Publications

23

Feb, 2021

What does 95% COVID-19 vaccine efficacy really mean?

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Author: Piero Olliaro

Published in: The Lancet

Introduction: It is imperative to dispel any ambiguity about how vaccine efficacy shown in trials translates into protecting individuals and populations. The mRNA-based Pfizer1,2 and Moderna3 vaccines were shown to have 94–95% efficacy in preventing symptomatic COVID-19, calculated as 100 × (1 minus the attack rate with vaccine divided by the attack rate with placebo). It means that in a population such as the one enrolled in the trials, with a cumulated COVID-19 attack rate over a period of 3 months of about 1% without a vaccine, we would expect roughly 0·05% of vaccinated people would get diseased. It does not mean that 95% of people are protected from disease with the vaccine—a general misconception of vaccine protection also found in a Lancet Infectious Diseases Editorial.

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19

Feb, 2021

ODYSSEY clinical trial design: a randomised global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate pragmatic WHO-weight-band based dolutegravir dosing

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Authors: Cecilia L. Moore, Anna Turkova , Hilda Mujuru , Adeodata Kekitiinwa, Abbas Lugemwa, Cissy M. Kityo, Linda N. Barlow-Mosha, et al, ODYSSEY trial team

Published in: BMC Infectious Diseases

 

Background: Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development.

Methods: ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks.

Results: Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ARTnaïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9–18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls.

Conclusions: By employing a basket design, to include ART-naïve and -experienced children, and nested PK substudies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children.

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21

Jan, 2021

Harmonising regulatory approval for antibiotics in children

 

Authors: Phoebe C M Williams, John Bradley, Emmanuel Roilides, Linus Olson, Sheldon Kaplan, Irja Lutsar, Carlo Giaquinto, Daniel K Benjamin, Mike Sharland

Published in: The Lancet

Introduction: Antimicrobial resistance represents a substantial threat to the Sustainable Development Goals (SDGs), with a large impact on the health of children worldwide. However, very few paediatric trials for new antibiotics have been done to inform the optimal treatment of multidrug-resistant infections in children.

The current drug regulatory framework has evolved from a system that rightly aimed to protect children, yet remains governed by interpretation of laws established in response to historical incidents involving agents that caused harm. This approach, particularly for medicines from well established classes with a long experience of safe use in children (such as β-lactam penicillins), now unnecessarily complicates the process of paediatric antibiotic development, and is one of the many barriers to children with multidrug-resistant infections being appropriately treated with licensed drugs.

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20

Jan, 2021

Inferring the effectiveness of government interventions against COVID-19

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Published in: The Science Mag

 

Abstract: Governments are attempting to control the COVID-19 pandemic with non-pharmaceutical interventions (NPIs). However, the effectiveness of different NPIs at reducing transmission is poorly understood.

We gathered chronological data on the implementation of NPIs for several European, and other, countries between January and the end of May 2020. We estimate the effectiveness of NPIs, ranging from limiting gathering sizes, business closures, and closure of educational institutions to stay-at-home orders.

To do so, we used a Bayesian hierarchical model that links NPI implementation dates to national case and death counts and supported the results with extensive empirical validation. Closing all educational institutions, limiting gatherings to 10 people or less, and closing face-to-face businesses each reduced transmission considerably. The additional effect of stay-at-home orders was comparatively small.

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12

Jan, 2021

Zika virus infection in pregnancy: a protocol for the join analysis of the prospective cohort studies of the ZIKAlliance, ZikaPLAN and ZIKAction consortia

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Authors: A E Ades, Elizabeth B Brickley, Neal Alexander, David Brown, Thomas Jaenisch, Demócrito de Barros Miranda-Filho, Moritz Pohl, Kerstin D Rosenberger, Antoni Soriano-Arandes , Claire Thorne et al.

Published in: BMJ Journals

 

Abstract: 

Introduction    Zika virus (ZIKV) infection in pregnancy has been associated with microcephaly and severe neurological damage to the fetus. Our aim is to document the risks of adverse pregnancy and birth outcomes and the prevalence of laboratory markers of congenital infection in deliveries to women experiencing ZIKV infection during pregnancy, using data from European Commission-funded prospective cohort studies in 20 centres in 11 countries across Latin America and the Caribbean.

Methods and analysis    We will carry out a centre-by- centre analysis of the risks of adverse pregnancy and birth outcomes, comparing women with confirmed and suspected ZIKV infection in pregnancy to those with no evidence of infection in pregnancy. We will document the proportion of deliveries in which laboratory markers of congenital infection were present. Finally, we will investigate the associations of trimester of maternal infection in pregnancy, presence or absence of maternal symptoms of acute ZIKV infection and previous flavivirus infections with adverse outcomes and with markers of congenital infection. Centre-specific estimates will be pooled using a two-stage approach.

Ethics and dissemination   Ethical approval was obtained at each centre. Findings will be presented at international conferences and published in peer-reviewed open access journals and discussed with local public health officials and representatives of the national Ministries of Health, Pan American Health Organization and WHO involved with ZIKV prevention and control activities.

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29

Dec, 2020

A population pharmacokinetics analysis assessing the exposure of raltegravir once‐daily 1200mg in pregnant women living with HIV

 

Authors: Vera E. Bukkems, Teun M. Post, Angela P. Colbers, David M. Burger, Elin M. Svensson

Published in: American Society for Clinical Pharmacology and Therapeutics

 

Abstract: Once‐daily two 600mg tablets (1200mg QD) raltegravir offers an easier treatment option compared to the twice‐daily regimen of one 400mg tablet. No pharmacokinetic, efficacy or safety data of the 1200mg QD regimen have been reported in pregnant women to date as it is challenging to collect these clinical data.

This study aimed to develop a population pharmacokinetic (popPK) model to predict the pharmacokinetic profile of raltegravir 1200mg QD in pregnant women and to discuss the expected pharmacodynamic properties of raltegravir 1200mg QD during pregnancy based on previously reported concentration‐effect relationships. Data from 11 pharmacokinetic studies were pooled (n=221).

A two‐compartment model with first‐order elimination and absorption through three sequential transit compartments best described the data. We assessed that the bio‐availability of the 600mg tablets was 21% higher as the 400mg tablets, and the bio‐availability in pregnant women was 49% lower. Monte‐Carlo simulations were performed to predict the pharmacokinetic profile of 1200mg QD in pregnant and non‐pregnant women.

The primary criteria for efficacy was that the lower bound of the 90% confidence interval (CI) of the concentration before next dose administration (Ctrough) geometric mean ratio (GMR) of simulated pregnant/non‐pregnant women had to be >0.75. The simulated raltegravir Ctrough GMR (90%CI) was 0.51 (0.41‐0.63), hence not meeting the primary target for efficacy. Clinical data from two pregnant women using 1200mg QD raltegravir showed a similar Ctrough ratio pregnant/non‐pregnant.

Our pharmacokinetic results support the current recommendation of not using the raltegravir 1200mg QD regimen during pregnancy until more data on the exposure‐response relationship becomes available.

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22

Dec, 2020

Clinical Charateristrics of 58 Children with a Pediatric Inflmmatory Multisystem Syndrome Temporally Associated with SARS-CoV-2

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Authors: Elizabeth Whittaker, Alasdair Bamford, Julia Kenny, Myrsini Kaforou, Christine E Jones, Priyen Shah, Padmanabhan Ramnarayan, Alain Fraisse, Owen Miller, Patrick Davies, Filip Kucera, Joe Brierley, Marilyn McDougall, Michael Carter, Adriana Tremoulet, Chisato Shimizu, Jethro Herberg, Jane C Burns, Hermione Lyall, Michael Levin, PIMS-TS Study Group and EUCLIDS and PERFORM Consortia

Published in: JAMA Network

 

Abstract: Importance: In communities with high rates of coronavirus disease 2019, reports have emerged of children with an unusual syndrome of fever and inflammation.

Objectives:To describe the clinical and laboratory characteristics of hospitalized children who met criteria for the pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PIMS-TS) and compare these characteristics with other pediatric inflammatory disorders.

Design, setting, and participants:Case series of 58 children from 8 hospitals in England admitted between March 23 and May 16, 2020, with persistent fever and laboratory evidence of inflammation meeting published definitions for PIMS-TS. The final date of follow-up was May 22, 2020. Clinical and laboratory characteristics were abstracted by medical record review, and were compared with clinical characteristics of patients with Kawasaki disease (KD) (n = 1132), KD shock syndrome (n = 45), and toxic shock syndrome (n = 37) who had been admitted to hospitals in Europe and the US from 2002 to 2019.

Exposures:Signs and symptoms and laboratory and imaging findings of children who met definitional criteria for PIMS-TS from the UK, the US, and World Health Organization.

Main outcomes and measures:Clinical, laboratory, and imaging characteristics of children meeting definitional criteria for PIMS-TS, and comparison with the characteristics of other pediatric inflammatory disorders.

Results:Fifty-eight children (median age, 9 years [interquartile range {IQR}, 5.7-14]; 20 girls [34%]) were identified who met the criteria for PIMS-TS. Results from SARS-CoV-2 polymerase chain reaction tests were positive in 15 of 58 patients (26%) and SARS-CoV-2 IgG test results were positive in 40 of 46 (87%). In total, 45 of 58 patients (78%) had evidence of current or prior SARS-CoV-2 infection. All children presented with fever and nonspecific symptoms, including vomiting (26/58 [45%]), abdominal pain (31/58 [53%]), and diarrhea (30/58 [52%]). Rash was present in 30 of 58 (52%), and conjunctival injection in 26 of 58 (45%) cases. Laboratory evaluation was consistent with marked inflammation, for example, C-reactive protein (229 mg/L [IQR, 156-338], assessed in 58 of 58) and ferritin (610 μg/L [IQR, 359-1280], assessed in 53 of 58). Of the 58 children, 29 developed shock (with biochemical evidence of myocardial dysfunction) and required inotropic support and fluid resuscitation (including 23/29 [79%] who received mechanical ventilation); 13 met the American Heart Association definition of KD, and 23 had fever and inflammation without features of shock or KD. Eight patients (14%) developed coronary artery dilatation or aneurysm. Comparison of PIMS-TS with KD and with KD shock syndrome showed differences in clinical and laboratory features, including older age (median age, 9 years [IQR, 5.7-14] vs 2.7 years [IQR, 1.4-4.7] and 3.8 years [IQR, 0.2-18], respectively), and greater elevation of inflammatory markers such as C-reactive protein (median, 229 mg/L [IQR 156-338] vs 67 mg/L [IQR, 40-150 mg/L] and 193 mg/L [IQR, 83-237], respectively).

Conclusions and relevance:In this case series of hospitalized children who met criteria for PIMS-TS, there was a wide spectrum of presenting signs and symptoms and disease severity, ranging from fever and inflammation to myocardial injury, shock, and development of coronary artery aneurysms. The comparison with patients with KD and KD shock syndrome provides insights into this syndrome, and suggests this disorder differs from other pediatric inflammatory entities.

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22

Dec, 2020

Multisystem Inflammatory Syndrome in U.S Children and Adolescents

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Authors: Leora R. Feldstein, Ph.D., Erica B. Rose, Ph.D., Steven M. Horwitz, M.D.

Published in: The New England Journal of Medicine

 

Abstract: Background: Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome.

Methods: We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms.

Results: We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki’s disease–like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%).

Conclusions: Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.)

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22

Dec, 2020

Multisystem Inflammatory Syndrome in Children in New York State

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Authors: Elizabeth M. Dufort, M.D., Emilia H. Koumans, M.D., M.P.H., Eric J. Chow, M.D., M.P.H., Elizabeth M. Rosenthal, M.P.H., Alison Muse, M.P.H.,  Jemma Rowlands, M.P.H., Meredith A. Barranco, M.P.H.,
Angela M. Maxted, D.V.M., Ph.D.,  Eli S. Rosenberg, Ph.D., Delia Easton, Ph.D.,  Tomoko Udo, Ph.D., et al
Jessica Kumar, D.O.,  for the New York State and Centers for Disease Control and Prevention Multisystem Inflammatory Syndrome in Children Investigation Team

Published in: NEJM

 

Abstract: Background: A multisystem inflammatory syndrome in children (MIS-C) is associated with coronavirus disease 2019. The New York State Department of Health (NYSDOH) established active, statewide surveillance to describe hospitalized patients with the syndrome.

Methods: Hospitals in New York State reported cases of Kawasaki’s disease, toxic shock syndrome, myocarditis, and potential MIS-C in hospitalized patients younger than 21 years of age and sent medical records to the NYSDOH. We carried out descriptive analyses that summarized the clinical presentation, complications, and outcomes of patients who met the NYSDOH case definition for MIS-C between March 1 and May 10, 2020.

Results: As of May 10, 2020, a total of 191 potential cases were reported to the NYSDOH. Of 95 patients with confirmed MIS-C (laboratory-confirmed acute or recent severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection) and 4 with suspected MIS-C (met clinical and epidemiologic criteria), 53 (54%) were male; 31 of 78 (40%) were black, and 31 of 85 (36%) were Hispanic. A total of 31 patients (31%) were 0 to 5 years of age, 42 (42%) were 6 to 12 years of age, and 26 (26%) were 13 to 20 years of age. All presented with subjective fever or chills; 97% had tachycardia, 80% had gastrointestinal symptoms, 60% had rash, 56% had conjunctival injection, and 27% had mucosal changes. Elevated levels of C-reactive protein, d-dimer, and troponin were found in 100%, 91%, and 71% of the patients, respectively; 62% received vasopressor support, 53% had evidence of myocarditis, 80% were admitted to an intensive care unit, and 2 died. The median length of hospital stay was 6 days.

Conclusions: The emergence of multisystem inflammatory syndrome in children in New York State coincided with widespread SARS-CoV-2 transmission; this hyperinflammatory syndrome with dermatologic, mucocutaneous, and gastrointestinal manifestations was associated with cardiac dysfunction.

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22

Dec, 2020

Multisystem Inflammatory Syndrome in Children Associated With Coronavirus Disease 2019 in a Children’s Hospital in New York City: Patient Characteristics and an Institutional Protocol for Evaluation, Management, and Follow-Up

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Authors: Brian Jonat, Mark Gorelik, Alexis Boneparth, Andrew S Geneslaw, Philip Zachariah, Amee Shah, Larisa Broglie, Juan Duran, Kimberly D Morel, Maria Zorrilla, Leanne Svoboda 9, Candace Johnson, Jennifer Cheng, Maria C Garzon , Wendy G Silver, Kara Gross Margolis, Cindy Neunert, Irene Lytrivi, Joshua Milner, Steven G Kernie, Eva W Cheung

Published in: Pediatric Critical Care Medicine

 

Abstract: Objectives: The disease caused by severe acute respiratory syndrome coronavirus 2, known as coronavirus disease 2019, has resulted in a global pandemic. Reports are emerging of a new severe hyperinflammatory syndrome related to coronavirus disease 2019 in children and adolescents. The Centers for Disease Control and Prevention has designated this disease multisystem inflammatory syndrome in children. Our objective was to develop a clinical inpatient protocol for the evaluation, management, and follow-up of patients with this syndrome.

Data Sources: The protocol was developed by a multidisciplinary team based on relevant literature related to coronavirus disease 2019, multisystem inflammatory syndrome in children, and related inflammatory syndromes, as well as our experience caring for children with multisystem inflammatory syndrome in children. Data were obtained on patients with multisystem inflammatory syndrome in children at our institution from the pre-protocol and post-protocol periods.

Data Synthesis: Our protocol was developed in order to identify cases of multisystem inflammatory syndrome in children with high sensitivity, stratify risk to guide treatment, recognize co-infectious or co-inflammatory processes, mitigate coronary artery abnormalities, and manage hyperinflammatory shock. Key elements of evaluation include case identification using broad clinical characteristics and comprehensive laboratory and imaging investigations. Treatment centers around glucocorticoids and IV immunoglobulin with biologic immunomodulators as adjuncts. Multidisciplinary follow-up after discharge is indicated to manage continued outpatient therapy and evaluate for disease sequelae. In nearly 2 months, we admitted 54 patients with multisystem inflammatory syndrome in children, all of whom survived without the need for invasive ventilatory or mechanical circulatory support. After institution of this protocol, patients received earlier treatment and had shorter lengths of hospital stay.

Conclusions: This report provides guidance to clinicians on evaluation, management, and follow-up of patients with a novel hyperinflammatory syndrome related to coronavirus disease 2019 known as multisystem inflammatory syndrome in children. It is based on the relevant literature and our experience. Instituting such a protocol during a global pandemic is feasible and is associated with patients receiving treatment and returning home more quickly.

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