Measles, pertussis, diphtheria epidemics, and bacterial pneumonia have historically taken a major toll on young children.1,2 Acute respiratory infections (ARI) are still a primary cause of hospitalization and outpatient visits in children aged <5 years even in wealthy countries representing a major burden both to families and nations.3,4
Pneumonia is the most serious ARI, caused by a wide range of bacteria and viruses.5–7 In wealthy countries, approximately 10 to 15 pneumonia cases/1000 children are diagnosed per year, with hospital admission in the 1 to 4/1000 range.8 The estimated risk among children aged <5 years for developing pneumonia is 0.03 episodes per child year in wealthy countries and 0.29 episodes per child year in resource-poor countries.9,10 Severe pneumonia remains a major challenge to the survival of children globally; it is estimated to be a cause of death for 2.1 million children aged <5 years annually, predominantly in resource-poor countries.11–13 HIV-infected children are much more prone to bacterial pneumonia, further increasing this burden.14 Consequences of childhood pneumonia and its significant morbidity and mortality are preventable by the optimized use of vaccines against measles and pertussis, and expanding the use of H.influenzae type b and pneumococcal conjugate vaccines (PCVs).15S. pneumoniae is a major pneumonia pathogen worldwide.
The 23-valent pneumococcal polysaccharide vaccine (PPV23), licensed for use in 1983 in the Unites States (US), prevents invasive pneumococcal diseases (IPD). PPV23 is recommended by the Advisory Committee on Immunization Practices for use in the elderly16 and children aged ≥2 years with high-risk medical conditions.17 However, PPV23 uptake has been suboptimal and its effectiveness against non bacteremic pneumonia remains controversial.18,19 In randomized controlled clinical trials, PCV prevented not only IPD, but also pneumonia.20,21,21a Routine infant immunization with a heptavalent PCV (PCV-7) initiated in 2000 has been associated with a substantial decline in the rate of IPD22,23 and pneumonia in the US.21
BACTERIAL RESPIRATORY TRACT DISEASES IN THE PAST
Respiratory infections continue to be common worldwide. Despite endemic high morbidity and mortality from pneumonia globally, it is the influenza pandemics such as that which occurred in 191824 coupled with a high prevalence of pneumococcal infections that is most striking. Past attempts at developing pneumococcal vaccines include a 4-valent vaccine which was tested in 1945 and licensed for use in 1946.25 The discovery of and treatment with penicillin and derivatives resulted in a vast reduction in respiratory infections among adults and children.26–28 Along with antibiotics, vaccines became available and “well-baby”–or “well-child”–clinics were established in Europe. In addition to vaccinations, food, water and sanitation were more carefully controlled, yielding a dramatic improvement in health in the 20th century, in those countries with moderate and high economies, but not in countries with poor economies.13
Causes of Global Child Mortality: Pneumonia the Forgotten Killer9
Pneumonia is the major cause of childhood mortality. Severe pneumonia is often of bacterial origin.9 Common bacterial causes of ARI in young children are S. pneumoniae, H.influenzae, Bordetella pertussis, and Staphylococcus aureus,29 less frequent causes are Chlamydophilia psittaci, Coxiella burnetii, Legionella pneumophila, Klebsiella pneumoniae and nontyphoidal Salmonella.30,31 Among these, S. pneumoniae is the leading bacterial cause of pneumonia.8Figure 1 shows a classic representation of the distribution of pneumococcal diseases. Invasive pneumococcal diseases (IPD) are sometimes very severe and can be associated with death and disability, but these invasive conditions are relatively rare when compared with other diseases caused by pneumococci, such as pneumonia and acute otitis media.
WHO and UNICEF indicate that pneumonia is the forgotten killer of children,9 especially in resource-poor countries, and in remote areas where access to basic healthcare is problematic. Pneumonia is one of the main diseases the burden of which needs to be tackled to reach the Millennium Development Goals set for increasing the survival of children worldwide.33
Despite the WHO ARI case-management program that was initiated in the early 1990s, and later integrated into a program of management of childhood illness, pneumonia outside of the neonatal period remains the leading cause of death in children globally. It is responsible for about 19% of the more than 10.5 million annual deaths that occur in childhood (Fig. 2). 13 This is probably an underestimate of the true mortality due to pneumonia.11
The Child Health Epidemiology Reference Group13 reviewed more than 17,000 research articles and other sources of information to establish causes of child mortality and morbidity worldwide. Africa plus South East Asia contribute about 70% of the 10.5 million global deaths (yearly average for 2000–2003 in the 6 WHO regions) in children aged <5 years (Fig. 3). Together with the East Mediterranean region, these are the regions with the preponderance of childhood mortality and with nearly identical mortality (19%–21%) attributed to pneumonia in children aged <5 years. In more wealthy countries (the Americas, Western Europe, and the Western Pacific region), the proportion of deaths attributed to pneumonia is close to 12%.13 Moreover, the estimate of about 1.9 million deaths due to pneumonia is probably an underestimate,11 as it is based on a single-cause of death model. Comorbidities were not accounted for in this model thereby ignoring an estimated 300,000 to 600,000 deaths due to neonatal sepsis which might be owing to pneumonia9; consequently the inclusion of pneumonia as a comorbidity contributing to death in a multicause model results in the more likely estimate of about 2.1 million deaths annually.3 This estimate is also slightly higher because it includes more recent studies, especially from sub-Saharan Africa and South East Asia. Furthermore, in sub-Saharan Africa these estimates have been made outside of the framework of HIV; in South Africa, 50% of all children hospitalized with pneumonia are HIV infected, although only 5% of the population is HIV infected.14 Ninety percent of all children who die of pneumonia in South Africa are HIV infected, a figure not dissimilar from many other sub-Saharan African countries.
Global Distribution of Childhood Pneumonia Mortality
The most important rates of pneumonia deaths occur in Africa and in the most populated part of the world, ie, Asia9,34 (Fig. 3). The study of deaths attributed to pneumonia among different countries shows a direct association between pneumonia mortality and the mortality among children aged <5 years. The lower the mortality for age <5, the lower the proportion of deaths due to pneumonia.11 In countries with a <5 mortality of 5/1000, the percentage of deaths due to pneumonia is about 11%. In countries where the <5 year childhood mortality is about 50/1000, 23% of deaths are attributed to pneumonia. In countries with very low mortality, the proportion of deaths due to pneumonia might be as low as 3% to 4% according to recent analyses.
Mortality Patterns of Pneumonia
The mortality patterns of pneumonia in resource-poor countries currently are not very different from what they were in wealthy countries in the recent past. Dowell et al examined the trends in mortality from pneumonia in the US from 1939 to 1996.27 There were 2 eras during which mortality from pneumonia dramatically declined (97%) and this decrease was much greater than the reduction in mortality from other causes (82%). During 1944–1950 the discovery and introduction of penicillin and its widespread use for the treatment of community-acquired pneumonia took place. Moreover, during 1966–1982 there was improved access to healthcare through the expansion of the Medicaid program to the very poor, although there were probably many other environmental and social changes that took place during this period. The narrowing of the differences in mortality among Caucasians and African Americans during these decades35 suggested that basic access to antibiotics and healthcare can influence mortality rates from pneumonia.
A meta-analysis examined the effect of the implementation of the WHO case management strategy for pneumonia in resource-poor countries. A backbone of the strategy is the appropriate early treatment with antibiotics of children with suspected pneumonia. In those countries where the intervention was implemented at a community level, all-cause mortality was reduced by 24% and pneumonia mortality by 36% among children aged <5 years.36
Global Distribution of Childhood Pneumonia Morbidity
Rudan et al10 analyzed the data for a 30-year period from 28 studies from which they were able to estimate morbidity related to pneumonia and the incidence of pneumonia in children in resource-poor and wealthy countries. South America produced a broad representation, while in Africa and South East Asia most of the studies were performed in a limited number of countries in highly researched areas.
The median incidence of pneumonia in these 28 studies was about 0.29 episodes per child year. In the majority of countries in Africa and South East Asia, the rate of pneumonia is 0.3 to 0.4 episode per child year. In the middle-income countries the incidence ranges from less than 0.1 episodes per child year to 0.11 to 0.20 episodes per child year in South America. For wealthy countries the estimate was about 0.03 episodes per child year. When adjusting for the demographics of populations across the world, it was found that each year more than 95% of the 155 million reported episodes of pneumonia occur in resource-poor countries, while 4 million episodes of pneumonia occur in wealthy countries. The proportion of severe cases of pneumonia (those that require hospitalization) was estimated to be 5.9% to 16.8%, translating to approximately 15 million cases per year.10
Risk Factors That Affect Pneumonia Incidence
To make these mean estimates relevant to individual countries and their healthcare planners and implementers one also needs to consider the prevalence of different risk factors that contribute to the development of childhood pneumonia. Malnutrition, low birth weight, lack of measles immunization, lack of exclusive breast-feeding, indoor air pollution, and overcrowding have been identified as the main risk factors for developing pneumonia.9,15,37
The 2007 WHO estimates15,38 suggest that many bacterial and viral respiratory infections, such as diphtheria, measles and Hib infections could have been prevented with more extensive vaccination. Effective vaccines against S. pneumoniae could prevent a substantial number of child deaths per year. Despite the substantial burden of pneumonia in poor and middle income countries, the access to life-saving vaccines is limited. Resource-poor countries have limited access to most vaccines.9 The recognition of this gap in vaccination has resulted in an action by the Global Alliance of Vaccines and Immunizations (GAVI), an alliance of industry and governments in wealthy and poor countries alike, civil societies, and foundations committed to increasing access of resource-poor countries to life-saving vaccines. Seventy-two countries have already met the eligibility criterion for support, of a national gross national income below US $1000.39 The number of countries that introduced Hib vaccine in their national program was increased from 28 in 1997 to 112 in 2007, in part owing to the support of GAVI. In spite of these progresses, much more needs to be done and now GAVI is supporting the introduction of PCV to eligible countries. An emerging problem is the growing number of countries that are too wealthy to meet the GAVI eligibility criterion, but are too poor to purchase the new vaccines without external support. This gap has only very recently been recognized; the GAVI eligibility criteria are soon to be reviewed and hopefully revised as no functioning international mechanisms are in place to secure the new vaccines for children living in these countries.
There are 2 types of pneumococcal vaccines currently available, Table 1 summarizes some of the differences between the conjugate vaccine and the polysaccharide pneumococcal vaccines. The older pure polysaccharide vaccine is not immunogenic for most serotypes in children aged <2 years.40 In addition, although pneumococcal polysaccharide vaccine can prevent invasive pneumococcal disease, its effectiveness against nonbacteremic pneumonia remains controversial. In contrast, the conjugated polysaccharides have the ability to induce a T cell-mediated immune response and are therefore considered to be immunogenic in this population.41 An additional advantage of the conjugate vaccine is that it can induce immune memory and facilitate a booster response and, thus, can induce long-term protection.40 One of the most important features of this vaccine is that it has the ability to reduce the nasopharyngeal colonization by pneumococcal vaccine serotypes.40,42 Nasopharyngeal colonization is important in the transmission of the bacteria from one person to another43 and, by interfering with pneumococcal colonization this vaccine has the ability to interrupt the transmission of the vaccine serotypes and protect nonvaccinated people. This indirect protection is also called “herd immunity.”44
Pneumococcal Conjugate Vaccines
A 7-valent PCV has been licensed in approximately 90 countries since the year 2000.45 Protection against invasive pneumococcal disease, pneumonia and otitis media has been demonstrated in clinical trials with differing formulations of this conjugate vaccine.46–48 Another PCV, containing 3 additional pneumococcal serotypes and using a different carrier protein, the protein d–a protein isolated from a nontypeable H.influenzae strain–for 8 of the ten serotypes has been recently licensed in Australia, Canada, EU, and few other countries, and a 13-valent PCV is in advanced stages of licensure.49
Impact of PCV on Pneumonia in the United States
In the US, as in many parts of the world, pneumonia is the leading infectious cause of death in children and an important cause of hospitalizations. Previous estimates suggest that S. pneumoniae, considered as the most common bacterial cause of childhood pneumonia, accounts for 17% to 44% of pneumonia hospitalizations in children.50 A US study examined hospitalization data from the Nationwide Inpatient Sample, the largest US inpatient database.21,51 In this study, changes in the rates of all-cause pneumonia and pneumococcal pneumonia hospitalizations after introduction of PCV-7 were evaluated. Using a time-series analysis, trends observed before introduction of PCV-7 (1997–1999) were projected as if no vaccination had been initiated. These projected trends were then compared with those observed at the end of 2004. The PCV-7 vaccine was licensed in the US in 2000, but its use was not substantial until late in that year; thus, 2000 was considered a transition year and excluded from the analyses. The rates for both all-cause pneumonias and pneumococcal pneumonia were substantially lower after the introduction of PCV-7 than before its use. Rates of dehydration hospitalization, used as controls, showed no significant differences. Rates of pneumococcal pneumonia admissions also decreased in children aged 2 to 4 years and adults aged 18 to 39 years, and all-cause pneumonia admissions declined in the latter group.21 The decreased admissions in these older age groups, that were not vaccinated, may represent “herd immunity.”
Impact of PCV on Healthcare Use for Pneumonia
Zhou et al examined data from the Marketscan databases, a large system that collects information from more than 100 insurance companies throughout the US.50 They evaluated the impact of this immunization program in children 0 to 24 months of age, on all-cause pneumonia and on pneumococcal pneumonia hospital admissions and also found substantial decreases in both admission rates 3 years after PCV-7 introduction (2004) compared with pre-PCV-7 (1997–1999) years (Fig. 4). In addition, rates of ambulatory visits for both pneumonia outcomes decreased, suggesting that the decline observed in pneumonia hospitalizations was not due to a change in admission practices. These decreased rates resulted in substantial monetary savings.50
Impact of PCV Introduction on Rates of Community-Acquired Pneumonia
Nelson et al examined data from the Group Health Cooperative databases in Washington State and compared pneumonia incidence during periods before (1998–2000), during (2001–2002), and after introduction of PCV-7 (2003–2004).20 The investigators identified pneumonia cases using ICD9 coding and confirmed pneumonia cases by review of chest radiograph reports or hospitalization records, when they were available. They observed that among infants aged <1 year, there was a significant 26% reduction in the risk of confirmed outpatient pneumonia in the period after PCV-7 introduction compared with introduction period. Moreover, in this age group, there was a nonstatistically significant 40% reduction in the rate of confirmed hospitalized pneumonia after PCV-7 introduction compared with the introduction period.
These 3 US studies strongly suggest that there is an important effect of the PCV-7 on pneumonia incidence in young children. These changes were temporally associated with the introduction of the PCV-7 and are very similar to what has been observed in invasive diseases. There is some suggestion that these effects could also be found in some older age groups.52
The substantial declines in the rates of pneumonia may have been bigger than initially suggested by the results of individually randomized clinical trials. These estimates suggest the relative importance of the serotypes included in the vaccine before the introduction of the immunization program in the US as support to the importance of the indirect effect of the vaccine.53
The future of bacterial infections depends on several factors including the host (social and nutritional status, existence of HIV infection and other comorbidities combined with poverty, etc), pathogen (potential serotype replacement, variations in serotypes prevalence), environment (influence of indoor and outdoor pollution, of climate changes, etc), and available interventions.
According to the WHO, a new measles aerosol vaccine should be available by 2015.54 Other respiratory virus vaccines, and particularly new RSV and influenza vaccines as well as improved PCVs, protein-based vaccines, and improved pertussis vaccines are also being developed.
Childhood respiratory bacterial infections represent an important factor that impacts morbidity and mortality worldwide. Today, prevention of several causative agents is possible. Although there is a need for further investment in epidemiologic studies, the implementation of proven cost-effective interventions that can save millions of lives appears both feasible and of utmost importance. Affordable, accessible and sustainable interventions are necessary for immediate reductions in childhood mortality, as agreed in the Millennium Development Goals, and vaccines play a critical role in this regard, being a rapidly feasible intervention with early and sustained impact.
The authors thank Dr. Armine Najand (Medical Education Global Solutions, France) for medical writing and Mr. Yann Colardelle (Medical Education Global Solutions, France) for manuscript coordination. GlaxoSmithKline Biologicals provided editorial assistance and sponsored this supplement.
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