Understanding the relation between Zika virus infection during pregnancy and adverse fetal, infant and child outcomes: a protocol for a systematic review and individual participant data meta-analysis of longitudinal studies of pregnant women and their infants and children

IntroductionZika virus (ZIKV) infection during pregnancy is a known cause of microcephaly and other congenital and developmental anomalies. In the absence of a ZIKV vaccine or prophylactics, principal investigators (PIs) and international leaders in ZIKV research have formed the ZIKV Individual Participant Data (IPD) Consortium to identify, collect and synthesise IPD from longitudinal studies of pregnant women that measure ZIKV infection during pregnancy and fetal, infant or child outcomes.Methods and analysisWe will identify eligible studies through the ZIKV IPD Consortium membership and a systematic review and invite study PIs to participate in the IPD meta-analysis (IPD-MA). We will use the combined dataset to estimate the relative and absolute risk of congenital Zika syndrome (CZS), including microcephaly and late symptomatic congenital infections; identify and explore sources of heterogeneity in those estimates and develop and validate a risk prediction model to identify the pregnancies at the highest risk of CZS or adverse developmental outcomes. The variable accuracy of diagnostic assays and differences in exposure and outcome definitions means that included studies will have a higher level of systematic variability, a component of measurement error, than an IPD-MA of studies of an established pathogen. We will use expert testimony, existing internal and external diagnostic accuracy validation studies and laboratory external quality assessments to inform the distribution of measurement error in our models. We will apply both Bayesian and frequentist methods to directly account for these and other sources of uncertainty.Ethics and disseminationThe IPD-MA was deemed exempt from ethical review. We will convene a group of patient advocates to evaluate the ethical implications and utility of the risk stratification tool. Findings from these analyses will be shared via national and international conferences and through publication in open access, peer-reviewed journals.Trial registration numberPROSPERO International prospective register of systematic reviews (CRD42017068915).</jats:sec

Serologic vaccination response after solid organ transplantation: a systematic review

BACKGROUND Infectious diseases after solid organ transplantation (SOT) are one of the major complications in transplantation medicine. Vaccination-based prevention is desirable, but data on the response to active vaccination after SOT are conflicting. METHODS In this systematic review, we identify the serologic response rate of SOT recipients to post-transplantation vaccination against tetanus, diphtheria, polio, hepatitis A and B, influenza, Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitides, tick-borne encephalitis, rabies, varicella, mumps, measles, and rubella. RESULTS Of the 2478 papers initially identified, 72 were included in the final review. The most important findings are that (1) most clinical trials conducted and published over more than 30 years have all been small and highly heterogeneous regarding trial design, patient cohorts selected, patient inclusion criteria, dosing and vaccination schemes, follow up periods and outcomes assessed, (2) the individual vaccines investigated have been studied predominately only in one group of SOT recipients, i.e. tetanus, diphtheria and polio in RTX recipients, hepatitis A exclusively in adult LTX recipients and mumps, measles and rubella in paediatric LTX recipients, (3) SOT recipients mount an immune response which is for most vaccines lower than in healthy controls. The degree to which this response is impaired varies with the type of vaccine, age and organ transplanted and (4) for some vaccines antibodies decline rapidly. CONCLUSION Vaccine-based prevention of infectious diseases is far from satisfactory in SOT recipients. Despite the large number of vaccination studies preformed over the past decades, knowledge on vaccination response is still limited. Even though the protection, which can be achieved in SOT recipients through vaccination, appears encouraging on the basis of available data, current vaccination guidelines and recommendations for post-SOT recipients remain poorly supported by evidence. There is an urgent need to conduct appropriately powered vaccination trials in well-defined SOT recipient cohorts

Watch and Wait Management of Inactive Cystic Echinococcosis – Does the Path to Inactivity Matter – Analysis of a Prospective Patient Cohort

<div><p>Background</p><p>Overdiagnosis and overtreatment are rarely discussed in the context of NTDs despite their relevance for patients under the care of health services with limited resources where the risks of therapy induced complications are often disproportionate to the benefit. The advantages of cyst staging-based management of patients with cystic echinococcosis (CE) are not yet fully explored. Questions are: Do inactive cysts (CE 4 and CE 5) need treatment and is there a difference between cysts which reach CE4 and CE5 naturally or by benzimidazole therapy?</p><p>Methodology/Principal findings</p><p>Analysis of long-term follow-up data from a prospective CE patient cohort of 223 patients of a national clinical center for echinococcosis. The event of interest “relapse” was defined as the reversal of a cyst from an inactive stage (CE4, CE5) back to an active stage. The watch &wait (ww) group included 30 patients with 46 inactive cysts who never received medical treatment. The benzimidazole-treated (med) group included 15 patients with 17 cysts. There was no relapse in the ww-group whereas 8/17 cysts showed relapse within 18 months after treatment in the med-group. Loss to follow-up was 15.5%.</p><p>Conclusions</p><p>Data from the watch & wait group impressively show how stable naturally inactivated cysts are in contrast to cysts which reach inactivity through treatment with benzimidazoles. A substantial proportion of patients can be spared from treatment through cyst staging. Cysts which inactivated through a natural course do not relapse with very high likelihood. We recommend follow up of 5 years to confirm the stability of the inactive stage. Cysts driven into inactivity through benzimidazole therapy instead need careful monitoring to identify those which reactivate (around 50% within 18 months). 5 years follow-up appears safe to make a final decision on the need for further monitoring.</p></div

Risk of microcephaly after Zika virus infection in Brazil, 2015 to 2016

Submitted by Adagilson Silva ([email protected]) on 2017-06-22T13:25:56Z No. of bitstreams: 1 28250532 2017 jae-ris.oa.pdf: 485093 bytes, checksum: a3a0105d13cf4745dacbc9cbdca2dcad (MD5)Approved for entry into archive by Adagilson Silva ([email protected]) on 2017-06-22T13:26:28Z (GMT) No. of bitstreams: 1 28250532 2017 jae-ris.oa.pdf: 485093 bytes, checksum: a3a0105d13cf4745dacbc9cbdca2dcad (MD5)Made available in DSpace on 2017-06-22T13:26:28Z (GMT). No. of bitstreams: 1 28250532 2017 jae-ris.oa.pdf: 485093 bytes, checksum: a3a0105d13cf4745dacbc9cbdca2dcad (MD5) Previous issue date: 2017-03-01Heidelberg University Hospital. Section of Clinical Tropical Medicine. Department of Infectious Diseases. Heidelberg, Germany.Heidelberg University Hospital. Section of Clinical Tropical Medicine. Department of Infectious Diseases. Heidelberg, Germany.Federal University of Pernambuco. Department of Internal Medicine. Recife, PE, Brazil.London School of Hygiene & Tropical Medicine. Department of Infectious Disease Epidemiology. London, England.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Laboratório de Virologia e Terapia Experimental. Recife, PE, Brasil.OBJECTIVE: To estimate the risk of microcephaly in babies born to women infected by the Zika virus during pregnancy in Brazil in an epidemic between 2015 and 2016. METHODS: We obtained data on the number of notified and confirmed microcephaly cases in each Brazilian state between November 2015 and October 2016 from the health ministry. For Pernambuco State, one of the hardest hit, weekly data were available from August 2015 to October 2016 for different definitions of microcephaly. The absolute risk of microcephaly was calculated using the average number of live births reported in each state in the corresponding time period between 2012 and 2014 and assuming two infection rates: 10% and 50%. The relative risk was estimated using the reported background frequency of microcephaly in Brazil of 1.98 per 10 000 live births. FINDINGS: The estimated absolute risk of a notified microcephaly case varied from 0.03 to 17.1% according to geographical area, the definition of microcephaly used and the infection rate. Assuming a 50% infection rate, there was an 18-127 fold higher probability of microcephaly in children born to mothers with infection during pregnancy compared with children born to mothers without infection during pregnancy in Pernambuco State. For a 10% infection rate, the probability was 88-635 folds higher. CONCLUSION: A large variation in the estimated risk of microcephaly was found in Brazil. Research is needed into possible effect modifiers, reliable measures of Zika virus infection and clear endpoints for congenital malformations

Characteristics and findings of all studies included (n = 72).

<p>In the column “Short-term response SOT” is the number of patients given that had a positive response >2 weeks and ≤3 months after the last vaccination while in the column “Long-term response SOT” the number of patients that kept a positive response after ≥12 months is given (exceptions are marked with number). Data presented as number of patients with vaccination response/total number of patients.</p><p><i>Design</i>: pu - prospective uncontrolled, pc - prospective controlled, r- retrospective, ra – randomized, c-case report <i>Patients</i>: A - adult, P – paediatric, HTX- heart transplantation, RTX - renal transplantation, LTX – liver transplantation, PTX- lung transplantation, ITX – intestinal transplantation, ESRD- end stage renal disease <i>Response</i>: SOT – solid organ transplant recipient, HC - healthy control group, <i>Vaccine, Vaccination schedule</i>: T – tetanus toxoid vaccine, d – diphtheria vaccine (adult formulation with reduced antigen amount), D - diphtheria vaccine (paediatric formulation with higher antigen amount), IPV – inactivated polio vaccine, HAV – hepatitis A vaccine, rHBV - recombinant hepatitis B vaccine, TIV - trivalent inactivated influenza vaccine, PPV23- 23-valent pneumococcal vaccine, PCV7- seven-valent pneumococcal conjugate vaccine, HibV – <i>Haemophilus influenzae</i> vaccine, TBEV - tick borne encephalitis vaccine, MMR – mumps, measles, rubella vaccine, RVV – rabies virus vaccine, VZVV – varicella zoster vaccine, MMRV – mumps, measles, rubella, varicella vaccine, NA - not applicable.</p>1<p>patients receiving a chimeric monoclonal antibody against CD20.</p>2<p>patients receiving conventional immunosuppressive medication.</p>3<p>after 1st dose, controls received a different vaccination scheme compared to SOT recipients (one vs. two doses of vaccine, respectively).</p>4<p>after 2nd dose, controls received a different vaccination scheme compared to SOT recipients (one vs. two doses of vaccine, respectively).</p>5<p>after 3rd dose, controls received a different vaccination scheme compared to SOT recipients (one vs. two doses of vaccine, respectively).</p>6<p>patients were randomized to vaccine vs. no vaccine for the purpose of studying rejection.</p>7<p>patients receiving calcineurin-inhibitors.</p>8<p>patients receiving sirolimus.</p>9<p>patients receiving mycophenolate mofetil.</p>10<p>patients receiving azathioprin.</p>11<p>SOT recipients received either one or two doses of vaccine, however data for the double-dose trial are not given and stated that no difference to the single dose trial.</p>12<p>subunit vaccine.</p>13<p>virosomal vaccine.</p>14<p>for controls exact numbers were not given but stated that no difference between patients and controls.</p>15<p>response measured by enzyme-linked immunoassay (ELISA).</p>16<p>response measured by opsophagonization assay (OPA).</p>17<p>response measured by enzyme-linked immunoassay (ELISA).</p>18<p>response measured by opsophagonization assay (OPA).</p>19<p>long-term response of PPV 23 vs. PCV7 by follow up of the cohort by Kumar et al. 2003, mean continued response from patients initially vaccinated against PPV23 from varying patient numbers of ranging from 2 to 10 patients.</p>20<p>long-term response of PPV 23 vs. PCV7 by follow up of the cohort by Kumar et al. 2003, mean continued response of patients initially vaccinated against PCV7 from varying patient numbers ranging from 4 to 11 patients.</p>21<p>mean response after PCV7 only to serotypes 4, 6B, 9V, 14, 18C, 19F, 23F.</p>22<p>mean response after PCV7 followed by PPV23 to serotype 1, 5 und 7F after additional PP23 vaccination in the cohort from 23.</p>23<p>response to measles component.</p>24<p>response to mumps component.</p>25<p>response to rubella component.</p>26<p>response to mumps component.</p>27<p>response to measles component.</p>28<p>response to rubella component.</p>29<p>long-term response was accepted as 6 months after vaccination.</p>30<p>adequate response was seen but which decreased rapidly.</p

Stability of cyst diameters of ww-cysts.

<p>There is no substantial reduction in cyst diameter over time.</p

Meta-analysis for case-control studies using the Mantel-Haenszel fixed effects method (M–H) and the DerSimonian and Laird random effects (D+L) method for response to influenza H1N1.

<p>Numbers in brackets refer to legend in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056974#pone-0056974-t003" target="_blank">Table 3</a>.</p

Forest plot for short-term response for vaccine category C (influenza) against influenza H1N1.

<p>All type of trials which assessed specific response to H1N1 are included. Numbers in brackets refer to legend in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056974#pone-0056974-t003" target="_blank">Table 3</a>.</p

Meta-analysis for case-control studies using the Mantel-Haenszel fixed effects method (M–H) and the DerSimonian and Laird random effects (D+L) method for response to influenza H3N2.

<p>Numbers in brackets refer to legend in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056974#pone-0056974-t003" target="_blank">Table 3</a>.</p

Treatment groups and patient selection of the Heidelberg CE patient cohort.

<p>Treatment groups and patient selection of the Heidelberg CE patient cohort.</p