Serious infections in young infants in developing countries: rationale for a multicenter study

Despite major advances in recent years, infant mortality rates remain high in many developing countries. In 1995, of ∼126 million infants born alive into the world, ∼8 million (6%) died during their first year, 5 million during the neonatal period and many during the second and third months of life.1 In many developing countries neonatal death is systematically underreported because of cultural reluctance to declare neonatal deaths.2 Despite this bias towards underreporting, 98% of the neonatal deaths in the world are believed to occur in developing countries, mainly in Asia and Africa, where the regional neonatal mortality rates average >40 per 1000 live births and where several countries have rates of >60.1 Because most neonatal deaths occur at home, there are few data on the causes of the deaths. It is believed that infection is a major cause, representing a progressively larger contribution in settings with higher neonatal death rates. WHO has developed a case management strategy to reduce mortality from acute respiratory infections (ARI) in developing countries.3 Health workers are trained to identify pneumonia in children >2 months of age using simple clinical signs (fast breathing and lower chest wall indrawing).4 This approach has recently been incorporated into the Integrated Management of Childhood Illness strategy, which combines ARI management with the management of the other important causes of childhood mortality, malaria, diarrheal disease, malnutrition and measles. In the first 2 months of life, when one-third of all childhood ARI deaths are believed to occur, this strategy is broadened to include sepsis and meningitis, in addition to pneumonia, because of the difficulty in distinguishing between these entities clinically. Separate guidelines have been developed for children <2 months of age and are currently being implemented in a number of developing countries as part of the Integrated Management of Childhood Illness strategy. For children age 2 months to 4 years the importance of bacteria in the etiology of pneumonia in developing countries is well-documented, with Streptococcus pneumoniae and Haemophilus influenzae causing the most severe cases.5, 6 In contrast there are inadequate data on the clinical signs and etiologic agents of serious infections in infants <2 months of age in developing countries. Bacterial infections can lead very rapidly to death in this age group, prevention of which requires early detection based on recognition of simple clinical signs by the family and health workers. Following expert clinical advice and published etiologic data, predominantly from developed countries, WHO manuals and training materials currently recommend referring young infants with suspected pneumonia, sepsis or meningitis for treatment with parenteral penicillin and gentamicin. To improve case management guidelines for health workers responsible for the care of young infants in both outpatient and inpatient settings, a multicenter study was set up under the auspices of WHO in four developing countries, Ethiopia, The Gambia, Papua New Guinea and The Philippines. This paper describes the rationale for the study and summarizes the data that existed before the study. ETIOLOGY OF SERIOUS BACTERIAL INFECTIONS IN YOUNG INFANTS IN DEVELOPING COUNTRIES The immunologically naive neonate is particularly susceptible to bacterial infections. For how long this high level of susceptibility to infection persists is unclear. During the second and third months there is a steady maturation of the immune system, although the child remains susceptible to infection with organisms like H. influenzae type b for several years. In developed countries serious neonatal bacterial infections are now usually caused by Escherichia coli or Streptococcus agalactiae (group B Streptococcus), although in the past Streptococcus pyogenes (group A Streptococcus) was a major cause and Staphylococcus aureus has been responsible for many serious nursery outbreaks. Gradual shifts in the organisms responsible for serious bacterial infections have been documented in several hospitals.7-9 Young infants in developing countries suffer a much higher mortality than in developed countries, and much of this mortality is caused by bacterial infection. There have been a number of studies on the etiology of neonatal sepsis in developing countries. The results of 15 studies describing >3000 blood culture-positive cases of neonatal sepsis in India, Africa, the Middle East and the West Indies were reviewed.10-24 In 6 studies Klebsiella spp. was the most frequently isolated organism, in 3 it was Staphylococcus aureus and in three it was E. coli. Overall the most frequently isolated organism was Klebsiella spp. followed by E. coli, Staphylococcus aureus and Pseudomonas spp. There were only 32 isolates of S. agalactiae, most from one small study in the West Indies,22 although in a more recent publication it was found to be the most important cause of neonatal meningitis in Harare, Zimbabwe.25 The other important feature of these data is the large number of infections with Klebsiella spp. and Staphylococcus aureus. Most of these studies were hospital-based and many of the infections are likely to have been hospital-acquired. However, one study from India of infections among home-delivered neonates also found many cases of Klebsiella spp. and Staphylococcus aureus infections.26 In the more recent studies the staphylococci were almost uniformly resistant to penicillin; 10 to 57% of Klebsiella were resistant to gentamicin.18 The particular problem of early neonatal sepsis associated with amnionitis was explored in detail in Addis Ababa, Ethiopia, in the 1970s. In that city the rate of fatal neonatal sepsis associated with amniotic fluid infection was estimated at 21.8/1000 live births.27 Cultures from a series of 339 autopsies yielded a wide variety of organisms. Ureaplasma urealyticum was the most commonly found organism, being found in 44% of infected placentas and in only 6% of control placentas from healthy infants. It was also recovered from 26% of infant lung specimens. In a prospective study from the same city, blood cultures were taken from 945 infants younger than 8 days of age with suspected sepsis; bacteremia was present in 344, of whom 260 were <72h old.28 These yielded a variety of organisms, particularly E. coli, Klebsiella spp. and Staphylococcus aureus. No pneumococci or H. influenzae were isolated although pneumococci were isolated from a few specimens (0.9%) in the postmortem study. There have been several studies from developing countries looking at meningitis in young infants. Soni, from the University of Garyounis, Libya, reporting on neonatal meningitis, found Klebsiella spp. and Staphylococcus aureus to be the dominant organisms.29 In two studies from Dakar, Senegal, where large numbers of patients with meningitis have been studied, enterobacteria, in particular Salmonella spp. and S. pneumoniae, were the main causes of meningitis in infants younger than the age of 3 months.30, 31 In the more recent of those studies 13 of 42 cases of meningitis in infants younger than 3 months of age were caused by S. pneumoniae and one was caused by H. influenzae. In a retrospective study of 36 cases of neonatal meningitis presenting to University College Hospital, Ibadan, Nigeria, 10 were caused by S. pneumoniae, 8 by E. coli and 2 by H. influenzae.32 Similar results were obtained in a smaller study from Yaoundé, Cameroon Republic.33 There, of 14 cases of meningitis in children younger than 2 months of age, 5 were caused by S. pneumoniae and one was caused by H. influenzae. In a recent study of H. influenzae meningitis in the Gambia, 6% of cases were <3 months old.34S. agalactiae was not found in most of these studies, but it has been shown to be an important cause of neonatal meningitis in Zimbabwe25 and South Africa (K Klugman, personal communication). Despite the large published studies of neonatal sepsis that focus on Klebsiella spp. and Staphylococcus aureus as the main causes of neonatal infections, there remained suspicion that H. influenzae and S. pneumoniae may play a previously unrecognized role in neonatal sepsis and pneumonia. Both these organisms are difficult to isolate from blood culture, and minor alterations in methodology can substantially reduce the number of isolates from a laboratory. Because vaccination of 3-month-old infants against H. influenzae type b is likely to become routine in many parts of the world and similar conjugate vaccines against S. pneumoniae are currently being evaluated, it is important to know how much disease caused by these organisms occurs before vaccination age, so that other specific measures to protect young infants, such as maternal immunization, can be explored. Several of the above studies support the suspicion that S. pneumoniae and H. influenzae are underestimated as causes of serious infections in young infants in developing countries.30-32 Both organisms are recognized as rare causes of neonatal sepsis in developed countries. Carriage rates of these organisms are much higher in neonates and older children in developing countries,35 so it is reasonable to expect that they may play a more significant role in neonatal sepsis in those countries. OBJECTIVES OF THE MULTICENTER STUDY The objectives of this study were to improve the recognition and the management of serious infections in young infants in developing countries. Recognition of serious infections must be undertaken at the community level by those health workers who have contact with young infants born into poor circumstances. In most cases these are community health workers or traditional birth attendants, usually with minimal training. Simple signs are needed that can be easily taught and applied to detect appropriate infants for referral to hospital. There are two approaches to developing an algorithm composed of such signs. One approach is to assemble a group of experienced experts in the field and develop a consensus opinion. The other is to conduct a prospective study to evaluate the possible signs. This is the course we chose to follow. Discussions held between clinicians working in developing countries before the start of the study revealed three general views of the etiology data. One view based on published studies held that because Klebsiella spp. and Staphylococcus aureus are the established causes of neonatal sepsis in developing countries, recommended therapy should be directed against these organisms and further studies are not required. The second view held that blood culture studies dominated by hospital-acquired infections from institutions with inadequate bacteriology should not be taken as a guide to the etiology of community-acquired infections that were the likely cause of most neonatal deaths and were probably caused by the same pathogens as in developed countries, S. agalactiae and E. coli. The third view, favored by most, held that existing studies were inadequate for the reasons outlined above and the causative organisms in developing countries are likely to be different to developed countries, with S. pneumoniae and H. influenzae probably being more important in developing countries. With this degree of uncertainly the need for a careful study with the use of high quality bacteriology was clear. There were so few data on the role of viruses and atypical organisms in this age group in developing countries that it was considered essential that these agents be sought in as many sites as possible. For reasons of sample size and representativeness a multicenter study was considered preferable. Sites were selected in Asia, Africa and Latin America for their ability to perform the study. The group in the Latin American site withdrew because of political instability leaving two African sites and two Asian sites, The Gambia, Ethiopia, The Philippines and Papua New Guinea.