Clinical impact of pleural fluid Streptococcus pneumoniae PCR testing in children with complicated pneumonia.

BACKGROUND: While Streptococcus pneumoniae (Spn) is the leading cause of pediatric complicated community acquired pneumonia (cCAP), it is infrequently recovered by culture-based methods. We studied the real-world clinical impact of an Spn PCR assay for pleural fluid. METHODS: This pre-post quasi-experimental cohort study compared pathogen detection, antibiotic usage, and outcomes in children hospitalized with cCAP requiring pleural effusion or empyema drainage at Children's Hospital Colorado between 2016 and 2023. Patients were compared across two diagnostic periods: pre-Spn PCR and post-Spn PCR. Cox proportional hazard models compared time from admission to pathogen detection, optimal therapy (narrowest pathogen-directed or guideline-recommended empiric therapy), and MRSA therapy discontinuation between periods. RESULTS: Compared to the pre-Spn PCR cohort (N=149), the post-Spn PCR cohort (N=79) was more likely to have a pathogen detected (73.4% post-PCR vs. 38.9% pre-PCR, p < 0.001), driven by more Spn detections (45.6% vs. 14.1%, p < 0.001). Time to pathogen detection during hospitalization was shorter in the post-Spn PCR period (p < 0.001). The post-PCR cohort was more likely to receive optimal therapy (84.8% vs. 53.0%, p < 0.001), with shorter median times to optimal antibiotics (4.9 vs. 10.0 days, p < 0.001) and MRSA therapy discontinuation (1.5 vs. 2.5 days, p = 0.03). There were no differences in hospital length of stay or readmissions. CONCLUSIONS: Spn molecular testing of pleural fluid in children with cCAP resulted in significantly more microbiologic diagnoses and was associated with the optimization of antibiotics and decreased exposure to MRSA therapy, suggesting its clinical impact for pediatric complicated pneumonia.

Reduced Risk of SARS-CoV-2 Infection Among Household Contacts with Recent Vaccination and Past COVID-19 Infection: Results from Two Multi-Site Case-Ascertained Household Transmission Studies.

Households are a primary setting for transmission of SARS-CoV-2. We examined the role of prior SARS-CoV-2 immunity on the risk of infection in household close contacts. Households in the United States with an individual who tested positive for SARS-CoV-2 during September 2021-May 2023 were enrolled if the index case's illness began ≤6 days prior. Household members had daily self-collected nasal swabs tested by RT-PCR for SARS-CoV-2. The effects of prior SARS-CoV-2 immunity (vaccination, prior infection, or hybrid immunity) on SARS-CoV-2 infection risk among household contacts were assessed by robust, clustered multivariable Poisson regression. Of 1,532 contacts (905 households), 8% had immunity from prior infection alone, 51% from vaccination alone, 29% hybrid immunity, and 11% had no prior immunity. Sixty percent of contacts tested SARS-CoV-2-positive during follow-up. The adjusted risk of SARS-CoV-2 infection was lowest among contacts with vaccination and prior infection (aRR: 0.81, 95% CI: 0.70, 0.93, compared with contacts with no prior immunity) and was lowest when the last immunizing event occurred ≤6 months before COVID-19 affected the household (aRR: 0.69, 95% CI: 0.57, 0.83). In high-transmission settings like households, immunity from COVID-19 vaccination and prior infection was synergistic in protecting household contacts from SARS-CoV-2 infection.

SARS-CoV-2 Viral Shedding and Rapid Antigen Test Performance - Respiratory Virus Transmission Network, November 2022-May 2023.

As population immunity to SARS-CoV-2 evolves and new variants emerge, the role and accuracy of antigen tests remain active questions. To describe recent test performance, the detection of SARS-CoV-2 by antigen testing was compared with that by reverse transcription-polymerase chain reaction (RT-PCR) and viral culture testing during November 2022-May 2023. Participants who were enrolled in a household transmission study completed daily symptom diaries and collected two nasal swabs (tested for SARS-CoV-2 via RT-PCR, culture, and antigen tests) each day for 10 days after enrollment. Among participants with SARS-CoV-2 infection, the percentages of positive antigen, RT-PCR, and culture results were calculated each day from the onset of symptoms or, in asymptomatic persons, from the date of the first positive test result. Antigen test sensitivity was calculated using RT-PCR and viral culture as references. The peak percentage of positive antigen (59.0%) and RT-PCR (83.0%) results occurred 3 days after onset, and the peak percentage of positive culture results (52%) occurred 2 days after onset. The sensitivity of antigen tests was 47% (95% CI = 44%-50%) and 80% (95% CI = 76%-85%) using RT-PCR and culture, respectively, as references. Clinicians should be aware of the lower sensitivity of antigen testing compared with RT-PCR, which might lead to false-negative results. This finding has implications for timely initiation of SARS-CoV-2 antiviral treatment, when early diagnosis is essential; clinicians should consider RT-PCR for persons for whom antiviral treatment is recommended. Persons in the community who are at high risk for severe COVID-19 illness and eligible for antiviral treatment should seek testing from health care providers with the goal of obtaining a more sensitive diagnostic test than antigen tests (i.e., an RT-PCR test).

Safety of Streptococcus pyogenes Vaccines: Anticipating and Overcoming Challenges for Clinical Trials and Post-Marketing Monitoring.

Streptococcus pyogenes (Strep A) infections result in a vastly underestimated burden of acute and chronic disease globally. The Strep A Vaccine Global Consortium's (SAVAC's) mission is to accelerate the development of safe, effective, and affordable S. pyogenes vaccines. The safety of vaccine recipients is of paramount importance. A single S. pyogenes vaccine clinical trial conducted in the 1960s raised important safety concerns. A SAVAC Safety Working Group was established to review the safety assessment methodology and results of more recent early-phase clinical trials and to consider future challenges for vaccine safety assessments across all phases of vaccine development. No clinical or biological safety signals were detected in any of these early-phase trials in the modern era. Improvements in vaccine safety assessments need further consideration, particularly for pediatric clinical trials, large-scale efficacy trials, and preparation for post-marketing pharmacovigilance.

Symptoms, viral loads, and rebound among COVID-19 outpatients treated with nirmatrelvir/ritonavir compared to propensity score matched untreated individuals.

BACKGROUND: Nirmatrelvir/ritonavir (N/R) reduces severe outcomes among patients with COVID-19; however, rebound after treatment has been reported. We compared symptom and viral dynamics in community-based individuals with COVID-19 who completed N/R and similar untreated individuals. METHODS: We identified symptomatic participants who tested SARS-CoV-2 positive and were N/R eligible from a COVID-19 household transmission study: index cases from ambulatory settings and their households were enrolled, collecting daily symptoms, medication use, and respiratory specimens for quantitative PCR for 10 days, March 2022-May 2023. Participants who completed N/R (treated) were propensity score matched to untreated participants. We compared symptom rebound, viral load (VL) rebound, average daily symptoms, and average daily VL by treatment status measured after N/R completion or, if untreated, seven days after symptom onset. RESULTS: Treated (n=130) and untreated participants (n=241) had similar baseline characteristics. After treatment completion, treated participants had greater occurrence of symptom rebound (32% vs 20%; p=0.009) and VL rebound (27% vs 7%; p<0.001). Average daily symptoms were lower among treated participants compared to untreated participants without symptom rebound (1.0 vs 1.6; p<0.01), but not statistically lower with symptom rebound (3.0 vs 3.4; p=0.5). Treated participants had lower average daily VLs without VL rebound (0.9 vs 2.6; p<0.01), but not statistically lower with VL rebound (4.8 vs 5.1; p=0.7). CONCLUSIONS: Individuals who completed N/R experienced fewer symptoms and lower VL but were more likely to have rebound compared to untreated individuals. Providers should still prescribe N/R, when indicated, and communicate possible increased rebound risk to patients.

Clinical and Economic Impact of COVID-19 on Agricultural Workers, Guatemala1.

We evaluated clinical and socioeconomic burdens of respiratory disease in banana farm workers in Guatemala. We offered all eligible workers enrollment during June 15-December 30, 2020, and annually, then tracked them for influenza-like illnesses (ILI) through self-reporting to study nurses, sentinel surveillance at health posts, and absenteeism. Workers who had ILI submitted nasopharyngeal swab specimens for testing for influenza virus, respiratory syncytial virus, and SARS-CoV-2, then completed surveys at days 0, 7, and 28. Through October 10, 2021, a total of 1,833 workers reported 169 ILIs (12.0 cases/100 person-years), and 43 (25.4%) were laboratory-confirmed infections with SARS-CoV-2 (3.1 cases/100 person-years). Workers who had SARS-CoV-2‒positive ILIs reported more frequent anosmia, dysgeusia, difficulty concentrating, and irritability and worse clinical and well-being severity scores than workers who had test result‒negative ILIs. Workers who had positive results also had greater absenteeism and lost income. These results support prioritization of farm workers in Guatemala for COVID-19 vaccination.

Initial Contraceptive Choices of Women Enrolled in a Cluster-Randomized Trial in Southwest Trifinio, Guatemala.

INTRODUCTION: The aim of this analysis is to present initial contraceptive choices of women offered postpartum contraception in rural Guatemala. METHODS: We trained community nurses participating in the delivery of a home-based antepartum and postpartum care program in rural Guatemala in contraceptive implant placement and had them offer condoms, pills, an injection, or an implant at women's home-based 40-day postpartum visit in intervention clusters of a non-blinded, cluster-randomized trial. Women who had already started postpartum contraception or were over the age of 35 were excluded from participation. The primary outcome of the trial was contraceptive use at 3 months postpartum, so this initial analysis describes immediate preferences in the population. RESULTS: Of 208 women enrolled in the study, 108 were in intervention clusters and 100 lived in control clusters. In the intervention group, 32 women declined contraception, 36 women received the injectable, 30 women had an implant placed, 5 women started pills, 2 women chose condoms, and data on 3 women were missing. In the control clusters, 43 women were planning on the injectable, 11 planned on the implant, 10 did not want to start a method, 5 planned on sterilization, 2 aimed for natural family planning, 2 wanted a copper IUD, 1 woman wanted condoms, 18 did not know, and data on 8 women were missing. DISCUSSION: The contraceptive implant, which was not previously available in this community, had high uptake at 27.8% in the intervention group. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04005391; Retrospectively Registered 7/2/2019, https://clinicaltrials.gov/ct2/show/NCT04005391 Protocol: https://doi.org/10.1186/s13063-019-3735-3.

Building momentum for malaria vaccine research and development: key considerations.

To maintain momentum towards improved malaria control and elimination, a vaccine would be a key addition to the intervention toolkit. Two approaches are recommended: (1) promote the development and short to medium term deployment of first generation vaccine candidates and (2) support innovation and discovery to identify and develop highly effective, long-lasting and affordable next generation malaria vaccines.

Interpregnancy Interval in a Rural Guatemalan Population: Results from a Quality Improvement Database.

OBJECTIVE: This analysis describes the interpregnancy interval (time from livebirth to subsequent conception) in a convenience sample of women living in Southwest Guatemala and the association of antepartum characteristics and postpartum outcomes with a short interpregnancy interval (< 24 months). METHODS: This is an observational study of a convenience sample of women enrolled in the Madres Sanas community antenatal/postnatal nursing program supported by the Center for Human Development in Southwest Trifinio, Guatemala, between October 1, 2018 and October 1, 2019. We observed the distribution of interpregnancy intervals among the population of women with a reported date of last live birth, and used bivariate comparisons to compare women with a short interpregnancy interval (< 24 months) to those with an optimal interval ([Formula: see text] 24 months) by antepartum, obstetric and delivery, and postpartum outcomes. RESULTS: 171 parous women enrolled in the Madres Sanas program between October 1, 2018 and October 1, 2019, and reported the date of their last live birth. One hundred-forty-one (82.5%) women delivered and 130 of those women (92.2%) were seen for their 40-day postpartum visit. The mean interval was 37.1 months with a 22.1-month standard deviation. The median interval was 33.7 months with an interquartile range of 19.6-49.5 months. Among these women, 113 (66.1%) the interpregnancy interval was at least 24 months. The only covariate of all sociodemographic, obstetric and antepartum, delivery, and postpartum characteristics that differed between women who achieved an interval ([Formula: see text] 24 months) compared to those that did not (< 24 months), was age (median 22.9, interquartile range (IQR) [19.1,27.0] vs median 24.8, IQR [21.6,27.9], respectively, p = 0.006). A regression model found that with each increasing year of age, the interpregnancy interval increases by 1.08 months, p = 0.025. CONCLUSION: Among parous women, two-thirds of women space pregnancies at least 24 months. Older women were more likely to have a longer interval between live births.

Primary and secondary three-month outcomes of a cluster-randomized trial of home-based postpartum contraceptive delivery in southwest Trifinio, Guatemala.

DESIGN: This a cluster-randomized parallel arm pragmatic trial to observe the association of home-based postpartum contraceptive provision, including the contraceptive implant, with implant utilization rates at 3 months post-enrollment. METHODS: In a region of rural Guatemala referred to as the Southwest Trifinio, twelve communities are served by a community-based antenatal and postnatal care program. The communities were combined into eight clusters based on 2017 birth rates and randomized to receive the home-based contraceptive delivery (condoms, pills, injection, implant) during the routine 40-day postpartum visit. All participants receive comprehensive contraceptive counseling beginning at the first antenatal visit, so control clusters received this as part of routine care; this education preceded the study intervention. RESULTS: Once the 12 communities were combined into 8 clusters by expected birth volume and nurse team, which we expected to translate to eventual postpartum visits, the allocation sequence was generated in SAS. Of 208 women enrolled in the study, 108 were in four intervention and 100 in four control clusters. We used descriptive statistics to produce counts and percentages of characteristics of the study population overall and by intervention arm followed by univariate modeling using a mixed effects regression adjusted for cluster. Three-month contraceptive initiation rates were 56.0% in the control clusters compared to 76.8% in the intervention clusters, p < 0.001. Women in control clusters overwhelmingly opted for the injectable contraceptive (94.6%) while women in intervention clusters chose both the injection (61.5%) and the implant (33.7%), p < 0.001. Implant use by 3 months, the primary outcome of the study, was significantly higher in the intervention arm (25.9%) compared to the control arm (3.6%), p < 0.001, RR 1.3 CI [1.2, 1.4]. CONCLUSION: Our study was designed to respond to previously identified barriers to contraceptive uptake, and it was successful. Not only did it increase overall use of contraception by 3 months, but it shifted that contraceptive use away from short-acting methods in favor of longer-acting methods, with high continuation and satisfaction rates and no adverse outcomes reported. TRIAL REGISTRATION: clinicaltrials.gov , NCT04005391 ; Retrospectively Registered 7/2/2019.

Reliability and Validity of an Adapted and Translated Version of the Mullen Scales of Early Learning (AT-MSEL) in Rural Guatemala.

BACKGROUND: A growing literature base supports the use of tests developed in high-income countries to assess children in low resource settings when carefully translated, adapted, and applied. Evaluation of psychometric properties of adapted and translated measures within populations is necessary. The current project sought to evaluate the reliability and validity of an adapted and translated version of the Mullen Scales of Early Learning (AT-MSEL) in rural Guatelama. METHODS: The reliability and validity of the AT-MSEL in rural Guatemala were analyzed for children ages 0-5 years. RESULTS: Interrater reliability coefficients (ICC = 0.99-1.0) and internal consistency (Cronbach's alpha = 0.91-0.93) were excellent for all subscales. General linear models utilizing paired data showed consistency between standard scores (p < 0.0001). Mean raw scores increased with chronological age, as expected. Across age groups, subscales were significantly, positively correlated with one another (p < 0.05 - < 0.001) with one exception, visual reception and expressive language at the 0-10 month age range (p = 0.43). CONCLUSIONS: The AT- MSEL showed strong psychometric properties in a sample of young children in rural Guatemala. Findings demonstrate that the AT-MSEL can be used validly and reliably within this specific population of children. This work supports the concept that tests developed in high-income countries can be used to assess children in low resource settings when carefully translated, adapted and applied.

The global school-based student health survey as a tool to guide adolescent health interventions in rural Guatemala.

BACKGROUND: Adolescents from rural areas in low-middle income countries face increasing physical and mental health challenges that are not well characterized or addressed due to resource limitations. We used the Global School-based Student Health Survey (GSHS) to describe adolescent health behaviors, and to inform prioritization of health promotion efforts in a resource-limited, rural, agricultural region in Guatemala. METHODS: In July 2015, a group of volunteers administered the GSHS to students from seven schools in four communities in the southwest Trifinio region of Guatemala. Prevalence and predictors of nutritional, mental, and sexual health behaviors were calculated from survey responses, and summarized in region- and school-level reports. Facilitated discussion of survey results with local leadership in January 2016 led to the identification of priorities for school-based health interventions. RESULTS: Five hundred fifty-four out of 620 (87%) students aged 12-18 years completed the survey. Prevalence of unhealthy dietary behaviors and body size was high: 61% reported high current soft drink intake, 18% were overweight, and 31% were moderate-severely stunted. In multivariable regression models, being food insecure was marginally associated with being underweight/stunted (OR = 1.95, 95%CI = 0.95-4.0). Boys were more likely than girls to report being sexually active (25% versus 6.4%, p < 0.001). Local school leadership identified food insecurity and sexual education as priority areas for intervention, and made plans for providing breakfast in schools, sexual education curriculum development and teacher training, and continued adolescent health reporting and evaluation. CONCLUSIONS: The GSHS is a rapid, cost-efficient, useful tool for surveillance of adolescent health behaviors in vulnerable, resource-limited populations. Results of a locally-administered GSHS informed school-based interventions to decrease food insecurity, early sexual initiation, and teen pregnancy in a rural Guatemalan region.

Evaluation of heat stress and cumulative incidence of acute kidney injury in sugarcane workers in Guatemala.

OBJECTIVE: Agricultural workers worldwide exposed to heat stress could be at the risk of kidney injury, which could lead to chronic kidney disease of an unknown origin (CKDu). Hydration has been promoted as a key measure to reduce kidney injury. In the presence of a hydration intervention, the incidence of acute kidney injury (AKI) was calculated in a sugarcane worker population in Guatemala and several risk factors were evaluated. METHODS: We measured kidney function at the beginning and end of the work shift at three time points in 517 sugarcane workers. We defined AKI as an increase in serum creatinine of 26.5 µmol/L or 50% or more from the pre-shift value. Associations between AKI and risk factors were examined, including interactions with hydration status. RESULTS: The prevalence of dehydration post-shift (> 1.020 specific gravity) was 11% in February, 9% in March, and 6% in April. Cumulative incidence of AKI was 53% in February, 54% in March, and 51% in April. AKI was associated with increasing post-shift specific gravity, a dehydration marker, (OR 1.24, 95% CI 1.02-1.52) and with lower electrolyte solution intake (OR 0.94, 95% CI 0.89-0.99). CONCLUSIONS: Dehydration and insufficient electrolyte consumption are risk factors for AKI. However even well-hydrated sugarcane workers routinely experience AKI. While hydration is important and protective, there is a need to understand other contributors to risk of AKI and identify prevention strategies with these workers.

Trends in the Mode of Delivery of Pregnant Women in Rural Guatemala from a Quality Improvement Database.

Purpose To evaluate trends and factors associated with mode of delivery in the rural Southwest Trifinio region of Guatemala. Description We conducted a retrospective analysis of self-reported antepartum factors and postpartum outcomes recorded in a quality improvement database among 430 women enrolled in a home-based maternal healthcare program between June 1, 2015 and August 1, 2017. Assessment Over the study period, the rates of cesarean delivery (CD) increased (from 30 to 45%) and rates of vaginal delivery (VD) decreased (70-55%) while facility-based delivery attendance remained stable around 70%. Younger age (23.5 years for VD vs. 21.6 years for CD, p < 0.001), nulliparity (25.1% for VD vs. 45.0% for CD, p < 0.001), prolonged/obstructed labor (2.4% for VD vs. 55.6% for CD, p < 0.001), and fetal malpresentation (0% for VD vs. 16.3% CD, p < 0.001) significantly influenced mode of delivery in univariate analysis. The leading indications for CD were labor dysfunction (47.5%), malpresentation (14.5%), and prior cesarean delivery (19.8%). The CD rate among the subpopulation of term, nulliparous women with singleton pregnancies in vertex presentation also increased from 20% of all CD in 2015, to 38% in 2017. Conclusion Among low-income women from rural Guatemala, the CD rate has increased above the World Health Organization (WHO) recommendations in a period of 3 years. Additional research on the factors affecting this trend are essential to guide interventions that might improve the appropriateness of CD, and to determine if reducing or stabilizing rates is necessary.

Receptive language skills among young children in rural Guatemala: The relationship between the Test de Vocabulario en Imagenes Peabody and a translated and adapted version of the Mullen Scales of Early Learning.

BACKGROUND: Children in low- and lower middle income countries (LMICs) often have poorer language skills compared with children from high-income countries. Limited availability of culturally and linguistically appropriate assessment measures in LMICs, especially for young children, can hinder early identification and prevention efforts. Here, we describe receptive language (RL) skills among young children in rural Guatemala and report on the validity of a translated and culturally adapted developmental measure of RL. METHODS: Children (n = 157; m = 53.6 months, range = 42-68 months) enrolled in a prospective cohort study of postnatally acquired Zika virus infection were administered the Test de Vocabulario en Imagenes Peabody (TVIP) and the RL scale from a translated and adapted version of the Mullen Scales of Early Learning (MSEL). Performance on the TVIP was compared with the Latin American normative sample. Correlational analysis examined the relationship between performance on the TVIP and the MSEL-RL. RESULTS: Mean scores were significantly below the normative sample mean on the TVIP, t(126) = -11.04, p < .001; d = 1.00. Performance on the TVIP among children who passed the practice items (n = 127) was significantly positively associated with performance on the MSEL-RL (r = .50, p < .001), but not significantly associated with age or gender. Older age (p < .0001) and female gender (p = .018) were associated with passing the TVIP practice items. CONCLUSIONS: Delays in RL vocabulary were identified among young children in rural Guatemala on the TVIP. The association between scores on the TVIP and the RL scale of the MSEL provides preliminary support for the construct validity of this translated and adapted version of the MSEL.

Impact of Maternal Antibody on the Immunogenicity of Inactivated Polio Vaccine in Infants Immunized With Bivalent Oral Polio Vaccine: Implications for the Polio Eradication Endgame.

Background: Quantifying interference of maternal antibodies with immune responses to varying dose schedules of inactivated polio vaccine (IPV) is important for the polio endgame as IPV replaces oral polio vaccine (OPV). Methods: Type 2 poliovirus humoral and intestinal responses were analyzed using pre-IPV type 2 seropositivity as proxy for maternal antibodies from 2 trials in Latin America. Infants received 1 or 2 doses of IPV in sequential IPV-bivalent oral polio vaccine (bOPV) or mixed bOPV-IPV schedules. Results: Among infants vaccinated with bOPV at age 6, 10, and 14 weeks of age and IPV at 14 weeks, those with type 2 pre-IPV seropositivity had lower seroprotection rates than seronegative infants at 4 weeks (92.7% vs 83.8%; difference, 8.9% [95% confidence interval, 0.6%-19.9%]; n = 260) and 22 weeks (82.7% vs 60.4%; difference, 22.3 [12.8%-32.4%]; n = 481) post-IPV. A second IPV at age 36 weeks resulted in 100% seroprotection in both groups. Among infants vaccinated with 1 IPV at age 8 weeks followed by 2 doses of bOPV, pre-IPV type 2-seropositive infants had lower seroprotection at age 28 weeks than those who were seronegative (93.0% vs 73.9%; difference, 19.6% [95% confidence interval, 7.3%-29.4%]; n = 168). A second dose of IPV at 16 weeks achieved >97% seroprotection at age 24 or 28 weeks, regardless of pre-IPV status. Poliovirus shedding after challenge with monovalent OPV, serotype 2, was higher in pre-IPV seropositive infants given sequential IPV-bOPV. No differences were observed in the mixed bOPV-IPV schedule. Conclusions: The presence of maternal antibody is associated with lower type 2 post-IPV seroprotection rates among infants who receive a single dose of IPV. This impact persists until late in infancy and is overcome by a second IPV dose.

Humoral and intestinal immunity induced by new schedules of bivalent oral poliovirus vaccine and one or two doses of inactivated poliovirus vaccine in Latin American infants: an open-label randomised controlled trial.

BACKGROUND: Replacement of the trivalent oral poliovirus vaccine (tOPV) with bivalent types 1 and 3 oral poliovirus vaccine (bOPV) and global introduction of inactivated poliovirus vaccine (IPV) are major steps in the polio endgame strategy. In this study, we assessed humoral and intestinal immunity in Latin American infants after three doses of bOPV combined with zero, one, or two doses of IPV. METHODS: This open-label randomised controlled multicentre trial was part of a larger study. 6-week-old full-term infants due for their first polio vaccinations, who were healthy on physical examination, with no obvious medical conditions and no known chronic medical disorders, were enrolled from four investigational sites in Colombia, Dominican Republic, Guatemala, and Panama. The infants were randomly assigned by permuted block randomisation (through the use of a computer-generated list, block size 36) to nine groups, of which five will be discussed in this report. These five groups were randomly assigned 1:1:1:1 to four permutations of schedule: groups 1 and 2 (control groups) received bOPV at 6, 10, and 14 weeks; group 3 (also a control group, which did not count as a permutation) received tOPV at 6, 10, and 14 weeks; group 4 received bOPV plus one dose of IPV at 14 weeks; and group 5 received bOPV plus two doses of IPV at 14 and 36 weeks. Infants in all groups were challenged with monovalent type 2 vaccine (mOPV2) at 18 weeks (groups 1, 3, and 4) or 40 weeks (groups 2 and 5). The primary objective was to assess the superiority of bOPV-IPV schedules over bOPV alone, as assessed by the primary endpoints of humoral immunity (neutralising antibodies-ie, seroconversion) to all three serotypes and intestinal immunity (faecal viral shedding post-challenge) to serotype 2, analysed in the per-protocol population. Serious and medically important adverse events were monitored for up to 6 months after the study vaccination. This study is registered with ClinicalTrials.gov, number NCT01831050, and has been completed. FINDINGS: Between May 20, 2013, and Aug 15, 2013, 940 eligible infants were enrolled and randomly assigned to the five treatment groups (210 to group 1, 210 to group 2, 100 to group 3, 210 to group 4, and 210 to group 5). One infant in group 1 was not vaccinated because their parents withdrew consent after enrolment and randomisation, so 939 infants actually received the vaccinations. Three doses of bOPV or tOPV elicited type 1 and 3 seroconversion rates of at least 97·7%. Type 2 seroconversion occurred in 19 of 198 infants (9·6%, 95% CI 6·2-14·5) in the bOPV-only groups, 86 of 88 (97·7%, 92·1-99·4) in the tOPV-only group (p<0·0001 vs bOPV-only), and 156 of 194 (80·4%, 74·3-85·4) infants in the bOPV-one dose of IPV group (p<0·0001 vs bOPV-only). A further 20 of 193 (10%) infants in the latter group seroconverted 1 week after mOPV2 challenge, resulting in around 98% of infants being seropositive against type 2. After a bOPV-two IPV schedule, all 193 infants (100%, 98·0-100; p<0·0001 vs bOPV-only) seroconverted to type 2. IPV induced small but significant decreases in a composite serotype 2 viral shedding index after mOPV2 challenge. 21 serious adverse events were reported in 20 patients during the study, including two that were judged to be possibly related to the vaccines. Most of the serious adverse events (18 [86%] of 21) and 24 (80%) of the 30 important medical events reported were infections and infestations. No deaths occurred during the study. INTERPRETATION: bOPV provided humoral protection similar to tOPV against polio serotypes 1 and 3. After one or two IPV doses in addition to bOPV, 80% and 100% of infants seroconverted, respectively, and the vaccination induced a degree of intestinal immunity against type 2 poliovirus. FUNDING: Bill & Melinda Gates Foundation.

Performance of a Mobile Phone App-Based Participatory Syndromic Surveillance System for Acute Febrile Illness and Acute Gastroenteritis in Rural Guatemala.

BACKGROUND: With their increasing availability in resource-limited settings, mobile phones may provide an important tool for participatory syndromic surveillance, in which users provide symptom data directly into a centralized database. OBJECTIVE: We studied the performance of a mobile phone app-based participatory syndromic surveillance system for collecting syndromic data (acute febrile illness and acute gastroenteritis) to detect dengue virus and norovirus on a cohort of children living in a low-resource and rural area of Guatemala. METHODS: Randomized households were provided with a mobile phone and asked to submit weekly reports using a symptom diary app (Vigilant-e). Participants reporting acute febrile illness or acute gastroenteritis answered additional questions using a decision-tree algorithm and were subsequently visited at home by a study nurse who performed a second interview and collected samples for dengue virus if confirmed acute febrile illness and norovirus if acute gastroenteritis. We analyzed risk factors associated with decreased self-reporting of syndromic data using the Vigilant-e app and evaluated strategies to improve self-reporting. We also assessed agreement between self-report and nurse-collected data obtained during home visits. RESULTS: From April 2015 to June 2016, 469 children in 207 households provided 471 person-years of observation. Mean weekly symptom reporting rate was 78% (range 58%-89%). Households with a poor (<70%) weekly reporting rate using the Vigilant-e app during the first 25 weeks of observation (n=57) had a greater number of children (mean 2.8, SD 1.5 vs mean 2.5, SD 1.3; risk ratio [RR] 1.2, 95% CI 1.1-1.4), were less likely to have used mobile phones for text messaging at study enrollment (61%, 35/57 vs 76.7%, 115/150; RR 0.6, 95% CI 0.4-0.9), and were less likely to access care at the local public clinic (35%, 20/57 vs 67.3%, 101/150; RR 0.4, 95% CI 0.2-0.6). Parents of female enrolled participants were more likely to have low response rate (57.1%, 84/147 vs 43.8%, 141/322; RR 1.4, 95% CI 1.1-1.9). Several external factors (cellular tower collapse, contentious elections) were associated with periods of decreased reporting. Poor response rate (<70%) was associated with lower case reporting of acute gastroenteritis, norovirus-associated acute gastroenteritis, acute febrile illness, and dengue virus-associated acute febrile illness (P<.001). Parent-reported syndromic data on the Vigilant-e app demonstrated agreement with nurse-collected data for fever (kappa=.57, P<.001), vomiting (kappa=.63, P<.001), and diarrhea (kappa=.61, P<.001), with decreased agreement as the time interval between parental report and nurse home visit increased (<1 day: kappa=.65-.70; ≥2 days: kappa=.08-.29). CONCLUSIONS: In a resource-limited area of rural Guatemala, a mobile phone app-based participatory syndromic surveillance system demonstrated a high reporting rate and good agreement between parental reported data and nurse-reported data during home visits. Several household-level and external factors were associated with decreased syndromic reporting. Poor reporting rate was associated with decreased syndromic and pathogen-specific case ascertainment.

Late Onset Hypomorphic RAG2 Deficiency Presentation with Fatal Vaccine-Strain VZV Infection.

PURPOSE: Hypomorphic mutations in RAG1 and RAG2 are associated with significant clinical heterogeneity and symptoms of immunodeficiency or autoimmunity may be late in appearance. As a result, immunosuppressive medications may be introduced that can have life-threatening consequences. We describe a previously healthy 13-month-old girl presenting with rash and autoimmune hemolytic anemia, while highlighting the importance of vigilance and consideration of an underlying severe immunodeficiency disease prior to instituting immunosuppressive therapy. METHODS: Given clinical deterioration of the patient and a temporal association with recently administered vaccinations, virus genotyping was carried out via 4 real-time Forster Resonance Energy Transfer PCR protocols targeting vaccine-associated single nucleotide polymorphisms. Genomic DNA was extracted from whole blood and analyzed via the next-generation sequencing method of sequencing-by-synthesis. Immune function studies included immunophenotyping of peripheral blood lymphocytes, mitogen-induced proliferation and TLR ligand-induced production of TNFα. Analysis of recombination activity of wild-type and mutant RAG2 constructs was performed. RESULTS: Virus genotyping revealed vaccine-strain VZV, mumps, and rubella. Next-generation sequencing identified heterozygosity for RAG2 R73H and P180H mutations. Profound lymphopenia was associated with intense corticosteroid therapy, with some recovery after steroid reduction. Residual, albeit low, RAG2 protein activity was demonstrated. CONCLUSIONS: Because of the association of RAG deficiency with late-onset presentation and autoimmunity, live virus vaccination and immunosuppressive therapies are often initiated and can result in negative consequences. Here, hypomorphic RAG2 mutations were linked to disseminated vaccine-strain virus infections following institution of corticosteroid therapy for autoimmune hemolytic anemia.

Multicentric Castleman disease presenting with fever.

Multicentric Castleman disease (MCD) is a rare lymphoproliferative disorder that usually manifests with nonspecific symptoms, including fever and lymphadenopathy. Treatment of pediatric MCD varies greatly. A 21-month-old child was diagnosed with MCD after presenting with fever. He had incomplete response to initial therapy directed at interleukin-6, but improved with subsequent chemotherapy.