Conclusions from the WHO multicenter study of serious infections in young infants

This supplement has presented the results of a large study of the etiology and clinical signs of serious infections in 4552 infants younger than 91 days of age in 4 developing countries, Papua New Guinea, The Philippines, Ethiopia and The Gambia.1-7 This paper summarizes the important findings of the study, discusses the implications for the management of infections in young infants in developing countries and discusses future work that could facilitate progress in this difficult area. ETIOLOGY The bacteriology results from these four very different countries produced remarkably similar results. Among infants with clinical signs indicating that infection was likely, the rate of positive blood culture ranged from 4% in The Philippines and 5% in Papua New Guinea (PNG) to 10% in Ethiopia and 11% in The Gambia. The low rate of positive culture in PNG is likely to be the result of the milder nature of illness in infants in that site compared with 16% for the other sites together. The lower culture positivity rate in The Philippines is likely to be the result of the high rate of early antibiotic administration in that community compared with the others. Among the 167 bacterial isolates from blood cultures in the study, 96 (57%) of the isolates were the three main Gram-positive pathogens, Streptococcus pneumoniae, Staphylococcus aureus and Streptococcus pyogenes. This pattern was seen across the sites, with all 3 organisms being isolated from infants in all sites. Staphylococcus aureus was seen more frequently in The Gambia than in the other sites, and S. pyogenes was seen more frequently in PNG than in the other sites. The major role of S. pneumoniae was an important finding of the study, particularly its role as a cause of meningitis in this age group. It will surprise many to find that S. pneumoniae was the cause of 43% of episodes of proven bacterial meningitis in this study and 50% of meningitis episodes in infants older than 1 week of age. Of particular concern is the serotype distribution of the pneumococcal cases. Eight of the 17 pneumococcal meningitis cases were caused by type 2, a rare cause of invasive pneumococcal disease in infants beyond the neonatal period, and a serotype not included in any of the current generation of pneumococcal conjugate vaccines. It appears that even if administered during the first few weeks of life, pneumococcal conjugate vaccines may have only a limited impact on pneumococcal meningitis in early infancy. This finding argues in favor of maternal immunization with the 23-valent pneumococcal polysaccharide vaccine, which does include type 2, as a potential strategy to prevent early infant pneumococcal disease. Other Gram-positive infections, particularly Streptococcus agalactiae (group B Streptococcus) infection, were uncommon in this study. The wide variety of enteric Gram-negative organisms causing invasive disease is as expected. Although most of these infections were found in infants younger than 2 months of age, there were infections caused by Acinetobacter spp., Klebsiella spp. and Escherichia coli in the third month of life, suggesting that susceptibility to these organisms does extend into the third month, although most cases of meningitis caused by these organisms occurred during the first month of life. E. coli was the most common Gram-negative organism found. Most of the E. coli isolates were in infants younger than 1 month of age and most were from Ethiopia. Salmonella spp. was a significant pathogen in all the sites except Papua New Guinea. This has significant implications for treatment. Before this study, recommended empiric therapy for suspected serious infections in young infants in developing countries was penicillin and gentamicin, for the reasons outlined in earlier papers.1 Although still the antibiotic of choice for S. pyogenes infections, penicillin is ineffective against staphylococcal infections in many parts of the world. Penicillin-resistant S. pneumoniae organisms are now found in most parts of the world.8 Although the clinical relevance of penicillin resistance in pneumococcal pneumonia is uncertain, few would feel comfortable treating penicillin-resistant pneumococcal pneumonia in very young infants with penicillin, and there is no doubt that penicillin is ineffective in the treatment of penicillin-resistant pneumococcal meningitis.9 Thus for penicillin-resistant pneumococcal infections in young infants, the drug of choice is a third generation cephalosporin such as cefotaxime, provided cephalosporin resistance is not a problem, This would also provide effective cover against Salmonella infection and other Gram-negative infections. Thus although this study supports the use of ampicillin and gentamicin for the initial therapy of suspected neonatal sepsis, where meningitis is present, or where infection with penicillin-resistant S. pneumoniae or Salmonella is suspected, a third generation cephalosporin should be used. Where skin sepsis or another marker of staphylococcal infection is present, an antistaphylococcal agent should be added. The virology results produced a similar picture across the different sites. Just as in developed countries respiratory syncytial virus is the most important virus affecting this age group, causing considerable respiratory morbidity, but little mortality.10 Indeed the isolation of viruses was associated with a lower risk of death in the Gambian study. Virus infections, particularly those caused by respiratory syncytial virus, are common in this age group in developing countries but appear to be rarely associated with an adverse outcome. In contrast the major role of Chlamydia trachomatis as a cause of neonatal pneumonia was well-demonstrated in Papua New Guinea.11 Particularly disturbing was the finding that C. trachomatis is associated with severe pneumonia and hypoxemia. Further information on this important finding will become available in the future after further assays of specimens from the Gambian study. OUTCOME In this study there were 247 deaths among the 4552 infants enrolled. This group provided a rare insight into early infant death in developing countries, which is a poorly understood area. Of those infants who died 63% (156 of 247) were younger than 1 month of age; of those 51% (80 of 156) were younger than 1 week of age. During the course of the analysis it was found that particular factors associated with mortality included inability to feed, low or high temperature, low white blood cell count and positive blood or CSF culture. The infant deaths in this study will be the subject of an ongoing analysis which will be reported at a later stage. CLINICAL SIGNS One of the primary objectives of this study was the use of the large amounts of clinical data collected to help derive a simple clinical algorithm that could be used to enable health workers in developing countries to identify young infants at high risk of dying for referral to the hospital for inpatient care. This analysis presented a number of challenges that were described in detail in this supplement. The huge data set was approached with a high level of statistical rigor, and the result of a careful, structured analysis was a relatively simple model involving weight, age, temperature, respiratory rate and five clinical signs.7 These were able to predict the presence of serious disease with a high degree of accuracy. Probability values attached to each score provide the clinician with real probability estimates corresponding to each score, allowing the physician to incorporate this information into a rational plan for each infant. This information should provide specialist clinicians working in developing countries with a useful guideline to predict the risk of serious illness in a very young infant. Unfortunately the use of complex probability information is not likely to be very useful for primary care situations in developing countries, where crucial decisions about the referral of infants are usually made by health workers with only minimal training. In such settings an algorithm to assist decision making must include a threshold score beyond which a child is referred. This study has shown that such a system is feasible, even for this most difficult group. Applied in settings similar to those in which this study was conducted, and using a cutoff score designed for maximum sensitivity and specificity for detecting any hypoxemia, radiographic abnormality or positive culture (12 points on the scale, 0.17 predicted probability), the algorithm described in the accompanying paper7 would result in the referral of 80% of infants with any hypoxemia, radiographic abnormality or positive culture, 88% of those with positive cultures or severe hypoxemia and 94% of those who would die of the current illness, at a cost of 49 referrals of infants without positive cultures, positive chest radiograph or hypoxemia for every 100 referrals. If this is judged to be too insensitive, the algorithm can be adjusted to produce 95% sensitivity for any hypoxemia, radiographic abnormality or positive culture (for which the cutoff in predicted risks is 0.10, corresponding to 8 points on the scale shown in Table 5 of Ref. 7). This would result in 60 referrals of infants without positive cultures, positive chest radiograph or hypoxemia for every 100 referrals. FUTURE PROSPECTS It is anticipated that during the coming decade infant mortality in developing countries will continue to decline as a result of vaccination and other specific strategies as well as general improvements in living standards and standards of health care. As the proportion of infant deaths occurring in the first 3 months increases the need to address this group will become more urgent. Although prevention must always be the first priority, the need to improve recognition and treatment of infectious diseases in this age group must also be addressed. As a result of this study we now have a clear view of the etiologic spectrum of agents causing serious infections in very young infants in developing countries. This information, combined with recent data on regional trends in antimicrobial resistance patterns, should help guide health planners and clinicians to the most appropriate antibiotic therapy for this group of infants. However, recognition and referral of sick infants remain a major challenge. The model proposed based on the analysis of this study may be usable in some settings as part of a strategy to train traditional birth attendants or other health workers in contact with neonates. It may need further simplification for use as part of a more general strategy for acute pediatric care such as the Integrated Management of Childhood Illness currently being promoted by WHO. The next step in this process should be the formal evaluation of the algorithm, using an appropriate control group, in a setting with a high neonatal mortality rate. This will demonstrate the true potential for this strategy.