In developing countries, acute respiratory tract infections are among the most important causes of morbidity and mortality in children, particularly those younger than 5 years.1 Although upper respiratory tract infections are the most common pulmonary illnesses occurring in early childhood, lower respiratory tract disease accounts for most severe or chronic illness. The spectrum of pediatrie acute lower respiratory tract infection includes pneumonia, measles, pertussis, and bronchiolitis.
Globally, pneumonia is a major contributor to childhood morbidity and mortality, with most deaths occurring among infants in developing countries.2 This problem has been exacerbated by the human immunodeficiency virus (HIV) epidemic in these countries because pulmonary disease, principally pneumonia, is the most common cause of morbidity and mortality in children infected with HIV.3 Moreover, pulmonary tuberculosis and respiratory disease associated with HIV are important contributors to chronic respiratory illness in children in developing countries.4
Differences in the population demographics of developed and developing countries further affect the spectrum and burden of pediatrie respiratory tract infections. Children younger than 15 years account for approximately 45% of the total population in developing countries, compared with 22% in developed countries.5 Developed and developing countries also differ markedly in the resources available for prevention, diagnosis, and management of pediatrie respiratory tract infections. Insufficient resources, inadequate diagnostic and therapeutic capability, limited access to care, and poor health care infrastructure make diagnosis, prevention, and treatment of childhood respiratory tract infections more difficult in developing countries. The HIV epidemic has further impacted on the global inequities in access to care and quality of care for children in developing countries.
EPIDEMIOLOGY OF RESPIRATORY ILLNESS IN CHILDREN IN DEVELOPING COUNTRIES
Respiratory illness constitutes a significant proportion of the global burden of childhood disease. In 1986, Leowski estimated that acute respiratory tract infection, predominantly pneumonia, accounted for approximately 4 million of the 15 million deaths annually among children younger than 5 years.6 Subsequent World Health Organization (WHO) estimates of the burden of disease suggested that 1.3 million of these deaths were due to measles or pertussis and 2.7 million could be attributed to other respiratory tract infections, mainly pneumonia.2-7 Dye estimated that a median of 19% of childhood deaths were attributed to pneumonia, with the frequency varying from 6% to 36% in diverse communities (C. Dye, unpublished data, May 2001). Differences in risk factors for severe pneumonia, populations studied, health care infrastructure, definition of pneumonia, and study methodologies may contribute to this wide variability. Nevertheless, these estimates confirm mat pneumonia remains a major cause of death in childhood.
The epidemiology of childhood respiratory illness has changed during the past two decades because of several factors. Improved immunization programs in some areas have reduced morbidity and mortality due to measles and pertussis. The HIV pandemic has caused a marked increase in the frequency and severity of childhood respiratory illness, particularly in subSaharan Africa. Worldwide, there are currently more man 1.5 million children infected with HIV, 80% of whom reside in sub-Saharan Africa.8 Pneumocystis carinii pneumonia and bacterial pneumonia have emerged as major causes of hospitalization and death among HIV-positive children in these countries.9"11 Chronic respiratory illness associated with HIV, including lymphocytic interstitial pneumonia, pulmonary tuberculosis, and bronchiectasis, contributes to the morbidity.4 Moreover, the rising incidence of tuberculosis in areas with a high prevalence of HIV has contributed to an increase in pediatrie tuberculosis, with approximately 3.1 million children younger than 15 years infected with tuberculosis.12
THE IMPACT OF HIV ON PEDIATRIC RESPIRATORY TRACT INFECTIONS IN DEVELOPING COUNTRIES
The HIV epidemic has had a major impact on the epidemiology of respiratory tract infections in children in developing countries because most MV-positive children now live in these countries; 90% of these children will have a lower respiratory tract illness during their lifetime.3 Pneumonia is the most common cause of hospitalization among African HIV-positive children. A prospective study of 4,480 pediatrie admissions in Abidjan, Côte d'Ivoire, found that pneumonia accounted for 26% of the admissions among HIV-positive patients compared with 19% of the seronegative children.13 Pneumonia was the most common reason for admission at a regional urban hospital in South Africa from 1992 to 1997 (occurring in 37% of children, 58% of whom were infected with HIV).14
The HTV epidemic has also altered the spectrum of pathogens responsible for childhood pneumonia, with P. carinii pneumonia emerging as an important cause of infant mortality.9'10 Bacterial pneumonia and invasive disease are a common cause of hospitalization and mortality, particularly in children younger than 5 years.11,15 HTV infection has also been associated with an increase in die antimicrobial resistance patterns of common bacterial pathogens that cause lower respiratory tract infection.11 Although viral respiratory tract infection accounts for fewer cases of pneumonia in hospitalized HIV-positive children than in HIV-negative children, it is nevertheless associated with more severe disease in HIV-positive children and a higher case fatality rate.16
The HIV epidemic has increased mortality rates for infants and children younger than 5 years in developing countries. Mortality rates for African HIV-positive children are 35% and 68% at 1 and 5 years, respectively. These are significantly higher man die reported rates for European HIV-positive children of 10% and 20%, respectively.3 A prospective study in Côte d'Ivoire reported the mortality rate for hospitalized HIV-positive children to be 20.8% compared with 8.7% for seronegative children; acute respiratory tract infection accounted for 24% of the deaths among HIV-positive children compared with 18% among seronegative children.13 A 5-year retrospective study of pediatrie hospital admissions in South Africa reported a mortality rate of 13% for HIV-positive children compared with 5% for HIV-negative patients. Pneumonia was the most common cause of mortality, accounting for 25% of the deaths.14
HIV infection increases pneumonia-specific mortality rates in children. Studies consistently report a higher risk of dying of acute lower respiratory tract infection among hospitalized HIVpositive children compared with HIV-negative children.9-11,15,16 The case fatality rate for pneumonia in 150 Malawian children (93 HIV-positive) hospitalized with pneumonia was 22%; deatii was independently and significantly associated with HTV infection.10 A prospective study of South African children hospitalized for pneumonia reported the mortality rate among HIV-positive children (29%) to be almost twice that of HIVnegative children (15%).15
ETIOLOGY OF CHILDHOOD PNEUMONIA IN DEVELOPING COUNTRIES
Bacterial and viral agents are important causes of acute lower respiratory tract infection, but the estimated case-fatality rates for bacterial pneumonia are much higher. In contrast to most viral acute respiratory tract infections, which are usually selflimited illnesses in immunocompetent children, bacteria are responsible for hospitalization or death of a major proportion of children with pneumonia.17 Precise data on the incidence of bacterial pneumonia in children in developing countries have been difficult to obtain because it is difficult to obtain microbiologie confirmation of infection. Nevertheless, the available data indicate that bacterial pneumonia remains a major cause of morbidity and mortality in young children in developing countries. This contrasts with the epidemiology of pneumonia in developed countries, where the incidence of bacterial pneumonia has declined substantially and where viral pneumonia now predominates. In addition, Mycobacterium tuberculosis is an important and prevalent cause of acute and chronic respiratory tract infection in children in developing countries.4,11,15
Studies of bacterial isolates obtained from lung aspirates of children hospitalized with pneumonia who had not received antibiotics provide the most reliable etiologic data on childhood pneumonia in developing countries.17-20 In these studies, bacteria were isolated from 72% of the aspirates (Streptococcus pneumoniae or Haemophilus influenzae in approximately 27% of cases and Staphylococcus aureus in 17%). In many studies, Streptococcus pneumoniae was the most frequently identified organism, occurring in more than 30% of the children. Studies in which blood cultures may have been used to indicate bacterial pneumonia confirmed that Streptococcus pneumoniae, H. influenzae, and Staphylococcus aureus were the most frequent bacterial pathogens in children with acute lower respiratory tract infection in developing countries.11,15
HIV-positive children are at increased risk for recurrent and severe bacterial infections, including pneumonia and bacteremia. Studies of African HIV-positive children with pneumonia reported bacteremia in approximately 15% of the cases.10,11,15 Postmortem studies suggest a much higher incidence of bacterial pneumonia. For Zimbabwean children who died outside of a hospital, lung aspirates revealed bacterial isolates in 86% of the HIVpositive children compared with 74% of the HIVnegative children. Bacterial growth was strongly correlated with malnutrition.21 Pyogenic pneumonia was reported on postmortem examination in 42% of HIV-positive children and 31% of HIV-negative children who died in a hospital in Côte d'Ivoire.22 An increased rate of pneumococcal and Escherichia coli bacteremia has been reported in hospitalized HIV-positive children compared with HIV-negative children with lower respiratory tract infection.11
Viral infections have been identified in 30% to 40% of acute respiratory tract infections in hospitalized children. Respiratory syncytial virus predominated among viral pathogens, accounting for 15% to 20% of such infections.17 Other viruses responsible for lower respiratory tract illness include parainfluenza, influenza, adenovirus, and measles. Mixed viral and bacterial infections occur in up to two-thirds of children with pneumonia,18 HIV-positive children with viral-associated lower respiratory tract infection have higher mortality rates than do HIV-negative children, but this may be partly due to concurrent infections with other pathogens.16
The importance of P. connu pneumonia as a cause of mortality among African HIV-positive children was demonstrated by postmortem studies in which P. carina, pneumonia was detected in 16% to 31% of HIV-positive children.21-22 Recent prospective African studies confirm the importance of P. carinii pneumonia as a cause of severe pneumonia in HIV-positive infants. P. carinii pneumonia was the AIDS-defining illness in 20% of HIV-positive children hospitalized for pneumonia in Cape Town, South Africa; the mortality rate in HIV-positive children with P. connu (47%) was much higher than mat in those without P. carinii pneumonia (18%).9 Cotrimoxazole prophylaxis reduced disease by approximately 90%.9 Of 93 HIV-positive Malawian children hospitalized with severe pneumonia, 17% had P. carinii pneumonia.10 Among children hospitalized in intensive care units in South Africa, P. carinii pneumonia has been reported to occur in 38% to 49% of HIV-positive children with pneumonia.
FACTORS INFLUENCING THE EPIDEMIOLOGY AND SEVERITY OF CHILDHOOD LOWER RESPIRATORY TRACT INFECTIONS
There are multiple environmental, socioeconomic, and health system factors that impact on the incidence and severity of respiratory tract infections in children in developing countries. Poverty, poor living conditions, and large family size promote transmission of infectious agents. Poverty also predisposes to malnutrition, which is an important risk factor for acute respiratory tract infection and severe disease. Malnutrition impairs immunity, respiratory muscle strength, host defense mechanisms, and recovery following infection. Furthermore, micronutrient deficiency has been associated with more severe respiratory illness and a higher mortality rate. Vitamin A deficiency is associated with an increased incidence of respiratory tract infections and a higher mortality rate.23 Zinc deficiency may be associated with a higher incidence of pneumonia.24 Bottle-feeding is associated with a higher mortality rate from acute respiratory tract infection compared with breastfeeding. Poverty may also affect health care access and utilization, because children are brought to health care facilities at a later stage in their illness, and lower rates of immunization coverage may occur.
Exposure to pollutants, including fumes from indoor fuel used for cooking or heating or secondhand smoke, may predispose to respiratory tract infections. Intrauterine exposure to secondhand smoke is associated with an increased prevalence of childhood wheezing, whereas postnatal exposure to smoke is associated with a higher incidence of acute respiratory tract infection. Low birth weight or young age may be associated with a higher risk of acute lower respiratory tract infection or more severe illness. Poorly developed immunity, less efficient respiratory muscles, and small energy stores are contributing factors.
The HIV epidemic further impacts on all of these factors. HIV infection in adult caregivers may perpetuate poverty and poor living conditions. Malnutrition is common in HIV-positive children in developing countries. In addition, HIV infection has been associated with a higher prevalence of micronutrient deficiencies, including vitamin A, vitamin B group, vitamin E, folate, zinc, selenium, and magnesium. Low birth weight is more common among infants born to HIV-positive mothers. The efficacy of standard immunizations may be reduced in HIV-positive children in developing countries, especially because the majority of these children do not have access to antiretroviral therapy.
MANAGEMENT OF CHILDHOOD RESPIRATORY TRACT INFECTIONS
Appropriate, timely therapy for respiratory illness reduces morbidity and mortality. The pneumonia case management strategy developed by the WHO for the treatment of childhood acute respiratory tract infections was based on the assumptions that bacterial pneumonia was largely responsible for death from acute respiratory tract infection in developing countries; that antibiotic treatment could reduce case fatality; and that a simple algorithm based on clinical signs could reliably detect children with pneumonia.25 The WHO case management guidelines for acute respiratory tract infection categorize children presenting with cough or difficulty breathing into three groups based on two key clinical signs: respiratory rate and lower chest indrawing (retractions). Children who have retractions are defined as having severe pneumonia requiring hospital admission. Children with tachypnea are defined as having pneumonia necessitating outpatient antibiotic therapy. Children without tachypnea or chest retractions are considered to have an upper respiratory tract infection and are treated symptomatically. These signs have high sensitivity for pneumonia. The sensitivity of tachypnea for detecting pneumonia ranges from 50% to 81%, whereas the specificity varies from 54% to 70%. The sensitivity of lower chest retractions (17% to 34%) is lower but the specificity (approximately 83%) is higher.26
Prompt therapy with oral antibiotics for children identified as having pneumonia has reduced the mortality rate of those younger man 5 years by 13% to 55%.1'25 A meta-analysis of 6 intervention studies found that in settings with high infant mortality rates (approximately 90 per 1,000 live births), the case management strategy for acute respiratory tract infection reduced the infant mortality rate by 20% and the mortality rate of children younger than 5 years by 25%.25 This compares favorably with the efficacy of measles immunization, which has been reported to reduce the childhood mortality rate by 20%, or the use of oral rehydration therapy for acute diarrhea, which results in a 1% to 8% reduction in the infant mortality rate and a 4% to 14% reduction in the mortality rate of children younger than 5 years. The incorporation of case management guidelines for acute respiratory tract infection into the Integrated Management of Childhood Illness guidelines has provided a more comprehensive approach to diagnosis, prevention, and treatment.27 However, current Integrated Management of Childhood Illness guidelines do not include management of HIV-associated respiratory illness.
Mortality from pneumonia is frequently due to hypoxemia, which can be effectively treated with oxygen. However, oxygen therapy is expensive and unavailable in many hospitals in developing countries.28
PREVENTION OF RESPIRATORY TRACT INFECTIONS
Effective tools exist for preventing pediatrie respiratory tract infections; these have been successfully used in many developed countries. Immunization programs have reduced the incidence of measles and pertussis dramatically. However, overall global coverage for the WHO Expanded Program of Immunization is only approximately 80%, with some countries in sub-Saharan Africa having coverage rates for measles or pertussis far below 50%.29 Globally, this means that 1 in 5 children is still unimmunized against the common respiratory illnesses, including measles, pertussis, and diphtheria. The burden of respiratory infectious diseases in children has been markedly decreased by vaccines that have recently become routinely available in developed countries, including those against H. influenzae type B (Hib) and Streptococcus pneumoniae. However, these vaccines are not widely given in developing countries, partly because immunization coverage for even the basic vaccination package is suboptimal and because these newer vaccines are expensive. In addition, the protective efficacy of standard vaccines may be reduced by HIV-associated immunosuppression. Although the protective efficacy of the Hib vaccine has been estimated to be 95% in fully vaccinated immunocompetent children, the efficacy may be much lower in HIV-positive children who are not receiving antiretroviral therapy. Data on the efficacy of the pneumococcal conjugate vaccine, especially in HIV-positive children, are needed to establish policies for use in developing countries.
The effects of immunization may extend beyond disease-specific protection to provide a reduction in mortality greater that which can be explained by prevention of a specific disease. Recently, measles and bacille Calmette-Guérin vaccination have been postulated to produce such an effect, possibly through nonspecific stimulation of the immune system.30 In a prospective study in Guinea-Bissau, measles or bacille Calmette-Guérin vaccination produced a greater improvement in overall survival than could be attributed to a reduction in deaths caused by measles or tuberculosis.30
General interventions that may prevent pediatrie respiratory tract infections include attention to adequate nutrition and micronutrient supplementation. A meta-analysis of vitamin A supplementation did not find a reduction in pneumonia morbidity and mortality, but there was an overall reduction in all-cause mortality.23 Vitamin A supplementation significantly reduces the morbidity and mortality of acute respiratory tract infection associated with measles. A pooled analysis of randomized trials of zinc supplementation in children in developing countries indicates a 41% reduction in the incidence of pneumonia.24 This effect is similar to the estimated contribution of eliminating malnutrition. Attention to environmental factors, including avoidance of exposure to indoor air pollution, may also reduce the incidence and severity of acute respiratory tract infections.
Disease-specific prevention strategies targeting at-risk pediatrie populations such as chemoprophylaxis for primary prevention of P. carinii pneumonia in HIV-positive children or tuberculosis prophylaxis for children exposed to an infectious contact are effective, but require infrastructure and resources for implementation. Finally, many respiratory complications associated with HIV may be prevented through antiretroviral therapy, which requires an improvement in health care infrastructure and a reduction in drug costs.
Acute lower respiratory tract infections continue to be a major cause of morbidity and mortality in children in developing countries. The magnitude of the HJV epidemic in these areas has increased the burden and severity of respiratory tract infections. Although most children live in developing countries, relatively poor resources in these areas limit me ability to prevent, diagnose, and treat childhood respiratory tract infections. More research on the morbidity and mortality of pneumonia in developing countries, and on the potential efficacy of different interventions, is needed. A global effort to improve health care in the developing world is critical to reduce preventable morbidity and mortality associated with acute respiratory tract infections among children in these countries.
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