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1.  Seasonal Drivers of Pneumococcal Disease Incidence: Impact of Bacterial Carriage and Viral Activity 
The drivers of invasive pneumococcal disease seasonality are unknown. We found that pediatric cases with a pneumonia diagnosis peaked in winter and were associated with respiratory syncytial virus (RSV), whereas nonpneumonia cases peaked in autumn and were associated with variations in bacterial carriage.
Background. Winter-seasonal epidemics of pneumococcal disease provide an opportunity to understand the drivers of incidence. We sought to determine whether seasonality of invasive pneumococcal disease is caused by increased nasopharyngeal transmission of the bacteria or increased susceptibility to invasive infections driven by cocirculating winter respiratory viruses.
Methods. We analyzed pneumococcal carriage and invasive disease data collected from children <7 years old in the Navajo/White Mountain Apache populations between 1996 and 2012. Regression models were used to quantify seasonal variations in carriage prevalence, carriage density, and disease incidence. We also fit a multivariate model to determine the contribution of carriage prevalence and RSV activity to pneumococcal disease incidence while controlling for shared seasonal factors.
Results. The seasonal patterns of invasive pneumococcal disease epidemics varied significantly by clinical presentation: bacteremic pneumococcal pneumonia incidence peaked in late winter, whereas invasive nonpneumonia pneumococcal incidence peaked in autumn. Pneumococcal carriage prevalence and density also varied seasonally, with peak prevalence occurring in late autumn. In a multivariate model, RSV activity was associated with significant increases in bacteremic pneumonia cases (attributable percentage, 15.5%; 95% confidence interval [CI], 1.8%–26.1%) but was not associated with invasive nonpneumonia infections (8.0%; 95% CI, −4.8% to 19.3%). In contrast, seasonal variations in carriage prevalence were associated with significant increases in invasive nonpneumonia infections (31.4%; 95% CI, 8.8%–51.4%) but not with bacteremic pneumonia.
Conclusions.The seasonality of invasive pneumococcal pneumonia could be due to increased susceptibility to invasive infection triggered by viral pathogens, whereas seasonality of other invasive pneumococcal infections might be primarily driven by increased nasopharyngeal transmission of the bacteria.
doi:10.1093/cid/cit721
PMCID: PMC3871795  PMID: 24190895
pneumococcal; co-infections; RSV; seasonality; pneumonia
2.  Childhood Anemia at High Altitude: Risk Factors for Poor Outcomes in Severe Pneumonia 
Pediatrics  2013;132(5):e1156-e1162.
BACKGROUND:
Pneumonia is the leading cause of mortality in young children globally, and factors that affect tissue delivery of oxygen may affect outcomes of pneumonia. We studied whether altitude and anemia influence disease severity and outcomes in young children with World Health Organization–defined severe pneumonia.
METHODS:
We analyzed data from the SPEAR (Severe Pneumonia Evaluation Antimicrobial Research) study, a World Health Organization– and USAID-sponsored multinational randomized controlled trial of antibiotics for severe pneumonia among children aged 2 to 59 months in resource-poor settings. The trial enrolled 958 children in 8 sites at varying elevations, classified as high (≥2000 m) or low (<2000 m) altitude. We compared illness severity and assessed the effect of anemia on treatment outcome at high and low altitudes, adjusting for potential confounders and study site.
RESULTS:
Children at high altitudes had significantly lower oxygen saturation on presentation, more cyanosis, lower systolic blood pressure, and higher hemoglobin. After adjusting for potential confounders, anemia predicted treatment failure in children living at high altitude (relative risk: 4.07; 95% confidence interval: 2.60–6.38) but not at low altitude (relative risk: 1.12; 95% confidence interval: 0.96–1.30). Children at high altitude took longer to reach normoxemia than did children at lower altitudes (5.25 vs 0.75 days; P < .0001).
CONCLUSIONS:
Children at high altitude present with more severe disease, and children with anemia at high altitude are at greater risk of poor outcome when being treated for severe pneumonia. Given the high global prevalence of anemia among young children, prevention and treatment of anemia should be a priority in children living at high altitude and could improve outcomes of pneumonia.
doi:10.1542/peds.2013-0761
PMCID: PMC3812558  PMID: 24101768
pneumonia; anemia; high altitude; international child health
3.  A Prospective Study of Agents Associated with Acute Respiratory Infection among Young American Indian Children 
Background
Native American children have higher rates of morbidity associated with acute respiratory infection than children in the general United States population, yet detailed information is lacking regarding their principal clinical presentations and infectious etiologies.
Methods
We pursued a comprehensive molecular survey of bacteria and viruses in nasal wash specimens from children with acute respiratory disease collected prospectively over one year (January 1 through December 31, 2009) from 915 Navajo and White Mountain Apache children in their second or third year of life who had been enrolled in an efficacy study of an RSV monoclonal antibody in the first year of life.
Results
During the surveillance period, 1476 episodes of disease were detected in 669 children. Rates of outpatient and inpatient lower respiratory tract illness were 391 and 79 per 1000 child-years, respectively, and were most commonly diagnosed as pneumonia. Potential pathogens were detected in 88% of specimens. Viruses most commonly detected were respiratory syncytial virus (RSV) and human rhinovirus (HRV); 2009 pandemic influenza A (H1N1) illnesses primarily occurred in the fall. Streptococcus pneumoniae was detected in 60% of subjects; only HRV was significantly associated with S. pneumoniae carriage. The presence of influenza virus, HRV, or S. pneumoniae was not associated with increased risk for lower respiratory tract involvement or hospitalization.
Conclusions
Acute lower respiratory illnesses occur at disproportionately high rates among young American Indian children, and are associated with a range of common pathogens. This study provides critical evidence to support reducing the disproportionate burden of acute respiratory disease among young Native Americans.
doi:10.1097/INF.0b013e31828ff4bc
PMCID: PMC3753779  PMID: 23470677
American Indian; respiratory infections; child; diagnosis; influenza
4.  Lung ultrasound for the diagnosis of pneumonia in adults: a systematic review and meta-analysis 
Respiratory Research  2014;15(1):50.
Background
Guidelines do not currently recommend the use of lung ultrasound (LUS) as an alternative to chest X-ray (CXR) or chest computerized tomography (CT) scan for the diagnosis of pneumonia. We conducted a meta-analysis to summarize existing evidence of the diagnostic accuracy of LUS for pneumonia in adults.
Methods
We conducted a systematic search of published studies comparing the diagnostic accuracy of LUS against a referent CXR or chest CT scan and/or clinical criteria for pneumonia in adults aged ≥18 years. Eligible studies were required to have a CXR and/or chest CT scan at the time of evaluation. We manually extracted descriptive and quantitative information from eligible studies, and calculated pooled sensitivity and specificity using the Mantel-Haenszel method and pooled positive and negative likelihood ratios (LR) using the DerSimonian-Laird method. We assessed for heterogeneity using the Q and I2 statistics.
Results
Our initial search strategy yielded 2726 articles, of which 45 (1.7%) were manually selected for review and 10 (0.4%) were eligible for analyses. These 10 studies provided a combined sample size of 1172 participants. Six studies enrolled adult patients who were either hospitalized or admitted to Emergency Departments with suspicion of pneumonia and 4 studies enrolled critically-ill adult patients. LUS was performed by highly-skilled sonographers in seven studies, by trained physicians in two, and one did not mention level of training. All studies were conducted in high-income settings. LUS took a maximum of 13 minutes to conduct. Nine studies used a 3.5-5 MHz micro-convex transducer and one used a 5–9 MHz convex probe. Pooled sensitivity and specificity for the diagnosis of pneumonia using LUS were 94% (95% CI, 92%-96%) and 96% (94%-97%), respectively; pooled positive and negative LRs were 16.8 (7.7-37.0) and 0.07 (0.05-0.10), respectively; and, the area-under-the-ROC curve was 0.99 (0.98-0.99).
Conclusions
Our meta-analysis supports that LUS, when conducted by highly-skilled sonographers, performs well for the diagnosis of pneumonia. General practitioners and Emergency Medicine physicians should be encouraged to learn LUS since it appears to be an established diagnostic tool in the hands of experienced physicians.
doi:10.1186/1465-9921-15-50
PMCID: PMC4005846  PMID: 24758612
Lung ultrasound; Pneumonia; Meta-analysis
5.  Nasopharyngeal Carriage and Transmission of Streptococcus pneumoniae in American Indian Households after a Decade of Pneumococcal Conjugate Vaccine Use 
PLoS ONE  2014;9(1):e79578.
Background
Young children played a major role in pneumococcal nasopharyngeal carriage, acquisition, and transmission in the era before pneumococcal conjugate vaccine (PCV) use. Few studies document pneumococcal household dynamics in the routine-PCV7 era.
Methods
We investigated age-specific acquisition, household introduction, carriage clearance, and intra-household transmission in a prospective, longitudinal, observational cohort study of pneumococcal nasopharyngeal carriage in 300 American Indian households comprising 1,072 participants between March 2006 and March 2008.
Results
Pneumococcal acquisition rates were 2–6 times higher in children than adults. More household introductions of new pneumococcal strains were attributable to children <9 years than adults ≥17 years (p<0.001), and older children (2–8 years) than younger children (<2 years) (p<0.008). Compared to children <2 years, carriage clearance was more rapid in older children (2–4 years, HRclearance 1.53 [95% CI: 1.22, 1.91]; 5–8 years, HRclearance 1.71 [1.36, 2.15]) and adults (HRclearance 1.75 [1.16, 2.64]). Exposure to serotype-specific carriage in older children (2–8 years) most consistently increased the odds of subsequently acquiring that serotype for other household members.
Conclusions
In this community with a high burden of pneumococcal colonization and disease and routine PCV7 use, children (particularly older children 2–8 years) drive intra-household pneumococcal transmission: first, by acquiring, introducing, and harboring pneumococcus within the household, and then by transmitting acquired serotypes more efficiently than household members of other ages.
doi:10.1371/journal.pone.0079578
PMCID: PMC3894936  PMID: 24465365
6.  Comparative Immunogenicity of 7 and 13-Valent Pneumococcal Conjugate Vaccines and the Development of Functional Antibodies to Cross-Reactive Serotypes 
PLoS ONE  2013;8(9):e74906.
Background
Protection against disease or colonization from serotypes related to those in pneumococcal conjugate vaccines (i.e. cross-protection) vary by serotype; the basis for this variation is not understood. The 13-valent pneumococcal conjugate vaccine (PCV13) replaced 7-valent conjugate (PCV7) in the USA in 2010 allowing assessment of PCV7 and PCV13 immunogenicity and functional cross-protection in vitro.
Methods
Post-primary, pre-booster and post-booster sera from American Indian children receiving exclusively PCV7 or PCV13 were collected. IgG was measured by ELISA for 13 vaccine serotypes; functional antibody was assessed by opsonophagocytic killing assays for serotypes 6A/B/C and 19A/F.
Results
Post-primary IgG geometric mean concentrations (GMC) for serotypes 4 and 9V were lower in PCV13 recipients while 19F GMCs were higher. Only 19F differences persisted after receipt of the booster dose. Functional antibody activity was higher among PCV13 recipients for 6A, 6C, 19A and 19F (p<0.04), and among PCV7 recipients for 6B (p = 0.01). Following PCV7, functional antibodies to 6A but not 19A were observed. High levels of 6C functional activity were seen after PCV13 but not PCV7.
Conclusions
Functional antibody activity against 6A/B/C and 19A/F suggest that PCV13 is likely to control the 19A disease and 6C disease remaining despite widespread use of PCV7.
doi:10.1371/journal.pone.0074906
PMCID: PMC3781100  PMID: 24086394
7.  Overcoming perceptions of financial barriers to rotavirus vaccine introduction in Asia 
Human Vaccines & Immunotherapeutics  2013;9(11):2418-2426.
Despite a WHO recommendation in 2009, reaffirmed in 2013, that all countries should consider introducing rotavirus vaccines into their National Immunization Programs, as of June 2013 only 45 have done so. One major consideration appears to have been the costs of the vaccine to countries. Of concern, is that Asian countries have been slow to introduce rotavirus vaccines despite having robust data that could inform the decision-making process. Although decisions on new vaccine introduction are very complex and vary by country and region, economic evaluations are often pivotal once vaccine efficacy and safety has been established, and disease burden documented and communicated. Unfortunately, with private sector list prices of vaccines often used in economic evaluations, rather than a potential public health sector pricing structure, policy-makers may defer decisions on rotavirus vaccine introduction based on the belief that “the vaccine price is too high,” even though this might be based on erroneous data. The Pan American Health Organization’s Revolving Fund provides one example of how vaccine price can be made more competitive and transparent through a regional tendering process. Other mechanisms, such as tiered pricing and UNICEF procurement, also exist that could help Asian and other countries move forward more quickly with rotavirus vaccine introduction.
doi:10.4161/hv.26107
PMCID: PMC3981852  PMID: 23955246
rotavirus vaccine; immunization financing; immunization policy; policy recommendations; advisory committee; National Immunization Technical Advisory Group; evidence-based decision making
8.  Nontypeable Pneumococcal Isolates Among Navajo and White Mountain Apache Communities: Are These Really a Cause of Invasive Disease? 
Background. Pneumococci could evade pneumococcal conjugate vaccines (PCV) by modifying, mutating, or deleting vaccine-serotype capsule genes or by downregulating capsule production. We sought to assess whether pneumococci that are nontypeable (NT) by the Quellung reaction truly lack capsule genes or are failing to produce capsule in vitro.
Methods. We applied multilocus sequence typing and a microarray for detection of pneumococcal polysaccharide capsule biosynthesis genes to NT carriage (children aged <5 years; years 1997–2000, 2006–2008) and NT invasive disease (IPD) (all ages; years 1994–2007) isolates from Native American communities.
Results. Twenty-seven of 28 (96.4%) NT IPD isolates had sequence types (STs) typically found among typeable IPD isolates and contained whole or fragments of capsule genes that matched known serotypes; 1 NT-IPD isolate had a profile resembling NT carriage isolates. Forty-nine of 76 (64.5%) NT carriage isolates had STs that typically lack capsule genes and were similar to NT carriage isolates found globally.
Conclusions. This is the first documentation of IPD from an NT strain confirmed to lack all known capsule genes. Most NT IPD isolates have or had the capacity to produce capsule, whereas a majority of NT carriage isolates lack this capacity. We found no evidence of pneumococcal adaptation to PCV7 via downregulation or deletion of vaccine-serotype capsule genes.
doi:10.1093/infdis/jis307
PMCID: PMC3415932  PMID: 22536000
9.  Nontypeable Pneumococcal Isolates Among Navajo and White Mountain Apache Communities: Are These Really a Cause of Invasive Disease? 
Background
Pneumococci could evade pneumococcal conjugate vaccines (PCV) by modifying, mutating, or deleting vaccine-serotype capsule genes or by downregulating capsule production. We sought to assess whether pneumococci that are nontypeable (NT) by the Quellung reaction truly lack capsule genes or are failing to produce capsule in vitro.
Methods
We applied multilocus sequence typing and a microarray for detection of pneumococcal polysaccharide capsule biosynthesis genes to NT carriage (children aged <5 years; years 1997–2000, 2006–2008) and NT invasive disease (IPD) (all ages; years 1994–2007) isolates from Native American communities.
Results
Twenty-seven of 28 (96.4%) NT IPD isolates had sequence types (STs) typically found among typeable IPD isolates and contained whole or fragments of capsule genes that matched known serotypes; 1 NT-IPD isolate had a profile resembling NT carriage isolates. Forty-nine of 76 (64.5%) NT carriage isolates had STs that typically lack capsule genes and were similar to NT carriage isolates found globally.
Conclusions
This is the first documentation of IPD from an NT strain confirmed to lack all known capsule genes. Most NT IPD isolates have or had the capacity to produce capsule, whereas a majority of NT carriage isolates lack this capacity. We found no evidence of pneumococcal adaptation to PCV7 via downregulation or deletion of vaccine-serotype capsule genes.
doi:10.1093/infdis/jis307
PMCID: PMC3415932  PMID: 22536000
10.  Global action plan for childhood diarrhoea: Developing research priorities 
Journal of Global Health  2013;3(1):010406.
Background
Childhood diarrhoea remains a major public health problem responsible for the deaths of approximately 800 000 children annually, worldwide. The present study was undertaken to further define research priorities for the prevention and treatment of diarrhoea in low and middle income countries. We used the Child Health and Nutrition Research Initiative (CHNRI) process for defining research priorities. This provided a transparent, systematic method of obtaining the opinions of experts regarding research priorities in childhood diarrhoea. The present report describes the deliberations of a workshop that reviewed these research priorities by stakeholders including colleagues from: government agencies, academic institutions, major funding agencies and non–governmental organizations.
Methods
The workshop included 38 participants, divided into four groups to consider issues in the categories of description, delivery, development and discovery. Each group received 20 to 23 questions/research priorities previously identified by the CHNRI process. Deliberations and conclusions of each group were summarized in separate reports that were further discussed in a plenary session including all workshop participants.
Results
The reports of the working groups emphasized the following five key points: 1) A common theme was the need to substantially increase the use of oral rehydration salts (ORS) and zinc in the prevention and treatment of diarrhoea. There is a need for better definitions of those factors that supported and interfered with the use of these agents; 2) There is an urgent need to determine the long–term effects of chronic and recurrent bouts of diarrhoea on the physical and intellectual development of affected children; 3) Improvements in water, sanitation and hygiene facilities are critical steps required to reduce the incidence and severity of childhood diarrhoea; 4)Risk factors enhancing the susceptibility and clinical response to diarrhoea were explored; implementation research of modifiable factors is urgently required; 5) More research is required to better understand the causes and pathophysiology of various forms of enteropathy and to define the methods and techniques necessary for their accurate study.
Conclusions
The participants in this workshop determined that use of the CHNRI process had successfully defined those research priorities necessary for the study of childhood diarrhoea. The deliberations of the workshop brought these research priorities to the attention of stakeholders responsible for the implementation of the recommendations. It was concluded that the deliberations of the workshop positively supplemented the research priorities developed by the CHNRI process.
doi:10.7189/jogh.03.010406
PMCID: PMC3700031  PMID: 23826510
11.  Setting Research Priorities to Reduce Mortality and Morbidity of Childhood Diarrhoeal Disease in the Next 15 Years 
PLoS Medicine  2013;10(5):e1001446.
Zulfi Bhutta and colleagues lay out research priorities for global child diarrheal disease over the next 15 years, which they developed using the Child Health and Nutrition Research Initiative (CHNRI) method.
Please see later in the article for the Editors' Summary
doi:10.1371/journal.pmed.1001446
PMCID: PMC3653794  PMID: 23690756
12.  Prospective multi-centre sentinel surveillance for Haemophilus influenzae type b & other bacterial meningitis in Indian children 
Background & objectives:
Haemophilus influenzae type b (Hib) is one of the leading bacterial causes of invasive disease in populations without access to Hib conjugate vaccines (Hib-CV). India has recently decided to introduce Hib-CV into the routine immunization programme in selected States. Longitudinal data quantifying the burden of bacterial meningitis and the proportion of disease caused by various bacteria are needed to track the impact of Hib-CV once introduced. A hospital-based sentinel surveillance network was established at four places in the country and this study reports the results of this ongoing surveillance.
Methods:
Children aged 1 to 23 months with suspected bacterial meningitis were enrolled in Chennai, Lucknow, New Delhi, and Vellore between July 2008 and June 2010. All cerebrospinal fluid (CSF) samples were tested using cytological, biochemical, and culture methods. Samples with abnormal CSF (≥10 WBC per μl) were tested by latex agglutination test for common paediatric bacterial meningitis pathogens.
Results:
A total of 708 patients with abnormal CSF were identified, 89 of whom had a bacterial pathogen confirmed. Hib accounted for the majority of bacteriologically confirmed cases, 62 (70%), while Streptococcus pneumoniae and group B Streptococcus were identified in 12 (13%) and seven (8%) cases, respectively. The other eight cases were a mix of other bacteria. The proportion of abnormal CSF and probable bacterial meningitis that was caused by Hib was 74 and 58 per cent lower at Christian Medical College (CMC), Vellore, which had a 41 per cent coverage of Hib-CV among all suspected meningitis cases, compared to the combined average proportion at the other three centres where a coverage between 1 and 8 per cent was seen (P<0.001 and P= 0.05, respectively).
Interpretation & conclusions:
Hib was found to be the predominant cause of bacterial meningitis in young children in diverse geographic locations in India. Possible indications of herd immunity was seen at CMC compared to sites with low immunization coverage with Hib-CV. As Hib is the most common pathogen in bacterial meningitis, Hib-CV would have a large impact on bacterial meningitis in Indian children.
PMCID: PMC3724251  PMID: 23703338
Haemophilus influenzae type B; meningitis; surveillance
13.  Effect of knowledge of community health workers on essential newborn health care: a study from rural India 
Health Policy and Planning  2011;27(2):115-126.
Background This study explored the relationship between the knowledge of community health workers (CHWs)—anganwadi workers (AWWs) and auxiliary nurse midwives (ANMs)—and their antenatal home visit coverage and effectiveness of the visits, in terms of essential newborn health care practices at the household level in rural India.
Methods We used data from 302 AWWs and 86 ANMs and data from recently delivered women (RDW) (n = 13 023) who were residents of the CHW catchment areas and gave birth to a singleton live baby during 2004–05. Using principal component analysis, knowledge scores for preventive care and danger signs were computed separately for AWWs and ANMs and merged with RDW data. A multivariate logistic regression model was used to estimate the adjusted effect of knowledge level. A generalized estimating equation (GEE) was used to account for clustering.
Results Coverage of antenatal home visits and newborn care practices were positively correlated with the knowledge level of AWWs and ANMs. Initiation of breastfeeding in the first hour of life (odds ratio 1.97; 95% confidence interval (CI): 1.55–2.49 for AWW, and odds ratio 1.62; 95% CI: 1.25–2.09 for ANM), clean cord care (odds ratio 2.03; 95% CI: 1.64–2.52 for AWW, and odds ratio 1.43; 95% CI: 1.17–1.75 for ANM) and thermal care (odds ratio 2.16; 95% CI: 1.64–2.85 for AWW and odds ratio 1.88; 95% CI: 1.43–2.48 for ANM) were significantly higher among women visited by AWWs or ANMs who had better knowledge compared with those with poor knowledge.
Conclusion CHWs’ knowledge is one of the crucial aspects of health systems to improve the coverage of community-based newborn health care programmes as well as adherence to essential newborn care practices at the household level.
doi:10.1093/heapol/czr018
PMCID: PMC3606030  PMID: 21385799
Knowledge level; community health workers; essential newborn health care practices; principal component analysis; logistic regression; generalized estimating equation
14.  Impact of More Than a Decade of Pneumococcal Conjugate Vaccine Use on Carriage and Invasive Potential in Native American Communities 
The Journal of Infectious Diseases  2011;205(2):280-288.
Background. We assessed the impact of 12 years of pneumococcal conjugate vaccine (PCV7) use on pneumococcal nasopharyngeal carriage and serotype-specific invasive disease potential among Native Americans.
Methods. Families were enrolled in a carriage study from 2006 to 2008; nasopharyngeal specimens and risk factor information were collected monthly for 7 visits. Pneumococcal carriage prevalence was compared with that before (1998–2000) and during (2001–2002) PCV7 introduction. We compared invasive disease incidence and carriage prevalence before and after PCV7 introduction to estimate changes in serotype-specific invasive potential.
Results. We enrolled 1077 subjects from 302 households. There was an absolute reduction in carriage prevalence of 8.0% (95% confidence interval [CI], 4.5%–11.4%) in children aged <5 years and 3.1% (95% CI, 1.1%–5.1%) in adults. In children aged <5 years, vaccine-serotype carriage prevalence decreased by 22.8% (95% CI, 20.1%–25.3%), and nonvaccine serotype (NVT) increased by 15.9% (95% CI, 12.4%–19.3%). No significant change was detected in serotype-specific invasive potential after PCV7 introduction.
Conclusions. Pneumococcal carriage prevalence decreased in all ages since PCV7 introduction; vaccine-serotype carriage has been nearly eliminated, whereas the prevalence of NVT carriage has increased. The increase in the NVT invasive disease rate seems to be proportional to the increase in colonization prevalence.
doi:10.1093/infdis/jir730
PMCID: PMC3244367  PMID: 22128315
15.  Strain Characteristics of Streptococcus pneumoniae Carriage and Invasive Disease Isolates during a Cluster-Randomized Clinical Trial of the 7-Valent Pneumococcal Conjugate Vaccine 
The Journal of Infectious Diseases  2007;196(8):1221-1227.
Widespread use of 7-valent pneumococcal conjugate vaccine (PCV7) has led to significant reductions in disease while changing pneumococcal population dynamics via herd immunity and serotype replacement. We performed multilocus sequence typing (MLST) on 590 pneumococcal isolates obtained during the American Indian clinical trial of PCV7, in which communities were randomized for eligible children to receive either PCV7 or a meningococcal conjugate vaccine (MCV). Sequence types (STs) were analyzed to determine the impact of the vaccine on pneumococcal population structure and to assess the possible impact of pneumococcal genetic background on vaccine effects. One hundred forty-three STs were obtained, the most frequent being ST199, the only one that included vaccine serotypes (VTs), non–vaccine-associated nonvaccine serotypes (NVA/NVTs), and vaccine-associated serotypes (VATs). Serotype replacement observed in the PCV communities was due to a diverse population of STs, most of which also existed in the MCV communities. Possible capsular switching to create novel ST associations with NVA/NVTs was detected only once. Reductions in VTs and changes in VATs in PCV communities did not show evidence of variation by ST, after accounting for lower vaccine effectiveness against serotype 19F. These observations suggest the hypothesis that the vaccine acts as a “serotype filter”: its effect on a particular strain can be predicted on the basis of the serotype of the strain, with little effect of genetic background (as assessed by MLST) over and above capsule. If sustained, such patterns provide some cause for optimism that rapid evolution of PCV escape strains with drug resistance or high virulence is unlikely.
doi:10.1086/521831
PMCID: PMC3350793  PMID: 17955441
16.  Streptococcus pneumoniae Serotype-2 Childhood Meningitis in Bangladesh: A Newly Recognized Pneumococcal Infection Threat 
PLoS ONE  2012;7(3):e32134.
Background
Streptococcus pneumoniae is a leading cause of meningitis in countries where pneumococcal conjugate vaccines (PCV) targeting commonly occurring serotypes are not routinely used. However, effectiveness of PCV would be jeopardized by emergence of invasive pneumococcal diseases (IPD) caused by serotypes which are not included in PCV. Systematic hospital based surveillance in Bangladesh was established and progressively improved to determine the pathogens causing childhood sepsis and meningitis. This also provided the foundation for determining the spectrum of serotypes causing IPD. This article reports an unprecedented upsurge of serotype 2, an uncommon pneumococcal serotype, without any known intervention.
Methods and Findings
Cases with suspected IPD had blood or cerebrospinal fluid (CSF) collected from the beginning of 2001 till 2009. Pneumococcal serotypes were determined by capsular swelling of isolates or PCR of culture-negative CSF specimens. Multicenter national surveillance, expanded from 2004, identified 45,437 patients with suspected bacteremia who were blood cultured and 10,618 suspected meningitis cases who had a lumber puncture. Pneumococcus accounted for 230 culture positive cases of meningitis in children <5 years. Serotype-2 was the leading cause of pneumococcal meningitis, accounting for 20.4% (45/221; 95% CI 15%–26%) of cases. Ninety eight percent (45/46) of these serotype-2 strains were isolated from meningitis cases, yielding the highest serotype-specific odds ratio for meningitis (29.6; 95% CI 3.4–256.3). The serotype-2 strains had three closely related pulsed field gel electrophoresis types.
Conclusions
S. pneumoniae serotype-2 was found to possess an unusually high potential for causing meningitis and was the leading serotype-specific cause of childhood meningitis in Bangladesh over the past decade. Persisting disease occurrence or progressive spread would represent a major potential infection threat since serotype-2 is not included in PCVs currently licensed or under development.
doi:10.1371/journal.pone.0032134
PMCID: PMC3316528  PMID: 22479314
17.  Nosocomial Sepsis Risk Score for Preterm Infants in Low-resource Settings 
Journal of Tropical Pediatrics  2009;56(2):82-89.
Sepsis is a leading cause of mortality for neonates in developing countries; however, little research has focused on clinical predictors of nosocomial infection of preterm neonates in the low-resource setting. We sought to validate the only existing feasible score introduced by Singh et al. in 2003 and to create an improved score. In a secondary analysis of daily evaluations of 497 neonates ≤33 weeks gestational age admitted to a tertiary care NICU in Dhaka, Bangladesh, we tested the Singh score and then constructed and internally validated our own bedside predictive score. The Singh score had low sensitivity of 56.6% but good positive predictive value (PPV) of 78.1% in our sample. Our five-sign model requiring at least one clinical sign of infection (apnea, hepatomegaly, jaundice, lethargy and pallor) had an area under the receiver operating characteristic of 0.70, sensitivity of 77.1%, and PPV of 64.9%. Our clinical sepsis score is the first bedside clinical screen exclusively for hospitalized, very premature neonates in a low-resource setting, and warrants external validation.
doi:10.1093/tropej/fmp061
PMCID: PMC3115678  PMID: 19622712
neonate; sepsis; prematurity; very low birth-weight; developing countries; nosocomial
18.  Household surveillance of severe neonatal illness by community health workers in Mirzapur, Bangladesh: coverage and compliance with referral 
Health Policy and Planning  2009;25(2):112-124.
Background Effective and scalable community-based strategies are needed for identification and management of serious neonatal illness.
Methods As part of a community-based, cluster-randomized controlled trial of the impact of a package of maternal-neonatal health care, community health workers (CHWs) were trained to conduct household surveillance and to identify and refer sick newborns according to a clinical algorithm. Assessments of newborns by CHWs at home were linked to hospital-based assessments by physicians, and factors impacting referral, referral compliance and outcome were evaluated.
Results Seventy-three per cent (7310/10 006) of live-born neonates enrolled in the study were assessed by CHWs at least once; 54% were assessed within 2 days of birth, but only 15% were attended at delivery. Among assessments for which referral was recommended, compliance was verified in 54% (495/919). Referrals recommended to young neonates 0–6 days old were 30% less likely to be complied with compared to older neonates. Compliance was positively associated with having very severe disease and selected clinical signs, including respiratory rate ≥70/minute; weak, abnormal or absent cry; lethargic or less than normal movement; and feeding problem. Among 239 neonates who died, only 38% were assessed by a CHW before death.
Conclusions Despite rigorous programmatic effort, reaching neonates within the first 2 days after birth remained a challenge, and parental compliance with referral recommendation was limited, particularly among young neonates. To optimize potential impact, community postnatal surveillance must be coupled with skilled attendance at delivery, and/or a worker skilled in recognition of neonatal illness must be placed in close proximity to the community to allow for rapid case management to avert early deaths.
doi:10.1093/heapol/czp048
PMCID: PMC2912547  PMID: 19917652
Community health worker; neonatal illness; referral; surveillance; care seeking
19.  Community-based Validation of Assessment of Newborn Illnesses by trained Community Health Workers in Sylhet district of Bangladesh 
Objectives
To validate trained community health workers' (CHWs') recognition of signs and symptoms of newborn illnesses and classification of illnesses using a clinical algorithm during routine home visits in rural Bangladesh.
Methods
Between August 2005 and May 2006, 288 newborns were assessed independently by a CHW and a study physician. Based on a 20-sign algorithm, sick neonates were classified as having very severe disease (VSD), possible very severe disease (PVSD) or no disease. Physician's assessment was considered as the gold standard.
Results
CHWs correctly classified VSD in newborns with a sensitivity of 91%, specificity of 95%, and kappa value of 0.85 (p<0.001) indicating almost perfect agreement with physicians' classification of VSD. CHWs' recognition showed a sensitivity of more than 60% and a specificity of 97–100% for almost all signs and symptoms.
Conclusion
CHWs with minimal training can use a diagnostic algorithm to identify severely ill newborns with high validity.
doi:10.1111/j.1365-3156.2009.02397.x
PMCID: PMC2929169  PMID: 19807901
newborn health; newborn illness; Community Health Workers; validation; Bangladesh; newborn assessment
20.  A policy framework for accelerating adoption of new vaccines 
Human Vaccines  2010;6(12):1021-1024.
Rapid uptake of new vaccines can improve health and wealth and contribute to meeting Millennium Development Goals. In the past, however, the introduction and use of new vaccines has been characterized by delayed uptake in the countries where the need is greatest. Based on experience with accelerating the adoption of Hib, pneumococcal and rotavirus vaccines, we propose here a framework for new vaccine adoption that may be useful for future efforts. The framework organizes the major steps in the process into a continuum from evidence to policy, implementation and finally access. It highlights the important roles of different actors at various times in the process and may allow new vaccine initiatives to save time and improve their efficiency by anticipating key steps and actions.
doi:10.4161/hv.6.12.13076
PMCID: PMC3060382  PMID: 21150269
vaccines; policy; Hib; rotavirus; pneumococcal; immunization
21.  Population-Based Incidence and Etiology of Community-Acquired Neonatal Bacteremia in Mirzapur, Bangladesh: An Observational Study 
The Journal of infectious diseases  2009;200(6):906-915.
Background
To devise treatment strategies for neonatal infections, the population-level incidence and antibiotic susceptibility of pathogens must be defined.
Methods
Surveillance for suspected neonatal sepsis was conducted in Mirzapur, Bangladesh, from February 2004 through November 2006. Community health workers assessed neonates on postnatal days 0, 2, 5, and 8 and referred sick neonates to a hospital, where blood was collected for culture from neonates with suspected sepsis. We estimated the incidence and pattern of community-acquired neonatal bacteremia and determined the antibiotic susceptibility profile of pathogens.
Results
The incidence rate of community-acquired neonatal bacteremia was 3.0 per 1000 person–neonatal periods. Among the 30 pathogens identified, the most common was Staphylococcus aureus (n = 10); half of all isolates were gram positive. Nine were resistant to ampicillin and gentamicin or to ceftiaxone, and 13 were resistant to cotrimoxazole.
Conclusion
S. aureus was the most common pathogen to cause community-acquired neonatal bacteremia. Nearly 40% of infections were identified on days 0–3, emphasizing the need to address maternal and environmental sources of infection. The combination of parenteral procaine benzyl penicillin and an aminoglycoside is recommended for the first-line treatment of serious community-acquired neonatal infections in rural Bangladesh, which has a moderate level of neonatal mortality. Additional population-based data are needed to further guide national and global strategies.
Trial registration
ClinicalTrials.gov identifier: NCT00198627.
doi:10.1086/605473
PMCID: PMC2841956  PMID: 19671016
22.  Effectiveness of Home-based Management of Newborn Infections by Community Health Workers in Rural Bangladesh 
Background
Infections account for about half of neonatal deaths in low-resource settings. Limited evidence supports home-based treatment of newborn infections by community health workers (CHW).
Methods
In one study arm of a cluster randomized controlled trial, CHWs assessed neonates at home using a 20-sign clinical algorithm and classified sick neonates as having very severe disease or possible very severe disease. Over a two-year period, 10 585 live births were recorded in the study area. CHWs assessed 8474 (80%) of the neonates within the first week of life and referred neonates with signs of severe disease. If referral failed but parents consented to home treatment, CHWs treated neonates with very severe disease or possible very severe disease with multiple signs, using injectable antibiotics.
Results
For very severe disease, referral compliance was 34% (162/478 cases), and home treatment acceptance was 43% (204/478 cases). The case fatality rate was 4.4% (9/204) for CHW treatment, 14.2% (23/162) for treatment by qualified medical providers, and 28.5% (32/112) for those who received no treatment or who were treated by other unqualified providers. After controlling for differences in background characteristics and illness signs among treatment groups, newborns treated by CHWs had a hazard ratio of 0.22 (95% confidence interval 0.07–0.71) for death during the neonatal period and those treated by qualified providers had a hazard ratio of 0.61 (95% confidence interval of 0.37–0.99), compared with newborns who received no treatment or were treated by untrained providers. Significantly increased hazards ratios of death were observed for neonates with convulsions (HR 6.54; 95% CI 3.98–10.76), chest in-drawing (HR 2.38, 95% CI 1.29–4.39), temperature < 35.3°C (HR 3.47, 95% CI 1.30–9.24), unconsciousness (HR 7.92, 95% CI 3.13–20.04).
Conclusions
Home treatment of very severe disease in neonates by CHWs was effective and acceptable in a low-resource setting in Bangladesh.
doi:10.1097/INF.0b013e31819069e8
PMCID: PMC2929171  PMID: 19289979
neonatal; infection; sepsis; community health workers; Bangladesh
23.  Prevention of rotavirus gastroenteritis in infants and children: rotavirus vaccine safety, efficacy, and potential impact of vaccines 
Rotavirus infection is the most common cause of severe gastroenteritis globally, with greater than 86% of deaths occurring in low-income and middle-income countries. There are two rotavirus vaccines currently licensed in the United States and prequalified by the World Health Organization. RV1 is a monovalent attenuated human rotavirus strain, given orally in two doses. RV5 is a pentavalent human-bovine reassortant rotavirus vaccine, given orally in three doses. A third rotavirus vaccine, LLV, is a lamb rotavirus strain given orally as a single dose, which is currently available only in China. RV1 and RV5 have been shown to be highly efficacious in developed countries, and initial results from trials in Africa and Asia are promising as well. At least three other vaccines are in development, which are being developed by manufacturers of developing countries. Further studies are needed to clarify issues including administration of oral rotavirus vaccines with breastfeeding and other oral vaccines, and alterations in dosing schedule. Using new data on global diarrheal burden, rotavirus is estimated to cause 390,000 deaths in children younger than 5 years. Should rotavirus vaccines be introduced in the routine immunization programs of all countries, a potential of 170,000 deaths could be prevented annually. The largest impact on mortality would be seen in low-income and middle-income countries, despite poor immunization coverage and lower efficacy. Therefore, international efforts are needed to ensure that rotavirus vaccines reach the populations with highest burden of rotavirus disease.
PMCID: PMC2921258  PMID: 20714358
vaccination; mortality; rotavirus; gastroenteritis
24.  Evaluation of a Cluster-Randomized Controlled Trial of a Package of Community-Based Maternal and Newborn Interventions in Mirzapur, Bangladesh 
PLoS ONE  2010;5(3):e9696.
Background
To evaluate a delivery strategy for newborn interventions in rural Bangladesh.
Methods
A cluster-randomized controlled trial was conducted in Mirzapur, Bangladesh. Twelve unions were randomized to intervention or comparison arm. All women of reproductive age were eligible to participate. In the intervention arm, community health workers identified pregnant women; made two antenatal home visits to promote birth and newborn care preparedness; made four postnatal home visits to negotiate preventive care practices and to assess newborns for illness; and referred sick neonates to a hospital and facilitated compliance. Primary outcome measures were antenatal and immediate newborn care behaviours, knowledge of danger signs, care seeking for neonatal complications, and neonatal mortality.
Findings
A total of 4616 and 5241 live births were recorded from 9987 and 11153 participants in the intervention and comparison arm, respectively. High coverage of antenatal (91% visited twice) and postnatal (69% visited on days 0 or 1) home visitations was achieved. Indicators of care practices and knowledge of maternal and neonatal danger signs improved. Adjusted mortality hazard ratio in the intervention arm, compared to the comparison arm, was 1.02 (95% CI: 0.80–1.30) at baseline and 0.87 (95% CI: 0.68–1.12) at endline. Primary causes of death were birth asphyxia (49%) and prematurity (26%). No adverse events associated with interventions were reported.
Conclusion
Lack of evidence for mortality impact despite high program coverage and quality assurance of implementation, and improvements in targeted newborn care practices suggests the intervention did not adequately address risk factors for mortality. The level and cause-structure of neonatal mortality in the local population must be considered in developing interventions. Programs must ensure skilled care during childbirth, including management of birth asphyxia and prematurity, and curative postnatal care during the first two days of life, in addition to essential newborn care and infection prevention and management.
Trial Registration
Clinicaltrials.gov NCT00198627
doi:10.1371/journal.pone.0009696
PMCID: PMC2844410  PMID: 20352087
25.  Impact of Clean Delivery-kit use on Newborn Umbilical Cord and Maternal Puerperal Infections in Egypt 
This cross-sectional cohort study explored the impact of the use of clean delivery-kit (CDK) on morbidity due to newborn umbilical cord and maternal puerperal infections. Kits were distributed from primary-care facilities, and birth attendants received training on kit-use. A nurse visited 334 women during the first week postpartum to administer a structured questionnaire and conduct a physical examination of the neonate and the mother. Results of bivariate analysis showed that neonates of mothers who used a CDK were less likely to develop cord infection (p=0.025), and mothers who used a CDK were less likely to develop puerperal sepsis (p=0.024). Results of multiple logistic regression analysis showed an independent association between decreased cord infection and kit-use [odds ratio (OR)=0.42, 95% confidence interval (CI) 0.18–0.97, p=0.041)]. Mothers who used a CDK also had considerably lower rates of puerperal infection (OR=0.11, 95% CI 0.01–1.06), although the statistical strength of the association was of borderline significance (p=0.057). The use of CDK was associated with reductions in umbilical cord and puerperal infections.
PMCID: PMC2928112  PMID: 20099758
Cohort studies; Cross-sectional studies; Delivery-kit; Evaluation studies; Impact studies; Morbidity; Sepsis; Umbilical cord infections; Egypt

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