Cost of illness due to respiratory syncytial virus acute lower respiratory tract infection among infants hospitalized in Argentina.

BACKGROUND: Information is scarce regarding the economic burden of respiratory syncytial virus (RSV) disease in low-resource settings. This study aimed to estimate the cost per episode of hospital admissions due to RSV severe disease in Argentina. METHODS: This is a prospective cohort study that collected information regarding 256 infants under 12 months of age with acute lower respiratory tract infection (ALRTI) due to RSV in two public hospitals of Buenos Aires between 2014 and 2016. Information on healthcare resource use was collected from the patient's report and its associated costs were estimated based on the financial database and account records of the hospitals. We estimated the total cost per hospitalization due to RSV using the health system perspective. The costs were estimated in US dollars as of December 2022 (1 US dollar = 170 Argentine pesos). RESULTS: The mean costs per RSV hospitalization in infants was US$587.79 (95% confidence interval [CI] $535.24 - $640.33). The mean costs associated with pediatric intensive care unit (PICU) admission more than doubled from those at regular pediatric wards ($1,556.81 [95% CI $512.21 - $2,601.40] versus $556.53 [95% CI $514.59 - $598.48]). CONCLUSIONS: This study shows the direct economic impact of acute severe RSV infection on the public health system in Argentina. The estimates obtained from this study could be used to inform cost-effectiveness analyses of new preventive RSV interventions being developed.

Coronavirus Disease 2019 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-Analysis of Individual Participant Data From 5 Randomized Trials.

BACKGROUND: Outpatient monoclonal antibodies are no longer effective and antiviral treatments for coronavirus disease 2019 (COVID-19) disease remain largely unavailable in many countries worldwide. Although treatment with COVID-19 convalescent plasma (CCP) is promising, clinical trials among outpatients have shown mixed results. METHODS: We conducted an individual participant data meta-analysis from outpatient trials to assess the overall risk reduction for all-cause hospitalizations by day 28 in transfused participants. Relevant trials were identified by searching Medline, Embase, medRxiv, World Health Organization COVID-19 Research Database, Cochrane Library, and Web of Science from January 2020 to September 2022. RESULTS: Five included studies from 4 countries enrolled and transfused 2620 adult patients. Comorbidities were present in 1795 (69%). The virus neutralizing antibody dilutional titer levels ranged from 8 to 14 580 in diverse assays. One hundred sixty of 1315 (12.2%) control patients were hospitalized, versus 111 of 1305 (8.5%) CCP-treated patients, yielding a 3.7% (95% confidence interval [CI], 1.3%-6.0%; P = .001) absolute risk reduction and 30.1% relative risk reduction for all-cause hospitalization. The hospitalization reduction was greatest in those with both early transfusion and high titer with a 7.6% absolute risk reduction (95% CI, 4.0%-11.1%; P = .0001) accompanied by at 51.4% relative risk reduction. No significant reduction in hospitalization was seen with treatment >5 days after symptom onset or in those receiving CCP with antibody titers below the median titer. CONCLUSIONS: Among outpatients with COVID-19, treatment with CCP reduced the rate of all-cause hospitalization and may be most effective when given within 5 days of symptom onset and when antibody titer is higher.

Respiratory syncytial virus prevention within reach: the vaccine and monoclonal antibody landscape.

Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a respiratory syncytial virus vaccine or immunoprophylaxis remain highly active. 33 respiratory syncytial virus prevention candidates are in clinical development using six different approaches: recombinant vector, subunit, particle-based, live attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. Nine candidates are in phase 3 clinical trials. Understanding the epitopes targeted by highly neutralising antibodies has resulted in a shift from empirical to rational and structure-based vaccine and monoclonal antibody design. An extended half-life monoclonal antibody for all infants is likely to be within 1 year of regulatory approval (from August, 2022) for high-income countries. Live-attenuated vaccines are in development for older infants (aged >6 months). Subunit vaccines are in late-stage trials for pregnant women to protect infants, whereas vector, subunit, and nucleic acid approaches are being developed for older adults. Urgent next steps include ensuring access and affordability of a respiratory syncytial virus vaccine globally. This review gives an overview of respiratory syncytial virus vaccines and monoclonal antibodies in clinical development highlighting different target populations, antigens, and trial results.

COVID-19 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-analysis of Individual Participant Data From Five Randomized Trials.

Background: Monoclonal antibody and antiviral treatments for COVID-19 disease remain largely unavailable worldwide, and existing monoclonal antibodies may be less active against circulating omicron variants. Although treatment with COVID-19 convalescent plasma (CCP) is promising, randomized clinical trials (RCTs) among outpatients have shown mixed results. Methods: We conducted an individual participant data meta-analysis from all outpatient CCP RCTs to assess the overall risk reduction for all-cause hospitalizations by day 28 in all participants who had transfusion initiated. Relevant trials were identified by searching MEDLINE, Embase, MedRxiv, WHO, Cochrane Library, and Web of Science from January 2020 to September 2022. Results: Five included studies from four countries enrolled and transfused 2,620 adult patients. Comorbidities were present in 1,795 (69%). The anti-Spike or virus neutralizing antibody titer range across all trials was broad. 160 (12.2%) of 1315 control patients were hospitalized, versus 111 (8.5%) of 1305 CCP-treated patients, yielding a 3.7% (95%CI: 1.3%-6.0%; p=.001) ARR and 30.1% RRR for all-cause hospitalization. The effect size was greatest in those with both early transfusion and high titer with a 7.6% ARR (95%CI: 4.0%-11.1%; p=.0001) accompanied by at 51.4% RRR. No significant reduction in hospitalization was seen with treatment > 5 days after symptom onset or in those receiving CCP with antibody titers below the median titer. Conclusions: Among outpatients with COVID-19, treatment with CCP reduced the rate of all-cause hospitalization. CCP may be most effective when given within 5 days of symptom onset and when antibody titer is higher. Key Points: While the outpatient COVID-19 randomized controlled trial meta-analysis indicated heterogeneity in participant risk factors and convalescent plasma, the combined CCP efficacy for reducing hospitalization was significant, improving with transfusion within 5 days of symptom onset and high antibody neutralization levels.

Assembling a global database of child pneumonia studies to inform WHO pneumonia management algorithm: Methodology and applications.

Background: The existing World Health Organization (WHO) pneumonia case management guidelines rely on clinical symptoms and signs for identifying, classifying, and treating pneumonia in children up to 5 years old. We aimed to collate an individual patient-level data set from large, high-quality pre-existing studies on pneumonia in children to identify a set of signs and symptoms with greater validity in the diagnosis, prognosis, and possible treatment of childhood pneumonia for the improvement of current pneumonia case management guidelines. Methods: Using data from a published systematic review and expert knowledge, we identified studies meeting our eligibility criteria and invited investigators to share individual-level patient data. We collected data on demographic information, general medical history, and current illness episode, including history, clinical presentation, chest radiograph findings when available, treatment, and outcome. Data were gathered separately from hospital-based and community-based cases. We performed a narrative synthesis to describe the final data set. Results: Forty-one separate data sets were included in the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) database, 26 of which were hospital-based and 15 were community-based. The PREPARE database includes 285 839 children with pneumonia (244 323 in the hospital and 41 516 in the community), with detailed descriptions of clinical presentation, clinical progression, and outcome. Of 9185 pneumonia-related deaths, 6836 (74%) occurred in children <1 year of age and 1317 (14%) in children aged 1-2 years. Of the 285 839 episodes, 280 998 occurred in children 0-59 months old, of which 129 584 (46%) were 2-11 months of age and 152 730 (54%) were males. Conclusions: This data set could identify an improved specific, sensitive set of criteria for diagnosing clinical pneumonia and help identify sick children in need of referral to a higher level of care or a change of therapy. Field studies could be designed based on insights from PREPARE analyses to validate a potential revised pneumonia algorithm. The PREPARE methodology can also act as a model for disease database assembly.

Neurodevelopmental and growth outcomes after invasive Group B Streptococcus in early infancy: A multi-country matched cohort study in South Africa, Mozambique, India, Kenya, and Argentina.

Background: Data are limited regarding long-term consequences of invasive GBS (iGBS) disease in early infancy, especially from low- and middle-income countries (LMIC) where most cases occur. We aimed to estimate risk of neurodevelopmental impairment (NDI) in children with a history of iGBS disease. Methods: A multi-country matched cohort study was undertaken in South Africa, India, Mozambique, Kenya, and Argentina from October 2019 to April 2021. The exposure of interest was defined as a history of iGBS disease (sepsis or meningitis) before 90 days of age, amongst children now aged 1·5-18 years. Age and sex-matched, children without history of GBS were also recruited. Age-appropriate, culturally-adapted assessments were used to define NDI across multiple domains (cognitive, motor, hearing, vision, emotional-behaviour, growth). Pooled NDI risk was meta-analysed across sites. Association of iGBS exposure and NDI outcome was estimated using modified Poisson regression with robust variance estimator. Findings: Amongst 138 iGBS survivors and 390 non-iGBS children, 38·1% (95% confidence interval [CI]: 30·0% - 46·6%) of iGBS children had any NDI, compared to 21·7% (95% CI: 17·7% - 26·0%) of non- iGBS children, with notable between-site heterogeneity. Risk of moderate/severe NDI was 15·0% (95% CI: 3·4% - 30·8%) among GBS-meningitis, 5·6% (95% CI: 1·5% - 13·7%) for GBS-sepsis survivors. The adjusted risk ratio (aRR) for moderate/severe NDI among iGBS survivors was 1.27 (95% CI: 0.65, 2.45), when compared to non-GBS children. Mild impairment was more frequent in iGBS (27.6% (95% CI: 20.3 - 35.5%)) compared to non-GBS children (12.9% (95% CI: 9.7% - 16.4%)). The risk of emotional-behavioural problems was similar irrespective of iGBS exposure (aRR=0.98 (95% CI: 0.55, 1.77)). Interpretation: Our findings suggest that iGBS disease is on average associated with a higher risk of moderate/severe NDI, however substantial variation in risk was observed between sites and data are consistent with a wide range of values. Our study underlines the importance of long-term follow-up for at-risk neonates and more feasible, standardised assessments to facilitate diagnosis in research and clinical practice. Funding: This work was supported by a grant (INV-009018) from the Bill & Melinda Gates Foundation to the London School of Hygiene &Tropical Medicine.

Group B streptococcus infection during pregnancy and infancy: estimates of regional and global burden.

BACKGROUND: Group B streptococcus (GBS) colonisation during pregnancy can lead to invasive GBS disease (iGBS) in infants, including meningitis or sepsis, with a high mortality risk. Other outcomes include stillbirths, maternal infections, and prematurity. There are data gaps, notably regarding neurodevelopmental impairment (NDI), especially after iGBS sepsis, which have limited previous global estimates. In this study, we aimed to address this gap using newly available multicountry datasets. METHODS: We collated and meta-analysed summary data, primarily identified in a series of systematic reviews published in 2017 but also from recent studies on NDI and stillbirths, using Bayesian hierarchical models, and estimated the burden for 183 countries in 2020 regarding: maternal GBS colonisation, iGBS cases and deaths in infants younger than 3 months, children surviving iGBS affected by NDI, and maternal iGBS cases. We analysed the proportion of stillbirths with GBS and applied this to the UN-estimated stillbirth risk per country. Excess preterm births associated with maternal GBS colonisation were calculated using meta-analysis and national preterm birth rates. FINDINGS: Data from the seven systematic reviews, published in 2017, that informed the previous burden estimation (a total of 515 data points) were combined with new data (17 data points) from large multicountry studies on neurodevelopmental impairment (two studies) and stillbirths (one study). A posterior median of 19·7 million (95% posterior interval 17·9-21·9) pregnant women were estimated to have rectovaginal colonisation with GBS in 2020. 231 800 (114 100-455 000) early-onset and 162 200 (70 200-394 400) late-onset infant iGBS cases were estimated to have occurred. In an analysis assuming a higher case fatality rate in the absence of a skilled birth attendant, 91 900 (44 800-187 800) iGBS infant deaths were estimated; in an analysis without this assumption, 58 300 (26 500-125 800) infant deaths from iGBS were estimated. 37 100 children who recovered from iGBS (14 600-96 200) were predicted to develop moderate or severe NDI. 40 500 (21 500-66 200) maternal iGBS cases and 46 200 (20 300-111 300) GBS stillbirths were predicted in 2020. GBS colonisation was also estimated to be potentially associated with considerable numbers of preterm births. INTERPRETATION: Our analysis provides a comprehensive assessment of the pregnancy-related GBS burden. The Bayesian approach enabled coherent propagation of uncertainty, which is considerable, notably regarding GBS-associated preterm births. Our findings on both the acute and long-term consequences of iGBS have public health implications for understanding the value of investment in maternal GBS immunisation and other preventive strategies. FUNDING: Bill & Melinda Gates Foundation.

Emotional and Behavioral Outcomes in Childhood for Survivors of Invasive Group B Streptococcus Disease in Infancy: Findings From 5 Low- and Middle-Income Countries.

BACKGROUND: Survivors of invasive group B Streptococcus (iGBS) disease, notably meningitis, are at increased risk of neurodevelopmental impairment. However, the limited studies to date have a median follow-up to 18 months and have mainly focused on moderate or severe neurodevelopmental impairment, with no previous studies on emotional-behavioral problems among iGBS survivors. METHODS: In this multicountry, matched cohort study, we included children aged 18 months to 17 years with infant iGBS sepsis and meningitis from health demographic surveillance systems, or hospital records in Argentina, India, Kenya, Mozambique, and South Africa. Children without an iGBS history were matched to iGBS survivors for sex and age. Our primary outcomes were emotional-behavioral problems and psychopathological conditions as measured with the Child Behavior Checklist (CBCL). The CBCL was completed by the child's primary caregiver. RESULTS: Between October 2019 and April 2021, 573 children (mean age, 7.18 years) were assessed, including 156 iGBS survivors and 417 non-iGBS comparison children. On average, we observed more total problems and more anxiety, attention, and conduct problems for school-aged iGBS survivors compared with the non-iGBS group. No differences were found in the proportion of clinically significant psychopathological conditions defined by the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition). CONCLUSIONS: Our findings suggested that school-aged iGBS survivors experienced increased mild emotional behavioral problems that may affect children and families. At-risk neonates including iGBS survivors need long-term follow-up with integrated emotional-behavioral assessments and appropriate care. Scale-up will require simplified assessments that are free and culturally adapted.

Fatal enhanced respiratory syncytial virus disease in toddlers.

In 1967, two toddlers immunized with a formalin-inactivated vaccine against respiratory syncytial virus (FIRSV) in the United States died from enhanced RSV disease (ERD), a severe form of illness resulting from aberrant priming of the antiviral immune response during vaccination. Up to 80% of immunized children subsequently exposed to wild-type virus were hospitalized. These events hampered RSV vaccine development for decades. Here, we provide a characterization of the clinical, immunopathological, and transcriptional signature of fatal human ERD, outlining evidence for safety evaluation of RSV vaccines and a framework for understanding disease enhancement for pathogens in general.

Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults.

BACKGROUND: Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible. RESULTS: A total of 160 patients underwent randomization. In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P = 0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed. CONCLUSIONS: Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19. (Funded by the Bill and Melinda Gates Foundation and the Fundación INFANT Pandemic Fund; Dirección de Sangre y Medicina Transfusional del Ministerio de Salud number, PAEPCC19, Plataforma de Registro Informatizado de Investigaciones en Salud number, 1421, and ClinicalTrials.gov number, NCT04479163.).

Asymptomatic COVID-19 in the elderly: dementia and viral clearance as risk factors for disease progression.

BACKGROUND: SARS-CoV-2 infected individuals ≥60 years old have the highest hospitalization rates and represent >80% fatalities. Within this population, those in long-term facilities represent >50% of the total COVID-19 related deaths per country. Among those without symptoms, the rate of pre-symptomatic illness is unclear, and potential predictors of progression for symptom development are unknown. Our objective was to delineate the natural evolution of asymptomatic SARS-CoV-2 infection in elders and identify determinants of progression. METHODS: We established a medical surveillance team monitoring 63 geriatric institutions. When an index COVID-19 case emerged, we tested all other eligible asymptomatic elders ≥75 or >60 years old with at least 1 comorbidity. SARS-CoV-2 infected elders were followed for 28 days. Disease was diagnosed when any COVID-19 manifestation occurred. SARS-CoV-2 load at enrollment, shedding on day 15, and antibody responses were also studied. RESULTS: After 28 days of follow-up, 74/113(65%) SARS-CoV-2-infected elders remained asymptomatic. 21/39(54%) pre-symptomatic patients developed hypoxemia and ten pre-symptomatic patients died(median day 13.5,IQR 12). Dementia was the only clinical risk factor associated with disease(OR 2.41(95%CI=1.08, 5.39). In a multivariable logistic regression model, dementia remained as a risk factor for COVID-19 severe disease. Furthermore, dementia status showed a statistically significant different trend when assessing the cumulative probability of developing COVID-19 symptoms(log-rank p=0.027). On day 15, SARS-CoV-2 was detectable in 30% of the asymptomatic group while in 61% of the pre-symptomatic(p=0.012). No differences were observed among groups in RT-PCR mean cycle threshold at enrollment(p=0.391) and in the rates of antibody seropositivity(IgM and IgG against SARS-CoV-2 nucleocapsid protein). CONCLUSIONS: In summary, 2/3 of our cohort of SARS-CoV-2 infected elders from vulnerable communities in Argentina remained asymptomatic after 28 days of follow-up with high mortality among those developing symptoms. Dementia and persistent SARS-CoV-2 shedding were associated with progression from asymptomatic to symptomatic infection.

Role for Maternal Asthma in Severe Human Metapneumovirus Lung Disease Susceptibility in Children.

BACKGROUND: Severity of human metapneumovirus (hMPV) lower respiratory illness (LRTI) is considered similar to that observed for respiratory syncytial virus (RSV). However, differences in severity between these pathogens have been noted, suggesting the degree of illness may vary in different populations. Moreover, a potential association between hMPV and asthma also suggests that hMPV may preferentially affect asthmatic subjects. METHODS: In a population-based surveillance study in children aged <2 years admitted for severe LRTI in Argentina, nasopharyngeal aspirates were tested by RT-PCR for hMPV, RSV, influenza A, and human rhinovirus. RESULTS: Of 3947 children, 383 (10%) were infected with hMPV. The hospitalization rate for hMPV LRTI was 2.26 per 1000 children (95% confidence interval [CI], 2.04-2.49). Thirty-nine (10.2%) patients infected with hMPV experienced life-threatening disease (LTD; 0.23 per 1000 children; 95% CI, .16-.31/1000), and 2 died (mortality rate 0.024 per 1000; 95% CI, .003-.086). In hMPV-infected children birth to an asthmatic mother was an increased risk for LTD (odds ratio, 4.72; 95% CI, 1.39-16.01). We observed a specific interaction between maternal asthma and hMPV infection affecting risk for LTD. CONCLUSIONS: Maternal asthma increases the risk for LTD in children <2 years old hospitalized for severe hMPV LRTI.

Respiratory Syncytial Virus Vaccination during Pregnancy and Effects in Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is the dominant cause of severe lower respiratory tract infection in infants, with the most severe cases concentrated among younger infants. METHODS: Healthy pregnant women, at 28 weeks 0 days through 36 weeks 0 days of gestation, with an expected delivery date near the start of the RSV season, were randomly assigned in an overall ratio of approximately 2:1 to receive a single intramuscular dose of RSV fusion (F) protein nanoparticle vaccine or placebo. Infants were followed for 180 days to assess outcomes related to lower respiratory tract infection and for 364 days to assess safety. The primary end point was RSV-associated, medically significant lower respiratory tract infection up to 90 days of life, and the primary analysis of vaccine efficacy against the primary end point was performed in the per-protocol population of infants (prespecified criterion for success, lower bound of the 97.52% confidence interval [CI] of ≥30%). RESULTS: A total of 4636 women underwent randomization, and there were 4579 live births. During the first 90 days of life, the percentage of infants with RSV-associated, medically significant lower respiratory tract infection was 1.5% in the vaccine group and 2.4% in the placebo group (vaccine efficacy, 39.4%; 97.52% CI, -1.0 to 63.7; 95% CI, 5.3 to 61.2). The corresponding percentages for RSV-associated lower respiratory tract infection with severe hypoxemia were 0.5% and 1.0% (vaccine efficacy, 48.3%; 95% CI, -8.2 to 75.3), and the percentages for hospitalization for RSV-associated lower respiratory tract infection were 2.1% and 3.7% (vaccine efficacy, 44.4%; 95% CI, 19.6 to 61.5). Local injection-site reactions among the women were more common with vaccine than with placebo (40.7% vs. 9.9%), but the percentages of participants who had other adverse events were similar in the two groups. CONCLUSIONS: RSV F protein nanoparticle vaccination in pregnant women did not meet the prespecified success criterion for efficacy against RSV-associated, medically significant lower respiratory tract infection in infants up to 90 days of life. The suggestion of a possible benefit with respect to other end-point events involving RSV-associated respiratory disease in infants warrants further study. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov NCT02624947.).

Respiratory Failure and Death in Vulnerable Premature Children With Lower Respiratory Tract Illness.

BACKGROUND: Efforts to better understand the risk factors associated with respiratory failure (RF) and fatal lower respiratory tract infection (LRTI) in premature children in developing countries are necessary to elaborate evidenced-based preventive interventions. We aim to characterize the burden of respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) LRTI in premature children and determine risk factors for RF and fatal illness in a vulnerable population. METHODS: This is a prospective, population-based, cross-sectional study. Subjects with severe LRTI were enrolled during respiratory season. Risk factors for RF and death in premature infants were investigated. RESULTS: A total of 664 premature children participated. Infant's hospitalization rate due to LRTI was 82.6/1000 (95% confidence interval [CI], 68.6-96.7/1000). Infant's RSV and hMPV rates were 40.9/1000 (95% CI, 36.3-45.6/1000) and 6.6/1000 (95% CI, 3.9-9.2/1000), respectively. The RF rate was 8.2/1000 (95% CI, 4.9-11.5/1000). The LRTI mortality was 2.2/1000 (95% CI, 0.7-3.7/1000); for RSV, the rate was 0.8/1000 (95% CI, 0-1.7/1000) with a case-fatality ratio of 1.8%. Never breastfeeding, malnutrition, younger than 6 months, congenital heart disease, and lower hematocrit were risk factors for RF. Experiencing pneumonia, pneumothorax, sepsis, or apnea were clinical determinants of poor outcomes. CONCLUSIONS: Premature children under 2 years old in vulnerable environments experience RF and death more often than term counterparts. Modifiable risk factors associated with poor outcomes should prompt evidence-based interventions.

Quantifying long-term health and economic outcomes for survivors of group B Streptococcus invasive disease in infancy: protocol of a multi-country study in Argentina, India, Kenya, Mozambique and South Africa.

Sepsis and meningitis due to invasive group B Streptococcus (iGBS) disease during early infancy is a leading cause of child mortality. Recent systematic estimates of the worldwide burden of GBS suggested that there are 319,000 cases of infant iGBS disease each year, and an estimated 147,000 stillbirths and young-infant deaths, with the highest burden occurring in Sub-Saharan Africa.  The following priority data gaps were highlighted: (1) long-term outcome data after infant iGBS, including mild disability, to calculate quality-adjusted life years (QALYs) or disability-adjusted life years (DALYs) and (2) economic burden for iGBS survivors and their families. Geographic data gaps were also noted with few studies from low- and middle- income countries (LMIC), where the GBS burden is estimated to be the highest. In this paper we present the protocol for a multi-country matched cohort study designed to estimate the risk of long-term neurodevelopmental impairment (NDI), socioemotional behaviors, and economic outcomes for children who survive invasive GBS disease in Argentina, India, Kenya, Mozambique, and South Africa. Children will be identified from health demographic surveillance systems, hospital records, and among participants of previous epidemiological studies. The children will be aged between 18 months to 17 years. A tablet-based custom-designed application will be used to capture data from direct assessment of the child and interviews with the main caregiver. In addition, a parallel sub-study will prospectively measure the acute costs of hospitalization due to neonatal sepsis or meningitis, irrespective of underlying etiology. In summary, these data are necessary to characterize the consequences of iGBS disease and enable the advancement of effective strategies for survivors to reach their developmental and economic potential. In particular, our study will inform the development of a full public health value proposition on maternal GBS immunization that is being coordinated by the World Health Organization.

Effect of Concomitant Antibiotic and Vaccine Administration on Serologic Responses to Rotavirus Vaccine.

Data from 1174 infants enrolled in a previous rotavirus vaccine study were analyzed to determine the effect of antibiotic exposure (from 14 days before to 7 days after vaccination) on rotavirus serum immunoglobulin A (IgA) responses. Serum IgA responses 1 month after the completion of vaccination were similar among antibiotic-exposed and nonexposed infants.

Neuraminidase Inhibitors and Hospital Length of Stay: A Meta-analysis of Individual Participant Data to Determine Treatment Effectiveness Among Patients Hospitalized With Nonfatal 2009 Pandemic Influenza A(H1N1) Virus Infection.

BACKGROUND: The effect of neuraminidase inhibitor (NAI) treatment on length of stay (LoS) in patients hospitalized with influenza is unclear. METHODS: We conducted a one-stage individual participant data (IPD) meta-analysis exploring the association between NAI treatment and LoS in patients hospitalized with 2009 influenza A(H1N1) virus (A[H1N1]pdm09) infection. Using mixed-effects negative binomial regression and adjusting for the propensity to receive NAI, antibiotic, and corticosteroid treatment, we calculated incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Patients with a LoS of <1 day and those who died while hospitalized were excluded. RESULTS: We analyzed data on 18 309 patients from 70 clinical centers. After adjustment, NAI treatment initiated at hospitalization was associated with a 19% reduction in the LoS among patients with clinically suspected or laboratory-confirmed influenza A(H1N1)pdm09 infection (IRR, 0.81; 95% CI, .78-.85), compared with later or no initiation of NAI treatment. Similar statistically significant associations were seen in all clinical subgroups. NAI treatment (at any time), compared with no NAI treatment, and NAI treatment initiated <2 days after symptom onset, compared with later or no initiation of NAI treatment, showed mixed patterns of association with the LoS. CONCLUSIONS: When patients hospitalized with influenza are treated with NAIs, treatment initiated on admission, regardless of time since symptom onset, is associated with a reduced LoS, compared with later or no initiation of treatment.

Seroprevalencia contra Bordetella pertussis en embarazadas vacunadas y no vacunadas y neonatos en un hospital universitario de la provincia de Buenos Aires / Seroprevalence of Bordetella pertussis among vaccinated and unvaccinated pregnant women and newborn infants in a university hospital of Buenos Aires

Introducción. La tos convulsa es una enfermedad altamente contagiosa causada por Bordetella pertussis. Tiene una alta tasa de morbilidad y mortalidad, especialmente, en los lactantes menores de seis meses de edad. En la Argentina, la incidencia y la mortalidad se han encontrado en aumento en las últimas 3 décadas. Objetivo. Determinar anticuerpos contra Bordetella pertussis en las mujeres embarazadas en el tercer trimestre de la gestación y en el recién nacido, medidos en la sangre del cordón. Métodos. Se disenó un estudio observacional, transversal. El estudio se inició en 2011 cuando la vacunación contra pertussis en la embarazada no estaba incluida en el Calendario Nacional de Vacunación y era opcional. Los anticuerpos se midieron en las madres en el tercer trimestre del embarazo y en la sangre del cordón umbilical al nacer. Las determinaciones de anticuerpos se realizaron con el kit de ELISA humano para IgG toxina pertussis ABCAMR. Se utilizó la prueba de chi² para comparar la prevalencia. Resultados. Se incluyó a 111 madres y a sus bebés, 35 hijos de madres no vacunadas (antes de la implementación de la vacuna en embarazadas) y 76 hijos de madres vacunadas. Los bebés de madres vacunadas presentaron anticuerpos IgG positivos en el 92% (70/76), mientras que los bebés de madres no vacunadas fueron negativos para anticuerpos IgG en el 100% (35/35) con una p < 0,001. Conclusión. En la población de vacunadas del estudio, se observó que sus hijos presentaron anticuerpos IgG positivos en el 92%. Este estudio apoya la necesidad de la inmunización materna contra Bordetella pertussis para proteger al recién nacido.

Introduction. Pertussis is a highly contagious disease caused by Bordetella pertussis. It poses a high morbidity and mortality rate, especially among infants younger than 6 months old. In Argentina, pertussis incidence and mortality have increased over the past three decades. Objective. To establish Bordetella pertussis antibody titers among pregnant women in their third trimester and among newborn infants, as measured in cord blood. Methods. This was an observational, crosssectional study. The study started in 2011; at that time, pertussis vaccination was not mandatory for pregnant women as per the national immunization schedule, only optional. Maternal antibodies were measured in the last trimester of pregnancy for women and in cord blood for newborn infants. Antibody titers were determined using Abcam's anti-Bordetella pertussis toxin (PT) IgG in vitro ELISA kit. The X2 test was used to compare prevalence rates. Results. The study included 111 mother-newborn infant dyads; 35 infants from unvaccinated mothers (before the introduction of the vaccine) and 76 from vaccinated mothers. Positive IgG antibodies were found in 92% (70/76) of infants born from vaccinated mothers whereas 100% (35/35) of infants born from unvaccinated mothers had negative results for antibodies; p < 0.001. Conclusion. In the vaccinated population of this study, 92% of infants had positive IgG antibodies. This study supports the need for maternal immunization against Bordetella pertussis to provide protection to newborn infants.

Seroprevalence of Bordetella pertussis among vaccinated and unvaccinated pregnant women and newborn infants in a university hospital of Buenos Aires. / Seroprevalencia contra Bordetella pertussis en embarazadas vacunadas y no vacunadas y neonatos en un hospital universitario de la provincia de Buenos Aires.

INTRODUCTION: Pertussis is a highly contagious disease caused by Bordetella pertussis. It poses a high morbidity and mortality rate, especially among infants younger than 6 months old. In Argentina, pertussis incidence and mortality have increased over the past three decades. OBJETIVE: To establish Bordetella pertussisantibody titers among pregnant women in their third trimester and among newborn infants, as measured in cord blood. METHODS: This was an observational, cross-sectional study. The study started in 2011; at that time, pertussis vaccination was not mandatory for pregnant women as per the national immunization schedule, only optional. Maternal antibodies were measured in the last trimester of pregnancy for women and in cord blood for newborn infants. Antibody titers were determined using Abcam's anti-Bordetella pertussis toxin (PT) IgG in vitro ELISA kit. The χ² test was used to compare prevalence rates. RESULTS: The study included 111 mother-newborn infant dyads; 35 infants from unvaccinated mothers (before the introduction of the vaccine) and 76 from vaccinated mothers. Positive IgG antibodies were found in 92% (70/76) of infants born from vaccinated mothers whereas 100% (35/35) of infants born from unvaccinated mothers had negative results for antibodies; p < 0.001. CONCLUSION: In the vaccinated population of this study, 92% of infants had positive IgG antibodies. This study supports the need for maternal immunization against Bordetella pertussis to provide protection to newborn infants.

INTRODUCCIÓN: La tos convulsa es una enfermedad altamente contagiosa causada por Bordetella pertussis. Tiene una alta tasa de morbilidad y mortalidad, especialmente, en los lactantes menores de seis meses de edad. En la Argentina, la incidencia y la mortalidad se han encontrado en aumento en las últimas 3 décadas. OBJETIVO: Determinar anticuerpos contra Bordetella pertussis en las mujeres embarazadas en el tercer trimestre de la gestación y en el recién nacido, medidos en la sangre del cordón. MÉTODOS: Se diseñó un estudio observacional, transversal. El estudio se inició en 2011 cuando la vacunación contra pertussis en la embarazada no estaba incluida en el Calendario Nacional de Vacunación y era opcional. Los anticuerpos se midieron en las madres en el tercer trimestre del embarazo y en la sangre del cordón umbilical al nacer. Las determinaciones de anticuerpos se realizaron con el kit de ELISA humano para IgG toxina pertussis ABCAM®. Se utilizó la prueba de chi2 para comparar la prevalencia. RESULTADOS: Se incluyó a 111 madres y a sus bebés, 35 hijos de madres no vacunadas (antes de la implementación de la vacuna en embarazadas) y 76 hijos de madres vacunadas. Los bebés de madres vacunadas presentaron anticuerpos IgG positivos en el 92% (70/76), mientras que los bebés de madres no vacunadas fueron negativos para anticuerpos IgG en el 100% (35/35) con una p < 0,001. CONCLUSIÓN: En la población de vacunadas del estudio, se observó que sus hijos presentaron anticuerpos IgG positivos en el 92%. Este estudio apoya la necesidad de la inmunización materna contra Bordetella pertussis para proteger al recién nacido.

Mortality due to Respiratory Syncytial Virus. Burden and Risk Factors.

RATIONALE: Respiratory syncytial virus (RSV) is the most frequent cause of hospitalization and an important cause of death in infants in the developing world. The relative contribution of social, biologic, and clinical risk factors to RSV mortality in low-income regions is unclear. OBJECTIVES: To determine the burden and risk factors for mortality due to RSV in a low-income population of 84,840 infants. METHODS: This was a prospective, population-based, cross-sectional, multicenter study conducted between 2011 and 2013. Hospitalizations and deaths due to severe lower respiratory tract illness (LRTI) were recorded during the RSV season. All-cause hospital deaths and community deaths were monitored. Risk factors for respiratory failure (RF) and mortality due to RSV were assessed using a hierarchical, logistic regression model. MEASUREMENTS AND MAIN RESULTS: A total of 2,588 (65.5%) infants with severe LRTI were infected with RSV. A total of 157 infants (148 postneonatal) experienced RF or died with RSV. RSV LRTI accounted for 57% fatal LRTI tested for the virus. A diagnosis of sepsis (odds ratio [OR], 17.03; 95% confidence interval [CI], 13.14-21.16 for RF) (OR, 119.39; 95% CI, 50.98-273.34 for death) and pneumothorax (OR, 17.15; 95% CI, 13.07-21.01 for RF) (OR, 65.49; 95% CI, 28.90-139.17 for death) were the main determinants of poor outcomes. CONCLUSIONS: RSV was the most frequent cause of mortality in low-income postneonatal infants. RF and death due to RSV LRTI, almost exclusively associated with prematurity and cardiopulmonary diseases in industrialized countries, primarily affect term infants in a developing world environment. Poor outcomes at hospitals are frequent and associated with the cooccurrence of bacterial sepsis and clinically significant pneumothoraxes.