to parents of children.
RESULTS
Of 137 included children (median age: 8.1 years; 33.3% with HIV infection), 14 (10.2%) were diagnosed with TB, 10 (71.4%) by ST and 12 (85.7%) by SI. Among 105 children with both ST and SI performed, 5 (4.8%) versus 4 (3.8%) were smear positive using ST and SI, respectively (McNemar P = 1.00). Nine (8.6%) in each group had positive cultures (P = 1.00). Of 64 children tested with XpertMTB/RIF, 3 (4.7%) of the ST group versus 4 (6.3%) of the SI group were TB positive (P = 1.00). No adverse serious events were reported. ST could not be performed in 22 of 137 (16.1%) children because they were unable to swallow the capsule.
CONCLUSIONS
TB detection yield was comparable between ST and SI. The tolerability of ST in young children might be improved by the reduction of the size of the capsule.