Key points

Introduction

Pneumonia and diarrhea are the 2 leading infectious causes of death in children younger than 5 years worldwide, responsible for more than 1.5 million deaths annually. They accounted for 15% and 9%, respectively, of the 6.3 million deaths in children younger than 5 years that occurred globally in 2013. There are an estimated 1.7 billion episodes annually of diarrhea and more than 150 million episodes of pneumonia. Marked decreases in mortality due to pneumonia and diarrhea over the past decade have been noted. Between 2000 and 2013, there was an estimated 44% reduction in deaths due to pneumonia and 54% reduction in deaths due to diarrhea among children younger than 5 years. Despite this, pneumonia and diarrhea continue to cause significant morbidity and mortality in young children worldwide, particularly those in Asia and Africa. Thus, efforts at optimizing prevention and control are needed. In this review, the authors describe strategies aimed at preventing and controlling childhood pneumonia and diarrhea.

Introduction

Pneumonia and diarrhea are the 2 leading infectious causes of death in children younger than 5 years worldwide, responsible for more than 1.5 million deaths annually. They accounted for 15% and 9%, respectively, of the 6.3 million deaths in children younger than 5 years that occurred globally in 2013. There are an estimated 1.7 billion episodes annually of diarrhea and more than 150 million episodes of pneumonia. Marked decreases in mortality due to pneumonia and diarrhea over the past decade have been noted. Between 2000 and 2013, there was an estimated 44% reduction in deaths due to pneumonia and 54% reduction in deaths due to diarrhea among children younger than 5 years. Despite this, pneumonia and diarrhea continue to cause significant morbidity and mortality in young children worldwide, particularly those in Asia and Africa. Thus, efforts at optimizing prevention and control are needed. In this review, the authors describe strategies aimed at preventing and controlling childhood pneumonia and diarrhea.

Global burden

The World Health Organization (WHO) estimates that each year, there are greater than 150 million cases of pneumonia in children younger than 5 years, including 20 million cases that require hospitalization. Most of the morbidity and mortality worldwide due to pneumonia occur in low- and middle-income countries (LMICs). Using vital registration and verbal autopsy data, the Child Health Epidemiology Reference Group estimated the total number of pneumonia deaths in children younger than 5 years worldwide to be approximately 935,000. Up to half of the deaths from pneumonia occurred in sub-Saharan Africa and approximately a third in Southern Asia. There were regional variations in the percentage of deaths attributable to pneumonia: from 5% of deaths in developed regions to 16% of deaths in sub-Saharan Africa. Most notably, 96% of episodes of pneumonia, and 99% of deaths from pneumonia, take place in LMICs.

Although second to pneumonia in mortality burden, diarrheal illnesses occur more frequently. Children in LMICs who are younger than 5 years have an average of 2.9 episodes per year of diarrhea, accounting for nearly 1.7 billion episodes of diarrhea yearly, resulting in more than 578,000 deaths per year. The peak age of diarrheal disease incidence is during , from 6 to 11 months of age ; most of the deaths due to diarrhea occur in the first 2 years of life.

Causes of pneumonia

Because of logistical and ethical limitations, direct sampling of infected lung tissue is not commonly performed; our knowledge of the causes of pediatric pneumonia is based mostly on studies using various indirect sampling methods, such as nasopharyngeal swab, blood cultures, or induced sputum ( Box 1 ). A large 10-country study conducted more than 25 years ago revealed respiratory viruses, especially respiratory syncytial virus (RSV), to be the leading cause of childhood pneumonia, with the most common bacterial causes being Streptococcus pneumoniae , followed closely by Haemophilus influenzae . More contemporary studies have continued to identify RSV as the most common respiratory virus responsible for pneumonia worldwide, though improved molecular diagnostics have also implicated rhinovirus, influenza virus, human metapneumovirus, and adenovirus, with significant geographic variations. Although viruses are detected in most cases of pneumonia, given the high frequency of copathogen isolation, their contribution to severe pneumonia is unclear. Notably, a recent study from Gambia involving lung aspirates in children younger than 5 years with severe pneumonia demonstrated S pneumoniae to be present in 91% of lung aspirates, followed by H influenzae at 23%, and Staphylococcus aureus in 6%; in this small study, no viruses were present in greater than 5% of samples. The authors have also shown that the causes of pneumonia in children with severe acute malnutrition differ from that of well-nourished children, with gram-negative bacteria being more common in those malnourished. The Pneumonia Etiology Research for Child Health study, a 7-country case-control study of severe pneumonia in hospitalized children and a similar study using the Global Approach to Biological Research, Infectious Diseases, and Epidemics in Low-Income Countries network in 9 countries are both ongoing and are expected to provide more updated and comprehensive data regarding the causes of pneumonia in LMICs.

Causes of diarrhea

The etiologic determination of diarrheal disease and deaths are limited by the large number of pathogens present in the stool of children in LMICs, even during periods of relative health. For example, Bangladeshi infants without evidence of diarrhea had an average of 4.3 enteropathogens detected, compared with an average of 0.5 in infants from the United States. The past decade saw the completion of 2 large multi-country studies using modern molecular diagnostic tools to provide insight into the cause and consequences of acute infectious diarrhea in children of LMICs (see Box 1 ).

The Global Enterics Multicenter Study, a 3-year cross-sectional case-control study, investigated the cause and incidence of moderate to severe diarrhea of more than 22,000 children at 7 sites in Africa and Asia. It found that most cases were due to 4 pathogens: rotavirus, Cryptosporidium , Shigella spp, and heat-stable toxin-producing enterotoxigenic Escherichia coli (ST-ETEC). Rotavirus was the top attributable cause of diarrhea in children younger than 24 months of age, and Shigella was the top cause for those 2 to 5 years old. Other notable pathogens among the top causes included Vibrio cholerae, Campylobacter jejuni, adenovirus 40/41, and Aeromonas spp ; but there was substantial geographic variation.

The Interactions of Malnutrition and Enteric Infections: Consequences for Child Health and Development project is a multi-site cohort that involved intensive surveillance for diarrhea and monthly asymptomatic stool collection from children, from birth to 24 months. Investigators found norovirus, rotavirus, Campylobacter, astrovirus, and Cryptosporidium to be the top causes of diarrhea in the first year of life, with the addition of Shigella spp in the second year. These studies combine to demonstrate that bacterial, viral, and protozoal causes all play important roles in childhood diarrhea.

Public health measures for prevention of childhood pneumonia and diarrhea

Pneumonia and diarrheal disease share several risk factors, including malnutrition, poor hygiene, poor socioeconomic status, lower education status, and lack of breastfeeding. The authors have shown in a systematic review that young children with severe malnutrition are at an increased risk of death from pneumonia and have high rates of death even after hospital discharge. The authors have reported that severe acute malnutrition is associated with concurrent pneumonia and diarrhea; children with both illnesses have a greater than 80-fold increased risk of death compared with those with diarrhea alone. Inpatient nutritional rehabilitation of malnourished children has been demonstrated to dramatically reduce case fatality rates, especially when implemented in units with standardized protocols and trained staff. Interventions used in such units include appropriate rehydration therapy, targeted feeding, empiric antibiotics directed against gram-negative organisms, vitamin A supplementation, and management of hypoglycemia. Of the nutritional supplementation interventions studied, preventative zinc supplementation has been shown to reduce the incidence of diarrhea and pneumonia by more than 20% and all-cause mortality by 18% among children 12 to 59 months of age. Additionally, exclusive breastfeeding of infants reduces deaths due to both pneumonia and diarrhea, especially in the first 6 months of life.

Diarrheal diseases have long been associated with ingestion of contaminated food and water. With the increasing recognition of viral causes of both pneumonia and diarrhea that may be transmitted person to person, efforts have also focused on strategies to improve water, sanitation, and hygiene (WASH) at the household level. Interventions, such as the encouragement of hand washing with soap, improving water quality, and proper disposal of excreta, have all been demonstrated to reduce diarrheal burden. There are limited data behind the prevention of pneumonia through WASH interventions, though a recent estimate suggested that hand washing with soap could prevent more than 600,000 deaths from diarrhea and pneumonia combined.

The aforementioned preventive and protective measures form the backbone of public health efforts for children in LMICs. The marked reductions in mortality in the past decade have been in large part due to such nonspecific interventions. The remainder of this review focuses on the use of preventive vaccines for diarrheal and respiratory pathogens. Conjugate vaccines for H influenza type B and S pneumoniae and rotavirus vaccines have significantly decreased the burden of pneumonia and diarrhea in high-income countries (HICs). The uptake of these vaccines and the potential development of new vaccines are expected to further enhance the reductions in childhood mortality in LMICs.

Vaccines to prevent childhood pneumonia

Children younger than 2 years bear a large burden of bacterial respiratory infections, and polysaccharide antigens are poorly immunogenic in such children. The development of polysaccharide-protein conjugate vaccines has dramatically enhanced the prevention of pneumonia worldwide. Conjugate vaccines take advantage of a carrier protein to elicit a T cell–dependent antibody response to bacterial polysaccharide antigens. Conjugate vaccines against S pneumoniae and H influenzae type B, the top 2 causes of bacterial lower respiratory tract infections worldwide, are highly effective. Vaccines against the influenza virus are available but not widely used in LMICs; no vaccine is yet available against RSV, the most common cause of viral pneumonia.

Vaccines against Streptococcus pneumoniae (pneumococcus)

The development of a pneumococcal vaccine that is effective in young children has been of great benefit to children worldwide. Available pneumococcal vaccines include 7-, 9-, 10-, 11-, 13-, and 15-valent conjugate vaccines and a 23-valent polysaccharide (nonconjugated) vaccine. Currently used conjugate vaccines worldwide include the 13-valent conjugate vaccines (pneumococcal conjugate vaccine 13 [PCV13]), which use CRM197 (diphtheria toxin mutant) as a carrier, and the 10-valent conjugate (PCV10), which uses 3 proteins: the diphtheria toxoid, the tetanus toxoid, and nontypeable H influenzae protein D.

PCVs prevent invasive pneumococcal disease (IPD), including meningitis, sepsis, and otitis media as well as pneumococcal pneumonia. In a meta-analysis that included 6 randomized controlled trials conducted in children younger than 2 years in Africa, the United States, Philippines, and Finland, the pooled efficacy of PCV7 was 80% for vaccine-serotype–associated IPD and 58% for all-serotype IPD. The effect of PCV7 on pneumonia was lower: the pooled efficacy for radiologically defined pneumonia was 27% and for clinical pneumonia 6%. This finding likely reflects the importance of other pathogens in addition to S pneumoniae in childhood pneumonia. Several studies have suggested additional benefits of PCV beyond prevention of pneumococcal pneumonia in those vaccinated, including prevention of viral-attributed pneumonia, reduction in IPD in older unvaccinated age groups due to herd immunity, and serotype-associated IPD in younger unvaccinated age groups.

The introduction of PCVs has had substantial impact on the burden of pneumococcal disease in every country where it has been widely adopted. The impact may be higher among young children in LMICs than those in HICs. A meta-analysis of serotypes causing IPD worldwide estimated that 49% to 88% of pneumococcal deaths in Africa and Asia are caused by serotypes covered in in PCV10 and PCV13. Since 2006, the WHO has recommended that PCV be included in all routine immunization programs.

The uptake of PCV in LMICs has been limited, however, in large part because of the high cost of PCV. In response to this, the Global Alliance for Vaccines and Immunization (GAVI) has worked to accelerate the introduction of PCVs in LMICs by working with manufacturers to commit supply and ensuring predictable vaccine pricing for the PCV10 and PCV13 vaccines. In total, more than 125 countries, including 50 GAVI-supported countries, have introduced universal PCV to their immunization programs, though greater than 50% of the world’s infants still do not have access to PCV, most notably many of those living in Asian LMICs.

Large randomized studies of 10- and 13-valent PCVs have not been conducted in LMICs, and their effectiveness is inferred from comparable immunogenicity as PCV7. With the use of PCV7, surveillance studies in HICs demonstrated a plateau in the reduction of pneumococcal infection rates in some populations due to serotype. Notably, there are more than 90 pneumococcal serotypes. Although the factors that drive the epidemiology of S pneumoniae are complex and poorly understood, further serotype replacement seems likely. Vaccines aimed at inducing serotype-independent immunity are in early stages of development and hold promise of not being subject to serotype replacement.