Treatment of bacterial meningitis and prediction of disease outcomes in children

Bacterial meningitis remains a significant cause of childhood morbidity and mortality, despite reductions to the global meningitis burden resulting from immunisations against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae. Meningitis poses a threat to child health especially in resource-limited settings, where mortality rates can reach up to 50%, even with the use of effective broad-spectrum antibiotics. The extent of the host’s immune response associates with bacterial meningitis outcomes. Consequently, new treatment modalities have focused on controlling the initial inflammatory burst. This doctoral thesis project evaluated the use of a continuous antibiotic infusion, in contrast to conventional boluses, combined with paracetamol as a treatment for childhood bacterial meningitis. In addition, this research attempted to identify new prognostic markers in the cerebrospinal fluid (CSF) of children with meningitis and examined the impact of children’s vitamin D status on disease outcomes. The use of a continuous four-day cefotaxime infusion combined with oral paracetamol was evaluated in a prospective, randomised, double-blind parallel-group trial conducted at the Paediatric Hospital of Luanda in Angola between 2012 and 2017. The control intervention consisted of conventional cefotaxime boluses four times daily and an oral placebo, using mortality by day 7 from treatment initiation as the primary outcome. The prognostic role of matrix metalloproteinases (MMPs), myeloperoxidase (MPO) and the antimicrobial protein cathelicidin in the CSF and vitamin D levels in serum were analysed retrospectively using a cohort from Latin America of children with bacterial meningitis. Our prospective clinical trial showed no benefit from using a continuous cefotaxime infusion combined with paracetamol as a treatment for childhood bacterial meningitis in Angola. By day 7, 61 of 187 (32.6%) children in the intervention group and 64 of 186 (34.4%) children in the control group died (absolute risk difference 1.8%, 95% confidence interval -7.8% to 11.4%). Similarly, no differences emerged between the study groups in terms of neurological sequelae. In addition, the retrospective studies identified MMP-8 as a promising prognostic marker for bacterial meningitis: upon admission, a CSF MMP-8 level greater than the median value increased the odds of death 4.9-fold. The other analysed MMP, MPO and cathelicidin were also expressed in the CSF of children with bacterial meningitis, but did not predict disease outcomes to a similar extent. Furthermore, children’s vitamin D status upon admission did not associate with survival. In conclusion, the prognosis of childhood bacterial meningitis in Angola could not be improved by using a continuous cefotaxime infusion and oral paracetamol. Many of the children in our study were severely ill when presenting at hospital, likely contributing to the poor outcomes and warranting further attention. CSF MMP-8, however, presented as a potential prognostic marker for the disease.Bakteeriperäinen aivokalvotulehdus eli bakteerimeningiitti on yhä maailmanlaajuisesti merkittävä lasten kuolleisuutta aiheuttava tauti, vaikka rokotukset Haemophilus influenzae tyyppi b ja Streptococcus pneumoniae -bakteereita vastaan ovatkin lähes hävittäneet taudin korkean tulotason maista. Köyhissä olosuhteissa jopa puolet bakteerimeningiittiin sairastuvista lapsista menehtyy hoidosta huolimatta taudin seurauksena. Huono ennuste vaikuttaisi osittain liittyvän potilaan liian voimakkaaseen immuunivasteeseen, ja taudin ennusteen parantamiseen tähtäävät hoidot ovat jo pitkään kohdistuneet nimenomaan liiallisen immuunireaktion hillitsemiseen. Tässä väitöskirjatyössä tutkittiin jatkuvan antibiootti-infuusion ja parasetamolin yhdistelmää lasten bakteerimeningiitin hoitona, etsittiin potilaiden aivo-selkäydinnesteestä uusia bakteerimeningiitin taudinkulkua ennustavia tekijöitä, sekä selvitettiin lasten immuunireaktioon vaikuttavan D-vitamiinipitoisuuden vaikutusta bakteerimeningiitin ennusteeseen. Jatkuvan neljä päivää kestävän kefotaksiimiantibiootti-infuusion ja suun kautta annostellun parasetamolin yhdistelmää lasten bakteerimeningiitin hoitona tutkittiin Angolan pääkaupungissa Luandassa sijaitsevassa lastensairaalassa satunnaistetussa, kaksoissokkoutetussa ja lumekontrolloidussa asetelmassa vuosina 2012–2017. Interventioryhmä sai edellä mainitun hoidon, kun taas vertailuryhmä sai kefotaksiimia tavanomaisin boluksin neljästi vuorokaudessa sekä lumelääkettä suun kautta. Tutkimuksen ensisijaisena lopputulosmuuttujana oli kuolema ensimmäisen viikon aikana hoidon aloituksesta. Latinalaisessa Amerikassa aikaisemmin kerätystä potilasaineistosta selvitettiin tulehdusmerkkiaineiden, matriksin metalloproteinaasien (MMP), myeloperoksidaasin (MPO) ja katelisidiinin, pitoisuuksia aivo-selkäydinnesteessä ja määritettiin niiden ennustearvoa taudinkulkuun. Lisäksi tutkittiin veren D-vitamiinipitoisuuden yhteyttä bakteerimeningiitin ennusteeseen. Angolassa tehdyn tutkimuksen perusteella jatkuva kefotaksiimi-infuusio yhdistettynä parasetamoliin ei parantanut lasten bakteerimeningiitin ennustetta. Viikon kohdalla 61/187 (32.6 %) interventioryhmän lapsista ja 64/186 (34.4 %) vertailuryhmän lapsista oli menehtynyt (absoluuttinen riskiero 1.8 %, 95 % luottamusväli -7.8 % – 11.4 %). Myöskään neurologisen vammautumisen suhteen ryhmien välille ei tullut merkitseviä eroja. Latinalaisessa Amerikassa kerätyistä näytteistä tehdyissä tutkimuksissa havaittiin bakteerimeningiittiä sairastavien lasten aivo-selkäydinnesteen korkean MMP-8 -pitoisuuden lisäävän menehtymisen kerroinsuhdetta 4,9-kertaisesti. Myös toista matriksin metalloproteinaasia (MMP-9), myeloperoksidaasia sekä katelisidiiniä todettiin aivo-selkäydinnesteessä, mutta näiden molekyylien ennustearvo oli pienempi. Veren D-vitamiinipitoisuudella ei ollut yhteyttä lasten kuolleisuuteen. Jatkuvan kefotaksiimi-infuusion ja parasetamolin yhdistelmä ei parantanut bakteerimeningiittiä sairastavien lasten ennustetta Angolassa. Merkittävä osa lapsista oli kriittisesti sairaita jo hoitoon tullessa, mikä osittain selittänee tutkimuksessa todettua korkeaa kuolleisuutta. Aivo-selkäydinnesteen MMP-8 vaikuttaisi lupaavalta ennustekijältä lasten bakteerimeningiitissä

Extended Continuous beta-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 beta-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/I%, 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 beta-lactam infusion combined with oral acetaminophen did not improve the gloomy outcomes of childhood bacterial meningitis in Angola.Peer reviewe

Gene Polymorphisms of TLR4 and TLR9 and Haemophilus influenzae Meningitis in Angolan Children

Bacterial meningitis (BM) is a severe disease caused by various bacterial pathogens. Toll-like receptors (TLRs) protect humans from invading pathogens. In this study, we determined whether single nucleotide polymorphisms (SNPs) ofTLR4andTLR9are associated with susceptibility to and outcome of BM in Angolan children. Samples were taken from 241 patients and 265 age-matched ethnic controls. The SNPsTLR4rs4986790 (896A > G) andTLR9rs187084 (-1486T > C) were determined by high-resolution melting analysis (HRMA). The frequency of variant genotypes inTLR4was significantly higher in patients withHaemophilus influenzaemeningitis than controls (odds ratio (OR), 2.5; 95% confidence interval (CI), 1.2-5.4;p= 0.021), whereas the frequency of variant genotypes inTLR9was significantly lower in patients withH. influenzaemeningitis than controls (OR, 0.4; 95% CI, 0.2-0.9;p= 0.036). No such differences were found with other causative pathogens, such asStreptococcus pneumoniaeandNeisseria meningitidis. At the time of discharge, patients with meningitis caused by Gram-negative bacteria who were carriers of variantTLR4genotypes had a higher risk of ataxia (OR, 12.91; 95% CI, 1.52-109.80;p= 0.019) and other neurological sequelae (OR, 11.85; 95% CI, 1.07-131.49;p= 0.044) than those with the wild-typeTLR4genotype. Our study suggests an association betweenH. influenzaemeningitis and genetic variation betweenTLR4andTLR9in Angolan children.Peer reviewe

Gene Polymorphisms of TLR4 and TLR9 and Haemophilus influenzae Meningitis in Angolan Children

Bacterial meningitis (BM) is a severe disease caused by various bacterial pathogens. Toll-like receptors (TLRs) protect humans from invading pathogens. In this study, we determined whether single nucleotide polymorphisms (SNPs) of TLR4 and TLR9 are associated with susceptibility to and outcome of BM in Angolan children. Samples were taken from 241 patients and 265 age-matched ethnic controls. The SNPs TLR4 rs4986790 (896A > G) and TLR9 rs187084 (−1486T > C) were determined by high-resolution melting analysis (HRMA). The frequency of variant genotypes in TLR4 was significantly higher in patients with Haemophilus influenzae meningitis than controls (odds ratio (OR), 2.5; 95% confidence interval (CI), 1.2–5.4; p = 0.021), whereas the frequency of variant genotypes in TLR9 was significantly lower in patients with H. influenzae meningitis than controls (OR, 0.4; 95% CI, 0.2–0.9; p = 0.036). No such differences were found with other causative pathogens, such as Streptococcus pneumoniae and Neisseria meningitidis. At the time of discharge, patients with meningitis caused by Gram-negative bacteria who were carriers of variant TLR4 genotypes had a higher risk of ataxia (OR, 12.91; 95% CI, 1.52–109.80; p = 0.019) and other neurological sequelae (OR, 11.85; 95% CI, 1.07–131.49; p = 0.044) than those with the wild-type TLR4 genotype. Our study suggests an association between H. influenzae meningitis and genetic variation between TLR4 and TLR9 in Angolan children

Gene Polymorphisms of TLR4 and TLR9 and Haemophilus influenzae Meningitis in Angolan Children

Bacterial meningitis (BM) is a severe disease caused by various bacterial pathogens. Toll-like receptors (TLRs) protect humans from invading pathogens. In this study, we determined whether single nucleotide polymorphisms (SNPs) of TLR4 and TLR9 are associated with susceptibility to and outcome of BM in Angolan children. Samples were taken from 241 patients and 265 age-matched ethnic controls. The SNPs TLR4 rs4986790 (896A > G) and TLR9 rs187084 (−1486T > C) were determined by high-resolution melting analysis (HRMA). The frequency of variant genotypes in TLR4 was significantly higher in patients with Haemophilus influenzae meningitis than controls (odds ratio (OR), 2.5; 95% confidence interval (CI), 1.2–5.4; p = 0.021), whereas the frequency of variant genotypes in TLR9 was significantly lower in patients with H. influenzae meningitis than controls (OR, 0.4; 95% CI, 0.2–0.9; p = 0.036). No such differences were found with other causative pathogens, such as Streptococcus pneumoniae and Neisseria meningitidis. At the time of discharge, patients with meningitis caused by Gram-negative bacteria who were carriers of variant TLR4 genotypes had a higher risk of ataxia (OR, 12.91; 95% CI, 1.52–109.80; p = 0.019) and other neurological sequelae (OR, 11.85; 95% CI, 1.07–131.49; p = 0.044) than those with the wild-type TLR4 genotype. Our study suggests an association between H. influenzae meningitis and genetic variation between TLR4 and TLR9 in Angolan children

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 Results 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. 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.Peer reviewe

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, PPeer reviewe

Pediatrisen elinsiirtopotilaan infektiot - tehokkaan hyljinnänestolääkityksen varjopuoli

Infektioihin liittyvät ongelmat ovat elinsiirteen saaneen lapsen sairaalahoidon tavallisin syy. Infektioalttiuteen myötävaikuttavat etenkin immunosuppressiivinen hyljinnänestolääkitys sekä alkuvaiheessa perioperatiiviset tekijät, ja vakavan infektion riski on suurimmillaan siirtoleikkauksen jälkeen. Toistuvat infektio-ongelmat voivat olla merkki liiallisesta immunosuppressiosta, jonka välttäminen on tärkeä osa infektioiden ehkäisyä. Muita keskeisiä asioita ovat rokotussuojan optimoiminen, jo ennen elinsiirtoa alkava aktiivinen infektioseulonta ja profylaktiset mikrobilääkehoidot.Peer reviewe

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.Peer reviewe

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

Peer reviewe