Standardization of Clinical Assessment and Sample Collection Across All PERCH Study Sites.

BACKGROUND.: Variable adherence to standardized case definitions, clinical procedures, specimen collection techniques, and laboratory methods has complicated the interpretation of previous multicenter pneumonia etiology studies. To circumvent these problems, a program of clinical standardization was embedded in the Pneumonia Etiology Research for Child Health (PERCH) study. METHODS.: Between March 2011 and August 2013, standardized training on the PERCH case definition, clinical procedures, and collection of laboratory specimens was delivered to 331 clinical staff at 9 study sites in 7 countries (The Gambia, Kenya, Mali, South Africa, Zambia, Thailand, and Bangladesh), through 32 on-site courses and a training website. Staff competency was assessed throughout 24 months of enrollment with multiple-choice question (MCQ) examinations, a video quiz, and checklist evaluations of practical skills. RESULTS.: MCQ evaluation was confined to 158 clinical staff members who enrolled PERCH cases and controls, with scores obtained for >86% of eligible staff at each time-point. Median scores after baseline training were ≥80%, and improved by 10 percentage points with refresher training, with no significant intersite differences. Percentage agreement with the clinical trainer on the presence or absence of clinical signs on video clips was high (≥89%), with interobserver concordance being substantial to high (AC1 statistic, 0.62-0.82) for 5 of 6 signs assessed. Staff attained median scores of >90% in checklist evaluations of practical skills. CONCLUSIONS.: Satisfactory clinical standardization was achieved within and across all PERCH sites, providing reassurance that any etiological or clinical differences observed across the study sites are true differences, and not attributable to differences in application of the clinical case definition, interpretation of clinical signs, or in techniques used for clinical measurements or specimen collection.

Microscopic Analysis and Quality Assessment of Induced Sputum From Children With Pneumonia in the PERCH Study.

BACKGROUND.: It is standard practice for laboratories to assess the cellular quality of expectorated sputum specimens to check that they originated from the lower respiratory tract. The presence of low numbers of squamous epithelial cells (SECs) and high numbers of polymorphonuclear (PMN) cells are regarded as indicative of a lower respiratory tract specimen. However, these quality ratings have never been evaluated for induced sputum specimens from children with suspected pneumonia. METHODS.: We evaluated induced sputum Gram stain smears and cultures from hospitalized children aged 1-59 months enrolled in a large study of community-acquired pneumonia. We hypothesized that a specimen representative of the lower respiratory tract will contain smaller quantities of oropharyngeal flora and be more likely to have a predominance of potential pathogens compared to a specimen containing mainly saliva. The prevalence of potential pathogens cultured from induced sputum specimens and quantity of oropharyngeal flora were compared for different quantities of SECs and PMNs. RESULTS.: Of 3772 induced sputum specimens, 2608 (69%) had <10 SECs per low-power field (LPF) and 2350 (62%) had >25 PMNs per LPF, measures traditionally associated with specimens from the lower respiratory tract in adults. Using isolation of low quantities of oropharyngeal flora and higher prevalence of potential pathogens as markers of higher quality, <10 SECs per LPF (but not >25 PMNs per LPF) was the microscopic variable most associated with high quality of induced sputum. CONCLUSIONS.: Quantity of SECs may be a useful quality measure of induced sputum from young children with pneumonia.

Mobile phone-delivered reminders and incentives to improve childhood immunisation coverage and timeliness in Kenya (M-SIMU): a cluster randomised controlled trial.

BACKGROUND: As mobile phone access continues to expand globally, opportunities exist to leverage these technologies to support demand for immunisation services and improve vaccine coverage. We aimed to assess whether short message service (SMS) reminders and monetary incentives can improve immunisation uptake in Kenya. METHODS: In this cluster-randomised controlled trial, villages were randomly and evenly allocated to four groups: control, SMS only, SMS plus a 75 Kenya Shilling (KES) incentive, and SMS plus 200 KES (85 KES = USD$1). Caregivers were eligible if they had a child younger than 5 weeks who had not yet received a first dose of pentavalent vaccine. Participants in the intervention groups received SMS reminders before scheduled pentavalent and measles immunisation visits. Participants in incentive groups, additionally, received money if their child was timely immunised (immunisation within 2 weeks of the due date). Caregivers and interviewers were not masked. The proportion of fully immunised children (receiving BCG, three doses of polio vaccine, three doses of pentavalent vaccine, and measles vaccine) by 12 months of age constituted the primary outcome and was analysed with log-binomial regression and General Estimating Equations to account for correlation within clusters. This trial is registered with ClinicalTrials.gov, number NCT01878435. FINDINGS: Between Oct 14, 2013, and Oct 17, 2014, we enrolled 2018 caregivers and their infants from 152 villages into the following four groups: control (n=489), SMS only (n=476), SMS plus 75 KES (n=562), and SMS plus 200 KES (n=491). Overall, 1375 (86%) of 1600 children who were successfully followed up achieved the primary outcome, full immunisation by 12 months of age (296 [82%] of 360 control participants, 332 [86%] of 388 SMS only participants, 383 [86%] of 446 SMS plus 75 KES participants, and 364 [90%] of 406 SMS plus 200 KES participants). Children in the SMS plus 200 KES group were significantly more likely to achieve full immunisation at 12 months of age (relative risk 1·09, 95% CI 1·02-1·16, p=0·014) than children in the control group. INTERPRETATION: In a setting with high baseline immunisation coverage levels, SMS reminders coupled with incentives significantly improved immunisation coverage and timeliness. Given that global immunisation coverage levels have stagnated around 85%, the use of incentives might be one option to reach the remaining 15%. FUNDING: Bill & Melinda Gates Foundation.

What drivers will influence global immunizations in the era of grand convergence in global health?

Recent projections suggest that by 2035 global health will look dramatically different than it does today. In what's called a 'grand convergence' the world is likely to be characterized by far more similarities than differences in the prevailing health and medical problems across populations. This manuscript considers how key drivers for vaccine use and uptake might change as a result of the grand convergence and how decisions taken now might anticipate those changes in ways that position immunizations to continue playing an important role in the future.

Maternal determinants of timely vaccination coverage among infants in rural Bangladesh.

BACKGROUND: Timely vaccination, i.e., the receipt of all scheduled vaccinations in an age-appropriate fashion, is critical for the prevention of deadly diseases in infants and achievement of the UN Millennium Development Goal to reduce infant mortality. Infants, especially in rural or underprivileged settings often receive delayed vaccinations leaving them susceptible to vaccine-preventable illnesses early in the first year of life. In this study, we examined rates of timely vaccination among 24,435 infants born in Gaibandha and Rangpur rural districts of Bangladesh from 2001 to 2007. METHODS: Vaccinations due by 14 weeks of age and administered through routine government immunization services were assessed using interviews with enrolled mothers between 11 and 18 weeks postpartum. We created a Timely Vaccination (TV) score to classify infants as vaccinated fully and on schedule (TV=1) or not (TV=0), and used multivariable logistic regression to identify maternal characteristics associated with infant's timely vaccination status. RESULTS: Our results suggest that only 19% of infants in this cohort received scheduled vaccinations on time by 11-18 weeks postpartum. Mothers' engagement in paid employment [OR=1.13, 95% CI: 1.03-1.23], receipt of tetanus toxoid vaccination [OR=1.24, 95% CI: 1.11-1.38], history of antenatal care [OR=1.22, 95% CI: 1.12-1.32], or higher socioeconomic status [OR=1.07, 95% CI: 1.03-1.11] were positively associated with timely vaccination of their infants. Mother's perception of small infant size at birth was negatively associated with timely vaccination [OR=0.89, 95% CI: 0.82-0.97]. CONCLUSION: Timely vaccination coverage of infants in rural Gaibandha and Rangpur districts is extremely low. This analysis identifies important shortcomings associated with the 1-year vaccination benchmark of routine immunization performance and suggests the need for specific interventions based on potential maternal determinants as well as known system and programmatic barriers of timely vaccination among infants in rural Bangladesh.

The feasibility of using mobile-phone based SMS reminders and conditional cash transfers to improve timely immunization in rural Kenya.

BACKGROUND: Demand-side strategies could contribute to achieving high and timely vaccine coverage in rural Africa, but require platforms to deliver either messages or conditional cash transfers (CCTs). We studied the feasibility of using short message services (SMS) reminders and mobile phone-based conditional cash transfers (CCTs) to reach parents in rural Western Kenya. METHODS: In a Health and Demographic Surveillance System (HDSS), mothers with children aged 0-3 weeks old were approached to determine who had access to a mobile phone. SMS reminders were sent three days prior to and on the scheduled day of immunization for 1st (age 6 weeks) and 2nd doses (age 10 weeks) of DTP-HepB-Hib (Pentavalent) vaccine, using open-source Rapid SMS software. Approximately $2.00 USD was sent as cash using mPESA, a mobile money transfer platform (2/3 of mothers), or airtime (1/3 of mothers) via phone if the child was vaccinated within 4 weeks of the scheduled date. Follow-up surveys were done when children reached 14 weeks of age. RESULTS: We approached 77 mothers; 72 were enrolled into the study (26% owned a phone and 74% used someone else's). Of the 63 children with known vaccination status at 14 weeks of age, 57 (90%) received pentavalent1 and 54 (86%) received pentavalent2 within 4 weeks of their scheduled date. Of the 61 mothers with follow-up surveys administered at 14 weeks of age, 55 (90%) reported having received SMS reminders. Of the 54 women who reported having received SMS reminders and answered the CCT questions on the survey, 45 (83%) reported receiving their CCT. Most (89%) of mothers in the mPESA group obtained their cash within 3 days of being sent their credit via mobile phone. All mothers stated they preferred CCTs as cash via mobile phone rather than airtime. Of the 9 participants who did not vaccinate their children at the designated clinic 2(22%) cited refusals by husbands to participate in the study. CONCLUSION: The data show that in rural Western Kenya mobile phone-based strategies are a potentially useful platform to deliver reminders and cash transfers. Follow-up studies are needed that provide evidence for the effectiveness of these strategies in improving vaccine coverage and timeliness.

Cost-effectiveness and economic benefits of vaccines in low- and middle-income countries: a systematic review.

BACKGROUND: Public health interventions that prevent mortality and morbidity have greatly increased over the past decade. Immunization is one of these preventive interventions, with a potential to bring economic benefits beyond just health benefits. While vaccines are considered to be a cost-effective public health intervention, implementation has become increasingly challenging. As vaccine costs rise and competing priorities increase, economic evidence is likely to play an increasingly important role in vaccination decisions. METHODS: To assist policy decisions today and potential investments in the future, we provide a systematic review of the literature on the cost-effectiveness and economic benefits of vaccines in low- and middle-income countries from 2000 to 2010. The review identified 108 relevant articles from 51 countries spanning 23 vaccines from three major electronic databases (Pubmed, Embase and Econlit). RESULTS: Among the 44 articles that reported costs per disability-adjusted life year (DALY) averted, vaccines cost less than or equal to $100 per DALY averted in 23 articles (52%). Vaccines cost less than $500 per DALY averted in 34 articles (77%), and less than $1000 per DALY averted in 38 articles (86%) in one of the scenarios. 24 articles (22%) examined broad level economic benefits of vaccines such as greater future wage-earning capacity and cost savings from averting disease outbreaks. 60 articles (56%) gathered data from a primary source. There were little data on long-term and societal economic benefits such as morbidity-related productivity gains, averting catastrophic health expenditures, growth in gross domestic product (GDP), and economic implications of demographic changes resulting from vaccination. CONCLUSIONS: This review documents the available evidence and shows that vaccination in low- and middle-income countries brings important economic benefits. The cost-effectiveness studies reviewed suggest to policy makers that vaccines are an efficient investment. This review further highlights key gaps in the available literature that would benefit from additional research, especially in the area of evaluating the broader economic benefits of vaccination in the developing world.

Benefits and effectiveness of administering pneumococcal polysaccharide vaccine with seasonal influenza vaccine: an approach for policymakers.

For the influenza pandemic of 2009-2010, countries responded to the direct threat of influenza but may have missed opportunities and strategies to limit secondary pneumococcal infections. Delivering both vaccines together can potentially increase pneumococcal polysaccharide vaccine (PPV23) immunization rates and prevent additional hospitalizations and mortality in the elderly and other high-risk groups. We used PubMed to review the literature on the concomitant use of PPV23 with seasonal influenza vaccines. Eight of 9 clinical studies found that a concomitant program conferred clinical benefits. The 2 studies that compared the cost-effectiveness of different strategies found concomitant immunization to be more cost-effective than either vaccine given alone. Policymakers should consider a stepwise strategy to reduce the burden of secondary pneumococcal infections during seasonal and pandemic influenza outbreaks.

The definition of pneumonia, the assessment of severity, and clinical standardization in the Pneumonia Etiology Research for Child Health study.

To develop a case definition for the Pneumonia Etiology Research for Child Health (PERCH) project, we sought a widely acceptable classification that was linked to existing pneumonia research and focused on very severe cases. We began with the World Health Organization's classification of severe/very severe pneumonia and refined it through literature reviews and a 2-stage process of expert consultation. PERCH will study hospitalized children, aged 1-59 months, with pneumonia who present with cough or difficulty breathing and have either severe pneumonia (lower chest wall indrawing) or very severe pneumonia (central cyanosis, difficulty breastfeeding/drinking, vomiting everything, convulsions, lethargy, unconsciousness, or head nodding). It will exclude patients with recent hospitalization and children with wheeze whose indrawing resolves after bronchodilator therapy. The PERCH investigators agreed upon standard interpretations of the symptoms and signs. These will be maintained by a clinical standardization monitor who conducts repeated instruction at each site and by recurrent local training and testing.

Specimen collection for the diagnosis of pediatric pneumonia.

Diagnosing the etiologic agent of pneumonia has an essential role in ensuring the most appropriate and effective therapy for individual patients and is critical to guiding the development of treatment and prevention strategies. However, establishing the etiology of pneumonia remains challenging because of the relative inaccessibility of the infected tissue and the difficulty in obtaining samples without contamination by upper respiratory tract secretions. Here, we review the published and unpublished literature on various specimens available for the diagnosis of pediatric pneumonia. We discuss the advantages and limitations of each specimen, and discuss the rationale for the specimens to be collected for the Pneumonia Etiology Research for Child Health study.

Monitoring the introduction of pneumococcal conjugate vaccines into West Africa: design and implementation of a population-based surveillance system.

Routine use of pneumococcal conjugate vaccines (PCVs) in developing countries is expected to lead to a significant reduction in childhood deaths. However, PCVs have been associated with replacement disease with non-vaccine serotypes. We established a population-based surveillance system to document the direct and indirect impact of PCVs on the incidence of invasive pneumococcal disease (IPD) and radiological pneumonia in those aged 2 months and older in The Gambia, and to monitor changes in serotype-specific IPD. Here we describe how this surveillance system was set up and is being operated as a partnership between the Medical Research Council Unit and the Gambian Government. This surveillance system is expected to provide crucial information for immunisation policy and serves as a potential model for those introducing routine PCV vaccination in diverse settings.

The future of immunisation policy, implementation, and financing.

Vaccines have already saved many lives and they have the potential to save many more as increasingly elaborate technologies deliver new and effective vaccines against both infectious diseases--for which there are currently no effective licensed vaccines--such as malaria, tuberculosis, and HIV and non-infectious diseases such as hypertension and diabetes. However, these new vaccines are likely to be more complex and expensive than those that have been used so effectively in the past, and they could have a multifaceted effect on the disease that they are designed to prevent, as has already been seen with pneumococcal conjugate vaccines. Deciding which new vaccines a country should invest in requires not only sound advice from international organisations such as WHO but also a well informed national immunisation advisory committee with access to appropriate data for local disease burden. Introduction of vaccines might need modification of immunisation schedules and delivery procedures. Novel methods are needed to finance the increasing number of new vaccines that have the potential to save lives in countries that are too poor to afford them. Here, we discuss some options.

During the 'decade of vaccines,' the lives of 6.4 million children valued at $231 billion could be saved.

Governments constantly face the challenge of determining how much they should spend to prevent premature deaths and suffering in their populations. In this article we explore the benefits of expanding the delivery of life-saving vaccines in seventy-two low- and middle-income countries, which we estimate would prevent the deaths of 6.4 million children between 2011 and 2020. We present the economic benefits of vaccines by using a "value of statistical life" approach, which is based on individuals' perceptions regarding the trade-off between income and increased risk of mortality. Our analysis shows that the vaccine expansion described above corresponds to $231 billion (uncertainty range: $116-$614 billion) in the value of statistical lives saved. This analysis complements results from analyses based on other techniques and is the first of its kind for immunizations in the world's poorest countries. It highlights the major economic benefits made possible by improving vaccine coverage.

Estimated economic benefits during the 'decade of vaccines' include treatment savings, gains in labor productivity.

In 2010 the Bill & Melinda Gates Foundation announced a $10 billion commitment over the next ten years to increase access to childhood vaccines in the world's poorest countries. The effort was labeled the "Decade of Vaccines." This study estimates both the short- and long-term economic benefits from the introduction and increased use of six vaccines in seventy-two of the world's poorest countries from 2011 to 2020. Increased rates of vaccination against pneumococcal and Haemophilus influenzae type b pneumonia and meningitis, rotavirus, pertussis, measles, and malaria over the next ten years would save 6.4 million lives and avert 426 million cases of illness, $6.2 billion in treatment costs, and $145 billion in productivity losses. Monetary estimates based on this type of analysis can be used to determine the return on investment in immunization from both the international community and local governments, and they should be considered in policy making.

Rethinking the benefits and costs of childhood vaccination: the example of the Haemophilus influenzae type b vaccine.

Economic evaluations of health interventions, such as vaccinations, are important tools for informing health policy. Approaching the analysis from the appropriate perspective is critical to ensuring the validity of evaluation results for particular policy decisions. Using the example of cost-benefit analysis (CBA) of Haemophilus influenzae type b (Hib) vaccination, we demonstrate that past economic evaluations have mostly adopted narrow evaluation perspectives, focusing primarily on health gains, health-care cost savings, and reductions in the time costs of caring, while usually ignoring other important benefits including outcome-related productivity gains (improved economic productivity due to prevention of mental and physical disabilities), behavior-related productivity gains (economic growth due to fertility reductions as vaccination improves child survival), and community externalities (herd immunity and prevention of antibiotic resistance). We further show that potential cost reductions that could be attained through changes in the delivery of the Hib vaccine have also generally been ignored in economic evaluations. Future economic evaluations of childhood vaccinations should take full account of benefits and costs, so that policymakers have sufficient information to make well-informed decisions on vaccination implementation.