Pneumonia in childhood bacterial meningitis-Experience from three continents.

INTRODUCTION: Although concomitant pneumonia is sometimes diagnosed in childhood bacterial meningitis, its role in the illness course and prognosis is not known. We examined these associations using prospectively collected data from Finland, Latin America and Angola. METHODS: This was a secondary descriptive analysis of prospectively collected data (clinical and laboratory findings at admission, during hospitalisation and outcome) from five clinical bacterial meningitis trials. We included children aged 2 months to 15 years from sites with confirmed bacterial meningitis and potential concomitant pneumonia (diagnosed clinically with or without a chest radiograph). RESULTS: Pneumonia was not observed in the 341 children included in Finland. Pneumonia was observed in 8% (51/606) of children in Latin America and in 46% (377/819) in Angola (p < 0.0001). In multivariate analyses, predisposing factors for pneumonia in Latin America were age <1 year, seizures and severe anaemia; the corresponding factors for Angola were preadmission duration of illness >3 days and non-meningococcal meningitis. Concomitant pneumonia increased the severity of the disease and disabling sequelae. CONCLUSION: Bacterial meningitis with pneumonia is a major, previously undescribed entity of severe bacterial meningitis, especially in Angola.

Seizures, focal neurological signs, and pneumococcal aetiology associate with impaired consciousness in childhood bacterial meningitis.

AIM: A low Glasgow Coma Scale Score (GCS) on admission is a known predictor of poor outcome from childhood bacterial meningitis. In turn, the factors associated with the admission GCS are less known. Our aim was to identify them, both for clinical alerts of reserved prognosis and to find potential targets for intervention. METHODS: This study is a secondary analysis of data collected prospectively in Angola and in Latin America between 1996 and 2007. Children with bacterial meningitis were examined on hospital admission and their GCS was assessed using the age-adjusted scale. Associations between on-admission GCS and host clinical factors were examined. RESULTS: A total of 1376 patients with confirmed bacterial meningitis were included in the analysis (609 from Latin America and 767 from Angola). The median GCS was 13 for all patients (12 in Angola and 13 in Latin America). In the multivariate analysis, in the areas combined, seizures, focal neurological signs, and pneumococcal aetiology associated with GCS <13, as did treatment delay in Latin America. CONCLUSION: Besides pneumococcal aetiology, we identified characteristics, easily registrable on admission, which are associated with a low GCS in childhood bacterial meningitis. Of these, expanding pneumococcal vaccinations and treatment delays could be modified.

PCR-confirmed malaria among children presenting with a decreased level of consciousness in Angola: a prospective, observational study.

BACKGROUND: In malaria-endemic areas, children presenting to hospitals with a decreased level of consciousness remain a diagnostic dilemma. The definition of cerebral malaria in a comatose child demands exclusion of other possible reasons, which requires in-depth investigations that are not easily available. The aim of this study was to investigate the frequency and clinical characteristics of PCR-confirmed malaria in a cohort of children with a decreased level of consciousness, look for potential features that would aid in differentiating children with malaria from those without, and assess the performance of traditional thick film microscopy against the cytb-qPCR-method. METHODS: A total of 345 children aged 30 days-15 years old, presenting to Hospital Pediátrico David Bernardino in Luanda, Angola, with a decreased level of consciousness (Glasgow coma scale score < 15) were prospectively enrolled during 2014-2017. Malaria was defined as a positive cytb-qPCR result on any occasion in hospital. The clinical course and laboratory parameters were compared between children with malaria and those without. The performance of thick film microscopy was analysed against the PCR method. RESULTS: 161 of 345 children (46.7%) had a positive malaria PCR test result. All cases were Plasmodium falciparum species, and 82.6% (133/161) fulfilled the WHO criteria for severe malaria. Overall, children with malaria presented to hospital with a shorter duration of symptoms and less convulsions pre-admission compared to those without malaria. The median GCS score on admission was 8, which did not differ between children with or without malaria. Clinical findings on admission were mostly similar across the whole cohort, but an infection focus outside the central nervous system was more common in malaria-negative children. Moreover, severe anaemia, thrombocytopenia, and high CRP levels occurred more frequently in children with malaria. The case fatality ratio was 28.5% (91/319) and did not differ between parasitaemic children and those without malaria, although parasitaemic children died sooner after hospital admission. When neurological sequelae were also considered, a positive malaria test was associated with a better outcome. The performance of thick film microscopy against PCR yielded a sensitivity of 96.8% and a specificity of 82.7%. CONCLUSIONS: In this cohort of children with a decreased consciousness, the frequent presence of a malarial infection could not be judged from the clinical findings on admission, but the combination of profound aneamia, thrombocytopenia, and a high CRP level increased the odds of a positive malaria test result. Mortality remained high regardless of etiology, but malaria infection associated with fewer neurological deficits at discharge. Thick film microscopy performed well compared to the cytb-qPCR method.

Unusual Gram-negative bacteria cause more severe bacterial meningitis than the three classical agents in children.

AIM: To compare the characteristics, mortality and sequelae at hospital discharge of childhood bacterial meningitis (BM) caused by the three "classical" agents Neisseria meningitidis, Haemophilus influenzae or Streptococcus pneumoniae versus BM due to other aetiology in Finland, Latin America and Angola. METHODS: This observational study is a secondary analysis of data from five prospective treatment trials on non-neonatal BM in Finland, Latin America and Angola in 1984-2017. RESULTS: Of the 1568 cases, 1459 (93%) were caused by the classics, 80 (5%) by other Gram-negative and 29 (2%) by other Gram-positive bacteria. Nonclassical Gram-negative disease was encountered especially in Angola (p < 0.0001). Overall, children in the nonclassical group presented later for treatment and were more often underweight and anaemic (p < 0.001). In multivariate analysis, even if the area was strongest predictor of poor outcome, nonclassical Gram-negative BM increased the odds for death twofold and the odds for death or severe sequelae 2.5-fold. CONCLUSION: BM of a nonclassical aetiology is a particularly severe disease affecting especially Angolan children poorly armoured to fight infections. Since vaccinations are diminishing the role of classical agents, that of nonclassical agents is growing.

Hearing impairment in Angolan children with acute bacterial meningitis with and without otitis media.

AIM: Bacterial meningitis (BM) is a common cause of hearing loss in childhood. Our aim was to investigate bacterial aetiology, hearing impairment and outcome in childhood BM with vs. without otitis media (OM) in Angola. METHODS: Hearing was tested by auditory brainstem response in 391 (76%) children with confirmed BM. The bacteria identified from the ear discharge were compared to those from cerebrospinal fluid (CSF). The hearing findings were compared among children with vs. without OM on days 1 and 7 of hospitalization, and at follow-ups of 1, 3 and 6 month(s). RESULTS: No correlation was found in bacteriology between the ear discharge and CSF. On day 7 in hospital, hearing impairment (>40 dB) was common, regardless of whether concomitant OM or not (in 27% vs. 30%, respectively). Any hearing deficit on day 7 was associated with a higher risk of complicated or fatal clinical course (OR 2.76, CI95% 1.43-5.29, p = 0.002). CONCLUSION: No significant difference prevailed in hearing thresholds between children with or without OM in hospital on day 7 or at later follow-ups. Any hearing impairment during hospital stay associated with a higher risk for complicated clinical course or death.

Extended Continuous ß-Lactam Infusion With Oral Acetaminophen in Childhood Bacterial Meningitis: A Randomized, Double-blind Clinical Trial.

BACKGROUND: In our previous study in Luanda, Angola, initial continuous ß-lactam infusion for 24 hours combined with oral acetaminophen for 48 hours showed promising results as a new treatment for childhood bacterial meningitis. We investigated whether extending this treatment regimen to 4 days would improve the outcomes further. METHODS: We conducted a randomized, double-blind, parallel-group study at the same hospital in Luanda. Children aged 2 months to 15 years presenting to hospital with symptoms and signs of bacterial meningitis were randomized to receive, for the first 4 days, a continuous infusion of cefotaxime (250 mg/kg/day) with simultaneous oral acetaminophen (first dose 30 mg/kg, then 20 mg/kg every 6 hours), or cefotaxime conventionally as boluses (62.5 mg/kg, 4 times per day) with placebo orally. All children received also glycerol orally. The primary outcome was mortality by day 7. RESULTS: In all, 375 patients were included in the study between 22 January 2012 and 21 January 2017. As 2 children succumbed before treatment initiation, 187 vs 186 participants remained in the intervention and control groups, respectively. On day 7, 61 of 187 (32.6%) children in the intervention group vs 64 of 186 (34.4%) in the control group had died (risk ratio, 0.95 [95% confidence interval {CI}, .71-1.26]; absolute risk difference, 1.8% [95% CI, -7.8 to 11.4]). At discharge from hospital, the corresponding numbers were 71 of 187 (38.0%) and 75 of 186 (40.3%), respectively. CONCLUSIONS: Prolonged continuous ß-lactam infusion combined with oral acetaminophen did not improve the gloomy outcomes of childhood bacterial meningitis in Angola. CLINICAL TRIALS REGISTRATION: NCT01540838.

Suppurative otitis media in Angola: clinical and demographic features.

OBJECTIVE: To describe the demographics and clinical findings in patients with otorrhoea in Angola. METHODS: A total of 411 patients with otorrhoea presenting in the ear, nose and throat clinic in Luanda and healthcare centres in other Angolan provinces underwent interview and clinical examination. We describe the demographics and clinical characteristics of the patients. RESULTS: The majority (64%) of patients were children <15 years (age ranged from 1 month to 77 years; median age 10.9 years) while 31% were children <5 years. In 83% of the patients, otorrhoea had lasted >14 days at the time of the examination indicating chronic suppurative otitis media (CSOM), which was confirmed with otoscopy in 72% of patients. Acute otitis media occurred in 16% of patients and was more common in children than in adults (22% vs. 10%; P = 0.007). Median duration of otorrhoea was >12 months. Earache (67%), fever (20%), dizziness (17%), nausea and/or vomiting (6%) were the main symptoms. Adult patients reported noticing hearing impairment (HI) more often than the parents of child patients (72% vs. 50%; P < 0.0001). Reported HI correlated with otorrhoea duration (P < 0.0001), presence of earache, dizziness, and measles or meningitis in history. The level of education in the family did not correlate with symptom duration. CONCLUSIONS: Otorrhoea is mainly due to CSOM and affects patients long-term in Angola. Otorrhoea duration is the strongest predictor of HI. Education on OM and its treatment is needed to prevent HI.

OBJECTIF: Décrire les données démographiques et les résultats cliniques chez les patients atteints d'otorrhée en Angola. MÉTHODES: Au total, 411 patients atteints d'otorrhée visitant la clinique ORL à Luanda et dans les centres de soins de santé d'autres provinces angolaises ont subi un entretien et un examen clinique. Nous décrivons les caractéristiques démographiques et cliniques des patients. RÉSULTATS: La majorité (64%) des patients étaient des enfants <15 ans (tranche d'âge de 1 mois à 77 ans; âge médian de 10,9 ans) tandis que 31% étaient des enfants <5 ans. Chez 83% des patients, l'otorrhée avait duré >14 jours au moment de l'examen indiquant une otite moyenne suppurée chronique (OMSC), qui a été confirmée par otoscopie chez 72% des patients. Une otite moyenne aiguë est survenue chez 16% des patients et était plus fréquente chez les enfants que chez les adultes (22% vs 10%; P = 0,007). La durée médiane de l'otorrhée était >12 mois. Les maux d'oreille (67%), la fièvre (20%), les étourdissements (17%), les nausées et/ou les vomissements (6%) étaient les principaux symptômes. Les patients adultes ont rapporté avoir remarqué une déficience auditive (DA) plus souvent que les parents d'enfants patients (72% vs 50%; P < 0,0001). La DA rapportée était en corrélation avec la durée de l'otorrhée (P < 0,0001), la présence de maux d'oreille, d'étourdissements et de rougeole ou de méningite dans les antécédents. Le niveau d'éducation dans la famille n'était pas corrélé à la durée des symptômes. CONCLUSIONS: L'otorrhée est principalement due à l'OMSC et affecte les patients à long terme en Angola. La durée de l'otorrhée est le meilleur prédicteur de la DA. L'éducation sur l'OM et son traitement est nécessaire pour prévenir la DA.

The Potential Role of Matrix Metalloproteinases 8 and 9 and Myeloperoxidase in Predicting Outcomes of Bacterial Meningitis of Childhood.

BACKGROUND: Matrix metalloproteinases (MMPs) and myeloperoxidase (MPO) contribute to the inflammatory cascade in the cerebrospinal fluid (CSF) during bacterial meningitis. We determined levels of MPO, MMP-8, MMP-9, and tissue inhibitor of metalloproteinase- (TIMP-) 1 in the CSF of children with bacterial meningitis and investigated how these inflammatory mediators relate to each other and to the disease outcomes. METHODS: Clinical data and the diagnostic CSF samples from 245 children (median age eight months) with bacterial meningitis were obtained from a clinical trial in Latin America in 1996-2003. MMP-9 levels in the CSF were assessed by zymography, while MMP-8, MPO, and TIMP-1 concentrations were determined with immunofluorometric and enzyme-linked immunosorbent assays. RESULTS: MPO correlated positively with MMP-8 (rho 0.496, P < 0.001) and MMP-9 (rho 0.153, P = 0.02) but negatively with TIMP-1 (rho -0.361, P < 0.001). MMP-8 emerged as the best predictor of disease outcomes: a CSF MMP-8 concentration above the median increased the odds of death 4.9-fold (95% confidence interval 1.8-12.9). CONCLUSIONS: CSF MMP-8 presented as an attractive prognostic marker in children with bacterial meningitis.

Vitamin D was not associated with survival or cerebrospinal fluid cathelicidin levels in children with bacterial meningitis.

AIM: Vitamin D deficiency impairs the immunological system and has been associated with worse outcomes of infectious diseases, but its role in bacterial meningitis remains unknown. We investigated whether serum 25-hydroxyvitamin D concentrations related to disease outcomes and to cerebrospinal fluid (CSF) cathelicidin concentrations in childhood bacterial meningitis. METHODS: All consecutively enrolled patients in a clinical trial on childhood bacterial meningitis in Latin America in 1996-2003 were considered, and 142 children, with a median age of seven months who had a confirmed bacterial aetiology and frozen serum available for further analyses, were included in this study. Serum 25-hydroxyvitamin D concentrations were determined with a chemiluminescence immunoassay analyser, while CSF cathelicidin was measured by enzyme-linked immunosorbent assay. RESULTS: The median serum 25-hydroxyvitamin D concentration was 96 (range 19-251) nmol/L. No relationship was found with patient survival, but children with any neurological sequelae had lower serum 25-hydroxyvitamin D levels than children without sequelae. Serum 25-hydroxyvitamin D was unrelated to cathelicidin concentrations in CSF. CONCLUSION: Although serum 25-hydroxyvitamin D in children with bacterial meningitis was not associated with survival or CSF cathelicidin concentrations, its relationship with more detailed disease outcomes warrants further study.

Fluoroquinolone-Resistant Alcaligenes faecalis Related to Chronic Suppurative Otitis Media, Angola.

We found that 20 (10.6%) of 188 patients with chronic suppurative otitis media in Angola were co-colonized with fluoroquinolone-resistant Alcaligenes faecalis, commonly found in birds. A likely explanation for our findings was the use of bird feces by residents as a traditional remedy to prevent ear secretions caused by primary ear infection.

Swiftly Decreasing Cerebrospinal Fluid Cathelicidin Concentration Predicts Improved Outcome in Childhood Bacterial Meningitis.

We investigated cerebrospinal fluid (CSF) cathelicidin concentrations in childhood bacterial meningitis on admission and during antimicrobial treatment. CSF cathelicidin concentrations on admission correlated with CSF white cell counts and protein levels but not with bacterial etiology. A greater decrease in the concentration in response to treatment was associated with a better outcome. Since the CSF cathelicidin concentration reflects the degree of central nervous system (CNS) inflammation, it may be used as a novel biomarker in childhood bacterial meningitis. An early decrease during treatment likely signals more rapid mitigation of the disease process and thus a better outcome.

Changes in MMP-9 and TIMP-1 Concentrations in Cerebrospinal Fluid after 1 Week of Treatment of Childhood Bacterial Meningitis.

We explored the changes of the initially highly upgraded cerebrospinal fluid matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of MMP 1 (TIMP-1) response during recovery of childhood bacterial meningitis and their association with outcome. The sizes of these changes varied substantially, but a steeper decrease in the MMP-9 and an increase of the TIMP-1 concentrations augured a better outcome.

Vaccine-induced waning of Haemophilus influenzae empyema and meningitis, Angola.

In Angola during 2003-2012, we detected Haemophilus influenzae in 18% of 2,634 and 26% of 2,996 bacteriologically positive pleural or cerebrospinal fluid samples, respectively, from children. After vaccination launch in 2006, H. influenzae empyema declined by 83% and meningitis by 86%. Severe H. influenzae pneumonia and meningitis are preventable by vaccination.

Gene polymorphisms of IL-17A and bacterial meningitis in Angolan children.

Interleukin (IL)-17 A plays a crucial role in protecting hosts from invading bacterial pathogens. In this study, we investigated if single nucleotide polymorphisms (SNPs) in IL-17A are associated with susceptibility and outcome of bacterial meningitis (BM) in Angolan children. The study sample comprised 241 confirmed BM patients and 265 controls, which were matched for age and ethnicity. Three IL-17A SNPs - rs2275913 (-197G > A), rs8193036 (-737C > T) and rs4711998 (-877 A > G) - were determined by high-resolution melting analysis (HRMA). The frequency of variant genotype rs4711998 was significantly higher in patients with BM caused by Haemophilus influenzae (odds ratio [OR] 3.5; 95% confidence interval [CI] 1.49-8.23; P = 0.0025) than in controls. Also, patients with BM caused by Gram-negative bacteria and who carried the variant genotype rs2275913 had a lower glucose level (P = 0.0051) in cerebrospinal fluid (CSF). Patients with BM caused by Streptococcus pneumoniae who carried the variant type rs8193036 had a reduced risk for severe neurological sequelae (OR: 0.14; 95% CI: 0.029-0.68; P = 0.0079), blindness (OR: 0.012; 95% CI: 0.012-0.87; P = 0.017) and ataxia (OR: 0.28; 95% CI: 0.091-0.83; P = 0.023). This study suggests an association of IL-17A genetic variations with susceptibility and outcome of bacterial meningitis in Angolan children.

Clinical Picture and Risk Factors for Poor Outcome in Streptococcus pneumoniae Meningitis of Childhood on Three Continents.

BACKGROUND: Streptococcus pneumoniae meningitis (SpM) remains a major health burden worldwide, particularly in low- and middle-income countries. Identifying the patients at highest risk for mortality and disabling sequelae may reveal potentially avoidable predisposing factors and identify patients most in need of intensive care. We searched for factors that do not require laboratory facilities. METHODS: This study was a secondary analysis of prospectively collected data from 5 clinical trials of childhood bacterial meningitis on 3 continents between 1984 and 2017. SpM cases were analyzed by study site and predictors for poor outcome (death or severe sequelae) were identified from the whole series, Latin America and Angola. RESULTS: Among a total of 1575 children (age range: 2 months to 15 years), 505 cases were due to pneumococci. Compared to other etiologies, SpM doubled the death rate (33% vs. 17%) and tripled poor outcome (15% vs. 6%). In SpM, Glasgow Coma Score <13 [odds ratio (OR): 4.73] and previous antibiotics in Angola (OR: 1.70) were independent predictors for death. Predictors for poor outcome were age <1 year (OR: 2.41) and Glasgow Coma Score <13 (OR: 6.39) in the whole series, seizures in Latin America (OR: 3.98) and previous antibiotics in Angola (OR: 1.91). Angolan children had a 17-fold increased risk for poor outcome when compared with Finnish children ( P = 0.011). CONCLUSIONS: Our study proved the severity of SpM when compared with other etiologies. The outcome was especially poor in Angola. Most patients at risk for poor outcome are easily identified by clinical factors on admission.

The Effect of Blood Transfusion on the Survival of Children with Both Severe Anemia and Bacterial Meningitis.

In areas with suboptimal resources, blood transfusion may not be feasible even when mandatory for severely anemic children with a life-threatening disease. We evaluated how much not having received a transfusion affected the survival in 171 children with an admission blood hemoglobin level of < 6 g/dL and bacterial meningitis in Luanda, Angola. Of these children, 75% (128 of 171) had received a blood transfusion during hospitalization, but 25% (43 of 171) had not. Within the first week, 33% of patients (40 of 121) with transfusion and 50% (25 of 50) without a transfusion died (P = 0.04). Early transfusion (days 1-2 of hospitalization) prolonged the time of survival from a median of 132 hours [interquartile range (IQR), 15-168] to 168 hours (IQR, 69-168; P = 0.004), and had odds of 0.49 (95% CI, 0.25-0.97; P = 0.040) for death compared with no transfusion. The effect of transfusion/no transfusion at any time during hospitalization on mortality within 30 days, and prolongation of the time of survival were similar to early transfusion but showed even clearer benefits. Our results emphasize the value of timely transfusion in facilities that care for severely anemic children with severe infections to maximize their chances of survival.

Clinical blindness in conjunction with childhood bacterial meningitis.

Although rarely reported, bilateral loss of vision is a severe complication of childhood bacterial meningitis. We assessed its frequency in five prospective treatment trials performed in Europe, Latin America, and Angola in 1984-2017. Course of illness, follow-up findings, and child's sight were recorded. Sight was examined at discharge, and conditions permitting, also at 1-3 months post-hospitalization and in Angola on hospital day 7. Experienced pediatricians diagnosed clinical blindness if the child did not make eye contact, did not blink or move the eyes, or remained unresponsive to bright light or movement of large objects before their eyes. Of 1515 patients, 351, 654, and 510 were from Finland, Latin America, and Angola, respectively. At discharge, blindness was observed in 0 (0%), 8 (1.2%), and 51 (10%) children, respectively. In Angola, 64 children appeared to be blind on day 7; 16 of these children died. Blindness found at discharge in Angola was not invariably irreversible; approximately 40% had restored the sight at follow-up visit. Clinical blindness rarely occurred in isolation and was usually associated with young age and poor general condition at hospital arrival. Various other serious sequelae were common among the survivors with clinical blindness.

Auditory Steady-State Response and Hearing Impairment in Survivors of Childhood Bacterial Meningitis in Luanda, Angola.

Survivors of childhood bacterial meningitis (BM) often develop hearing impairment (HI). In low- and middle-income countries (LMICs), BM continues to be a significant cause of hearing disability. We assessed hearing among BM survivors using auditory steady-state responses (ASSR), providing frequency-specific estimated audiograms, and examined whether ASSR would provide a greater understanding of BM-induced HI. Survivors from two prospective BM trials (ISRCTN62824827; NCT01540838) from Luanda Children's Hospital were examined in a follow-up visit with a median duration of 26 months after BM. The hearing of 50 BM survivors and 19 control children was evaluated using ASSR and auditory brainstem response (ABR) after interview and neurological and otorhinolaryngological examinations. The median age of survivors was 80 (IQR 86) months. We diagnosed HI (better ear hearing ≥ 26 dB) in 9/50 (18%) children. Five of the fifty survivors (10%) and 14/100 ears (14%) had profound HI (>80 dB). Severe-to-profound HI affected all frequencies steadily, affecting only the ears of BM survivors (18/100 vs. 0/38, p = 0.003). When looking only at the severely or profoundly affected ears, young age, low Glascow coma score, pneumococcal aetiology, and ataxia were associated with a worse hearing outcome.

High Concentration of Protein Oxidation Biomarker O-Tyr/Phe Predicts Better Outcome in Childhood Bacterial Meningitis.

Neuronal damage in bacterial meningitis (BM) partly stems from the host´s inflammatory response and induced oxidative stress (OS). We studied the association of cerebrospinal fluid (CSF) biomarkers indicating oxidative damage to proteins with course of illness and outcome in childhood BM in Angola. Ortho-tyrosine/phenylalanine (o-Tyr/Phe), 3-chlorotyrosine/para-tyrosine (3Cl-Tyr/p-Tyr), and 3-nitrotyrosine/para-tyrosine (3NO2-Tyr/p-Tyr) concentration ratios were measured in 79 BM admission CSF samples, employing liquid chromatography coupled to tandem mass spectrometry. Besides death, disease outcomes were registered on Day 7 of treatment and one month after discharge (control visit). The outcome was graded according to the modified Glasgow Outcome Scale (GOS), which considers neurological and audiological sequelae. Children with a o-Tyr/Phe ratio below the median were more likely to present focal convulsions and secondary fever during recovery and suboptimal outcome (GOS < 5) on Day 7 and at control visit (odds ratio (OR) 2.85; 95% CI 1.14-7.14 and OR 5.23; 95% CI 1.66-16.52, respectively). Their most common sequela was ataxia on Day 7 and at control visit (OR 8.55; 95% CI 2.27-32.22 and OR 5.83; 95% CI 1.12-30.4, respectively). The association of a higher admission CSF o-Tyr/Phe ratio with a better course and outcome for pediatric BM points to a beneficial effect of OS.

Spatiotemporal variation in risk of Shigella infection in childhood: a global risk mapping and prediction model using individual participant data.

BACKGROUND: Diarrhoeal disease is a leading cause of childhood illness and death globally, and Shigella is a major aetiological contributor for which a vaccine might soon be available. The primary objective of this study was to model the spatiotemporal variation in paediatric Shigella infection and map its predicted prevalence across low-income and middle-income countries (LMICs). METHODS: Individual participant data for Shigella positivity in stool samples were sourced from multiple LMIC-based studies of children aged 59 months or younger. Covariates included household-level and participant-level factors ascertained by study investigators and environmental and hydrometeorological variables extracted from various data products at georeferenced child locations. Multivariate models were fitted and prevalence predictions obtained by syndrome and age stratum. FINDINGS: 20 studies from 23 countries (including locations in Central America and South America, sub-Saharan Africa, and south and southeast Asia) contributed 66 563 sample results. Age, symptom status, and study design contributed most to model performance followed by temperature, wind speed, relative humidity, and soil moisture. Probability of Shigella infection exceeded 20% when both precipitation and soil moisture were above average and had a 43% peak in uncomplicated diarrhoea cases at 33°C temperatures, above which it decreased. Compared with unimproved sanitation, improved sanitation decreased the odds of Shigella infection by 19% (odds ratio [OR]=0·81 [95% CI 0·76-0·86]) and open defecation decreased them by 18% (OR=0·82 [0·76-0·88]). INTERPRETATION: The distribution of Shigella is more sensitive to climatological factors, such as temperature, than previously recognised. Conditions in much of sub-Saharan Africa are particularly propitious for Shigella transmission, although hotspots also occur in South America and Central America, the Ganges-Brahmaputra Delta, and the island of New Guinea. These findings can inform prioritisation of populations for future vaccine trials and campaigns. FUNDING: NASA, National Institutes of Health-The National Institute of Allergy and Infectious Diseases, and Bill & Melinda Gates Foundation.