Chapter 11Acute Respiratory Infections

Madhi SA, Klugman KP.

Acute respiratory infections (ARI), particularly lower respiratory tract infections (LRTI), are the leading cause of death among children under five years of age and are estimated to be responsible for between 1.9 million and 2.2 million childhood deaths globally. Forty-two percent of these ARI-associated deaths occur in Africa (Williams 2002). Despite its importance in regard to morbidity as well as childhood mortality, the epidemiology and pathogenesis of LRTI, particularly in Africa, remains understudied and consequently underappreciated. Although structured management programs coordinated by the World Health Organization (WHO) made some strides during the 1980s and early 1990s toward reducing childhood mortality from LRTI (Sazawal and Black 2003; WHO 1990), the HIV epidemic in many countries of Sub-Saharan Africa has reversed many of these gains (Walker, Schwartlander, and Bryce 2002). The reduction of morbidity and mortality in Sub-Saharan Africa requires a multifaceted approach that includes addressing risk factors associated with increased susceptibility to LRTI among children. These factors include lack of access to basic amenities, such as adequate housing, electricity, and running tap water. Availability of these amenities would help to reduce exposure to such risk factors as indoor smoke pollution and overcrowding in households. Reducing these risk factors may take some time, but recent advances in medical science hold promise in regard to preventing morbidity and possibly mortality from the most common perceived causes of severe LRTI—those due to bacteria, such as Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae (Cutts et al. 2005; Klugman et al. 2003; Mulholland et al. 1997). Despite these advances, the challenge remains to address the inequity in health care accessibility and affordability of new-generation vaccines that have been found to be effective in preventing disease caused by these bacteria in developed and developing countries. Furthermore, a priority for most countries in Sub-Saharan Africa in dealing with the reversal of gains that occurred during the late 1980s and early 1990s is to work to prevent the transmission of HIV to children through effective HIV mother-to-child transmission prevention programs.

The Epidemiology of ARI and LRTI

Despite the recognition of LRTI as the leading cause of childhood mortality in Sub-Saharan Africa (Williams 2002), data on the epidemiology of LRTI in these countries are sparse. The most recent community- and hospital-based longitudinal studies aimed at measuring the burden of LRTI in African countries were conducted during the mid-1980s (Bale 1990; Selwyn 1990), prior to the HIV epidemic that has engulfed most of these countries (Asamoah-Odel et al. 2003). These studies were supported as part of an effort by the Board of Science and Technology for International Development (BOSTID) of the U.S. National Research Council to define the burden of LRTI among developing countries (Bale 1990; Selwyn 1990). Based on an estimate of ARI, it was concluded that approximately 4 million deaths from ARI occurred annually (Leowski 1986). In addition to the African studies sponsored by BOSTID, namely, rural Kenya and urban Nigeria (Oyejide and Osinusi 1990; Wafula et al. 1990), the only other areas from which there are reliable estimates of the burden of LRTI are rural areas in The Gambia and Ghana (Afari 1991; Campbell et al. 1989).

The literature published between 1966 and 2000 on the incidence of LRTI (including that in Sub-Saharan Africa) has recently been reviewed by Rudan and colleagues, who estimated the median incidence of LRTI in developing countries at 44 episodes per 100 child-years, equal to approximately 150.7 million new cases each year, 7 to 13 percent of which were severe enough to warrant hospitalization (Rudan et al. 2004). They estimate that there were approximately 33.7 million cases of LRTI annually in African children, with an incidence rate of 31 to 33 per 100 child-years, which was higher than the overall average for all developing countries (23 per 100 child-years) (Rudan et al. 2004). These estimates were, however, exclusive of the impact that the HIV epidemic may have had on the incidence of LRTI. Rudan and colleagues (2004) also found that the burden of LRTI, albeit from studies outside of Africa, was greatest among children less than one year old, and, relative to an incidence of 1.0 in the first year of life, the mean ratios for the subsequent four years of life were 0.58 (year 2), 0.48 (year 3), 0.31 (year 4), and 0.19 (year 5).

Although the few published studies allow an analysis of the burden of LRTI mainly during the mid-1980s and early 1990s, a major pitfall in the studies was the differences in the methodology, not only of diagnostic tests, but also of the clinical definitions used in the studies, all of which may have a bearing on the measured incidence rates as well as the described etiology of LRTI. Although the studies sponsored by BOSTID aimed at reducing the differences in methodology between studies, the wide range of the incidence of LRTI (0.4–8.1 per 100 child-weeks) between the studies, despite a similar incidence rate of ARI (12.7–16.1 per 100 child-weeks) in most studies, except the study from Thailand (Selwyn 1990), suggest widely varying risk factors, which may have predisposed the children to progression from upper respiratory tract infections to LRTI. Another possibility is that there remain significant differences in the study methodology, including the implementation of different study definitions between the studies. This underlines the importance of recent initiatives by the WHO to standardize the definition of pneumonia so that comparisons may be made between bacterial conjugate vaccines efficacy trials on the burden of LRTI in developing countries (Black et al. 2002; Cherian et al. 2005; Cutts et al. 2005; Klugman et al. 2003; Mulholland et al. 1997).

The study in Kenya suggested that, in addition to the high burden of ARI and LRTI among children, on average, ARI accounted for their illness 21.7 percent of the time and LRTI 0.4 percent of the time (Selwyn 1990). Studies from other non-African developing countries suggest that the burden of disease may be even greater elsewhere, with children being affected for 40 to 60 percent and 14 percent of the year with ARI and LRTI, respectively (Black et al. 1982; Selwyn 1990). The prolonged morbidity associated with ARI, in addition to being associated with mortality, may also affect the physical, emotional, and intellectual development of the child. This situation is further compounded by the finding that the rates of ARI are greatest during the initial years of life (about 7.5 to 8 episodes per year among infants versus about 4 to 6 episodes per year among children 48 to 59 months of age; Selwyn 1990). Furthermore, the proportion of time that children are affected by an ARI ranged from about one-third of the year among infants to less than 20 percent of the time among older children (Oyejide and Osinusi 1990; Wafula et al. 1990). The study from Nigeria also documented the benefits of measles immunization on the incidence of LRTI, showing that children vaccinated for measles had a 2.8-fold reduction in the incidence of LRTI (Oyejide and Osinusi 1990).

The only longitudinal burden-of-disease study in Africa to have defined the incidence of radiologically confirmed pneumonia was performed in The Gambia (Campbell et al. 1989). In that study the incidence of LRTI was 45 per 100 child-years, and 35.5 percent of episodes were associated with radiologically confirmed pneumonia. Another cross-sectional study done in the Central African Republic also found that, although radiologically confirmed pneumonia was present in only 41 percent of children hospitalized for LRTI, the presence on chest radiograph of the involvement of three or more lobes was associated with a 4.6-fold greater risk of death than that of a single lobe (Demers et al. 2000). The overall mortality rate from LRTI among children in developing countries based on the longitudinal studies reviewed by Rudan and colleagues (2004) ranged from 6.6 to 14.1 percent.

The high burden of LRTI among developing countries is partly related to the increased exposure of children in these countries to those poverty-linked risk factors that predispose them to developing LRTI. In a multivariate analysis of data from various studies, Rudan and colleagues (forthcoming) identified the risk factors most consistently associated with LRTI as malnutrition (relative risk [RR] 1.8), low birthweight (less than 2,500 grams at birth, RR 1.4), lack of exclusive breastfeeding in the first four months of life (RR 1.3), overcrowding in the household (more than five people in the household, RR 1.2), and lack of measles immunization (RR 0.7). It was estimated that these risk factors were prevalent among 27.4 percent, 14.7 percent, 54.1 percent, 80.3 percent, and 52.5 percent, respectively, of the world's 523 million children age zero to four years. Additional poverty-related factors that predispose to LRTI include domestic smoke and air pollution (Anderson 1978; Sofoluwe 1968). Consequently, it can be extrapolated that a significant burden of LRTI among children in the developing world is avoidable by addressing factors associated with poverty and lower socioeconomic development.

The Impact of the HIV Epidemic on the Epidemiology of LRTI

A further limitation of the published longitudinal studies is that they were conducted at an early stage or even prior to the HIV epidemic. This is particularly pertinent when considering that in some centers more than 80 percent of deaths from LRTI occur among children infected with the human immunodeficiency virus (HIV), despite only 4 to 6 percent of children in the general pediatric population being so infected (Madhi, Petersen, Madhi, Khoolsal, et al. 2000; Zwi, Pettifor, and Soderlund 1999). Although a few studies have looked at differences in the etiology of LRTI between HIV-infected and HIV-uninfected children, only one published study has described the impact that the HIV epidemic has had on the relative burden of LRTI among children in Africa. This study was limited to hospital-based surveillance and underestimates the overall burden of LRTI. Nevertheless, the study emphasized that despite only an estimated 4.5 percent of children in the study population being HIV infected, these children accounted for 45 percent of all LRTI-associated hospitalizations (Madhi, Petersen, Madhi, Khoolsal, et al. 2000).

Although there are no longitudinal studies from Sub-Saharan Africa, including surveillance at the community–health care level, of the incidence of LRTI among HIV-infected children, data from developed countries illustrate the heightened burden of LRTI among HIV-infected children. In a recent review of 3,331 children infected with HIV-1 who participated in several different clinical trials, the incidence rate of any clinically or radiologically diagnosed pneumonia was estimated to be 11.1 (95 percent confidence interval [CI], 10.3–12.0) per 100 child-years (Dankner, Lindsey, and Levin 2001). The trials included children who were on one to three antiretroviral drugs, excluding protease inhibitors. The mean age of children in this study was 39 months; the oldest subject was 20.9 years of age (Dankner, Lindsey, and Levin 2001). In an earlier cohort study evaluating the efficacy of intravenous immunoglobulin prophylaxis, performed among HIV-infected children in the United States, the incidence of LRTI was estimated to be 24 per 100 child-years (Mofenson et al. 1998). This was sevenfold greater than historical incidence rates of 3 to 4.2 per 100 child-years observed among pre-school children in the United States and Finland prior to the HIV-1 epidemic (Foy et al. 1973; Murphy et al. 1981). Mofenson and colleagues (1998) described the increased burden of LRTI among HIV-infected children but underestimated the true burden of disease in young children, since the mean age of children recruited into the study (40 months) was greater than the ages (less than 18 months of age) when HIV-infected and HIV-uninfected children are most susceptible to developing and dying of pneumonia (Chintu et al. 1995; Langston et al. 2001; Mofenson et al. 1998; Pillay et al. 2001; Selwyn 1990). During the course of the study by Mofenson and colleagues (1998), pneumonia was second (12 percent) only to upper respiratory tract infections as a cause of bacterial infections among HIV-infected children. Thirty-seven percent of the children with acute pneumonia had multiple episodes of pneumonia, which was also a risk factor for mortality (odds ratio [OR], 2.1; 95 percent CI, 1.3–3.4).

Data from South Africa indicated that the incidence of hospitalization for LRTI among nearly 20,000 placebo recipients (who all received Hib conjugate vaccine) participating in a pneumococcal conjugate vaccine trial, of whom an estimated 6.04 percent were infected with HIV-1, was approximately 6.6 times greater among HIV-infected children (16.7 cases per 100 child-years) than HIV-uninfected children (2.6 cases per 100 child-years) (Madhi et al. 2005). Although the incidence rates observed for HIV-infected children were less than the rate observed by Mofenson and colleagues (1998) among HIV-infected children in the United States (24 per 100 child-years), the data from South Africa included only children who were hospitalized for LRTI as opposed to children who were hospitalized for LRTI and ARI and those who were outpatients in the United States. Although differences in the age of children are also important, these data may illustrate the increased burden of LRTI among African HIV-infected children compared with HIV-infected children in industrial countries.

Williams (2002) recently reviewed the estimates of childhood deaths due to ARI mainly based on published data prior to the current HIV epidemic. It was estimated that globally ARI causes 1.9 million (95 percent CI, 1.6 million to 2.2 million) deaths annually of children under five, 794,000 (40 percent) of which occur in Africa (Williams 2002). The proportion of deaths attributable to ARI was found to be related to the under-five childhood mortality rate of the countries. In countries where the under-five childhood mortality rate is 50 per 1,000, as in most of Sub-Saharan Africa (UNICEF 1996, pp. 90–98), ARI is estimated to be responsible for 23 percent of deaths, compared with only 15 percent of deaths in countries where the under-five mortality rate is 10 per 1,000 per year (Williams 2002). The lower contribution of ARI as a cause of childhood deaths as under-five mortality rates improve was further characterized by trends in under-five mortality among black South Africans that were observed between the 1960s and 1980s (Von Schirnding, Yach, and Klein 1991). In the indigenous South African population of black people from 1968 to 1973, a corrected estimate of 22.5 percent of the under-five mortality of 40 per 1,000 was attributed to ARI, compared with 1980–85, when, with an under-five mortality rate of 17.3 per 1,000, the proportion of deaths due to ARI decreased to 17.7 percent (Von Schirnding, Yach, and Klein 1991). Similarly, ARI was linked to a high proportion (21 to 24 percent) of deaths in other African countries, where the under-five mortality rate ranged between 35 and 63 per 1,000 children during the 1980s (de Francisco et al. 1993; Fantahun 1998; Greenwood et al. 1987; Mtango and Neuvians 1986; Williams 2002).

Much of the improvement in under-five mortality as well as the reduction in the proportion of deaths due to ARI that has been observed in other Sub-Saharan Africa countries, however, have possibly been reversed due to the impact that the HIV epidemic has had on childhood mortality in Sub-Saharan Africa since 1990 (Walker, Schwartlander, and Bryce 2002). In addition to the increased predisposition of HIV-infected children to bacterial- and viral-associated LRTI, HIV-infected children (13.1 percent) have also been found to have a 6.5 times greater (95 percent CI, 3.5–12.1) case-fatality rate than HIV-uninfected children (2.3 percent) even in a country with relatively good resources, such as South Africa (Madhi, Petersen, Madhi, Khoolsal, et al. 2000). Although the case-fatality rate for children with pneumococcal bacteremic pneumonia was similar among those infected with HIV (18 percent) compared with those uninfected (11 percent, P = 0.18), the overall higher case-fatality rate for LRTI among HIV-infected children may be explained by the poor outcome of African HIV-infected children who have Pneumocystis carinii pneumonia (PCP) (case-fatality rate 20 to 65 percent) (Graham et al. 2000; Madhi et al. 2002).

The Etiology of LRTI

Unfortunately, the sensitivity of current diagnostic tools in defining the etiology of LRTI is woefully suboptimal, particularly for diagnosing bacterial infections, even in the countries with the most resources, such as Finland and the United States (Heiskanen-Kosma et al. 1998; Wubbel et al. 1999). Among industrial countries, where the common respiratory viruses, particularly respiratory syncytial virus, are the dominant (40 to 50 percent of episodes) pathogens identified among children with LRTI, no etiological agent was identified among 30 to 40 percent of children with LRTI, despite the use of an array of advanced microbiologi-cal methods, including some that had not been validated against "gold standards" (Heiskanen-Kosma et al. 1998; Wubbel et al. 1999).

The case-management strategy of the WHO is based on the premise that bacteria are the leading cause of LRTI, especially as a cause of severe illness, among children in developing countries (WHO 1990). Nevertheless, most of the etiological studies performed in developing countries suggest that respiratory viruses are as important a cause of LRTI among these children as among those in developed countries (Forgie et al. 1991a, 1991b; Heiskanen-Kosma et al. 1998; Selwyn 1990; Wubbel et al. 1999).

The common respiratory viruses isolated among African infants hospitalized for LRTI in The Gambia include respiratory syncytial virus (37 percent), adenovirus (5 percent), parainfluenza virus (3 percent), rhinovirus (6 percent), and influenza virus (1 percent) (Forgie et al. 1991a, 1991b). Furthermore, more recently, a newly discovered respiratory virus named metapneumovirus (van den Hoogen et al. 2001) has also been identified as a cause of severe LRTI among 10 percent of HIV-uninfected and 3 percent of HIV-infected infants (Madhi et al. 2003). Bacteria were, however, proportionally as common and were identified in 30 percent of the infants, albeit using unvalidated diagnostic methods, with the dominant identified pathogens being S. pneumoniae (20 percent) and H. influenzae (11 percent) (Forgie et al. 1991a). Mixed bacterial-viral infections were identified among 15 percent of infants. Although 73 percent of infants had radiological evidence of pneumonia, only 28 percent had evidence of a lobar pneumonia (Forgie et al. 1991a). Among older children (one to four years of age) hospitalized with LRTI in The Gambia, identification of bacteria was relatively more common (75 percent) than identification of common respiratory viruses (40 percent) (Forgie et al. 1991b). Although S. pneumoniae (60.9 percent) and H. influenzae (13.8 percent) remained the most dominant bacterial isolates, other bacteria identified included Staphylococcus aureus and Moraxella catarrhalis (6.2 percent each) (Forgie et al. 1991b). These studies, similar to others from developing countries, including those that were sponsored by BOSTID, underpin the importance of respiratory syncytial virus as well as S. pneumoniae, H. influenzae, and viruses as the etiology of LRTI among children in developing countries (Selwyn 1990).

The spectrum of pathogens and proportional representation thereof appeared to be similar between children with moderate and severe LRTI in the BOSTID-sponsored studies (Selwyn 1990). The clinical relevance of distinguishing between respiratory viral and bacterial infections has, however, gained renewed interest with the recent observation that pneumococcal coinfections are prevalent in at least 30 to 40 percent of children with documented respiratory viral infections (Madhi, Klugman, and Pneumococcal Vaccine Trialist Group 2004).

Other factors that may affect the spectrum of bacteria that causes pneumonia include environmental factors and nutritional status (Adegbola et al. 1994; O'Dempsey et al. 1994). Gram-negative bacteria that include Salmonella and coliforms were found to be more common than S. pneumoniae and Hib as causes of LRTI during those rainy months of the year when malaria transmission is at its greatest in a malaria-endemic area in The Gambia (O'Dempsey et al. 1994).

Advances in preventing LRTI caused by S. pneumoniae and H. influenzae type b have refocused attention to measuring the burden of disease due to these pathogens in order to define the burden of LRTI that may be prevented through vaccination of children with the bacterial conjugate vaccines (Black et al. 2002; Klugman et al. 2003; Mulholland et al. 1997). Although fine needle aspiration of the lung is the gold standard for identifying bacterial infections of the lung, it only has a sensitivity of 70 percent and is limited to being performed mainly on children with clearly defined alveolar consolidation, accessible to aspiration (Vuori-Holopainen and Peltola 2001). Because of the empirical management of severe LRTI with antibiotics, the use of fine needle aspirates of the lung has waned (Vuori-Holopainen and Peltola 2001) but has recently received more attention as a diagnostic approach in Finland (Vuori-Holopainen et al. 2002).

The majority of studies that have used fine needle aspirates as a potential diagnostic modality have been performed in Africa (Vuori-Holopainen and Peltola 2001). The performance of lung aspirates is, however, associated with some risk (less than 2 percent), such as that of pneumothoraces and hemoptysis, which may preclude its use in clinical practice as well as in large-scale epidemiological studies (Vuori-Holopainen and Peltola 2001). Furthermore, the yield from lung aspirates may be operator dependent and could also be influenced by other factors, such as preceding exposure to antibiotics, age of the study participants, and the extent of lung infiltrate. This may, at least in part, explain why the yield ranged from 17 percent to 100 percent in various studies. On average, a bacterial pathogen from lung aspirates was isolated in 52 percent (17 to 77 percent) of cases, compared with a blood isolation rate of 25 percent (2 to 45 percent) in studies in which both procedures were done concurrently (Adegbola et al. 1994; Garcia de Olarte et al. 1971; George, Bai, and Cherian 1996; Rapkin 1975; Silverman et al. 1977; Vuori-Holopainen and Peltola 2001; Wall et al. 1986).

Table 11.1 illustrates those studies that included only children with pneumonia who had not received antibiotics prior to having had a fine needle aspirate performed. Except for a small study from South Africa, all the studies confirmed S. pneumoniae as the leading isolate among children with pneumonia, although there was a wide range of positive pneumococcal isolates (18 to 51 percent) among other studies performed in developing countries. A summary of lung aspirate studies performed in Africa has, however, suggested that S. aureus may also be an important cause of LRTI (20 percent of children) (Vuori-Holopainen et al. 2002; Mimica et al. 1971).

Table 11.1. Results of Lung Aspirations of Children Who Had Not Received Antibiotics and Not Mentioned Underlying Illness.

Table 11.1

Results of Lung Aspirations of Children Who Had Not Received Antibiotics and Not Mentioned Underlying Illness.

Additionally, investigators in Chile and India reported that S. aureus was the dominant isolate (25 to 27 percent), whereas S. pneumoniae was isolated in only 2 to 5 percent of children, among whom 50 to 70 percent had received antibiotics prior to the performance of the lung aspirate (Mimica et al. 1971). In another report among children who were receiving antibiotics (77 percent) prior to the lung aspirate, S. pneumoniae was isolated more frequently than S. aureus (11 percent as opposed to 6 percent, respectively) (Prakash et al. 1996). Silverman and colleagues (1977) showed that although the yield of bacteria in Nigerian children with an ill-defined infiltrate (bronchopneumonia) was similar to that in children with lobar consolidation or empyema, the spectrum of isolates differed, with the yield of S. pneumoniae being 53.6 and 15.9 percent, respectively (Silverman et al. 1977). Similarly, Mimica and colleagues (1971) in Chile showed that although a bacterium was isolated in 28 percent compared with 45 percent of children with lobar consolidation and bronchopneumonia, respectively, the rates of isolation of S. pneumoniae were much lower among children with bronchopneumonia (1 percent versus 24 percent) (Mimica et al. 1971).

Data regarding the relative risk of bacterial pneumonia as well as common respiratory viral-associated LRTI among African HIV-infected children are few (Madhi, Petersen, Madhi, Khoolsal, et al. 2000; Madhi, Schoub, et al. 2000). Although many studies have investigated the etiology of LRTI among African HIV-infected children (Graham et al. 2000; Nathoo et al. 1996; Zar et al. 2001), only limited data exist regarding the pathogen-specific relative risk of LRTI among HIV-infected compared with uninfected children. Table 11.2 illustrates the heightened burden of pathogen-specific bac-teremic pneumonia among HIV-infected as compared with HIV-uninfected children. Significantly, although a broader spectrum of bacteria is implicated in HIV-infected children—in particular, gram-negative pathogens—S. pneumonia and Hib remained the dominant causes of pneumonia among HIV-infected children in the absence of vaccination with any of the bacterial conjugate vaccines. In addition to the heightened burden of bacterial pneumonia, although proportionately less commonly isolated, the burden of hospitalization for common respiratory viral infections was also found to have increased, albeit less so than for bacterial pneumonia, among HIV-infected children (table 11.3).

Table 11.2. Estimated Incidence of Organism-Specific, Bacteremic, Community-Acquired Severe LRTI in HIV-1-Infected and HIV-1-Uninfected Children Age 2 to 24 Months.

Table 11.2

Estimated Incidence of Organism-Specific, Bacteremic, Community-Acquired Severe LRTI in HIV-1-Infected and HIV-1-Uninfected Children Age 2 to 24 Months.

Table 11.3. Estimated Incidence for Specific Viral-Associated Severe LRTI in HIV-1-Infected and HIV-1-Uninfected Children Age 2 to 23 Months.

Table 11.3

Estimated Incidence for Specific Viral-Associated Severe LRTI in HIV-1-Infected and HIV-1-Uninfected Children Age 2 to 23 Months.

Further compounding the impact of the HIV epidemic on the etiology of LRTI and possibly the WHO case-management strategy for its empirical management in Sub-Saharan Africa is the dominance of other opportunistic pathogens. Pneumocystis jiroveci, which is an uncommon cause of LRTI in HIV-uninfected children, except perhaps those that are malnourished or who have other immuno-suppressive underlying illness (Hughes et al. 1974; Pifer et al. 1978), is commonly (10 to 45 percent of cases) identified among African HIV-infected children with LRTI (Graham et al. 2000; Madhi et al. 2002). Although PCP is prevalent in various age groups according to one study in South Africa (Madhi et al. 2002), both the burden of the disease and its poor outcome have consistently been found to be greatest among children less than six months of age.

A further recent observation has been the underrecog-nized importance of Mycobacterium tuberculosis as a cause of acute LRTI. Three separate studies from South Africa and Malawi consistently reported that M. tuberculosis was cultured from 8 percent of children with acute pneumonia (Graham et al. 2000; Madhi, Petersen, Madhi, Khoolsal, et al. 2000; Zar et al. 2001). This is even more alarming considering that most of these studies were performed among children who were mainly investigated for tuberculosis by gastric washing or induced sputum samples—modalities that have a sensitivity of only 25 to 40 percent for diagnosing pulmonary tuberculosis. Consequently, it can be postulated that as many as three times more children than diagnosed by positive M. tuberculosis culture have acute pneumonia caused by this pathogen. Further investigation of these observations are required and, if verified, would have profound implications for the clinical algorithms used in diagnosing pulmonary tuberculosis as well as the management strategies for treating LRTI in children.

The Impact of WHO Management Strategy

Following the realization that LRTI is a major contributor to childhood mortality, the WHO developed a strategy aimed at allowing primary health workers to manage LRTI speedily and effectively. The strategy, which subsequently has been incorporated into the integrated management of childhood illness (IMCI) program, is based on the premises that the majority of severe LRTI in developing countries is due to bacteria, particularly S. pneumoniae and H. influenzae, and that proper management of the disease needs to include consideration of the scarcity of health care facilities in those countries, which also coincidentally happen to be the most burdened by LRTI. A meta-analysis of this strategy has shown that it has been most effective when implemented in those countries where the infant mortality rate was greater than 100 per 1,000 live births (Sazawal and Black 2003). The meta-analysis found that the WHO LRTI case-management strategy reduced LRTI mortality by 42 percent (95 percent CI, 22–57 percent), 36 percent (95 percent CI, 20–48 percent), and 36 percent (95 percent CI, 20–49 percent) among neonates, infants between one and twelve months of age, and children one to four years of age, respectively (Sazawal and Black 2003). The WHO LRTI management strategy has more recently also been evaluated in a program in Malawi (Enarson and Pio 2003; Pio and Enarson 2003). The infant mortality rate in the study area prior to the intervention was 138 per 1,000, and approximately 20 percent of pregnant women were HIV infected, resulting in approximately 4.5 percent of the birth cohort being HIV infected. Implementation of a strategy aimed at the training of district health care workers was associated with a 52 percent reduction in the LRTI mortality if the child survived beyond 24 hours of having presented at a health care facility. There was, however, only a modest nonsignificant reduction (15 percent, P > 0.05) in the deaths that occurred within 24 hours of attention at a health care center. Overall, the case-fatality rate for LRTI decreased from 18 percent at the time of the start of the study to 8 percent 26 months later. These reductions were observed within two years of having implemented the training of health care workers in the management of LRTI in accordance with the WHO/IMCI strategy as well as ensuring adequate access to essential drugs. The overall success of treating LRTI also improved from 55 percent at the time of the start of the program in 1999 to 82 percent 26 months later. These results, from one of the poorest nations on earth, show that standard inpatient case management of severe and very severe pneumonia by trained staff with a regular supply of antibiotics produced a striking impact on the number of deaths occurring after 24 hours of hospital admission, even in the adverse conditions of Malawi, where the prevalence of HIV infection is high, malnutrition is rife, the level of maternal literacy is low, and an efficient transport system from peripheral to district hospitals is lacking.

Considering the numerous challenges to expand and maintain health care provision in resource-poor countries, prevention rather than treatment of LRTI assumes even greater importance. Although some of the risk factors discussed earlier can be addressed only by a general improvement of socioeconomic conditions in these countries, a potentially more immediate measure would be vaccination. That immunization may affect the incidence of LRTI-associated mortality is probably best indicated by the success of the measles vaccine in reducing LRTI-associated deaths in Nigeria (Oyejide and Osinusi 1990). In the Nigerian study, the under-five mortality rate due to LRTI was twofold less common among children who had been immunized with measles vaccine than among children who had not received measles vaccine.

The Impact of Hib Conjugate Vaccines in Preventing LRTI

The potential of further preventing LRTI through vaccination was shown in The Gambia during the course of evaluating the efficacy of a Hib conjugate vaccine among infants (Mulholland et al. 1997). In addition to reducing invasive Hib disease, including Hib meningitis, the vaccine was also shown to reduce the incidence of radiologically confirmed pneumonia by 21 percent (reduction of 1.3 cases per 1,000 children). The overall reduction in clinically diagnosed pneumonia was, however, more modest, with a non-significant reduction of 4.4 percent (95 percent CI, −5 to 12.9), although the study was not statistically powered to measure such small differences against clinically diagnosed LRTI. Interestingly, the incidence rate of clinically diagnosed LRTI requiring hospitalization in The Gambian study was only 3.6 per 1,000 children among the placebo group.

The findings from The Gambia were subsequently corroborated by an effectiveness study in Chile, where a similar reduction in radiologically (21 percent) and clinically diagnosed (5 percent) pneumonia was observed (Levine et al. 1999). The Hib conjugate vaccine was also found to prevent 2.5 cases of hospitalization for LRTI per 1,000 child-years of observation. Although the effectiveness of the Hib conjugate vaccine against pneumonia has not been evaluated among HIV-infected children, data from South Africa suggest that the vaccine is less effective among HIV-infected than HIV-uninfected children, reducing invasive disease by 54 percent and 91 percent, respectively (Madhi et al. 2005). Consequently, it can be extrapolated that the Hib conjugate vaccine may also be less effective in preventing nonbacteremic pneumonia among HIV-infected children than HIV-uninfected children.

In The Gambia, prior to the introduction of the Hib conjugate vaccine, H. influenzae was identified as the second most important cause of bacterial pneumonia, with 75 percent of the isolates being of type b. The importance of H. influenzae is further highlighted by lung aspirate studies in children with pneumonia who did not receive antibiotics. Here, Hib accounted for an average of 27 percent (range of 14 to 45 percent) of all bacterial isolates. Indeed H. influenzae has been shown to be as common as S. pneumoniae (average of 27 percent; range of 12 to 88 percent) as a cause of pneumonia in some studies (Berman and McIntosh 1985). The incidence of bacteremic Hib pneumonia in children less than five years of age ranged between 1 and 7 per 100,000 children in developed countries, such as Finland and Israel (Dagan et al. 1998; Takala et al. 1989), whereas it was estimated to be 370 per 100,000 in developing countries if nonbacteremic cases were included (Peltola 2000). Prior to the introduction of the Hib conjugate vaccine in The Gambia, it was estimated that Hib resulted in a pneumonia-specific mortality rate of 40 per 100,000 in children zero to four years old (Greenwood 1992).

Despite Hib conjugate vaccines being available since the late 1980s, the only Sub-Saharan African country using its own resources to introduce the Hib conjugate vaccine into its routine childhood immunization program since June 1999 was, until very recently, South Africa. The vaccine has been introduced into other Sub-Saharan African countries through donor support from the Global Alliance for Vaccines and Immunisation (GAVI). GAVI has committed itself to financially supporting the introduction of the Hib conjugate vaccine into countries that have a gross domestic product of less than US$2,000 per capita for a period of five years, following which the governments of those countries would be expected to assume the responsibility of continuing to finance the use of the Hib conjugate vaccine. Whether these programs are sustainable is currently being debated. Even in an African country with relatively good resources, such as South Africa, the modest price of the vaccine (approximately US$2 per dose) has almost quadrupled the cost of vaccine procurement for the expanded program of immunization, and its continued use is under debate by policy makers. The cost of the full primary series of vaccines administered during the initial four months of life prior to the introduction of the Hib conjugate vaccine was approximately US$1.5.

The Impact of S. pneumoniae Conjugate Vaccines in Preventing Pneumonia in Children

Despite S. pneumoniae having first been isolated in the 1880s and having been recognized as the leading cause of pneumonia among children, a successful vaccine aimed at preventing pneumococcal pneumonia has remained elusive until 2000 (Black et al. 2002; Klugman et al. 2003). Although Riley and colleagues (1986) showed a benefit for a pneumococcal polysaccharide vaccine in reducing childhood mortality in Papua New Guinea, other studies failed to show any benefit for the use of this vaccine, particularly among children less than 18 months of age (Broome and Breiman 1991). Following the success of the Hib conjugate vaccine, the same technology was used to produce a pneumococcal serotype-specific polysaccharide-protein conjugate vaccine. Those serotypes that were recognized as causing the majority of invasive disease among children were selected for inclusion into the vaccine. The first and currently the only licensed such vaccine is one that includes polysaccharide from seven of the pneumococcal serotypes (Prevenar), based on those serotypes that were most prevalent as a cause of invasive pneumococcal disease (IPD) among children in the United States (Zangwill et al. 1996). Inclusion of these seven serotypes was estimated to have the potential of preventing 90 percent of IPD among children in the United States (Zangwill et al. 1996). The vaccine was subsequently proved to be highly efficacious among those children and was associated with the reduction of vaccine-serotype-specific invasive disease in fully vaccinated children of 97.4 percent (95 percent CI, 82.7–99.9), with an overall reduction of invasive pneumococcal disease of 89.1 percent (95 percent CI, 73.7–95.8) (Black et al. 2000). More important, however, the vaccine was shown to reduce pneumonia associated with any chest radiograph infiltrate by 20.5 percent (95 percent CI, 4.4–34.0) and any clinically diagnosed pneumonia by 4.3 percent (95 percent CI, −3.5–11.5 percent) (Black et al. 2002). The incidence rate of pneumonia, mainly ambulant cases, in the control group in the latter study was 55.9 per 1,000 person-years. The reduction in pneumonia confirmed by chest radiograph was striking insofar as previous epidemiological studies have shown that between 25 and 35 percent of cases of pneumonia in children are due to S. pneumoniae (Heiskanen-Kosma et al. 1998; Wubbel et al. 1999), indicating that the vaccine is highly efficacious even for this end point for which there was no microbiologic evaluation.

A different formulation of the vaccine that included two more serotypes than those included in Prevenar was subsequently evaluated among children in South Africa and The Gambia. These additional serotypes—serotypes 1 and 5—account for about 15 percent of IPD in Africa (Hausdorff, Siber, and Paradiso 2001; Madhi, Petersen, Madhi, Wasas, et al. 2000). In regard to the serotype-specific vaccine efficacy against IPD as well as radiologically confirmed pneumonia among HIV-uninfected children, the results from the South African study were strikingly similar to the findings in children from the United States. Among South African children, the nonavalent pneumococcal conjugate vaccine was shown to reduce culture-confirmed IPD by 83 percent and radiologically confirmed pneumonia, irrespective of microbiological diagnosis, by 20 percent (Klugman et al. 2003). Impressively, the vaccine was also shown to reduce IPD by 65 percent among HIV-infected children; however, there was no significant reduction in first-episode, radiologically confirmed pneumonia among these children (13 percent, 95 percent CI, −7–29) (Klugman et al. 2003). Further analysis of this study, however, indicated that when considering any LRTI irrespective of the chest radiograph features, the vaccine reduced LRTI by 15 percent (95 percent CI, 6–24) among HIV-infected children. This reduction in LRTI translated into a reduction of 25.7 cases of LRTI per 1,000 child-years, compared with a case reduction of 2.7 cases per 1,000 child-years in HIV-uninfected children (efficacy 17 percent; 95 percent CI, 7–26) (Madhi et al. 2005). Interestingly, the reductions in radiologically confirmed alveolar consolidation–associated LRTI were 1 and 9 per 1,000 child-years in HIV-uninfected and HIV-infected children, respectively (Madhi et al. 2005). These data suggest that the sensitivity of radiologically diagnosed pneumonia, based on WHO criteria, detected only about one-third of the cases of pneumococcal pneumonia that were prevented by vaccination. Studies that aim to define the burden of pneumonia preventable by the pneumococcal conjugate vaccine among children in other countries of Sub-Saharan Africa need to take these factors into consideration when determining the tools to be used in defining LRTI, including radiologically confirmed LRTI. Significantly, the data from the South African study included only children who required hospitalization for their episode of LRTI. Considering that only 7 to 13 percent of children with LRTI may have been hospitalized, the total burden of LRTI that may be prevented through vaccination may be much greater, especially considering that the spectrum of pathogens that cause LRTI requiring hospitalization were found to be similar to those that caused LRTI that did not require hospitalization (Selwyn 1990).

The nonavalent pneumococcal conjugate vaccine also reduced invasive pneumococcal disease (77 percent; 95 percent CI, 51–90) and radiologically confirmed pneumonia (37 percent; 95 percent CI, 25–48) in The Gambia, which is much less developed than South Africa. Impressively, in addition to a reduction in cases of pneumonia of 16 per 1,000 child-years among vaccinees in The Gambia, the non-avalent pneumococcal conjugate vaccine was also found to reduce all-cause hospitalization by 15 percent (95 percent CI, 7–21) and all-cause mortality by 16 percent (95 percent CI, 3–28) (Cutts et al. 2005). These data clearly indicate the urgency attendant on the introduction of this new vaccine into developing countries. Modification of the currently licensed product, so as to include pneumococcal serotypes that are important in Africa serotypes (1 and 5) but which are not included in the current seven-valent formulation of the vaccine, would be required to optimize the benefits of the introduction of such a vaccine into Sub-Saharan Africa.

A challenge for other Sub-Saharan Africa countries in regard to defining the potential benefit of pneumococcal conjugate vaccination would, however, include the need to define the spectrum of serotypes that cause disease among children elsewhere, as geographic variation in serotypes that cause IPD have been described even within continents (Hausdorff, Siber, and Paradiso 2001). Hence, the overall proportion of IPD and possibly pneumonia that may be prevented through vaccination may differ between geographic regions, depending on the prevalent serotypes.

Despite these positive findings, and the theoretical benefits of the pneumococcal conjugate vaccine, the greatest impending limiting factor to the introduction of the vaccine into Sub-Saharan Africa is the cost of the vaccine. Currently the vaccine is priced at $48 for the public sector in the United States. Considering the costs of the vaccine and that there are no other competing pneumococcal conjugate vaccines that are likely to be licensed any time soon, unless there is external funding support or major price tiering to assist in introducing the vaccine, it is likely to lag even beyond the 20 years that it has taken for the Hib conjugate vaccine to be introduced into Sub-Saharan Africa. Provisional data from the South African study indicate that the vaccine would be potentially cost-effective if it cost approximately US$4 per dose, based on health expenditure costs in South Africa (Ginsberg et al. unpublished data). Considering that health care expenditure in other Sub-Saharan Africa countries is much lower than in South Africa, the price at which the vaccine may be cost-effective would possibly be even lower.

Other Potential Intervention Strategies in Reducing the Burden of LRTI

The burden of LRTI may be reduced by as much as 45 percent in countries of Sub-Saharan Africa (Madhi, Petersen, Madhi, Wasas, et al. 2000) if effective strategies targeted at preventing HIV transmission from mother to children are implemented. Although a number of proven strategies could reduce the vertical transmission of HIV to between 2 and 13 percent, lack of infrastructure in Sub-Saharan Africa results in less than 5 percent of HIV-infected women being able to access health care to allow these interventions to be implemented (United Nations General Assembly Special Session on HIV/AIDS, unpublished data). Nevertheless, programs aimed at the prevention of the vertical transmission of HIV need to be considered a priority in reducing the overall burden of LRTI among children in Sub-Saharan Africa.

Another priority for those children who are infected with HIV is the introduction of effective strategies aimed at reducing the burden of PCP, especially considering that P. jiroveci has been found to be the etiological agent in as many as 15 to 45 percent of African HIV-infected children with LRTI. Although no randomized trial has evaluated the efficacy of trimethoprim-sulfamethoxazole (TMP-SMX) in preventing PCP among children, this strategy has had profound benefits when it has been implemented in developed countries as well as in such developing countries as Thailand (Chokephaibulkit et al. 2000; Simonds et al. 1995). Although recommended by the WHO and UNAIDS, data from South Africa suggest that there may be structural problems with implementing an effective TMP-SMX prophylaxis even in areas with relatively good resources, such as South Africa (Madhi et al. 2002). Of further importance regarding the widespread use of TMP-SMX is its potential to predispose to developing strains of pneumococcus that are resistant to it as well as to other classes of antibiotics (Madhi, Petersen, Madhi, Wasas, et al. 2000). Such resistance would possibly compromise the WHO management strategy in Sub-Saharan Africa, where in many areas, TMP-SMX remains the mainstay of therapy for the treatment of LRTI. It is likely that the emergence of resistant strains of pneumococcus, coupled with further dissemination of resistant strains, may render TMP-SMX obsolete in the empirical management of LRTI in Sub-Saharan Africa.

The importance of TMP-SMX in reducing morbidity and mortality in African HIV-infected children has recently been highlighted by a study in Malawi. Chintu and colleagues (2004) showed that TMP-SMX prophylaxis reduced mortality in African HIV-infected children, the majority of whom were symptomatic for AIDS, by 43 percent (hazards ratio 0.57; 95 percent CI, 0.43–0.77).

Other Potential Ways to Prevent LRTI

Despite all the promise that the bacterial conjugate vaccines hold in preventing LRTI, it is sobering that the total burden of LRTI reduced by these vaccines is relatively small, albeit important, given the overall magnitude of the burden of LRTI in Sub-Saharan Africa. In The Gambia, the Hib conjugate vaccine prevented only 1.3 cases of hospitalization related to LRTI for every 35.1 cases (about 4 percent) that occurred per 1,000 children enrolled in the study (Mulholland et al. 1997). The nonavalent pneumococcal conjugate vaccine in The Gambia reduced the overall rate of pneumonia by 18 cases per 1,000 child-years, with an incidence rate of 249 per 1,000 child-years among the placebo group (Cutts et al. 2005). The case reduction among South African HIV-uninfected children, including only hospitalized children, was 2.7 per 1,000 child-years with the incidence in the placebo group being 15.7 cases of LRTI per 1,000 child-years (Madhi et al. 2005). These data indicate that although the most severe causes of pneumonia may have been prevented with modest to good success, there remains a large burden of LRTI that even the expensive new generation of vaccines is not able to prevent. Efforts aimed at developing vaccines against respiratory syncytial virus holds the promise that greater inroads may be made in reducing the overall LRTI morbidity even in Sub-Saharan Africa countries. Furthermore, there is a need to continue support for developing more effective vaccines against M. tuberculosis that are effective in preventing not only disseminated tuberculosis but also pulmonary tuberculosis, which may be responsible for 25 percent of LRTI cases requiring hospitalization.

Conclusion

Although the LRTI management strategies of the WHO have the potential of reducing the burden of death from LRTI among countries where under-five mortality is greater than 100 per 1,000 live births, further advances in reducing childhood morbidity and possibly mortality depend on the effective use of bacterial conjugate vaccines in those countries that require them, but where, unjustly for the children, they are least affordable. Furthermore, the reversal of gains in reducing childhood mortality currently being experienced in Sub-Saharan Africa, largely a result of the HIV epidemic, has been associated with almost a doubling of the burden of LRTI in those countries that are heavily burdened by the epidemic. An effective approach to reducing LRTI-associated childhood mortality in Sub-Saharan Africa requires a concerted effort to prevent the vertical transmission of HIV infection, timely and effective rollout of bacterial conjugate vaccines, as well as addressing predominantly poverty-linked, predisposing factors that heighten the risk of children to develop severe and often fatal LRTI.

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