Abstract
Informal slums are growing exponentially in the developing world and these will serve as the breeding ground for a future global pandemic. Virtually every sustainable development goal is ...unmet in slums around the globe thus we must act now to divert a global humanitarian crisis.
•Poliovirus eradication endgame requires IPV-only immunization schedules.•A 14-week/9-month IPV schedule is superior to a 6 and 14-week schedule.•A 14-week/9-month and 6-week/9-month schedules ...achieved a cumulative immune response of >=98%.•Findings support current SAGE guidelines for IPV immunization schedules.
After global oral poliovirus vaccine (OPV) cessation, the Strategic Advisory Group of Experts on Immunization (SAGE) currently recommends a two-dose schedule of inactivated poliovirus vaccine (IPV) beginning ≥14-weeks of age to achieve at least 90% immune response. We aimed to compare the immunogenicity of three different two-dose IPV schedules started before or at 14-weeks of age.
We conducted a randomized, controlled, open-label, inequality trial at two sites in Dhaka, Bangladesh. Healthy infants at 6-weeks of age were randomized into one of five arms to receive two-dose IPV schedules at different ages with and without OPV. The three IPV-only arms are presented: Arm C received IPV at 14-weeks and 9-months; Arm D received IPV at 6-weeks and 9-months; and Arm E received IPV at 6 and 14-weeks. The primary outcome was immune response defined as seroconversion from seronegative (<1:8) to seropositive (≥1:8) after vaccination, or a four-fold rise in antibody titers and median reciprocal antibody titers to all three poliovirus types measured at 10-months of age.
Of the 987 children randomized to Arms C, D, and E, 936 were included in the intention-to-treat analysis. At 10-months, participants in Arm C (IPV at 14-weeks and 9-months) had ≥99% cumulative immune response to all three poliovirus types which was significantly higher than the 77–81% observed in Arm E (IPV at 6 and 14-weeks). Participants in Arm D (IPV at 6-weeks and 9-months) had cumulative immune responses of 98–99% which was significantly higher than that of Arm E (p value < 0.0001) but not different from Arm C.
Results support current SAGE recommendations for IPV following OPV cessation and provide evidence that the schedule of two full IPV doses could begin as early as 6-weeks.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: There is limited evidence regarding the proportion of wheeze in young children attributable to respiratory syncytial virus lower respiratory tract infections (RSV-LRTI) occurring early in ...life. This cohort study prospectively determined the population attributable risk (PAR) and risk percent (PAR%) of wheeze in 2–<6-year-old children previously surveilled in a primary study for RSV-LRTI from birth to their second birthday (RSV-LRTI<2Y). Methods: From 2013 to 2021, 2-year-old children from 8 countries were enrolled in this extension study (NCT01995175) and were followed through quarterly surveillance contacts until their sixth birthday for the occurrence of parent-reported wheeze, medically-attended wheeze or recurrent wheeze episodes (≥4 episodes/year). PAR% was calculated as PAR divided by the cumulative incidence of wheeze in all participants. Results: Of 1395 children included in the analyses, 126 had documented RSV-LRTI<2Y. Cumulative incidences were higher for reported (38.1% vs. 13.6%), medically-attended (30.2% vs. 11.8%) and recurrent wheeze outcomes (4.0% vs. 0.6%) in participants with RSV-LRTI<2Y than those without RSV-LRTI<2Y. The PARs for all episodes of reported, medically-attended and recurrent wheeze were 22.2, 16.6 and 3.1 per 1000 children, corresponding to PAR% of 14.1%, 12.3% and 35.9%. In univariate analyses, all 3 wheeze outcomes were strongly associated with RSV-LRTI<2Y (all global P < 0.01). Multivariable modeling for medically-attended wheeze showed a strong association with RSV-LRTI after adjustment for covariates (global P < 0.0001). Conclusions: A substantial amount of wheeze from the second to sixth birthday is potentially attributable to RSV-LRTI<2Y. Prevention of RSV-LRTI<2Y could potentially reduce wheezing episodes in 2–<6-year-old children.
To inform response strategies, we examined type 1 humoral and intestinal immunity induced by 1) one fractional inactivated poliovirus vaccine (fIPV) dose given with monovalent oral poliovirus vaccine ...(mOPV1), and 2) mOPV1 versus bivalent OPV (bOPV).
We conducted a randomized, controlled, open-label trial in Dhaka, Bangladesh. Healthy infants aged 5 weeks were block randomized to one of four arms: mOPV1 at age 6–10–14 weeks/fIPV at 6 weeks (A); mOPV1 at 6–10–14 weeks/fIPV at 10 weeks (B); mOPV1 at 6–10–14 weeks (C); and bOPV at 6–10–14 weeks (D). Immune response at 10 weeks and cumulative response at 14 weeks was assessed among the modified intention-to-treat population, defined as seroconversion from seronegative (<1:8 titers) to seropositive (≥1:8) or a four-fold titer rise among seropositive participants sustained to age 18 weeks. We examined virus shedding after two doses of mOPV1 with and without fIPV, and after the first mOPV1 or bOPV dose. The trial is registered at ClinicalTrials.gov (NCT03722004).
During 18 December 2018 – 23 November 2019, 1,192 infants were enrolled (arms A:301; B:295; C:298; D:298). Immune responses at 14 weeks did not differ after two mOPV1 doses alone (94% 95% CI: 91–97%) versus two mOPV1 doses with fIPV at 6 weeks (96% 93–98%) or 10 weeks (96% 93–98%). Participants who received mOPV1 and fIPV at 10 weeks had significantly lower shedding (p < 0·001) one- and two-weeks later compared with mOPV1 alone. Response to one mOPV1 dose was significantly higher than one bOPV dose (79% versus 67%; p < 0·001) and shedding two-weeks later was significantly higher after mOPV1 (76% versus 56%; p < 0·001) indicating improved vaccine replication. Ninety-nine adverse events were reported, 29 serious including two deaths; none were attributed to study vaccines.
Given with the second mOPV1 dose, fIPV improved intestinal immunity but not humoral immunity. One mOPV1 dose induced higher humoral and intestinal immunity than bOPV.
U.S. Centers for Disease Control and Prevention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The current global initiative to end Cholera by 2030 emphasizes the use of oral cholera vaccine (OCV) combined with feasible household Water-Sanitation-Hygiene (WASH) interventions. However, little ...is known about how improved WASH practices and behaviors and OCV interact to reduce the risk of cholera.
We reanalyzed two arms of a cluster-randomized trial in urban Bangladesh, to evaluate the effectiveness of OCV given as a 2-dose regimen. One arm (30 clusters, n = 94,675) was randomized to vaccination of persons aged one year and older with OCV, and the other arm (30 clusters, n = 80,056) to no intervention. We evaluated the prevention of cholera by household WASH, classified at baseline using a previously validated rule, and OCV over 2 years of follow-up. When analyzed by assignment to OCV clusters rather than receipt of OCV, in comparison to persons living in “Not Better WASH” households in the control clusters, reduction of severe cholera (the primary outcome) was similar for persons in “Not Better WASH” households in vaccine clusters (46%, 95% CI:24,62), for persons in “Better WASH” households in the control clusters (48%, 95% CI:25,64), and for persons in “Better WASH” households in the vaccine clusters (48%, 95% CI:16,67). In contrast, when analyzed by actual receipt of a complete OCV regimen, , in comparison to persons in “Not Better WASH” households in the control clusters, protection against severe cholera increased steadily from 39% (95% CI:13,58) in residents of “Better WASH” households in the control clusters to 57% (95% CI:35,72) in vaccinated persons in “Not Better WASH” households to 63% (95% CI:21,83) in vaccinated persons in “Better WASH” households.
This analysis suggests that improved household WASH and OCV received may interact to provide greater protection against cholera. However, the divergence between findings related to intent to vaccinate versus those pertaining to actual receipt of OCV underscores the need for further research on this topic.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In 2012, the World Health Organization revised treatment guidelines for childhood pneumonia with lower chest wall indrawing (LCWI) but no 'danger signs', to recommend home-based treatment. We ...analysed data from children hospitalized with LCWI pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) study to identify sub-groups with high odds of mortality, who might continue to benefit from hospital management but may not be admitted by staff implementing the 2012 guidelines. We compare the proportion of deaths identified using the criteria in the 2012 guidelines, and the proportion of deaths identified using an alternative set of criteria from our model.
PERCH enrolled a cohort of 2189 HIV-negative children aged 2-59 months who were admitted to hospital with LCWI pneumonia (without obvious cyanosis, inability to feed, vomiting, convulsions, lethargy or head nodding) between 2011-2014 in Kenya, Zambia, South Africa, Mali, The Gambia, Bangladesh, and Thailand. We analysed risk factors for mortality among these cases using predictive logistic regression. Malnutrition was defined as mid-upper-arm circumference <125mm or weight-for-age z-score <-2.
Among 2189 cases, 76 (3·6%) died. Mortality was associated with oxygen saturation <92% (aOR 3·33, 1·99-5·99), HIV negative but exposed status (4·59, 1·81-11·7), moderate or severe malnutrition (6·85, 3·22-14·6) and younger age (infants compared to children 12-59 months old, OR 2·03, 95%CI 1·05-3·93). At least one of three risk factors: hypoxaemia, HIV exposure, or malnutrition identified 807 children in this population, 40% of LCWI pneumonia cases and identified 86% of the children who died in hospital (65/76). Risk factors identified using the 2012 WHO treatment guidelines identified 66% of the children who died in hospital (n = 50/76).
Although it focuses on treatment failure in hospital, this study supports the proposal for better risk stratification of children with LCWI pneumonia. Those who have hypoxaemia, any malnutrition or those who were born to HIV positive mothers, experience poorer outcomes than other children with LCWI pneumonia. Consistent identification of these risk factors should be prioritised and children with at least one of these risk factors should not be managed in the community.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pneumonia remains the leading infectious cause of death among children <5 years, but its cause in most children is unknown. We estimated etiology for each child in 2 Bangladesh sites that represent ...rural and urban South Asian settings with moderate child mortality.
As part of the Pneumonia Etiology Research for Child Health study, we enrolled children 1-59 months of age with World Health Organization-defined severe and very severe pneumonia, plus age-frequency-matched controls, in Matlab and Dhaka, Bangladesh. We applied microbiologic methods to nasopharyngeal/oropharyngeal swabs, blood, induced sputum, gastric and lung aspirates. Etiology was estimated using Bayesian methods that integrated case and control data and accounted for imperfect sensitivity and specificity of the measurements.
We enrolled 525 cases and 772 controls over 24 months. Of the cases, 9.1% had very severe pneumonia and 42.0% (N = 219) had infiltrates on chest radiograph. Three cases (1.5%) had positive blood cultures (2 Salmonella typhi, 1 Escherichia coli and Klebsiella pneumoniae). All 4 lung aspirates were negative. The etiology among chest radiograph-positive cases was predominantly viral 77.7%, 95% credible interval (CrI): 65.3-88.6, primarily respiratory syncytial virus (31.2%, 95% CrI: 24.7-39.3). Influenza virus had very low estimated etiology (0.6%, 95% CrI: 0.0-2.3). Mycobacterium tuberculosis (3.6%, 95% CrI: 0.5-11.0), Enterobacteriaceae (3.0%, 95% CrI: 0.5-10.0) and Streptococcus pneumoniae (1.8%, 95% CrI: 0.0-5.9) were the only nonviral pathogens in the top 10 etiologies.
Childhood severe and very severe pneumonia in young children in Bangladesh is predominantly viral, notably respiratory syncytial virus.
Abstract
Background
In 2015, pneumonia remained the leading cause of mortality in children aged 1–59 months.
Methods
Data from 1802 human immunodeficiency virus (HIV)–negative children aged 1–59 ...months enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study with severe or very severe pneumonia during 2011–2014 were used to build a parsimonious multivariable model predicting mortality using backwards stepwise logistic regression. The PERCH severity score, derived from model coefficients, was validated on a second, temporally discrete dataset of a further 1819 cases and compared to other available scores using the C statistic.
Results
Predictors of mortality, across 7 low- and middle-income countries, were age <1 year, female sex, ≥3 days of illness prior to presentation to hospital, low weight for height, unresponsiveness, deep breathing, hypoxemia, grunting, and the absence of cough. The model discriminated well between those who died and those who survived (C statistic = 0.84), but the predictive capacity of the PERCH 5-stratum score derived from the coefficients was moderate (C statistic = 0.76). The performance of the Respiratory Index of Severity in Children score was similar (C statistic = 0.76). The number of World Health Organization (WHO) danger signs demonstrated the highest discrimination (C statistic = 0.82; 1.5% died if no danger signs, 10% if 1 danger sign, and 33% if ≥2 danger signs).
Conclusions
The PERCH severity score could be used to interpret geographic variations in pneumonia mortality and etiology. The number of WHO danger signs on presentation to hospital could be the most useful of the currently available tools to aid clinical management of pneumonia.
We developed a severity score for childhood pneumonia cases presenting to hospital and compared its ability to predict mortality with other tools. The findings reinforce the utility of World Health Organization danger signs and pulse oximetry for clinical management of pneumonia cases.
Arsenic in drinking water causes increased coronary artery disease (CAD) and death from CAD, but its association with stroke is not known.
Prospective cohort study with arsenic exposure measured in ...well water at baseline. 61074 men and women aged 18 years or older on January 2003 were enrolled in 2003. The cohort was actively followed for an average of 7 years (421,754 person-years) through December 2010. Based on arsenic concentration the population was categorized in three groups and stroke mortality HR was compared to the referent. The risk of stroke mortality Hazard Ratio (HR) and 95% Confidence Interval was calculated in relation to arsenic exposure was estimated by Cox proportional hazard models with adjustment for potential confounders.
A total of 1033 people died from stroke during the follow-up period, accounting for 23% of the total deaths. Multivariable adjusted HRs (95% confidence interval) for stroke for well water arsenic concentrations <10, 10-49, and ≥50 μg/L were 1.0 (reference), 1.20 (0.92 to 1.57), and 1.35 (1.04 to 1.75) respectively (Ptrend=0.00058). For men, multivariable adjusted HRs (95%) for well water arsenic concentrations <10, 10-49, and ≥50 μg/L were 1.0 (reference), 1.12 (0.78 to 1.60), and 1.07 (0.75 to 1.51) respectively (Ptrend=0.45) and for women 1.0 (reference),1.31 (0.87 to 1.98), and 1.72 (1.15 to 2.57) respectively (Ptrend=0.00004).
The result suggests that arsenic exposure was associated with increased stroke mortality risk in this population, and was more significant in women compared to men.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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