Epidemiology and clinical features of pneumonia according to radiographic findings in Gambian children

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1 Tropical Medicine and International Health doi: /j x volume 12 no 11 pp november 2007 Epidemiology and clinical features of according to radiographic findings in Gambian children Godwin Enwere 1, Yin Bun Cheung 2, Syed M. A. Zaman 1, Alieu Akano 3, Claire Oluwalana 1, Okoko Brown 1, Adeola Vaughan 1, Richard Adegbola 1, Brian Greenwood 2 and Felicity Cutts 1 1 Medical Research Council Laboratories, Fajara, The Gambia 2 London School of Hygiene & Tropical Medicine, London, UK 3 National Hospital Abuja, Abuja, Nigeria Summary objective To assess the effect of vaccines against in Gambian children. methods Data from a randomized, controlled trial of a 9-valent pneumococcal conjugate vaccine (PCV) were used. Radiographic findings, interpreted using WHO definitions, were classified as primary end point, other infiltrates and with no abnormality. We calculated the incidence of the different types of radiological, and compared clinical and laboratory features between these groups. results Among children who did not receive PCV, the incidence of with no radiographic abnormality was about twice that of other infiltrates and three times that of primary. Most respiratory symptoms, reduced feeding and vomiting occurred most frequently in children with primary. These children were more likely to be malnourished, to have bronchial breath sounds or invasive bacterial diseases, and to die within 28 days of consultation than children in the other groups. Conversely, a history of convulsion, diarrhoea or fast breathing, malaria parasitaemia and isolation of salmonellae were commoner in children with with no radiographic abnormality. Lower chest wall indrawing and rhonchi on auscultation were seen most frequently in children with other infiltrates. conclusion is strongly associated with bacterial aetiology and severe. Since this category of is significantly reduced after vaccination with Hib and pneumococcal vaccines, the risk-benefit of antimicrobial prescription for clinical for children with increased respiratory rate may warrant re-examination once these vaccines are in widespread use. keywords, epidemiology, clinical features, radiographic findings Introduction An estimated 150 million cases and 2 million deaths from occur in children under 5 years old each year (Williams et al. 2002; Wardlaw et al. 2006). These figures have led to a recent call to action to improve the implementation of proven interventions to prevent and treat (Wardlaw et al. 2006). At the same time, better methods are needed to determine the burden of more precisely (Williams et al. 2002; Mulholland 2003; Rudan et al. 2004). Vaccine trials may be used as a probe to estimate the burden of due to any particular organism (Lucero & Williams 2005), but require appropriate outcome measures to determine the vaccine effect. Blood culture lacks sensitivity as it is only positive in about one third of cases of bacterial, while antigen tests lack specificity due to the presence of circulatory antigen produced in non-pulmonary sites such as the nasopharynx (WHO 2001). Lung aspirate studies, widely regarded as the gold standard for defining the aetiology of, have reported bacterial isolation rates between 28% and 84% in patients with and consolidation (WHO 2001) and some studies have given high bacterial yields in patients with broncho (ill-defined infiltrates) (Mimica et al. 1971; Silverman et al. 1977). Thus, a practicable and reliable method to diagnose bacterial s has remained elusive. The World Health Organization (WHO) recently developed a standardized method to define radiographic changes considered most likely to indicate bacterial for use in epidemiological studies (WHO 2001; Cherian et al. 2005). The WHO defines primary as the presence of a dense or fluffy opacity that occupies a portion or whole of a lobe or of ª 2007 Blackwell Publishing Ltd 1377

2 the entire lung, and or the presence of fluid in the lateral pleural space between the lung and chest wall (WHO 2001; Cherian et al. 2005). This definition has been used in two recent trials of pneumococcal conjugate vaccine (PCV) in Africa. In the Gambia, PCV showed efficacy against cases of primary but not other s (Cutts et al. 2005), whilst in South Africa, viral-associated s (Madhi & Klugman 2004) and clinical s diagnosed by paediatricians (Madhi et al. 2005) were also prevented by PCV. To enhance our ability to interpret studies using the new definition, we obtained prospective clinical and radiological data on children that met the WHO criteria for lower respiratory tract infection (Gove 1997) and compared epidemiological and clinical features of s with different radiographic findings. Subjects and methods A randomized, double blind trial of PCV was conducted in eastern Gambia, where child mortality is high, malaria transmission intense in the rainy season (July to November), and HIV-1 prevalence is about 1% in adults. The study methods and main outcomes of the trial were described by Cutts et al. (2005). Briefly, we enrolled approximately children aged 6 51 weeks when they attended government vaccination clinics that serve an area of approximately 5000 km 2. Children were randomized to receive three doses of PCV or placebo, which were identical-looking powders, mixed with liquid Diphtheria- Pertussis-Tetanus-Haemophilus Influenzae type b (DPT- Hib) vaccine before administration. Trial staff conducted around the clock surveillance to investigate children with signs of or invasive pneumococcal disease at Basse health centre and Bansang hospital, and visited peripheral health centres and outreach sites at 2- to 4-week intervals. Hospital referrals were made from these peripheral facilities. Children were followed until the age of 30 months or until 30 April 2004, the end of the trial, with a median of 87 weeks [95% confidence interval (CI) 69 98] of follow-up. Case ascertainment All study children who presented to Basse health centre or Bansang hospital were assessed for a history of cough or breathing difficulty; trained study staff counted the respiratory rate and assessed the severity of illness following WHO guidelines (Gove 1997). Symptoms, signs, weight and initial diagnoses were recorded on standard case report forms before any radiological investigation was done. Children with signs of severe illness were referred to study paediatricians who also recorded the presence of lower chest wall indrawing and auscultatory findings. If a child was admitted to hospital, the oxygen saturation was measured using a Model 511 Pulse Oximeter (Novametrix Medical Systems Inc., Wallingford, CT, USA) with the appropriate sensor placed on a big toe or thumb. During the first 18 months of the trial, children were referred for a chest radiograph if a paediatrician suspected that the child had severe. In the last 27 months, all children who met WHO criteria for an acute lower respiratory tract infection (Gove 1997; fast breathing for age and or lower chest wall indrawing) (henceforth called ) were referred for a radiograph. Although these children met the WHO definition of an acute lower respiratory tract infection, many were considered by the nurse or doctor to be more likely to have malaria or another illness and, in these cases, this was recorded as the primary diagnosis. As previously described (Cutts et al. 2005), a paediatrician and paediatric radiologist read chest radiographs independently following WHO radiology working group standards and procedures (WHO 2001; Cherian et al. 2005). A WHO panel read films on which these two readers did not agree on the presence of primary. We defined clinical as a history of cough or breathing difficulty of less than 30 days duration, with a raised respiratory rate for age and or lower chest wall indrawing. If a physician identified lower chest wall indrawing, we classified the as severe. Radiographic findings were classified according to the WHO Pneumococcal Trialist Ad Hoc Committee recommendations (WHO 2001; Cherian et al. 2005). For the definition of primary, the WHO criteria specify that either the paediatrician and paediatric radiologist both diagnose the presence of primary or that one of these readers plus the WHO consultant panel does so. The WHO group did not specify similar criteria for other infiltrates. Hence, we have classified radiological findings in hierarchical fashion as follows: : presence of or pleural effusion as defined by WHO criteria. Other infiltrates : no and any of the readers indicated the presence of other infiltrates. with no radiographic abnormality : no, no reader indicated the presence of other infiltrates and all readers considered the film readable ª 2007 Blackwell Publishing Ltd

3 Unreadable film : any of the readers considered the film unreadable. No radiograph taken. Statistical analysis We calculated incidence rates (per 1000 person-years) for each type of by age, gender and season, classifying the seasons as previously reported (Cutts et al. 2005) and grouping together children with no readable radiograph and those with no radiograph. We also calculated the incidence rates according to age, gender and season for the period after the change in method of surveillance described above. This period contributed 84% of follow up time, 86% of the cases of were seen during this period and the results obtained then are hereafter referred to as restricted analysis. Except where indicated, the results presented here refer to the analysis for the whole trial duration. We based 95% CIs on the Poisson distribution with robust standard errors. Multiple episodes of were included, thus incidence rates differ from those reported previously (Cutts et al. 2005). Children who presented with were considered to have a new episode if 30 days or more had passed since their first consultation for. Characteristics of s were compared between children who received PCV and children who received placebo, using the Kruskal Wallis test for continuous variables and the Fisher s exact test for categorical variables. Nutritional status and anaemia were defined as previously reported (Enwere et al. 2006). Analyses of oxygen saturation, lower chest wall indrawing, and auscultatory findings (bronchial breath sounds, rhonchi and crepitations) were limited to children admitted to hospital. We restricted tabulations of comparisons of clinical and laboratory features by type of to children who did not receive PCV to facilitate future comparison of our findings with burden of disease studies that use the WHO definition of radiological. In these analyses, children with clinical for whom a readable radiograph was not obtained were excluded. Ethical approval The pneumococcal vaccine trial was approved by the ethics committees of the Gambia Government MRC and the London School of Hygiene & Tropical Medicine, and by the WHO Secretariat Committee for Research Involving Human Subjects. Results We identified 9109 episodes of clinical, in 5842 children. A chest radiograph was obtained in 7813 (85.8%) episodes, of which 104 (1.3%) were judged unreadable. was diagnosed in 1085 (13.9%) episodes; other infiltrates in 2209 (28.3%) and with no radiographic abnormality in 4415 (56.5%) episodes. The agreement between the reading of the paediatrician and that of paediatric radiologist was highest for primary, followed by unreadable films and least for other infiltrates with kappa scores (95% CI) of 0.58 ( ), 0.37 ( ) and 0.23 ( ) respectively. The median (inter quartile range) ages of children with primary, other infiltrates and with no radiographic abnormality did not differ significantly and were 13.2 ( ), 15.6 ( ) and 14.2 ( ) months respectively. There was a male preponderance for all s that was most marked for other infiltrates. Incidence of The incidence of clinical was 280 (95% CI, ) per 1000 person years overall; 287 (95% CI, ) for children who did not receive PCV and 274 (95% CI, ) for PCV-vaccinated children (Table 1). Results from the restricted analysis were slightly higher for each of the groups, although the confidence limits overlapped (Table 2). The incidence of primary, but not of other radiographically confirmed s, was much lower among PCV-vaccinated than non-vaccinated children [26 (95% CI, 24 29) vs. 40 (95% CI, 37 43)]. Among non- PCV-vaccinated children, the incidence of with no abnormal chest radiograph [134 (95% CI, )] was about twice that of other infiltrates and three times that of primary (Table 1). Results from the restricted analysis followed a similar pattern. The incidence of all s increased from the youngest age group to a peak at months and fell thereafter, the decrease in the age group months being steepest for primary. The incidence of all s was lowest in the cool season between December and February. The incidence of primary was similar in the hot dry season and rainy seasons, while that of other radiographic s ª 2007 Blackwell Publishing Ltd 1379

4 Table 1 Incidence of community-acquired in Gambian children aged 2 months per 1000 person-years (95% CI) by pneumococcal conjugate vaccination status Unvaccinated children Vaccinated children No, or unreadable radiograph Other infiltrates All clinical No, or unreadable radiograph Other infiltrates All clinical Characteristic Overall 287 ( ) 40 (37 43) 69 (64 73) 134 ( ) 45 (41 49) 274 ( ) 26 (24 29) 68 (63 72) 138 ( ) 43 (40 47) Age (months) <6 289 ( ) 32 (25 41) 47 (39 57) 118 ( ) 93 (80 107) 289 ( ) 26 (20 34) 53 (44 63) 119 ( ) 90 (78 104) ( ) 49 (42 56) 59 (52 67) 125 ( ) 59 (52 67) 269 ( ) 31 (26 37) 54 (47 62) 130 ( ) 54 (47 62) ( ) 46 (40 54) 94 (84 104) 161 ( ) 49 (42 57) 330 ( ) 31 (25 37) 84 (75 94) 170 ( ) 46 (39 53) ( ) 42 (36 50) 72 (64 82) 142 ( ) 17 (13 22) 263 ( ) 23 (18 29) 81 (71 91) 140 ( ) 20 (15 25) ( ) 20 (15 27) 52 (44 63) 103 (91 118) 9 (6 14) 184 ( ) 14 (10 20) 53 (44 63) 108 (95 122) 10 (6 15) Sex Male 316 ( ) 42 (38 47) 82 (75 89) 143 ( ) 50 (44 55) 288 ( ) 29 (25 33) 74 (68 81) 142 ( ) 44 (39 49) Female 258 ( ) 38 (34 43) 54 (49 60) 125 ( ) 41 (36 46) 260 ( ) 24 (20 28) 60 (54 66) 134 ( ) 42 (38 47) Season March June 243 ( ) 49 (43 56) 66 (60 74) 92 (84 101) 36 (31 41) 214 ( ) 29 (25 34) 63 (56 70) 89 (81 98) 33 (19 39) July November 409 ( ) 45 (40 50) 90 (83 98) 206 ( ) 68 (62 75) 399 ( ) 32 (28 37) 89 (81 97) 214 ( ) 65 (59 71) December February 160 ( ) 23 (19 28) 38 (32 44) 77 (69 86) 22 (18 27) 161 ( ) 14 (11 18) 40 (35 47) 84 (76 94) 23 (19 28) was highest in the rainy season among both vaccinated and unvaccinated children (Table 1). The restricted analysis showed a similar pattern except that the incidence of primary for both vaccinated and unvaccinated children peaked at 6 11 months of age, and the incidence of all types of was highest in the rainy season in vaccinated children. Clinical signs There were few differences in the clinical features of primary between children who had received PCV and those who had not, and no evidence of a decrease in severity in PCV-vaccinated children (data not tabulated). Children who did not receive PCV had slightly higher median temperatures than PCV-vaccinated children (median 38.6 C vs C, respectively, P = 0.001) but were less likely to have oxygen saturation below 90% than PCV-vaccinated children (10% vs. 16%, respectively, P = 0.03). All subsequent results refer to children who did not receive PCV. Histories of cough, chest pain, difficulty with breathing, reduced feeding and vomiting were significantly more frequent in children who had primary than in those without. Conversely, a report of fast breathing, a convulsion or diarrhoea was significantly more common in children who had with a normal chest radiograph than in those with chest radiographic. The distribution of duration of illness prior to consultation was slightly, but significantly, longer in children with primary (Table 3). Children with primary had a higher median temperature, and a higher proportion appeared sick on examination than children with other infiltrates or with a normal chest radiograph. Lower chest wall indrawing was found most commonly in children with other infiltrates. On auscultation, bronchial breath sounds were strongly associated with primary ; rhonchi were heard more frequently in children with other infiltrates, and crepitations were heard more frequently in children with a primary or other infiltrates than in children with no abnormality on chest radiograph (Table 3). Malnutrition and severe malnutrition were more common in children with primary than in those in the other groups. Children with primary were more than twice as likely to require admission to hospital as children in the other groups. The median oxygen saturation was slightly lower in children with an abnormal chest radiograph, but there was no 1380 ª 2007 Blackwell Publishing Ltd

5 Table 2 Incidence of community-acquired in Gambian children aged 2 29 months per 1000 person-years (95% CI) by pneumococcal conjugate vaccination status (analysis restricted to the last 27 months of follow up) Unvaccinated children Vaccinated children No, or unreadable radiograph Other infiltrates All clinical No, or unreadable radiograph Other infiltrates All clinical Characteristic Overall 295 ( ) 44 (41 48) 78 (73 83) 156 ( ) 16 (14 19) 284 ( ) 28 (26 32) 77 (73 83) 160 ( ) 18 (16 21) Age (months) <6 311 ( ) 38 (29 50) 57 (47 71) 157 ( ) 58 (47 72) 315 ( ) 33 (25 44) 67 (55 82) 162 ( ) 53 (42 67) ( ) 58 (50 67) 74 (65 84) 164 ( ) 14 (10 19) 293 ( ) 36 (30 44) 69 (60 80) 171 ( ) 17 (13 22) ( ) 51 (44 60) 108 (97 120) 188 ( ) 14 (11 18) 348 ( ) 34 (28 41) 99 (89 111) 199 ( ) 16 (13 21) ( ) 44 (37 52) 76 (67 87) 149 ( ) 7 (5 11) 266 ( ) 24 (19 30) 84 (75 95) 147 ( ) 11 (8 16) ( ) 20 (15 27) 52 (44 63) 104 (91 118) 9 (6 14) 185 ( ) 14 (10 20) 53 (45 64) 108 (95 122) 10 (7 15) Sex Male 323 ( ) 45 (40 51) 94 (86 102) 166 ( ) 18 (15 22) 300 ( ) 31 (27 36) 85 (78 93) 165 ( ) 19 (16 23) Female 265 ( ) 44 (39 49) 62 (56 69) 145 ( ) 15 (12 18) 269 ( ) 26 (22 31) 70 (63 78) 156 ( ) 17 (14 20) Season March June 240 ( ) 51 (45 58) 73 (65 81) 101 (92 111) 15 (12 19) 217 ( ) 31 (27 37) 69 (62 77) 98 (90 108) 19 (15 23) July November 424 ( ) 50 (44 56) 104 (96 114) 247 ( ) 23 (19 28) 421 ( ) 36 (31 41) 105 (97 115) 256 ( ) 25 (21 29) December February 170 ( ) 27 (22 33) 45 (38 53) 91 (81 102) 7 (5 11) 171 ( ) 14 (11 19) 48 (41 56) 101 (91 112) 8 (5 11) significant difference in the proportion of children with hypoxia between the groups (Table 3). Investigation, diagnosis and outcome Invasive bacterial disease was found most frequently in children with primary (Table 4) and least frequently in those with other infiltrates. Pneumococci were the most frequent isolate from children with primary (54 of 61 isolates) while non-typhoid salmonellae organisms were isolated most frequently from children with a normal chest radiograph (14 of 17 isolates) (Table 4). The median white blood cell count was significantly higher in children with primary than in children in the other groups (Table 3). Anaemia and severe anaemia were common in children in all groups although severe anaemia was slightly less common in children with other infiltrates than in those in the other groups. Malaria parasitaemia was one-third to onehalf as frequent in children with primary as in children in the other groups (Table 3). Children with primary were more likely to have an initial primary diagnosis of (67.0%) than those with other infiltrates (55.6%) or those with with no radiological abnormality (46.3%). Conversely, an initial primary diagnosis of malaria was more common in children with and a normal radiograph (48.3%) than in those with other infiltrates (39.4%) or primary (26.3%). Approximately 3% of non-pcv vaccinated children with who were admitted to hospital died in hospital, with little variation according to radiographic findings. However, death within 28 days of consultation occurred significantly more frequently in children with primary than in those with other infiltrates or with a normal radiograph (3.0%, 0.8% and 1.2% respectively). The risk ratios for death within 28 days were 2.55 (P = 0.001) and 0.68 (P = 0.314) in the primary and other infiltrates groups as compared with the normal radiography group. After adjusting for weightfor-age, the risk ratios for death for primary was 1.98 (P = 0.026) and for other infiltrates s, 0.66 (P = 0.283) compared to with no radiographic abnormality. Similar patterns emerged for vaccinated children: 4% of those with primary died within 28 days of presentation compared to 0.7% of children with other infiltrates and 1.2% ª 2007 Blackwell Publishing Ltd 1381

6 Table 3 Clinical characteristics by radiological type of, among children who had not received pneumococcal conjugate vaccine* Clinical signs (n = 658) Other infiltrates (n = 1112) no chest X-ray abnormality (n = 2171) P value Symptoms Duration of illness before 3 (2 4) 3 (2 3) 3 (2 3) <0.001 consultation (n = 3925), median (IQR) (%) (days) Fever (n = 3935) Cough (n = 3937) <0.001 Chest pain (n = 3894) <0.001 Breath difficulty (n = 3908) <0.001 Fast breathing (n = 3908) Vomiting (n = 3915) Reduced feeding (n = 3908) <0.001 Convulsions (n = 3910) Diarrhoea (n = 3907) Signs Appear sick very sick (n = 3912) <0.001 Temperature, C (n = 3937), 38.6 ( ) 38.2 ( ) 38.4 ( ) <0.001 median (IQR) Chest indrawing (n = 982) Crepitation (n = 987) Rhonchi (n = 977) <0.001 Bronchial breathing (n = 982) 18.3% 3.3% 2.8% <0.001 Admitted to hospital (n = 3941) <0.001 Oxygen saturationà (n = 984), 96 (94 97) 96 (93 97) 97 (95 98) <0.001 median (IQR) Oxygen sat. <90% Weight-for-age (n = 3899), 2.2 ( 3.2 to 1.4) 2.1 ( 3.1 to 1.2) 2.0 ( 2.9 to 1.0) <0.001 median (IQR) Weight-for-age < 3 SD Duration of hospitalisation (days) (n = 961), median (IQR) 3 (2 4) 3 (2 5) 3 (2 5) IQR, interquartile range. *Children with no readable radiographs excluded. The significant difference arose from the fact that the consolidation group had a longer tail in the distribution. The third quartile was slightly longer in children with consolidation than infiltrate and normal chest radiography (4, 3 and 3 days respectively). The 19th percentile was even longer among children with consolidation (7, 5 and 4 days respectively). àlast five rows for inpatients only. those with and a normal radiograph (data not tabulated). Discussion Our study has shown the continuing high frequency of clinical in rural Gambia, 12 years after community-based interventions for prevention and management of were advocated (Bobadilla et al. 1994; Gove 1997) and despite the elimination of Hib disease through vaccination (Adegbola et al. 2005). The overall incidence rates were underestimates because not all children had easy access to health facilities or referral for investigation. This underestimation would have been most marked in the beginning of the study, but even after the change in case ascertainment methods we did not have the resources to detect and refer all cases of clinical. The observed incidence of clinical was very close to the global estimate of 0.29 episodes per child-year in children under 5 years in developing countries estimated by Rudan et al. (2004) and about 10 times the estimated incidence in developed countries. The results of studies of the incidence of may be influenced by the intensity of surveillance, definition of 1382 ª 2007 Blackwell Publishing Ltd

7 Table 4 Laboratory findings by type of radiological, among children who did not receive pneumococcal conjugate vaccine* Characteristics (number investigated) (n = 658) Other Infiltrates (n = 1112) (n = 2171) P Value Invasive bacterial infection (n = 2152), % <0.001 S. e <0.001 Non-typhoidal Salmonella <0.001 Other bacteria <0.001 Malaria positive (n = 2252), % <0.001 White blood cell ( 10 3 ll) (n = 1693), median (IQR) 16.0 ( ) 12.0 ( ) 12.1 ( ) <0.001 Haemoglobin (HB) (g dl) (n = 2465), median (IQR) 8.3 ( ) 8.6 ( ) 8.3 ( ) Anaemia (HB < 11 g dl), % Severe Anaemia (HB < 8 g dl), % *Children with no readable radiographs excluded. Other bacteria include E. coli, other coliforms, S. aureus, meningococcus, Streptocococcus spp., Shigella spp., Pseudomonas and Klebsiella spp., prevalence of conditions such as malaria that mimic clinically, and the age group studied. Our study was conducted among children aged 2 29 months and incidence fell after age 17 months. A clinicbased surveillance study in the same area of The Gambia in , before Hib vaccine was introduced, reported a incidence of child-years in 0- to 59-month-old children (O Dempsey et al. 1996), with rates somewhat lower than ours of 225, 147 and year in children aged 6 11, and months respectively (Greenwood BM, personal communication). A community-based study in one village near Basse in found an incidence approximately 10 times higher using active weekly surveillance (Forgie et al. 1992). The definitions used in all these studies followed the WHO criteria for ALRI (Gove 1997). In The Gambia, prior to the introduction of Hib vaccine, this definition had 81% sensitivity and 89% specificity for the detection of compared to a physician s diagnosis (Weber et al. 1997), despite the overlap of clinical signs between and malaria (O Dempsey et al. 1993). Among non-pcv-vaccinated children, 16.7% of cases from whom a radiograph was obtained had primary, and 45% had primary and or other infiltrates. The lower proportion of s with radiographic changes in our clinic-based study than in the earlier community-based study (28% consolidation and 73% consolidation or infiltrates) (Forgie et al. 1992) may reflect different processes and criteria used for classifying radiographs as well as the impact of Hib vaccine in reducing with consolidation (Mulholland et al. 1997). Although a herd immunity effect on reducing transmission to unvaccinated persons has been reported with PCVs (Centers for Disease Control and Prevention 2005), this would have been minimal in our study because of the individual randomization and the long duration of recruitment which meant that in any one village the proportion of young children who received PCV was low. The WHO definition of primary aimed to identify s most likely to have a bacterial origin, for use in trials of bacterial vaccines such as PCV, and in studies of the burden of bacterial s (Cherian et al. 2005; Magree et al. 2005). There is some evidence that the association between this definition and bacterial can vary in different settings (Madhi et al. 2005). In The Gambia, there are several indications that primary is likely to have a bacterial aetiology. First, as previously reported, PCV efficacy against primary was 37% (955 CI 25 48) but that against clinical without these radiographic changes was zero (95% CI ) (Cutts et al. 2005). Second, in the current analysis, bacterial isolates were much more common in children with primary than in those with other types of. The pneumococcus was by far the commonest cause of primary with bacteraemia, as previously found in The Gambia (Forgie et al. 1991; Falade et al. 1997) and elsewhere (WHO 2001). Third, fever was slightly higher, and leucocytosis was more common in primary than in other s, while evidence of malarial infection was much less common, consistent with the negative relationship between invasive bacterial infection and malaria reported in Kenya (Berkley et al. 2005). We found that lower chest wall indrawing and rhonchi on ª 2007 Blackwell Publishing Ltd 1383

8 auscultation were more common in other infiltrates than in other types of, and that hypoxia was equally common in other infiltrate and primary. These data suggest that lower chest wall indrawing may not necessarily be a sign of severe bacterial and other infiltrates probably comprises a mixture of cases of viral or bacterial aetiology (Virkki et al. 2002). Our data showed that children with primary appeared more ill, and were more severely malnourished and severely anaemic than those with other radiological findings. These children were also more likely to require inpatient care, have a slightly, but significantly, longer duration of illness and to die within 28 days of admission. The reason for more deaths within 28 days of discharge was not apparent as these children were apyrexic for at least 48 h before discharge, completed a total of at least 7 days of antibiotics treatment and the relationship persisted after controlling for nutritional status. Magree et al. (2005) also found that was more severe among children with primary than among those with no radiographic changes. Pneumococcal conjugate vaccine significantly reduced the frequency of primary, but the severity of cases that did occur differed little between vaccinated and unvaccinated children, presumably because such cases were due to pneumococcal serotypes not included in the vaccine, or to other organisms. This underscores the importance of effective surveillance in places where pneumococcal vaccine is introduced so as to monitor the possible changes that may occur in the bacterial aetiology of. Vaccination with Hib and PCVs will be complementary to, but not replace, other interventions for which include improved child nutrition, hand washing, improvement in living conditions and appropriate case management with antimicrobials (Bryce et al. 2006). Among children who received PCV in addition to Hib vaccine, the rate of primary was 9.5% of the rate of all clinical s, much less than the 24 36% reported in studies conducted before the introduction of conjugate vaccines (Rudan et al. 2004). Berkley et al. (2005) showed that only 1 in 33 children with WHO-defined mild clinical and a positive malaria slide had an identified invasive bacterial infection. In our data, over half the cases of clinical accompanied by fever who had a chest radiograph and blood film examined had malaria parasitaemia. Thus, the development of simple diagnostic tests to identify bacterial s among children with signs of clinical remains an important challenge. The findings of this study show that primary is strongly associated with bacterial aetiology and severe. Since this category of is significantly reduced following vaccination with Hib and pneumococcal vaccines, the risk-benefit of antimicrobial prescription for for children with increased respiratory rate may warrant re-examination once these vaccines are in widespread use. Acknowledgements The trial was funded by grants from NIAID, NIH through contract N01-AI-25477; by WHO through contract V , by the Childrens Vaccine Program at PATH and USAID, with vaccine kindly donated by Wyeth Vaccines. We thank all contributors to the pneumococcal vaccine trial. The Gambian Government provided staff and the infrastructure for vaccination and supervisory support from District Health teams. We acknowledge the invaluable role of the children who participated in the trial, and their parents. References Adegbola RA, Secka O, Lahai G et al. (2005) Elimination of Haemophilus influenzae type b (Hib) disease from The Gambia after the introduction of routine immunisation with a Hib conjugate vaccine: a prospective study. Lancet 366, Berkley JA, Lowe BS, Mwangi I et al. (2005) Bacteremia among children admitted to a rural hospital in Kenya. New England Journal of Medicine 352, Bobadilla JL, Cowley P, Musgrove P & Saxenian H (1994) Design, content and financing of an essential national package of health services. Bulletin of World Health Organisation 72, Bryce J, Terreri N, Victora CG et al. (2006) Countdown to 2015: tracking intervention coverage for child survival. Lancet 368, Centers for Disease Control and Prevention (2005) Direct and indirect effects of routine vaccination of children with 7-valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease United States, Morbidity and Mortality Weekly Report 54 (36), Cherian T, Mulholland EK, Carlin JB et al. (2005) Standardized interpretation of paediatric chest radiographs for the diagnosis of in epidemiological studies. Bulletin of World Health Organisation 83, Cutts FT, Zaman SM, Enwere G et al. (2005) Efficacy of ninevalent pneumococcal conjugate vaccine against and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial. Lancet 365, Enwere G, Biney E, Cheung YB et al. (2006) Epidemiologic and clinical characteristics of community-acquired invasive bacterial 1384 ª 2007 Blackwell Publishing Ltd

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