Publications

26

Apr, 2020

Aetiology and outcome of children hospitalised for acute respiratory tract infections in Europe: findings from a multi-country combined case-control and cohort study

 

Authors: M. Kohns Vasconcelos; on behalf of the PED-MERMAIDS Study Group

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

Background: Recently, major aetiology and outcome studies on paediatric acute respiratory tract infections (ARI) have been reported from LMICs. In contrast, studies using standardised protocols across Europe are lacking.

Materials/methods: The EU-funded Paediatric Multi-centre EuRopean study of MAjor Infectious Disease Syndromes (PED-MER- MAIDS) enrolled children under 5 years hospitalised for ARI and well controls across 11 EU countries. Information on symptoms, course of disease and clinical management was collected prospectively. Admission day nasopharyngeal swabs were analysed for influenza, parainfluenza, rhinovirus, coronavirus, metapneumovirus, bocavirus, respiratory syncytial virus (RSV), parechovirus, enterovirus and adenovirus and Streptococcus pneumoniae (Sp), Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae and Staphyloccous aureus.

Results: 353 ARI children, median age 1.13 years (IQR:0.44-2.56) and 352 controls, median age 1.76 years (IQR:0.96-3.73) were enrolled over 21⁄2 years. Swabs were analysed from 327 ARI children and 302 controls. No potential pathogen was detect- ed in 4.6% of ARI, only bacteria in 10.9%, only viruses in 33.9% and both bacterial and viral potential pathogens in 51.4%. Codetection of multiple (up to 4) viruses occurred in 31.2% of ARI and codetection of multiple bacteria in 16.9%. The most commonly detected pathogens are listed in table 1. Respiratory pathogens were detected in 62.8% of controls. Of the frequently detected pathogens, only RSV and influenza were strongly associated with hospitalisation for ARI (table 1). The population attributable fractions (PAF) were 33.6% for RSV and 18.0% for Sp. 209 ARI children (60.6%) received antibiotics, but this was not associated with detection of bacterial pathogens in study samples (OR=0.78, 95%-CI:0.48-1.28). Length of stay in hospital ranged between 0 and 49 days (median 3, IQR:2-5) and no child in the study died after admission for ARI.

Conclusions: Similarly to LMIC studies, RSV had the highest PAF for ARI hospitalisation in Europe, but with considerably lower mortality.

26

Apr, 2020

Application of WISCA (Weighted Incidence Syndromic Combination Antibiogram) to guide empiric therapy in oncological paediatric patients with febrile neutropenia

 

Authors: E. Barbieri, D. Bottigliengo, P. Costenaro, A. Marzollo, M. Petris, M. Pierobon, G. Biddeci, C. Giaquinto, A. Biffi, D. Donà

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

Background: Febrile neutropenia (FN) is an acute potentially life-threatening oncological complication which should be treated promptly with antibiotics. With the spread of antibiotic resistance, the choice of an empiric therapy is driven by local epidemiology usually described by cumulative pathogens susceptibilities antibiograms. The WISCA attempts to address the unmet need for syndRome-specific local susceptibility data to guide empirical prescribing, providing estimates for different treatment reg- imens as a weighted average of pathogens susceptibilities. Our aim was to create a WISCA model to inform empirical antibiotic regimens selection for FN in children.

Materials/methods: We included all non-duplicate blood cultures from patients aged 0-17 years with FN admitted to the paediatric oncology/hematology wards in Padua from January 2016 to August 2019. WISCA was developed by estimating the sensibility of 29 antibiotic regimens with a Bayesian probabilities distribution. Moreover, we created a second model with 57 blood cultures excluding potentially contaminant bacteria.

Results: We collected 69 blood cultures, 41 Gram- and 28 Gram+ bacteria. Considering most used combinations such as piperacillin-tazobactam + amikacin the median sensibility was 58% (BUI 33-84%) that increased to 70% (BUI 42-85%) in the second model. When adding a glycopeptide to this combination the median sensibility increased dramatically (Figure 1). The highest median sensibility for a beta-lactam + aminoglycoside combination was 66% (BUI 37-86%; meropenem + amikacin) in the first model and 75% (BUI 46-85%) in the second model; the lowest was 42% (BUI 26-75%; ceftriaxone + amikacin) and 50% (BUI 32- 76%) respectively. Overall mono-treatments had median sensibility lower than 50%, exept meropenem (65%; BUI 35-85) and gentamycin (60%; BUI 33-84%), but in the second model most median sensibilities increased above 50%. WISCA model with median sensibilities and uncertainty intervals is shown in Figure 1.

Conclusions: WISCAs represent a valid tool to maximize the clinical utility of microbiological surveillance data supporting appropriate empirical antibiotic treatment selection, while contributing to conservation of broad-spectrum antibiotics.

26

Apr, 2020

Antibiotic treatment for paediatric outpatients with community-acquired pneumonia: findings from 10 years of prescribing habits in Italy

 

Authors: P. Costenaro, A. Cantarutti, E. Barbieri, A. Scamarcia, A. Oletto, P. Sacerdoti, R. Lundin, L. Cantarutti, C. Giaquinto, D. Dona’

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

Background: Despite national and international efforts to promote appropriate antibiotic prescribing, Italian paediatric antimicrobial prescription rates are among the highest in Europe, with an overuse of broad-spectrum antibiotics. Community-acquired pneumonia (CAP) is one of the most common infections in pediatrics, and a main cause of antibiotic prescriptions. Aim of this study is to describe the first-line treatment approach for CAP at primary care level in Italian children.

Materials/methods: Retrospective observational study conducted among children with CAP enrolled in Pedianet, a network of community-based paediatricians from 12 Italian regions (http://www.pedianet.it). Children (3 months-14 years of age) with at least one reported CAP from 01/01/2009 to 31/12/2018 were included, if treated with antibiotics (ABT). CAP was defined according to ICD-9-CM (codes 485, 486, 482.9, 481), a new episode was recorded if occurring >=30 days after previous CAP. We defined “narrow-spectrum” (NS) ABT if treatment was amoxicillin and “broad-spectrum” (BS) if amoxicillin/clavulanic acid, cephalosporins or any combination ABT. Chi-squared and Fisher’s test were used for categorical or continuous variables. Crude and adjusted logistic regression for the ODDS of receiving a NS-ABT were conducted (all episodes of CAP and per patient). A p-value <0,05 was considered statistically significant.

Results: Among 9691 CAP, 7260 episodes from 6409 children followed by 147 pediatricians were included. The 16.7% of CAP (95% C.I.15,9%-17,6%) received a narrow-spectrum ABT while 53.3% (95% C.I.52%-54,4%) received a broad-spectrum ABT and 30% (95% C.I. 28,9%-31,1%) a macrolide. Within 10 years, an increasing trend of NS-ABT prescription was observed (p<0.001, Chi-square test for linear trend). Factors independently associated with reduced ODDS of receiving a NS-ABT compared to BS- ABT including macrolides were being older than 5 years (OR 0.45, 95% C.I.0.39 – 0.52), living in Center/South of Italy (OR 0.13, 95% C.I.0.10 – 0.16) and being exposed to ABT 3 months before (OR 0.61, 95% C.I. 0.53 – 0.70). These findings were confirmed comparing NS-ABT versus BS-ABT excluding macrolides (n=5079) and when adjusted analysis was limited to index CAP.

Conclusions: Our findings provide an alarming overview of the Italian prescribing habits, reporting a very limited use of NS-ABT for children with CAP.

21

Apr, 2020

An optimised dosing regimen versus a standard dosing regimen of vancomycin for the treatment of late onset sepsis due to Gram-positive microorganisms in neonates and infants aged less than 90 days (NeoVanc): study protocol for a randomised controlled trial

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Authors: Hill LF, Turner MA, Lutsar I, et al; NeoVanc Consortium.

Published in: Trials. 2020;21(1):329

Background Vancomycin has been used in clinical practice for over 50 years; however, validated, pharmacokinetic (PK) data relating clinical outcomes to different dosing regimens in neonates are lacking. Coagulase negative staphylococci (CoNS) are the most commonly isolated organisms in neonatal, late–onset sepsis (LOS). Optimised use to maximise efficacy while minimising toxicity and resistance selection is imperative to ensure vancomycin‘s continued efficacy.

Methods NeoVanc is a European, open-label, Phase IIb, randomised, controlled, non-inferiority trial comparing an optimised vancomycin regimen to a standard vancomycin regimen when treating LOS known/suspected to be caused by Gram-positive organisms (excluding Staphylococcus aureus) in infants aged ≤ 90 days. Three hundred infants will be recruited and randomised in a 1:1 ratio. Infants can be recruited if they have culture confirmed (a positive culture from a normally sterile site and at least one clinical/laboratory criterion) or clinical sepsis (presence of any ≥ 3 clinical/laboratory criteria) in the 24 h before randomisation. The optimised regimen consists of a vancomycin loading dose (25 mg/kg) followed by 5 ± 1 days of 15 mg/kg q12h or q8h, dependent on postmenstrual age (PMA). The standard regimen is a 10 ± 2 day vancomycin course at 15 mg/kg q24h, q12h or q8h, dependent on PMA. The primary endpoint is a successful outcome at the test of cure visit (10 ± 1 days after the end of vancomycin therapy). A successful outcome consists of the patient being alive, having successfully completed study vancomycin therapy and having not had a clinical/microbiological relapse/new infection requiring treatment with vancomycin or other anti-staphylococcal antibiotic for > 24 h. Secondary endpoints include clinical/microbiological relapse/new infection at the short-term follow-up visit (30 ± 5 days after the initiation of vancomycin), evaluation of safety (renal/hearing), vancomycin PK and assessment of a host biomarker panel over the course of vancomycin therapy.

Discussion Based on previous pre-clinical data and a large meta-analysis of neonatal, PK/pharmacodynamic data, NeoVanc was set up to provide evidence on whether a loading dose followed by a short vancomycin course is non-inferior, regarding efficacy, when compared to a standard, longer course. If non-inferiority is demonstrated, this would support adoption of the optimised regimen as a way of safely reducing vancomycin exposure when treating neonatal, Gram-positive LOS.

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17

Apr, 2020

Genomic and epidemiological surveillance of Zika virus in the Amazon region

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Authors: Giovanetti M, Faria NR, Lourenco J, et al.

Published in:  Cell Rep. 2020;30(7):2275-2283

Abstract Zika virus (ZIKV) has caused an explosive epidemic linked to severe clinical outcomes in the Americas. As of June 2018, 4,929 ZIKV suspected infections and 46 congenital syndrome cases had been reported in Manaus, Amazonas, Brazil. Although Manaus is a key demographic hub in the Amazon region, little is known about the ZIKV epidemic there, in terms of both transmission and viral genetic diversity. Using portable virus genome sequencing, we generated 59 ZIKV genomes in Manaus. Phylogenetic analyses indi- cated multiple introductions of ZIKV from northeastern Brazil to Manaus. Spatial genomic analysis of virus movement among six areas in Manaus suggested that populous northern neighborhoods acted as sources of virus transmission to other neighborhoods. Our study revealed how the ZIKV epidemic was ignited and maintained within the largest urban metropolis in the Amazon. These results might contribute to improving the public health response to outbreaks in Brazil.

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12

Apr, 2020

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

 

Authors: Dhummakupt A, Reubens JH, Anderson T, et al.

Published: Poster presented at 27th Conference on Retroviruses and Opportunistic Infections, March 8th –11th, 2020 – Boston.

Abstract The HIV latent reservoir in resting memory CD4+ T cells prevents cure. Novel therapies to reactivate and eliminate the reservoir are in clinical trials in adults, but not yet in pediatric populations.

HIV proviral reservoir size was determined in perinatal (N=11) and adult infections (N=10) by digital droplet PCR (ddPCR) and with the intact proviral DNA assay (IPDA) in perinatal samples. The inducibility of the latent reservoir was determined with the Tat/rev Induced Limiting Dilution Assay (TILDA) that uses single-round (12 hr) T cell stimulation of CD4+ T cells with PMA/ ionomycin to maximally activate cells to induce proviral expression, measured as multiply-spliced HIV RNA Units per 106 CD4 cells (msRUPM). Markers of immune activation (CD69, CD25 and HLA-DR) and exhaustion (PD-1, TIM-3 and TIGIT) were also assessed. An enhanced TILDA with addition of PHA and for 18 hours was performed to enhance proviral expression in perinatal infections. Non-parametric tests were used for differences between paired and unpaired measurements; correlations were quantified by Spearman rank coefficient.

The median age was 15.8 yrs with a median duration of suppression of 6.7 yrs for perinatal infections, and 40.5 yrs with a median duration of suppression of 7.3 yrs for adult infections.  We found that despite a higher proviral reservoir size (median 132.1 vs. 66.7 c/106 PBMCs) and similar rates of T cell activation with PMA/ionomycin (median %CD69 = 96.7% and 93.0%) in perinatal and adult infections, respectively, the size of the induced reservoir was significantly lower in perinatal than in adult infections (median msRUPM of 2.99 vs 11.92, p=0.020). With the enhanced TILDA, the size of the induced reservoir increased significantly in perinatal infections (1.5-fold to a median of 4.5 msRUPM; p=0.034), but not in adult infections. The proportion of induced provirus was significantly lower in perinatal infections at 1.6% compared with 4.0% in adult infections (p=0.030). At baseline, the proportion of HLA-DR+ T cells was significantly lower in perinatal compared with adult infections (median HLA-DR+ cells = 4.56% vs 10.5%, p=0.012), but not correlated with the induced reservoir size.

The inducibility of the latent reservoir is substantially lower in perinatal compared with adult infections, possibly due to differences in baseline states of immune activation, with implications for latency reversal strategies towards ART-free remission.

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6

Apr, 2020

How is immunosuppressive status affecting children and adults in SARS-CoV-2 infection? A systematic review

 

Authors: Minotti C, Tirelli F, Barbieri E, Giaquinto C, Donà D.

Published in: J Infect. 2020 Apr 23

Objectives SARS-CoV-2 infection has now a global resonance. Data on how COVID-19 is affecting immunocompromised patients are however few. With our study we aimed to systematically review the current knowledge on SARS-CoV-2 cases in children and adults with immunosuppression, to evaluate outcomes in this special population.

Methods A systematic review of literature was carried out to identify relevant articles, searching the EMBASE, Medline, and Google Scholar databases. Studies reporting data on pre-defined outcomes and related to immunosuppressed adults and children with SARS-CoV-2 were included.

Results Sixteen relevant articles were identified with 110 immunosuppressed patients, mostly presenting cancer, along with transplantation and immunodeficiency. Cancer was more often associated with a more severe course, but not necessarily with a bad prognosis. Our data show that both children and adults with immunosuppression seem to have a favorable disease course, as compared to the general population.

Conclusion Immunosuppressed patients with COVID-19 seem to be few in relation to the overall figures, and to present a favorable outcome as compared to other comorbidities. This might be explained by a hypothetical protective role of a weaker immune response, determining a milder disease presentation and thus underdiagnosis. Nevertheless, surveillance on this special population should be encouraged.

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6

Apr, 2020

Fecal-oral transmission of Sars-Cov-2 in children: is it time to change our approach?

 

Authors: Donà D, Minotti C, Costenaro P, Da Dalt L, Giaquinto C.

Published in: Pediatr Infect Dis J. 2020 Apr 16.

Abstract Starting from 2 pediatric cases of COVID-19, with confirmation at nasopharyngeal and rectal swabs, we considered the lesson learnt from previous Coronavirus epidemics and reviewed evidence on the current outbreak. Surveillance with rectal swabs might be extended to infants and children, for the implications for household contacts and isolation timing.

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27

Mar, 2020

Time to viral suppression in perinatally HIV-infected infants depends on the viral load and CD4 T-cell percentage at the start of treatment

 

Authors: Schröter J, Anelone A,  Yates A, de Boer RJ;  on behalf of the EPIICAL Consortium

Published in: J Acquir Immune Defic Syndr. 2020;83(5):522-529

 

Background Interventions aiming for an HIV cure would benefit from rapid elimination of virus after the onset of antiretroviral therapy (ART), by keeping the latent HIV reservoir small.

Setting We investigated HIV suppression in 312 perinatally infected infants starting ART within 6 months after birth from the EPPICC (European Pregnancy and Paediatric HIV Cohort Collaboration).

Methods To better understand kinetic differences in HIV suppression among infants, we investigated their individual viral load (VL) decay dynamics. We identified VL decay patterns and determined times to viral suppression (TTS). For infants with strictly declining VLs (n = 188), we used parameter fitting methods to estimate baseline VLs, decay rates, and TTS. We subsequently identified the parameters determining TTS by linear modeling.

Results The majority of infants suppress HIV VL after the onset of ART. Some children experienced a long TTS due to an “erratic” VL decay pattern. We cannot exclude that this is partly due to treatment complications and subsequent treatment changes, but these children were characterized by significantly lower CD4 percentages (CD4%) at start of treatment compared with those with a “clean” VL decline. Focusing on this “clean” subset, the TTS could be predicted by mathematical modeling, and we identified baseline VL and CD4% as the major factors determining the TTS.

Conclusions As VL steeply increases and CD4% constantly decreases in untreated HIV-infected infants, the progression of an HIV infection is largely determined by these 2 factors. To prevent a further disease progression, treatment should be initiated early after contracting HIV, which consequently shortens TTS.

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16

Mar, 2020

Mothers’ adherence helps in identifying more infants in need of extended prophylaxis

 

Authors: Dominguez-Rodriguez S, Rojo P, Lain MG,  Barnabas S, Lopez-Varela E, Otwombe K, Danaviah S, Nastouli E, Serna-Pasqual M, Gianuzzi V, Giaquointo C, Kuhn L, Tagarro A on behalf of the EPIICAL Consortium

Published in: 27th Conference on Retroviruses and Opportunistic Infections, March 8th –11th, 2020 – Boston.

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