Bradford D. Gessner

Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis

Summary Background The global burden of disease attributable to respiratory syncytial virus (RSV) remains unknown. We aimed to estimate the global incidence of and mortality from episodes of acute lower respiratory infection (ALRI) due to RSV in children younger than 5 years in 2005. Methods We estimated the incidence of RSV-associated ALRI in children younger than 5 years, stratified by age, using data from a systematic review of studies published between January, 1995, and June, 2009, and ten unpublished population-based studies. We estimated possible boundaries for RSV-associated ALRI mortality by combining case fatality ratios with incidence estimates from hospital-based reports from published and unpublished studies and identifying studies with population-based data for RSV seasonality and monthly ALRI mortality. Findings In 2005, an estimated 33·8 (95% CI 19·3–46·2) million new episodes of RSV-associated ALRI occurred worldwide in children younger than 5 years (22% of ALRI episodes), with at least 3·4 (2·8–4·3) million episodes representing severe RSV-associated ALRI necessitating hospital admission. We estimated that 66 000–199 000 children younger than 5 years died from RSV-associated ALRI in 2005, with 99% of these deaths occurring in developing countries. Incidence and mortality can vary substantially from year to year in any one setting. Interpretation Globally, RSV is the most common cause of childhood ALRI and a major cause of admission to hospital as a result of severe ALRI. Mortality data suggest that RSV is an important cause of death in childhood from ALRI, after pneumococcal pneumonia and Haemophilus influenzae type b. The development of novel prevention and treatment strategies should be accelerated as a priority. Funding WHO; Bill & Melinda Gates Foundation.

Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis

BACKGROUND The global burden of disease attributable to seasonal influenza virus in children is unknown. We aimed to estimate the global incidence of and mortality from lower respiratory infections associated with influenza in children younger than 5 years. METHODS We estimated the incidence of influenza episodes, influenza-associated acute lower respiratory infections (ALRI), and influenza-associated severe ALRI in children younger than 5 years, stratified by age, with data from a systematic review of studies published between Jan 1, 1995, and Oct 31, 2010, and 16 unpublished population-based studies. We applied these incidence estimates to global population estimates for 2008 to calculate estimates for that year. We estimated possible bounds for influenza-associated ALRI mortality by combining incidence estimates with case fatality ratios from hospital-based reports and identifying studies with population-based data for influenza seasonality and monthly ALRI mortality. FINDINGS We identified 43 suitable studies, with data for around 8 million children. We estimated that, in 2008, 90 million (95% CI 49-162 million) new cases of influenza (data from nine studies), 20 million (13-32 million) cases of influenza-associated ALRI (13% of all cases of paediatric ALRI; data from six studies), and 1 million (1-2 million) cases of influenza-associated severe ALRI (7% of cases of all severe paediatric ALRI; data from 39 studies) occurred worldwide in children younger than 5 years. We estimated there were 28,000-111,500 deaths in children younger than 5 years attributable to influenza-associated ALRI in 2008, with 99% of these deaths occurring in developing countries. Incidence and mortality varied substantially from year to year in any one setting. INTERPRETATION Influenza is a common pathogen identified in children with ALRI and results in a substantial burden on health services worldwide. Sufficient data to precisely estimate the role of influenza in childhood mortality from ALRI are not available. FUNDING WHO; Bill & Melinda Gates Foundation.

Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis.

Summary Background The annual number of hospital admissions and in-hospital deaths due to severe acute lower respiratory infections (ALRI) in young children worldwide is unknown. We aimed to estimate the incidence of admissions and deaths for such infections in children younger than 5 years in 2010. Methods We estimated the incidence of admissions for severe and very severe ALRI in children younger than 5 years, stratified by age and region, with data from a systematic review of studies published between Jan 1, 1990, and March 31, 2012, and from 28 unpublished population-based studies. We applied these incidence estimates to population estimates for 2010, to calculate the global and regional burden in children admitted with severe ALRI in that year. We estimated in-hospital mortality due to severe and very severe ALRI by combining incidence estimates with case fatality ratios from hospital-based studies. Findings We identified 89 eligible studies and estimated that in 2010, 11·9 million (95% CI 10·3–13·9 million) episodes of severe and 3·0 million (2·1–4·2 million) episodes of very severe ALRI resulted in hospital admissions in young children worldwide. Incidence was higher in boys than in girls, the sex disparity being greatest in South Asian studies. On the basis of data from 37 hospital studies reporting case fatality ratios for severe ALRI, we estimated that roughly 265 000 (95% CI 160 000–450 000) in-hospital deaths took place in young children, with 99% of these deaths in developing countries. Therefore, the data suggest that although 62% of children with severe ALRI are treated in hospitals, 81% of deaths happen outside hospitals. Interpretation Severe ALRI is a substantial burden on health services worldwide and a major cause of hospital referral and admission in young children. Improved hospital access and reduced inequities, such as those related to sex and rural status, could substantially decrease mortality related to such infection. Community-based management of severe disease could be an important complementary strategy to reduce pneumonia mortality and health inequities. Funding WHO.

Incidences of vaccine-preventable Haemophilus influenzae type b pneumonia and meningitis in Indonesian children: hamlet-randomised vaccine-probe trial.

BACKGROUND Most studies of Haemophilus influenzae type b (Hib) disease in Asia have found low rates, and few Asian countries use Hib vaccine in routine immunisation programmes. Whether Hib disease truly is rare or whether many cases remain undetected is unclear. METHODS To estimate incidences of vaccine-preventable Hib pneumonia and meningitis among children younger than 2 years in Lombok, Indonesia, during 1998-2002, we undertook a hamlet-randomised, controlled, double-blind vaccine-probe study (818 hamlets). Children were immunised (WHO schedule) with diphtheria, tetanus, pertussis (DTP) or DTP-PRP-T (Hib conjugate) vaccine. Vaccine-preventable disease incidences were calculated as the difference in rates of clinical outcomes between DTP and DTP-PRP-T groups. Analyses included all children who received at least one vaccine dose. FINDINGS We enrolled 55073 children: 28147 were assigned DTP-PRP-T and 26926 DTP. The proportion of pneumonia outcomes prevented by vaccine ranged from less than 0 to 4.8%. Calculated incidences of vaccine-preventable Hib disease (per 10(5) child-years of observation) for outcome categories were: substantial alveolar consolidation or effusion, less than zero (-43 [95% CI -185 to 98]); all severe pneumonia, 264 (95% CI less than zero to 629); all clinical pneumonia, 1561 (270 to 2853); confirmed Hib meningitis, 16 (1.4 to 31); meningitis with cerebrospinal-fluid findings consistent with a bacterial aetiology, 67 (22 to 112); and admission for suspected meningitis or presenting to a clinic with convulsions, 158 (42 to 273). INTERPRETATION Hib vaccine did not prevent the great majority of pneumonia cases, including those with alveolar consolidation. These results do not support a major role for Hib vaccine in overall pneumonia-prevention programmes. Nevertheless, the study identified high incidences of Hib meningitis and pneumonia; inclusion of Hib vaccine in routine infant immunisation programmes in Asia deserves consideration.

Bacterial Meningitis in Burkina Faso: Surveillance Using Field-Based Polymerase Chain Reaction Testing

BACKGROUND In addition to frequent epidemics of group A meningococcal disease, endemic bacterial meningitis due mostly to Neisseria meningitidis, pneumococcus, and Haemophilus influenzae type b is a serious problem in sub-Saharan Africa. The improved ability to identify the etiologic agent in cases of bacterial meningitis will facilitate more rapid administration of precise therapy. METHODS To describe the epidemiology of bacterial meningitis and evaluate the usefulness of field-based polymerase chain reaction (PCR) testing, we implemented population-based meningitis surveillance in Burkina Faso during 2002-2003 by use of PCR, culture, and antigen detection tests. RESULTS Among persons aged 1 month to 67 years, the incidences of meningococcal meningitis, pneumococcal meningitis, and Haemophilus influenzae type b meningitis were 19 cases (n=179), 17 cases (n=162), and 7.1 cases (n=68) per 100,000 persons per year, respectively. Of the cases of meningococcal meningitis, 72% were due to N. meningitidis serogroup W135. Pneumococcal meningitis caused 61% of deaths and occurred in a seasonal pattern that was similar to that of meningococcal meningitis. Of cases of pneumococcal meningitis and N. meningitidis serogroup W135 meningitis, 71% occurred among persons >2 years of age. Most patients, regardless of the etiology of their illness and the existence of an epidemic, received short-course therapy with oily chloramphenicol. Compared with culture as the gold standard, the sensitivity and specificity of PCR in the field were high; this result was confirmed in Burkina Faso and Paris. CONCLUSIONS Precise and rapid identification of etiologic agents is critical for improvement in the treatment and prevention of meningitis, and, thus, PCR should be considered for wider use in Africa. Vaccines against Streptococcus pneumoniae, N. meningitidis (including serogroup W135), and H. influenzae type b all will have a major impact on the bacterial meningitis burden. Antibiotic recommendations need to consider the importance of S. pneumoniae, even during the epidemic season.

Epidemiological and Molecular Characteristics of a Highly Lethal Pneumococcal Meningitis Epidemic in Burkina Faso

BACKGROUND Public health and clinical strategies for meningitis epidemics in sub-Saharan Africa usually assume that Neisseria meningitidis infection causes most disease. METHODS During 24 months from 2002 to 2005, we collected clinical and laboratory information for suspected acute bacterial meningitis cases from 3 districts in Burkina Faso. Streptococcus pneumoniae was identified by culture, polymerase chain reaction, or antigen detection in cerebrospinal fluid. Pneumococcal genotyping was performed on strains using multilocus variable-number tandem repeat typing and multilocus sequence typing. RESULTS Samples of cerebrospinal fluid were collected from 1686 persons; 249 (15%) had S. pneumoniae identified (annual incidence, 14 cases per 100,000 persons). Of these patients, 115 (46%) died, making S. pneumoniae the most commonly identified organism and responsible for two-thirds of deaths due to bacterial meningitis. During the meningitis epidemic season, an average of 38 cases of S. pneumoniae infection were identified each month, compared with an average of 8.7 cases during other months. Of 48 pneumococci that were tested, 21 (44%) were identified as serotype 1, and the remaining 27 (56%) were identified as 15 different serogroups and/or serotypes. Both serotype 1 and other serogroups and/or serotypes were seasonal. The genotypes of serotype 1 isolates were closely related but diversified over the study period and were similar to, but not identical to, the predominant genotypes found previously in Ghana. CONCLUSIONS Intervention strategies during the epidemic season in Burkina Faso (and perhaps elsewhere) must now account for pneumococcal meningitis occurring in an epidemic pattern similar to meningococcal meningitis. Although a serotype 1 clone was commonly isolated, over half of the cases were caused by other serogroups and/or serotypes, and genetic diversification increased over a relatively short period.

Emergence of epidemic Neisseria meningitidis serogroup X meningitis in Togo and Burkina Faso.

Serogroup X meningococci (NmX) historically have caused sporadic and clustered meningitis cases in sub-Saharan Africa. To study recent NmX epidemiology, we analyzed data from population-based, sentinel and passive surveillance, and outbreak investigations of bacterial meningitis in Togo and Burkina Faso during 2006–2010. Cerebrospinal fluid specimens were analyzed by PCR. In Togo during 2006–2009, NmX accounted for 16% of the 702 confirmed bacterial meningitis cases. Kozah district experienced an NmX outbreak in March 2007 with an NmX seasonal cumulative incidence of 33/100,000. In Burkina Faso during 2007–2010, NmX accounted for 7% of the 778 confirmed bacterial meningitis cases, with an increase from 2009 to 2010 (4% to 35% of all confirmed cases, respectively). In 2010, NmX epidemics occurred in northern and central regions of Burkina Faso; the highest district cumulative incidence of NmX was estimated as 130/100,000 during March–April. Although limited to a few districts, we have documented NmX meningitis epidemics occurring with a seasonal incidence previously only reported in the meningitis belt for NmW135 and NmA, which argues for development of an NmX vaccine.

Endemic Iron Deficiency Associated With Helicobacter pylori Infection Among School-Aged Children in Alaska

OBJECTIVES. Rural Alaska Natives have a high prevalence of iron deficiency and Helicobacter pylori infection. The objective of this study was to estimate the prevalence of iron deficiency, iron-deficiency anemia, and active H pylori infection among school-aged children in rural Alaska. METHODS. We enrolled 68% (688) of the 7- to 11-year-old children from 10 predominantly Alaska Native villages in southwestern Alaska. We collected venous blood samples to assess iron deficiency and anemia. Each child was tested for active H pylori infection by 13C-urea breath test (UBT). Evaluated risk factors included age, gender, village of residence, number of household members, number of household members who were younger than 5 years, recent antibiotic use, and household water source. RESULTS. Of 688 enrolled children, iron deficiency was present in 38%, iron-deficiency anemia was present in 7.8%, and H pylori infection by UBT was present in 86%. Iron deficiency was independently associated with living in a household with >6 people and village of residence. H pylori infection by UBT was independently associated with childs age ≥10 years and village of residence. Ninety-one percent of children with iron deficiency had H pylori infection by UBT, and children with active H pylori infection were more likely to be iron deficient than uninfected children. Children with H pylori infection by UBT were also more likely to have iron-deficiency anemia than uninfected children. CONCLUSIONS. In this study of nearly 700 children in 10 different villages in Alaska, we confirmed that the high prevalence of iron deficiency persists among school-aged children. We found that active H pylori infection was independently associated with iron deficiency and iron-deficiency anemia among children in this region. H pylori infection may account for a portion of the iron deficiency and iron-deficiency anemia in rural Alaska and other areas with high prevalences of both conditions. Innovative approaches are critically needed to address the iron deficiency in high prevalence areas such as rural Alaska and most of the developing world.

Effectiveness of Haemophilus influenzae type B conjugate vaccine on prevention of pneumonia and meningitis in Bangladeshi children : A case-control study

Background: Few Asian countries have introduced Haemophilus influenzae type b (Hib) conjugate vaccine because of its cost and uncertainty regarding disease burden. Methods: To estimate the effectiveness of Hib conjugate vaccine in preventing pneumonia and meningitis in children age <2 years, an incident case–control study was conducted in a birth cohort of about 68,000 infants in Dhaka city, Bangladesh. DPT vaccine was systematically replaced by a combined Hib-DPT vaccine in selected immunization centers of the study area. Four matched community- and 2 hospital-controls were randomly selected for each confirmed case of pneumonia and meningitis from the study area. Results: About 35% of the infants received each of the 3 doses of Hib-DPT vaccine. There were 2679 children who had a chest roentgenogram. For 475 children, a radiologist and a pediatrician independently identified substantial alveolar consolidation. Following at least 2 doses of Hib vaccine, the preventable fractions [95% confidence intervals (CI)] using community and hospital controls were 17% (−10% to 38%) and 35% (13% to 52%) respectively. Of these 475 cases, 2 radiologists with the World Health Organization concurred with the findings for 343 patients, yielding preventable fractions of 34% (6% to 53%) and 44% (20% to 61%). Fifteen confirmed Hib meningitis cases were identified; the preventable fractions (95% CI) using community and hospital controls, respectively, were 89% (28% to 100%) and 93% (53% to 100%). Conclusions: The study documented that significant fractions of pneumonia and meningitis in Bangladeshi children age <2 years can be prevented by the Hib conjugate vaccine.

The Rise and Fall of Epidemic Neisseria meningitidis Serogroup W135 Meningitis in Burkina Faso, 2002–2005

BACKGROUND During the period 2001-2002, Burkina Faso reported its first meningitis epidemic due to Neisseria meningitidis (Nm) serogroup W135, prompting concerns that this serogroup would persist as a cause of epidemic disease. METHODS During the period 2002-2005, hospital- and population-based surveillances were conducted in 3 districts in Burkina Faso. Etiology was determined by culture, polymerase chain reaction (PCR), and latex agglutination. Reference laboratories determined phenotype and genotype. RESULTS Of 2004 subjects who received a lumbar puncture, 265 were identified as having Nm, including 93 who had Nm serogroup A (NmA) and 146 who had Nm serogroup W135 (NmW135). Over the study period, the proportion of cases due to NmW135 decreased by >75%, primarily because of decreased occurrence among young children and in a single district. During peak epidemic months, the annualized incidence of NmW135 decreased from 146 cases to <1 case per 100,000 population. All but 2 NmW135 isolates were phenotype W135:2a:P1.5,2 (sequence type [ST]-11 clonal complex). All NmA isolates were phenotype A:4:P1-9 (ST-2859 of the ST-5 clonal complex). We identified 1 isolate from serogroup Y (ST-11 clonal complex), 1 isolate from serogroup X that was similar to strains previously associated with epidemic disease, and 1 isolate from serogroup W135 of the newly described ST-4375 complex. CONCLUSIONS For unknown reasons, serogroup W135 achieved epidemic status, primarily among young children, and then largely disappeared over a short time period. The continued circulation of multiple strains with epidemic potential emphasizes the need for ongoing surveillance and the potential benefit of vaccines that are protective across serogroups.