Interventions
Interventions to control ARIs can be divided into four basic categories: immunization against specific pathogens, early diagnosis and treatment of disease, improvements in nutrition, and safer environments (John 1994). The first two fall within the purview of the health system, whereas the last two fall under public health and require multisectoral involvement.
Vaccinations
Widespread use of vaccines against measles, diphtheria, pertussis, Hib, pneumococcus, and influenza has the potential to substantially reduce the incidence of ARIs in children in developing countries. The effects of measles, diphtheria, and pertussis vaccines are discussed in chapter 20. The limited data on influenza in developing countries do not permit detailed analysis of the potential benefits of that vaccine. This chapter, therefore, focuses on the potential effects of Hib and pneumococcal vaccines on LRIs.
Hib Vaccine
Currently three Hib conjugate vaccines are available for use in infants and young children. The efficacy of Hib vaccine in preventing invasive disease (mainly meningitis, but also pneumonia), has been well documented in several studies in industrialized countries (Black and others 1992; Booy and others 1994; Eskola and others 1990; Fritzell and Plotkin 1992; Heath 1998; Lagos and others 1996; Santosham and others 1991) and in one study in The Gambia (Mulholland and others 1997). All studies showed protective efficacy greater than 90 percent against laboratory-confirmed invasive disease, irrespective of the choice of vaccine. Consequently, all industrialized countries include Hib vaccine in their national immunization programs, resulting in the virtual elimination of invasive Hib disease because of immunity in those vaccinated and a herd effect in those not vaccinated. Available data from a few developing countries show a similar herd effect (Adegbola and others 1999; Wenger and others 1999).
The initial promise and consequent general perception was that Hib vaccine was to protect against meningitis, but in developing countries the vaccine is likely to have a greater effect on preventing LRIs. The easily measured effect is on invasive disease, including bacteraemic pneumonia. The vaccine probably has an effect on non-bacteremic pneumonia, but this effect is difficult to quantify because of the lack of an adequate method for establishing bacterial etiology. In Bangladesh, Brazil, Chile, and The Gambia, Hib vaccine has been associated with a reduction of 20 to 30 percent in those hospitalized with radiographically confirmed pneumonia (de Andrade and others 2004; Levine and others 1999; Mulholland and others 1997; WHO 2004a). However, results of a large study in Lombok, Indonesia, were inconclusive with regard to the effect of Hib vaccine on pneumonia (Gessner and others 2005).
Pneumococcal Vaccines
Two kinds of vaccines are currently available against pneumococci: a 23-valent polysaccharide vaccine (23-PSV), which is more appropriate for adults than children, and a 7-valent protein-conjugated polysaccharide vaccine (7-PCV). A 9-valent vaccine (9-PCV) has undergone clinical trials in The Gambia and South Africa, and an 11-valent vaccine (11-PCV) is being tried in the Philippines.
Studies of the efficacy of the polysaccharide vaccine in preventing ARIs or ear infection in children in industrialized countries have shown conflicting results. Whereas some studies of this vaccine show no significant efficacy (Douglas and Miles 1984; Sloyer, Ploussard, and Howie 1981), studies from Finland show a generally protective effect against the serotypes contained in a 14-PSV (Douglas and Miles 1984; Karma and others 1980; Makela and others 1980). The efficacy was more marked in children over two years of age than in younger children. The only studies evaluating the effect of the polysaccharide vaccine in children in developing countries are a series of three trials conducted in Papua New Guinea (Douglas and Miles 1984; Lehmann and others 1991; Riley and others 1981; Riley, Lehmann, and Alpers 1991). The analysis of the pooled data from these trials showed a 59 percent reduction in LRI mortality in children under five at the time of the vaccination and a 50 percent reduction in children under two. On the basis of these and other studies, the investigators concluded that the vaccine had an effect on severe pneumonia. The greater-than-expected efficacy in these trials was attributed to the greater contribution of the more immunogenic adult serotypes in pneumonia in Papua New Guinea (Douglas and Miles 1984; Riley, Lehmann, and Alpers 1991). On account of the poor immunogenicity of the antigens in the 23-PSV against prevalent pediatric serotypes, attention is now directed at more immunogenic conjugate vaccines (Mulholland 1998; Obaro 1998; Temple 1991).
The 7-PCV and 9-PCV have been evaluated for efficacy against invasive pneumococcal disease in four trials, which demonstrated a vaccine efficiency ranging from 71.0 to 97.4 percent (58 to 65 percent for HIV-positive children, among whom rates of pneumococcal disease are 40 times higher than in HIV-negative children) (Black and others 2000; Cutts and others 2005; Klugman and others 2003; O'Brien and others 2003).
In the United States, the 7-PCV was included in routine vaccinations of infants and children under two in 2000. By 2001 the incidence of all invasive pneumococcal disease in this age group had declined by 69 percent and disease caused by the serotypes included in the vaccine and related serotypes had declined by 78 percent (Whitney and others 2003). Similar reductions were confirmed in a study in northern California (Black and others 2001). A slight increase in rates of invasive disease caused by serotypes of pneumococcus not included in the vaccine was observed, but it was not large enough to offset the substantial reduction in disease brought about by the vaccine. The studies also found a significant reduction in invasive pneumococcal disease in unvaccinated older age groups, especially adults age 20 to 39 and age 65 and older, suggesting that giving the vaccine to young children exerted a considerable herd effect in the community. Such an advantage is likely to occur even where the prevalence of adult HIV disease is high and pneumococcal disease may be recurrent and life threatening.
The effect of the vaccine on pneumococcal pneumonia as such is difficult to define given the problems of establishing the bacterial etiology of pneumonia. Three studies have evaluated the effect of the vaccine on radiographic pneumonia (irrespective of the etiological agent) and have shown a 20.5 to 37.0 percent reduction in radiographically confirmed pneumonia (9.0 percent for HIV-positive individuals) (Black and others 2000; Cutts and others 2005; Klugman and others 2003).
Several field trials have evaluated the efficacy of PCV against ear infection. Even though the vaccine resulted in a significant reduction in culture-confirmed pneumococcal otitis, no net reduction of ear infection was apparent among vaccinated children, probably because of an increase in the rates of otitis caused by types of pneumococci not covered by the vaccine, H. influenzae and Moraxella catarrhalis (Eskola and others 2001; Kilpi and others 2003). However, a trial in northern California showed that the vaccine had a protective effect against frequent ear infection and reduced the need for tympanostomy tube placement (Fireman and others 2003). Thus, a vaccine for ear infection may be beneficial in developing countries with high rates of chronic otitis and conductive hearing loss and should be evaluated by means of clinical trials.
The most striking public health benefit of a vaccine in developing countries would be a demonstrable reduction in mortality. Although the primary outcome in The Gambia trial was initially child mortality, it was changed to radiological pneumonia. Nevertheless, the trial showed a 16 percent (95 percent confidence level, 3 to 38) reduction in mortality. This trial was conducted in a rural area in eastern Gambia where access to round-the-clock curative care, including case management, is difficult to provide. This trial demonstrates that immunization delivered through outreach programs will have substantial health and economic benefits in such populations. One additional study evaluating the effect of an 11-PCV on radiological pneumonia is ongoing in the Philippines; results are expected in the second half of 2005.
Case Management
The simplification and systematization of case management for early diagnosis and treatment of ARIs have enabled significant reductions in mortality in developing countries, where access to pediatricians is limited. WHO clinical guidelines for ARI case management (WHO 1991) use two key clinical signs: respiratory rate, to distinguish children with pneumonia from those without, and lower chest wall indrawing, to identify severe pneumonia requiring referral and hospital admission. Children with audible stridor when calm and at rest or such danger signs of severe disease as inability to feed also require referral. Children without these signs are classified as having an ARI but not pneumonia. Children showing only rapid breathing are treated for pneumonia with outpatient antibiotic therapy. Children who have a cough for more than 30 days are referred for further assessment of tuberculosis and other chronic infections.
Pneumonia Diagnosis Based on Rapid Breathing
The initial guidelines for detecting pneumonia based on rapid breathing were developed in Papua New Guinea during the 1970s. In a study of 200 consecutive pediatric outpatients and 50 consecutive admissions (Shann, Hart, and Thomas 1984), 72 percent of children with audible crackles in the lungs had a respiratory rate of 50 or more breaths per minute, whereas only 19 percent of children without crackles breathed at such a rapid rate. Therefore, the initial WHO guidelines used a threshold of 50 breaths per minute, at or above which a child with a cough was regarded as having pneumonia.
The major concern was the relatively low sensitivity of this approach, which could miss 25 to 40 percent of cases of pneumonia. A study in Vellore, India, found that sensitivity could be improved by lowering the threshold to 40 for children age 1 to 4, while keeping the 50 breaths per minute cutoff for infants age 2 months through 11 months (Cherian and others 1988). Subsequent studies showed that when these thresholds were used, sensitivity improved from 62 to 79 percent in the Philippines and from 65 to 77 percent in Swaziland, but at the same time, the specificity fell from 92 to 77 percent in the Philippines and 92 to 80 percent in Swaziland (Mulholland and others 1992). On the basis of these and other data (Campbell, Byass, and others 1989; Kolstad and others 1997; Perkins and others 1997; Redd 1994; Simoes and others 1997; Weber and others 1997), WHO recommends a respiratory rate cutoff of 50 breaths per minute for infants age 2 through 11 months and 40 breaths per minute for children age 12 months to 5 years.
Rapid breathing, as defined by WHO, detects about 85 percent of children with pneumonia, and more than 80 percent of children with potentially fatal pneumonia are probably successfully identified and treated using the WHO diagnostic criteria. Antibiotic treatment of children with rapid breathing has been shown to reduce mortality (Sazawal and Black 2003). The problem of the low specificity of the rapid breathing criterion is that some 70 to 80 percent of children who may not need antibiotics will receive them. Nevertheless, for primary care workers for whom diagnostic simplicity is essential, rapid breathing is clearly the most useful clinical sign.
Pneumonia Diagnosis Based on Chest Wall Indrawing
Children are admitted to hospital with severe pneumonia when health workers believe that oxygen or parenteral antibiotics (antibiotics administered by other than oral means) are needed or when they lack confidence in mothers' ability to cope. The rationale of parenteral antibiotics is to achieve higher levels of antibiotics and to overcome concerns about the absorption of oral drugs in ill children.
The Papua New Guinea study (Shann, Hart, and Thomas 1984) used chest wall indrawing as the main indicator of severity, but studies from different parts of the world show large differences in the rates of indrawing because of variable definitions. Restriction of the term to lower chest wall indrawing, defined as inward movement of the bony structures of the chest wall with inspiration, has provided a better indicator of the severity of pneumonia and one that can be taught to health workers. It is more specific than intercostal indrawing, which frequently occurs in bronchiolitis.
In a study in The Gambia (Campbell, Byass, and others 1989), a cohort of 500 children from birth to four years old was visited at home weekly for one year. During this time, 222 episodes of LRI (rapid breathing, any chest wall indrawing, nasal flaring, wheezing, stridor, or danger signs) were referred to the clinic. Chest indrawing was present in 62 percent of these cases, many with intercostal indrawing. If all children with any chest indrawing were hospitalized, the numbers would overwhelm pediatric inpatient facilities.
Studies in the Philippines and Swaziland (Mulholland and others 1992) found that lower chest wall indrawing was more specific than intercostal indrawing for a diagnosis of severe pneumonia requiring hospital admission. In the Vellore study (Cherian and others 1988), lower chest wall indrawing correctly predicted 79 percent of children with an LRI who were hospitalized by a pediatrician.
Antimicrobial Options for Oral Treatment of Pneumonia
The choice of an antimicrobial drug for treatment is based on the well-established finding that most childhood bacterial pneumonias are caused by S. pneumoniae or H. influenzae. A single injection of benzathine penicillin, although long lasting, does not provide adequate penicillin levels to eliminate H. influenzae. WHO has technical documents to help assess the relevant factors in selecting first- and second-line antimicrobials and comparisons of different antimicrobials in relation to their antibacterial activity, treatment efficacy, and toxicity (WHO 1990).
The emergence of antimicrobial resistance in S. pneumoniae and H. influenzae is a serious concern. In some settings, in vitro tests show that more than 50 percent of respiratory isolates of both bacteria are resistant to co-trimoxazole, and penicillin resistance to S. pneumoniae is gradually becoming a problem worldwide.
In pneumonia, unlike in meningitis, in vitro resistance of the pathogen does not always translate into treatment failure. Reports from Spain and South Africa suggest that pneumonia caused by penicillin-resistant S. pneumoniae can be successfully treated with sufficiently high doses of penicillin. Amoxicillin is concentrated in tissues and in macrophages, and drug levels are directly correlated with oral dosages. Therefore, higher doses than in the past—given twice a day—are now being used to successfully treat ear infections caused by penicillin-resistant S. pneumoniae. Amoxicillin is clearly better than penicillin for such infections. The situation with co-trimoxazole is less clear (Strauss and others 1998), and in the face of high rates of co-trimoxazole resistance, amoxicillin may be superior for children with severe pneumonia.
Intramuscular Antibiotics for Treatment of Severe Pneumonia
Even though chloramphenicol is active against both S. pneumoniae and H. influenzae, its oral absorption is erratic in extremely sick children. Thus, the WHO guidelines recommend giving intramuscular chloramphenicol at half the daily dose before urgent referral of severe pneumonia cases. An additional rationale is that extremely sick children may have sepsis or meningitis that are difficult to rule out and must be treated immediately. Although intravenous chloramphenicol is superior to intramuscular chloramphenicol, the procedure can delay urgently needed treatment and adds to its cost.
Investigators have questioned the adequacy and safety of intramuscular chloramphenicol. Although early studies suggested that adult blood levels after intramuscular administration were significantly less than those achieved after intravenous administration, the intramuscular route gained wide acceptance following clinical reports that confirmed its efficacy. Local complications of intramuscular chloramphenicol succinate are rare, unlike the earlier intramuscular preparations. Although concerns about aplastic anemia following chloramphenicol are common, this complication is extremely rare in young children. There is no evidence that intramuscular chloramphenicol succinate is more likely to produce side effects than other forms and routes of chloramphenicol.
Hypoxemia Diagnosis Based on WHO Criteria
The ARI case-management and integrated management of infant and childhood illness (IMCI) strategies depend on accurate referral of sick children to a hospital and correct inpatient management of LRI with oxygen or antibiotics. Hypoxemia (deficiency of oxygen in the blood) in children with LRI is a good predictor of mortality, the case-fatality rate being 1.2 to 4.6 times higher in hypoxemic LRI than nonhypoxemic LRI (Duke, Mgone, and Frank 2001; Onyango and others 1993), and oxygen reduces mortality. Thus, it is important to detect hypoxemia as early as possible in children with LRI to avert death. Although diagnoses of acute LRIs are achieved very easily by recognizing tachypnoea, and although severe LRI is associated with chest wall indrawing, the clinical recognition of hypoxemia is more problematic. Different sets of clinical rules have been studied to predict the presence of hypoxemia in children with LRI (Cherian and others 1988; Onyango and others 1993; Usen and others 1999). Although some clinical tools have a high sensitivity for detecting hypoxemia, a good number of hypoxemic children would still be missed using these criteria. Pulse oximetry is the best tool to quickly detect hypoxemia in sick children. However, pulse oximeters are expensive and have recurring costs for replacing probes, for which reasons they are not available in most district or even referral hospitals in developing countries.
Treatment Guidelines
Current recommendations are for co-trimoxazole twice a day for five days for pneumonia and intramuscular penicillin or chloramphenicol for children with severe pneumonia. The problems of increasing resistance to co-trimoxazole and unnecessary referrals of children with any chest wall indrawing have led to studies exploring alternatives to the antibiotics currently used in ARI case management. One study indicated that amoxicillin and co-trimoxazole are equally effective for nonsevere pneumonia (Catchup Study Group 2002), though amoxicillin costs twice as much as co-trimoxazole. With respect to the duration of antibiotic treatment, studies in Bangladesh, India, and Indonesia indicate that three days of oral co-trimoxazole or amoxicillin are as effective as five days of either drug in children with nonsevere pneumonia (Agarwal and others 2004; Kartasasmita 2003). In a multicenter study of intramuscular penicillin versus oral amoxicillin in children with severe pneumonia, Addo-Yobo and others (2004) find similar cure rates. Because patients were treated with oxygen when needed for hypoxemia and were switched to other antibiotics if the treatment failed, this regimen is not appropriate for treating severe pneumonia in an outpatient setting.
WHO recommends administering oxygen, if there is ample supply, to children with signs and symptoms of severe pneumonia and, where supply is limited, to children with any of the following signs: inability to feed and drink, cyanosis, respiratory rate greater than or equal to 70 breaths per minute, or severe chest wall retractions (WHO 1993). Oxygen should be administered at a rate of 0.5 liter per minute for children younger than 2 months and 1 liter per minute for older children. Because oxygen is expensive and supply is scarce, especially in remote rural areas in developing countries, WHO recommends simple clinical signs to detect and treat hypoxemia. Despite those recommendations, a study of 21 first-level facilities and district hospitals in seven developing countries found that more than 50 percent of hospitalized children with LRI were inappropriately treated with antibiotics or oxygen (Nolan and others 2001)—and in several, oxygen was in short supply. Clearly, providing oxygen to hypoxemic babies is lifesaving, though no randomized trials have been done to prove it.
Prevention and Treatment of Pneumonia in HIV-Positive Children
Current recommendations of a WHO panel for managing pneumonia in HIV-positive children and for pro-phylaxis of Pneumocystis jiroveci are as follows (WHO 2003):
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Nonsevere pneumonia up to age 5 years. Oral co-trimoxazole should remain the first-line antibiotic, but oral amoxicillin should be used if it is affordable or if the child has been on co-trimoxazole prophylaxis.
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Severe or very severe pneumonia. Normal WHO case-management guidelines should be used for children up to 2 months old. For children from 2 to 11 months, injectable antibiotics and therapy for Pneumocystis jiroveci pneumonia are recommended, as is starting Pneumocystis jiroveci pneumonia prophylaxis on recovery. For children age 12 to 59 months, the treatment consists of injectable antibiotics and therapy for Pneumocystis jiroveci pneumonia. Pneumocystis jiroveci pneumonia prophylaxis should be given for 15 months to children born to HIV-infected mothers; however, this recommendation has seldom been implemented.
