Causes of ARIs and the Burden of Disease
ARIs in children take a heavy toll on life, especially where medical care is not available or is not sought.
Upper Respiratory Tract Infections
URIs are the most common infectious diseases. They include rhinitis (common cold), sinusitis, ear infections, acute pharyngitis or tonsillopharyngitis, epiglottitis, and laryngitis—of which ear infections and pharyngitis cause the more severe complications (deafness and acute rheumatic fever, respectively). The vast majority of URIs have a viral etiology. Rhinoviruses account for 25 to 30 percent of URIs; respiratory syncytial viruses (RSVs), parainfluenza and influenza viruses, human metapneumovirus, and adenoviruses for 25 to 35 percent; corona viruses for 10 percent; and unidentified viruses for the remainder (Denny 1995). Because most URIs are self-limiting, their complications are more important than the infections. Acute viral infections predispose children to bacterial infections of the sinuses and middle ear (Berman 1995a), and aspiration of infected secretions and cells can result in LRIs.
Acute Pharyngitis
Acute pharyngitis is caused by viruses in more than 70 percent of cases in young children. Mild pharyngeal redness and swelling and tonsil enlargement are typical. Streptococcal infection is rare in children under five and more common in older children. In countries with crowded living conditions and populations that may have a genetic predisposition, poststreptococcal sequelae such as acute rheumatic fever and carditis are common in school-age children but may also occur in those under five. Acute pharyngitis in conjunction with the development of a membrane on the throat is nearly always caused by Corynebacterium diphtheriae in developing countries. However, with the almost universal vaccination of infants with the DTP (diphtheria-tetanus-pertussis) vaccine, diphtheria is rare.
Acute Ear Infection
Acute ear infection occurs with up to 30 percent of URIs. In developing countries with inadequate medical care, it may lead to perforated eardrums and chronic ear discharge in later childhood and ultimately to hearing impairment or deafness (Berman 1995b). Chronic ear infection following repeated episodes of acute ear infection is common in developing countries, affecting 2 to 6 percent of school-age children. The associated hearing loss may be disabling and may affect learning. Repeated ear infections may lead to mastoiditis, which in turn may spread infection to the meninges. Mastoiditis and other complications of URIs account for nearly 5 percent of all ARI deaths worldwide (Williams and others 2002).
Lower Respiratory Tract Infections
The common LRIs in children are pneumonia and bronchiolitis. The respiratory rate is a valuable clinical sign for diagnosing acute LRI in children who are coughing and breathing rapidly. The presence of lower chest wall indrawing identifies more severe disease (Mulholland and others 1992; Shann, Hart, and Thomas 1984).
Currently, the most common causes of viral LRIs are RSVs. They tend to be highly seasonal, unlike parainfluenza viruses, the next most common cause of viral LRIs. The epidemiology of influenza viruses in children in developing countries deserves urgent investigation because safe and effective vaccines are available. Before the effective use of measles vaccine, the measles virus was the most important viral cause of respiratory tract-related morbidity and mortality in children in developing countries.
Pneumonia
Both bacteria and viruses can cause pneumonia. Bacterial pneumonia is often caused by Streptococcus pneumoniae (pneumococcus) or Haemophilus influenzae, mostly type b (Hib), and occasionally by Staphylococcus aureus or other streptococci. Just 8 to 12 of the many types of pneumococcus cause most cases of bacterial pneumonia, although the specific types may vary between adults and children and between geographic locations. Other pathogens, such as Mycoplasma pneumoniae and Chlamydia pneumoniae, cause atypical pneumonias. Their role as a cause of severe disease in children under five in developing countries is unclear.
The burden of LRIs caused by Hib or S. pneumoniae is difficult to determine because current techniques to establish bacterial etiology lack sensitivity and specificity. The results of pharyngeal cultures do not always reveal the pathogen that is the cause of the LRI. Bacterial cultures of lung aspirate specimens are often considered the gold standard, but they are not practical for field application. Vuori-Holopainen and Peltola's (2001) review of several studies indicates that S. pneumoniae and Hib account for 13 to 34 percent and 1.4 to 42.0 percent of bacterial pneumonia, respectively, whereas studies by Adegbola and others (1994), Shann, Gratten, and others (1984), and Wall and others (1986) suggest that Hib accounts for 5 to 11 percent of pneumonia cases.
Reduced levels of clinical or radiological pneumonia in clinical trials of a nine-valent pneumococcal conjugate vaccine provide an estimate of the vaccine-preventable disease burden (valency indicates the number of serotypes against which the vaccine provides protection; conjugate refers to conjugation of polysaccharides to a protein backbone). In a study in The Gambia, 37 percent of radiological pneumonia was prevented, reflecting the amount of disease caused by S. pneumoniae, and mortality was reduced by 16 percent (Cutts and others 2005).
Upper respiratory tract colonization with potentially pathogenic organisms and aspiration of the contaminated secretions have been implicated in the pathogenesis of bacterial pneumonia in young children. Infection of the upper respiratory tract with influenza virus or RSVs has been shown to increase the binding of both H. influenzae (Jiang and others 1999) and S. pneumoniae (Hament and others 2004; McCullers and Bartmess 2003) to lining cells in the nasopharynx. This finding may explain why increased rates of pneumococcal pneumonia parallel influenza and RSV epidemics. A study in South Africa showed that vaccination with a nine-valent pneumococcal conjugate vaccine reduced the incidence of virus-associated pneumonia causing hospitalization by 31 percent, suggesting that pneumococcus plays an important role in the pathogenesis of virus-associated pneumonia (Madhi, Petersen, Madhi, Wasas, and others 2000).
Entry of bacteria from the gut with spread through the bloodstream to the lungs has also been proposed for the pathogenesis of Gram-negative organisms (Fiddian-Green and Baker 1991), but such bacteria are uncommon etiological agents of pneumonia in immune-competent children. However, in neonates and young infants, Gram-negative pneumonia is not uncommon (Quiambao forthcoming).
Viruses are responsible for 40 to 50 percent of infection in infants and children hospitalized for pneumonia in developing countries (Hortal and others 1990; John and others 1991; Tupasi and others 1990). Measles virus, RSVs, parainfluenza viruses, influenza type A virus, and adenoviruses are the most important causes of viral pneumonia. Differentiating between viral and bacterial pneumonias radiographically is difficult, partly because the lesions look similar and partly because bacterial superinfection occurs with influenza, measles, and RSV infections (Ghafoor and others 1990).
In developing countries, the case-fatality rate in children with viral pneumonia ranges from 1.0 to 7.3 percent (John and others 1991; Stensballe, Devasundaram, and Simoes 2003), with bacterial pneumonia from 10 to 14 percent and with mixed viral and bacterial infections from 16 to 18 percent (Ghafoor and others 1990; Shann 1986).
Bronchiolitis
Bronchiolitis occurs predominantly in the first year of life and with decreasing frequency in the second and third years. The clinical features are rapid breathing and lower chest wall indrawing, fever in one-third of cases, and wheezing (Cherian and others 1990). Inflammatory obstruction of the small airways, which leads to hyperinflation of the lungs, and collapse of segments of the lung occur. Because the signs and symptoms are also characteristic of pneumonia, health workers may find differentiating between bronchiolitis and pneumonia difficult. Two features that may help are a definition of the seasonality of RSVs in the locality and the skill to detect wheezing. RSVs are the main cause of bronchiolitis worldwide and can cause up to 70 or 80 percent of LRIs during high season (Simoes 1999; Stensballe, Devasundaram, and Simoes 2003). The recently discovered human metapneumovirus also causes bronchiolitis (Van den Hoogen and others 2001) that is indistinguishable from RSV disease. Other viruses that cause bronchiolitis include parainfluenza virus type 3 and influenza viruses.
Influenza
Even though influenza viruses usually cause URIs in adults, they are increasingly being recognized as an important cause of LRIs in children and perhaps the second most important cause after RSVs of hospitalization of children with an ARI (Neuzil and others 2002). Although influenza is considered infrequent in developing countries, its epidemiology remains to be investigated thoroughly. The potential burden of influenza as a cause of death in children is unknown. Influenza virus type A may cause seasonal outbreaks, and type B may cause sporadic infection. Recently, avian influenza virus has caused infection, disease, and death in small numbers of individuals, including children, in a few Asian countries. Its potential for emergence in human outbreaks or a pandemic is unknown, but it could have devastating consequences in developing countries (Peiris and others 2004) and could pose a threat to health worldwide. New strains of type A viruses will almost certainly arise through mutation, as occurred in the case of the Asian and Hong Kong pandemics in the 1950s and 1960s.
HIV Infection and Pediatric LRIs
Worldwide, 3.2 million children are living with HIV/AIDS, 85 percent of them in Sub-Saharan Africa (UNAIDS 2002). In southern Africa, HIV-related LRIs account for 30 to 40 percent of pediatric admissions and have a case-fatality rate of 15 to 34 percent, much higher than the 5 to 10 percent for children not infected with HIV (Bobat and others 1999; Madhi, Petersen, Madhi, Khoosal, and others 2000; Nathoo and others 1993; Zwi, Pettifior, and Soderlund 1999). Pneumocystis jiroveci and cytomegalovirus are important opportunistic infections in more than 50 percent of HIV-infected infants (Jeena, Coovadia, and Chrystal 1996; Lucas and others 1996). Gram-negative bacteria are also important in more than 70 percent of HIV-infected malnourished children (Ikeogu, Wolf, and Mathe 1997). Patient studies have confirmed the frequent association of these bacteria but added S. pneumoniae and S. aureus as important pathogens (Gilks 1993; Goel and others 1999). The first South African report on the overall burden of invasive pneumococcal disease reported a 41.7-fold increase in HIV-infected children compared with uninfected children (Farley and others 1994).
