Jul, 2020

A machine learning approach for predicting probability of death or disease progression in an early-treated pediatric African cohort


Authors: Domínguez-Rodríguez S, Tagarro A, Serna Pascual M, Otwombe K, Violari A, Fernández S, Nhampossa T, Lain M,  Vaz P , Behuhuma NO, Danaviah S, Dobbels E, Barnabas S, Cotugno N, Zangari P, Palma P, Oletto A,  Nardone A, Nastouli E, Spyer M, Kuhn L, Rossi P, Giaquinto C, Rojo P on behalf of EPIICAL consortium.

Published in: 23rd international AIDS Conference, July 6th-10th 2020

Background In perinatally HIV infected children, mortality and morbidity are highest in the first months after ART initiation and is linked to advanced disease and late diagnosis. The random forest approach can deal with more predictors than classical models and has no model assumptions such as normality, linearity or hazard proportionality. The aim of this study was to predict the probability of death or clinical progression at a specific time of follow-up.

Methods EARTH (EPIICAL consortium) is an African multi-centre cohort enrolling HIV-infected infants treated within 3 months of life (n=151). A total of 134 infants with >1 follow-up visit were included in this analysis. The primary endpoint was the right-censored time to death or progression to AIDS. To predict the outcome, a log-rank random survival forest with imbalance correction was performed in a training subset (n=95, 70%). The algorithm was validated on the remaining 30% (n=39).

Results A total of 22 infants reached the primary endpoint with 13 (10%) patients dead and 9 (7%) with an AIDS defining condition. A total of 10000 trees were built with an error rate of 20%. The most important predictors of reaching the primary endpoint were baseline HIV viral load, age at diagnosis, weight-for-age, gender, age at ART initiation, and baseline CD4 count. In the validation, the model predicted a higher probability of reaching the primary endpoint among children who did indeed die or progress to AIDS, as compared to the group of children who did well (1-month: 14% vs. 0.01%, p-value=0.045; 6-months: 62% vs. 0.03%, p-value=0.019; 12-months: 76% vs. 16%, p-value=0.012). The AUC for predicting survival or progression was 0.83, 0.84, and 0.72 for 1-month, 6-months, and 1-year respectively.

Conclusions This model helps clinicians individualize the probability of death or progression to AIDS at time of diagnosis and may be useful for the early identification of high-risk patients.



Jul, 2020

Global sales of oral antibiotics formulated for children

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Authors: Li G, Jackson C, Bielicki J, Ellis S, Hsiac Y, Sharland M

Published in: Bulletin of the World Health Organization, July 2020

Objective To investigate international consumption patterns of child-appropriate oral formulations of antibiotics by formulation type, with a focus on dispersible tablets, using data from a global sales database.

Methods Antibiotic sales data for 2015 covering 74 countries and regional country groups were obtained from the MIDAS® pharmaceutical sales database, which includes samples of pharmacy wholesalers and retailers. The focus was on sales of child-appropriate oral formulations of Access antibiotics in the 2017 World Health Organization’s WHO Model list of essential medicines for children. Sales volumes are expressed using a standard unit (i.e. one tablet, capsule, ampoule or vial or 5 mL of liquid). Sales were analysed by antibiotic, WHO region and antibiotic formulation.

Findings Globally, 17.7 billion standard units of child-appropriate oral antibiotic formulations were sold in 2015, representing 24% of total antibiotic sales of 74.4 billion units (both oral and parenteral) in the database. The top five child-appropriate Access antibiotics by sales volume were amoxicillin, amoxicillin with clavulanic acid, trimethoprim–sulfamethoxazole, cefalexin and ampicillin. The proportion of the top five sold for use as a syrup varied between 42% and 99%. Dispersible tablets represented only 22% of all child-appropriate oral formulation sales and made up only 15% of sales of 10 selected Access antibiotics on the model list for children.

Conclusion Globally most child-appropriate oral antibiotics were not sold as dispersible tablets in 2015, as recommended by WHO. There is a clear need for novel solid forms of antibiotics suitable for use in children.



May, 2020

The HIV-1 antibody response: a footprint of the viral reservoir in children vertically infected with HIV


Authors: Palma P, McManus M, Cotugno N, Rocca S, Rossi P, Luzuriaga K

Published in: Lancet HIV. 2020;7(5):e359-e365

Abstract Several assays have been developed to measure and characterise the replication-competent HIV-1 reservoir, which constitutes the barrier to cure. To date, the application of these assays to studies in children and in limited-resource settings has been minimal, primarily because of their expense, the large required blood volumes, and labour-intensive technologies. For children vertically infected with HIV-1 who initiated suppressive antiretroviral therapy (ART) regimens in infancy, HIV-1-specific antibody concentrations are associated with viral persistence and could be used to estimate the size of the residual latent reservoir on ART. This strategy could be particularly useful for screening children on suppressive ART for enrolment into therapeutic vaccine trials and other protocols aimed at achieving HIV-1 remission.


May, 2020

Clinical outcomes of a Zika virus mother–child pair cohort in Spain


Authors: Soriano-Arandes A, Frick MA, García López-Hortelano M, et al.

Published in: Pathogens 2020;9(5):E352

Background: Zika virus (ZIKV) infection has been associated with congenital microcephaly and other neurodevelopmental abnormalities. There is little published research on the effect of maternal ZIKV infection in a non-endemic European region. We aimed to describe the outcomes of pregnant travelers diagnosed as ZIKV-infected in Spain, and their exposed children.

Methods: This prospective observational cohort study of nine referral hospitals enrolled pregnant women (PW) who travelled to endemic areas during their pregnancy or the two previous months, or those whose sexual partners visited endemic areas in the previous 6 months. Infants of ZIKV-infected mothers were followed for about two years.

Results: ZIKV infection was diagnosed in 163 PW; 112 (70%) were asymptomatic and 24 (14.7%) were confirmed cases. Among 143 infants, 14 (9.8%) had adverse outcomes during follow-up; three had a congenital Zika syndrome (CZS), and 11 other potential Zika-related outcomes. The overall incidence of CZS was 2.1% (95%CI: 0.4–6.0%), but among infants born to ZIKV-confirmed mothers, this increased to 15.8% (95%CI: 3.4–39.6%).

Conclusions: A nearly 10% overall risk of neurologic and hearing adverse outcomes was found in ZIKV-exposed children born to a ZIKV-infected traveler PW. Longer-term follow-up of these children is needed to assess whether there are any later-onset manifestations.



May, 2020

Differences in inducibility of the latent HIV reservoir in perinatal and adult infection


Authors: Dhummakupt A, Rubens JH, Andeson T, et al.

Published in: JCI Insight. 2020;5(4)

Abstract The HIV latent reservoir in resting memory CD4+ T cells precludes cure. Therapeutics to reactivate and eliminate this reservoir are in clinical trials in adults, but not yet in pediatric populations. We determined, ex vivo, the inducibility of the latent reservoir in perinatal infection as compared with adult infections using the Tat/rev induced limiting dilution assay (TILDA), in which a single round (12 hours) of CD4+ T cell stimulation with PMA/ionomycin maximally activates T cells and leads to proviral expression with multiply spliced HIV RNA production. Markers of immune activation and exhaustion were measured to assess interactions with inducibility. Although rates of T cell activation with PMA/ionomycin were similar, the latent reservoir in perinatal infection was slower to reactivate and of lower magnitude compared with adult infection, independent of proviral load. An enhanced TILDA with the addition of phytohemagglutin and a duration of 18 hours augmented proviral expression in perinatal but not adult infection. The baseline HLA-DR+CD4+ T cell level was significantly lower in perinatal compared with adult infections, but not correlated with induced reservoir size. These data support the hypothesis that there are differences in kinetics of latency reversal and baseline immune activation in perinatal compared with adult infections, with implications for latency reversal strategies toward reservoir clearance and remission.



Apr, 2020

A comparison of five paediatric dosing guidelines for antibiotics


Authors: Mathur S, Jackson C, Urus H, Ziarko I, Goodbun M, Hsia Y, Ellis S, Sharland M.

Published in: Bulletin of the World Health Organization, April 2020

Objective To compare dosing guidance in the paediatric formularies of high-income countries and emerging economies for 32 commonly prescribed antibiotics on the World Health Organization’s (WHO’s) 2017 Model List of Essential Medicines for Children.

Methods We identified paediatric antibiotic guidelines that were either widely used internationally or originated in countries in which antibiotic use has increased markedly in recent years (i.e. Brazil, China, India, the Russian Federation and South Africa).

Findings The study analysis considered five leading antibiotic guidelines: (i) the Manual of childhood infections: the blue book; (ii) the BNF (British national formulary) for children; (iii) the Red book®: 2018–2021 report of the committee on infectious diseases; (iv)WHO’s Pocket book of hospital care for children; and (v) Indian national treatment guidelines for antimicrobial use in infectious diseases. There was marked heterogeneity in the recommended dosing (i.e. daily dose, age dosing bands and dose frequency) for most commonly used antibiotics. The rationale for dosing recommendations was generally unclear.

Conclusion The pharmacokinetic, pharmacodynamic and clinical evidence supporting paediatric antibiotic dosing, particularly on total doses and on age or weight dosing bands, needs to be improved. Future research should consider whether the variations in guidance identified stem from different clinical disease patterns, varying levels of antibiotic resistance or drug availability rather than historical preferences. Interested global parties could collaborate with WHO’s Model list of essential medicines antibiotic working group to develop an evidence-based consensus and identify research priorities.



Apr, 2020

Interim pharmacokinetic analysis of a multi-centre randomised open label phase IIb study in neonates to validate the meta-analysis population pharmacokinetic model used to simulate an optimised dosing regimen in neonates and infants aged < 90 days: the NeoVanc trial


Authors: L. Hill, E. Jacqz-Aigrain, V. Elie, W. Zhao, M. Clements, M. Turner, I. Lutsar, P. Heath, E. Roilides, S. Walker, M. Sharland

Published in: 30th European Congress on Clinical Microbiology and Infectious Diseases (ECCMID), April 2020

Background: Vancomycin remains one of the most widely prescribed antibiotics for Gram-positive neonatal late onset sepsis (LOS), however, a consensus on optimal vancomycin dosing and duration is lacking. Robust neonatal clinical pharmacokinetic (PK) data comparing different vancomycin dosing regimens remain sparse. NeoVanc (NCT02790996) is a European, randomised controlled, non-inferiority trial comparing an optimised and standard vancomycin regimen in infants aged ≤90 days with suspected/proven Gram-positive LOS. The optimised regimen was determined through pre-clinical studies including a population PK meta-analysis of individual data from >1600 babies.

Materials/methods: Babies with clinical sepsis (≥3 clinical/laboratory criteria) or confirmed sepsis (Gram-positive blood culture and ≥1 clinical/laboratory criterion) were recruited. Participants were randomised 1:1 to the optimised regimen (vancomycin loading dose (25 mg/kg) followed by 5±1 day course) or a standard regimen (no loading dose;10±2 day vancomycin course). An interim PK analysis was performed; the validation dataset was collected from 8 centres in 5 European countries. Data collected included demographic variables (gestational and postnatal age, birth and current weight), vancomycin admin- istration (dose, time of start and end of infusion, exact sampling time), creatinine concentrations (Jaffe, enzymatic), vancomycin concentrations (ultraperformance liquid chromatography-tandem mass spectrometry).

Results: 68 babies recruited between March 2017 and April 2018 were included in the interim analysis. Gestational age was <29 (n=16), 29–36 (n=22), >35 (n=30) weeks. Median (IQR) birthweight was 1258 (455–4040)g with median weight at randomisation being 1525 (590–4156)g. Median post-menstrual age at randomisation was 33.8(25.1–47) weeks. Median se- rum creatinine was 41.5(8.84–96.36) μmol/L. 240/255 PK and scavenged PK samples were evaluable. Vancomycin concen- trations were used to confirm the reliability of the meta-analysis model where clearance (CL) was dependant on current weight, method used to quantify creatininaemia, renal maturation (RM) and renal function (RF) according to CL= θ6×(CW/1350) θ7×RM×RF×FJaffé-Enzymatic × Frace

Conclusions: External validation with NeoVanc trial PK data confirmed the predictive performance of the model developed fromthe PK meta-analysis.


Apr, 2020

An optimised dosing regimen vs. a standard dosing regimen of vancomycin for the treatment of late onset sepsis due to Gram-positive microorganisms in infants less than 90 days: the NeoVanc trial


Authors: L. Hill, M. Clements, M. Turner, I. Lutsar, E. Jacqz-Aigrain, P. Heath, E. Roilides, S. Walker, M. Sharland

Published in: 30th European Congress on Clinical Microbiology and Infectious Diseases (ECCMID), April 2020

Background: Vancomycin remains one of the most widely prescribed antibiotics for Gram-positive neonatal late onset sep- sis (LOS). Robust neonatal clinical outcome data comparing different vancomycin dosing regimens is lacking. NeoVanc (NCT02790996) is a European, multicentre, phase IIb, randomised controlled, non-inferiority trial comparing an optimised and standard vancomycin regimen in infants aged ≤90 days with known/suspected Gram-positive LOS.

Materials/methods: Infants with clinical sepsis (≥3 clinical/laboratory criteria) or confirmed sepsis (Gram-positive blood culture and ≥1 clinical/laboratory criterion) were included. Participants were randomised 1:1 to an optimised regimen (loading dose [25 mg/kg] followed by 5±1 days of 15 mg/kg q12h or q8h dependent on postmenstrual age [PMA] or a standard regimen [10±2 day course at 15 mg/kg q24h, q12h, or q8h dependent on PMA]). The primary endpoint was successful outcome at end of vancomycin therapy and no clinically/microbiologically significant relapse/new infection requiring treatment with anti-staphylococcal antibiotics within 10 days of stopping vancomycin.

Secondary endpoints included safety and pharmacokinetics. ‘Per protocol’ was all participants receiving/not receiving the loading dose as randomised and ≥48h of study vancomycin.

Results: 242 infants were randomised between March 2017 and July 2019 from 22 neonatal intensive care units in 5 European countries. Per-protocol population is presented (183 participants): 55% were male, with a median (IQR) postmenstrual age of 32(29–37) weeks and postnatal age at onset of LOS of 14(8–25) days. Mean weight was 1663g(924g SD) and central lines were present in 115/183(63%) participants at randomisation. 133/183(73%) received antibiotics in the 7 days before randomi- sation. 25/183(14%) had positive blood culture for Gram-positive organisms of interest at randomisation, and 179/183(98%) had ≥3 clinical/laboratory signs on randomisation. 141/183(77%) received vancomycin according to the randomised duration. There were 4 deaths and 4 withdrawals/loss to follow-up prior to TOC.

There were 40 post-randomisation exclusions.

128/179(72%) had a successful primary outcome. 2/165(1%) of all randomised infants had abnormal renal function at short- term follow-up.

Conclusions: NeoVanc is the largest LOS vancomycin trial to provide clinical efficacy and safety outcome data associated with alternative dosing strategies. Preliminary results are included (some events not yet adjudicated): final results comparing randomised groups and outcomes will be presented.


Apr, 2020

Respiratory pathogens detected in children with community-acquired sepsis-like syndrome in 6 European countries


Authors: V. Matheeussen, K. Loens, K. Jacobs, P. Horby, H. Goossens, M. Kohns Vasconcelos, M. Sharland, M. De Jong, M. P. G. Koopmans, P. Fraaij, M. Ieven

Published in: 30th European Congress on Clinical Microbiology and Infectious Diseases (ECCMID), April 2020

Background: The management of infants admitted to hospital with sepsis-like syndrome (SLS) without apparent focus remains challenging. There is growing evidence indicating that this clinical picture is triggered by viral pathogens, like adenovirus, enterovirus or parechovirus with a possible respiratory point of entry. We aimed to identify an association in the presence of respiratory pathogens in nasopharyngeal swabs between children with SLS and controls.

Materials/methods: A total of 102 children (≤ 6 months old) admitted to hospital with community-acquired SLS and 308 asymptomatic controls (0-6 years old) were enrolled in a prospective case-control study as part of the MERMAIDS Trial (Multi-centre EuRopean study of MAjor Infectious Disease Syndromes, in 12 hospitals in 6 European countries. The Fast Track Diagnostics Respiratory pathogens 21 plus real-time PCR assay was used to determine the presence of respira- tory pathogens in nasopharyngeal swabs

Results: The most prevalent respiratory viral targets detected in the nasopharyngeal swabs of SLS patients were rhinovirus (28%), RSV A/B (9%), enterovirus (8%) and parainfluenzavirus (5%). All other viruses (influenzavirus, coronavirus, parechovirus, human metapneumovirus, adenovirus and bocavirus) were detected in <5%. Also bacterial targets like Staphylococcus aureus and Streptococcus pneumoniae, possibly colonizers, were often detected, both in 30% of the samples. Neither Myco- plasma pneumoniae, Chlamydophila pneumoniae nor Haemophilus influenzae type B were present. Compared to the control group, enterovirus and RSV A/B were detected more frequently in the SLS patients (8 versus 2% for enterovirus, p=0.01 and 9 versus 2% for RSV A/B, p=0.01). Adeno- and bocavirus were found more often in the control group (7 versus 1% for both viruses, p=0.02). No respiratory target was detected in 25% of the SLS samples.

Conclusions: Most (75%) of the nasopharyngeal samples from SLS patients contained one or more viral or bacterial respiratory targets. In our study, the role of influenza viruses was relatively limited. The possible role of enterovirus and RSV A/B in the pathophysiology of SLS should be further elucidated.


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