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Incidence of pneumonia, bacteremia, and invasive pneumococcal disease in Pakistani children

2010; Wiley; Linguagem: Inglês

10.1111/j.1365-3156.2010.02591.x

1365-3156

Aatekah Owais, Shiyam Sunder Tikmani, Shazia Sultana, Umber Zaman, Imran Ahmed, Salim Allana, Anita K. M. Zaidi,

Emergency and Acute Care Studies

Objective To determine the incidence of pneumonia, bacteremia, and invasive pneumococcal disease (IPD) in Pakistani children <5 years old. Methods Household surveillance from 1st February 2007 to 12th May 2008 was conducted in two low-income, coastal communities of Karachi. Community health workers referred each sick child <5 years old to the local clinic. Blood culture was obtained whenever possible from children meeting inclusion criteria. Results Overall, 5570 children contributed 3949 observation years. There were 1039 clinical cases of pneumonia, of which 54 were severe pneumonia and four cases of very severe disease according to WHO criteria. The overall pneumonia incidence was 0.26 (95% CI: 0.25–0.28) episodes per child-year. A pathogen was isolated from the blood of 29 (2.8%) pneumonia cases. Bacteremia incidence was 912 (95% CI: 648–1248) episodes per 100 000 child-years with a case fatality rate of 8%. The detected IPD incidence was 25 (95% CI: 1–125) episodes per 100 000 child-years. The under-five mortality rate was 55 per 1000 live births, with pneumonia causing 12 (22%) deaths among children <5 years old. Conclusion Clinical pneumonia is common in Pakistani children, with one in four deaths attributable to the disease. Bacteremia occurs at a high rate but surveillance for pneumococcus underestimates the burden of IPD. Incidence de la pneumonie, de la bactériémie et des maladies invasives à pneumocoque (MIP) chez les enfants pakistanais Objectif: Déterminer l’incidence de la pneumonie, la bactériémie et des MIP chez les enfants pakistanais de moins de 5 ans. Méthodes: Surveillance des ménages du 1er février 2007 au 12 mai 2008 dans 2 communautés côtières de Karachi à faibles revenus. Les agents de santé communautaires ont référé chaque enfant de moins de 5 ans malade à la clinique locale. Une hémoculture a été obtenue dans la mesure du possible chez les enfants répondant aux critères d’inclusion. Résultats: Au total, 5.570 enfants ont contribuéà 3.949 observations années. Il y avait 1.039 cas cliniques de pneumonie, dont 54 étaient une pneumonie sévère et 4 cas de maladie très grave selon les critères de l’OMS. L’incidence globale de la pneumonie était de 0,26 (IC95%: 0,25-0,28) épisodes par enfant-année. Un agent pathogène a été isolé du sang de 29 (2,8%) cas de pneumonie. L’incidence de bactériémie était de 912 (IC95%: 648-1,248) épisodes pour 100.000 enfants-années avec un taux de létalité de 8%. L’incidence détectée de MIP était de 25 (IC95%: 1-125) épisodes pour 100.000 enfants-années. Le taux de mortalité chez les moins de 5 ans était de 55 pour 1.000 naissances vivantes, la pneumonie en causant 12 (22%). Conclusion: la pneumonie clinique est fréquente chez les enfants pakistanais, avec 1 sur 4 décès imputables à la maladie. La bactériémie survient à un taux élevé, mais la surveillance des pneumocoques sous-estime la charge des MIP. Incidencia de neumonía, bacteremia y enfermedad neumocócica invasiva en niños Paquistanies Objetivo: Determinar la incidencia de neumonía, bacteremia, y enfermedad neumocócica invasiva (ENI) en niños paquistanies menores de 5 años. Métodos: Vigilancia en hogares entre el 1 Febrero 2007 y el 12 Mayo 2008 en 2 comunidades costeras de bajos ingresos de Karachi. Los trabajadores sanitarios refirieron a los niños enfermos, menores de 5 años, al centro sanitario local. Se obtuvo un hematocultivo siempre que fué posible de los niños que cumplían los criterios de inclusión. Resultados: 5,570 niños contribuyeron a 3,949 años de observación. Se detectaron 1,039 casos clínicos de neumonía, de los cuales 54 eran de neumonía severa, y 4 casos de enfermedad muy severa según los criterios de la OMS. La incidencia total de neumonía era0.26 (95% IC: 0.25-0.28) episodios por niño-año. Se aisló un patógeno de sangre en 29 (2.8%) casos de neumonía. La incidencia de bacteremia era 912 (95% IC: 648-1,248) episodios por 100,000 niños-años con una tasa de letalidad del 8%. La incidencia detectada de ENI era 25 (95% IC: 1-125) episodios por 100,000 niños-años. La tasa de mortalidad para menores de 5 años era de 55 por 1,000 nacidos vivos, con la neumonía causando 12 (22%) muertes entre niños menores de 5 años de edad. Conclusión: La neumonía clínica es común en niños paquistaníes, con 1 en 4 muertes atribuíbles a esta enfermedad. La bacteremia ocurre con una tasa alta pero la vigilancia de pneumococo subestima la carga de ENI. Childhood pneumonia is among the leading causes of death in low-income countries, causing 18% of deaths in children under 5 years of age (Black et al. 2010). With 151 million new episodes each year, of which 7–13% require hospitalization (Rudan et al. 2008), pneumonia also creates substantial economic and financial burden on the health care system of countries with limited resources. Prospective, microbiology-based studies have identified Streptococcus pneumoniae, or pneumococcus, to be contributing substantially to this burden (Rudan et al. 2008). With an estimated 10 million cases occurring each year, childhood pneumonia is also a primary cause of under-five mortality in Pakistan (Black et al. 2010, Rudan et al. 2008). Information about the burden of invasive pneumococcal disease (IPD) and serotype distribution among children in Sindh, a province of over 35 million people in southern Pakistan, is extremely limited (Zaidi et al. 2004). Previous studies, sponsored by the United States Board of Science and Technology for International Development (BOSTID) in the 1980s, focused on urban areas of northern Punjab, an area climatically and geographically distinct from southern Pakistan, which is hot, humid, and arid (Ghafoor et al. 1990; Mastro et al. 1991). These studies found pneumococci to be the most common bacterial pathogen isolated from the blood of children with severe pneumonia in Islamabad and Rawalpindi (Ghafoor et al. 1990; Mastro et al. 1991). This study was undertaken to determine the incidence of pneumonia, bacteremia, and IPD in Pakistani under-fives and to study the clinical presentation, serotype distribution, seasonality, and antimicrobial resistance pattern of invasive pneumococcal isolates. The main objective of the study was to establish population-based surveillance for IPD in children with clinical pneumococcal syndromes (pneumonia, sepsis, meningitis, documented febrile illness) in two semi-urban areas of Sindh, located near Karachi. We carried out population-based surveillance for pneumonia, bacteremia, and IPD by conducting household visits from 1st February 2007 to 12th May 2008. The surveillance was carried out in two low-income, contiguous areas located 20 km outside of Karachi. The Aga Khan University’s Department of Pediatrics and Child Health has been conducting several studies related to neonatal health and outcomes in these areas since 2003. Both areas are semi-urban to rural settings, with fishing and livestock rearing as the major income-generating activities. Biomass, specifically cow dung, is the major source of household fuel used for cooking in a large number of households. There is a 30-bed public sector hospital, but it is barely functioning and does not admit patients overnight. Selecting these communities as surveillance sites to establish the true burden of pneumonia, bacteremia, and IPD in children in Pakistan had several advantages: (i) this is a semi-urban area typical of settings in Pakistan, with poor access to care and a high burden of childhood infections; (ii) we have an ongoing surveillance system for the most vulnerable subset of population (neonates), with well-established ties and rapport with the community; and (iii) there is minimal formal healthcare available in the area, and the Department-run local health centre is the major healthcare provider. Our household surveillance system thus maximized chances of detecting children with pneumonia, bacteremia, and IPD. As a preliminary activity, all children under 5 years of age in our study areas were assigned a unique identification number (surveillance ID) so that the community health workers (CHWs) could carry out house-to-house visits to identify sick children <5 years of age. Consent from community elders and local political representatives was obtained. This was an open cohort, with new births in the households under surveillance included and children reaching age 5 years excluded. At the outset, the CHW visited each household once every week to motivate people to seek care at the community health centre for any febrile illness. Families were counselled about danger signs in children and advised against antibiotic self-prescription. CHWs continued to visit houses weekly to check the child’s status. Any child found to have at least two key signs or one danger sign based on the WHO/UNICEF Integrated Management of Childhood Illness (IMCI) Guidelines (WHO & UNICEF 2000) was referred to the local health centre by the CHW, using standardized referral protocols (Table 1). The CHW recorded data for all children <5 years of age, living in the surveillance areas including births, deaths, cause of death (using verbal autopsy), occurrence of any serious illness, including severe ARI, and whether medical care was sought. All children under the age of 5 years presenting at the health centre were triaged for possible pneumococcal clinical syndromes (using core case definitions developed by the PneumoADIP investigator’s group (PneumoADIP 2009); see Table 2) after obtaining informed consent. All children identified as possible pneumococcal clinical syndrome (pneumonia, severe pneumonia, very severe disease, or meningitis) underwent a blood culture. Additionally, blood for culture was also obtained from children with documented fever ≥38 °C, with or without otitis media, to detect children with bacteremia who did not present with the syndromes defined earlier. Clinical information recorded included history, prior treatment and therapy sought, full physical examination findings (all the core variables defined in the PneumoADIP pneumococcal clinical syndrome definitions (PneumoADIP 2009)) as well as pulse oximetry results, blood culture results, diagnosis assigned, management given, and final patient outcome. Any patient sick enough to be hospitalized was transported to the public sector National Institute of Child Health in Karachi, which currently serves as our referral hospital for the field sites and is also a sentinel site in the pneumococcal meningitis surveillance programme. The laboratory of this hospital has been up-graded by WHO EMRO and has been isolating pneumococci routinely. Blood was drawn for culture using aseptic precautions. Approximately 2–3 ml of blood was obtained from those who gave consent. Samples were inoculated into BACTEC Peds Plus® (Becton Dickinson, Sparks, MD, USA) bottles on-site and transported to an AKU laboratory collection site approximately 30 min away from the study sites. Every effort was made to ensure that bottles got loaded into the BACTEC 9240 (Becton Dickinson) system within 4 h of collection. Laboratory technicians visually inspected bottles before loading and gram-stained and sub-cultured any bottles with turbid appearing broth before loading on the system, as pneumococci are very fragile and can die quickly from autolysis of a large number of organisms, paradoxically yielding negative cultures. The Aga Khan University Hospital Laboratory is a state-of-the art, high-quality laboratory, processing more than 200 000 specimens per year, and offering advanced microbiologic testing, including molecular diagnostics. It follows external quality assurance programmes. The laboratory routinely isolates fastidious organisms such as pneumococci and Haemophilus influenzae type b. All records are computerized and maintained electronically. Standard isolation and antimicrobial susceptibility testing procedures were utilized, with appropriate recording and timely reporting of results, as per usual practice. All pneumococcal isolates were frozen in duplicate. The size of the population under surveillance was determined using the expected combined annual pneumonia, severe pneumonia rate and very severe disease episode rates of 0.25 (95% CI: 0.24–0.26) per child per year, and 5% level of precision (Rudan et al. 2004). Statistical analysis was performed using spss 15.0. Observation period for a child began when consent was obtained and continued for 52 weeks, or until the child died, withdrew from the study, or reached the age of 5 years, whichever came first. Children who were born during the study period were enrolled on a continuing basis. Their observation period also began at consent and continued until the child died, withdrew from the study, or May 12, 2008, whichever came first. Incidence was calculated as the number of cases per child-years of observation. Mean incidence per month was used to determine seasonality. The study was approved by the Ethical Review Committee of AKU, and confidentiality of patients was maintained at all times. From 1st February 2007 to 12th May 2008, 5570 children were included in the study, contributing 3949 observation years (Figure 1). Following study criteria, CHWs referred 3372 episodes of illness among 1412 children to the local study clinic. Of these, families of 1259 children, contributing 1388 episodes of suspected bacteremic illness consented to be referred and examined by a physician at the primary health centre to obtain a clinical diagnosis. Flow diagram of numbers lost during the study period. The most common presenting complaints were fever (91.9%) and cough (88.5%). Chest indrawing was the primary complaint in 17 (1.2%) episodes. Among 1388 episodes of illness, caretakers of 540 (38.9%) reported having taken previous medication for their illness, either self-prescribed or obtained through local stores that also sell medicines, licensed or unlicensed doctor. Of these, 9.6% reported having taken antibiotics. During the study period, there were 1039 clinical cases of pneumonia, of which 54 (5.2%) were severe pneumonia and 4 (0.4%) were cases of very severe disease using WHO/UNICEF classification according to IMCI criteria (WHO & UNICEF 2000). The overall pneumonia incidence for the period was 0.26 (95% CI: 0.25–0.28) episodes per child-year. The age-specific distribution of pneumonia cases and incidence is presented in Table 3. Pneumonia incidence ranged from 0 in July 2007 to 3925 episodes per 100 000 child-years in January 2008 (Figure 2). The incidence of pneumonia peaked during the drier, cooler months (November–March) and was the lowest during the monsoon season. Seasonal variation in the incidence of acute respiratory infections (ARI). Of the 1388 episodes, families of 223 cases did not consent to give blood for culture. Among the 1165 cases whose families consented, blood was successfully obtained for 1147 (98.5%) episodes of suspected IPD. Phlebotomy was unsuccessful for 1.5% of cases. Overall, at least one blood culture was drawn from approximately 20% of children contributing person-time to the surveillance system during the study period. There were 36 bacterial pathogens isolated from blood during the period, for an isolation rate of 3.1% among 1147 blood cultures obtained (excluding contaminants, such as coagulase-negative staphylococci, diphtheroids and viridans streptococci). Of these, 1 (2.8%) was S. pneumoniae. This was a female, aged 7 months, and was diagnosed with pneumonia or possibly enteric fever on presentation at the local study clinic. She presented with fever, fast breathing, runny nose, and diarrhoea, but no chest indrawing. According to her primary caretaker, these symptoms had persisted for the past 7 days. She had previously been taken to another hospital but was only prescribed medication to manage her diarrhoea. Other isolates included 16 (44.4%) Salmonella typhi, 8 (22.2%) Acinetobacter spp., 1 (2.8%) Pseudomonas spp., 1 (2.8%) Escherichia coli, 3 (8.3%) Campylobacter jejuni, 2 (5.6%) Salmonella paratyphi A, 1 (2.8%) Salmonella Paratyphi B, 1 (2.8%) Haemophilus influenzae type b, 1 (2.8%) Kingella spp., and 1 (2.8%) β-haemolytic Group B streptococcus. A further 71 blood cultures grew contaminants for a contamination rate of 6.2%. The overall detected IPD incidence was 25 (95% CI: 1–125) episodes per 100 000 child-years. Among the 1039 episodes of pneumonia, 29 (2.8%) had a pathogen isolated from blood (excluding contaminants). Bacteremia incidence was 912 (95% CI: 648–1248) episodes per 100 000 child-years. The mean age of children with bacteremia was 22 months (range: 1–56 months). Age-specific bacteremia incidence is summarized in Table 4. With three deaths among the 36 bacteremia cases, the case fatality rate among children with bacteremia was 8.3%, 1 week after initial presentation (Table 5). In contrast, there was 1 (0.7%) death among the non-bacteremia cases (OR = 120.1; 95% CI: 12.5–3230.0). There were a total of 980 live births and 54 deaths because of all causes, during the surveillance period, for an under-five mortality rate of 55 per 1000 live births. The age-specific all-cause mortality rates are presented in Table 6. Pneumonia, including very severe disease and severe pneumonia, caused 12 (22%) deaths among children less than 5 years of age. Case fatality rates according to severity of disease are presented in Table 7. Other causes of death included diarrhoea (22%), neonatal causes including neonatal sepsis, pneumonia, birth asphyxia, and prematurity (22%), bacteremia (6%), and meningitis (6%) (Figure 3). Cause specific mortality (n = 54a) among children <59 months of age. aOne child had bacteremia and pneumonia. We observed an overall pneumonia incidence of 0.26 episodes per child-year, with the incidence peaking in the drier, cooler months. The incidence of disease was highest among children <12 months of age at 0.42 episodes per child-year and decreased with age. Pneumonia was also identified as the main cause of childhood mortality, with almost 28% of all deaths, including pneumonia deaths in the neonatal period, attributed to the disease. The detected incidence of IPD was 25 cases per 100 000 child-years in our study population. This estimate of IPD burden is lower than findings from other developing country populations in Africa, Asia, and Latin America (Usen et al. 1998; Lagos et al. 2002; Campbell et al. 2004; Brent et al. 2006; Brooks et al. 2007; Arifeen et al. 2009). However, our detected incidence is an underestimate because only a third of febrile episodes could be cultured and because of the unexpectedly high prior medication use rate in this population, despite active surveillance. In Africa, disease rates of 15, 171, and 436 cases per 100 000 child-years have been reported from Mali, the Gambia, and Kenya, respectively (Usen et al. 1998; Campbell et al. 2004; Brent et al. 2006). In Asia, studies from Bangladesh reported IPD rates of 86 and 447 cases per 100 000 child-years from two different areas of the country (Brooks et al. 2007; Arifeen et al. 2009). In Latin America, a population-based surveillance study conducted in Chile found an IPD incidence of 34 cases per 100 000 child-years (Lagos et al. 2002). A multitude of factors may explain this variation in the reported incidence of IPD, even within the same country. Even though differences in study methodologies, in terms of case definitions, intensity and type of surveillance, study inclusion criteria, case detection, prior exposure to antimicrobials, and laboratory procedures may explain some of the variation in the disease burden across these regions, there may also be true differences in disease rates observed because of levels of indoor air pollution, crowding, nutritional status, as well as host genetic susceptibility (Arifeen et al. 2009). Using standard WHO definitions (WHO & UNICEF 2000) to identify suspected episodes of IPD in the community by active surveillance has shown good sensitivity (Brooks et al. 2007; Arifeen et al. 2009). However, active surveillance results in the early detection and treatment of children who may have otherwise developed severe disease, thereby resulting in decreasing rates of the disease under study, as well as disease-associated mortality. Passive surveillance, on the other hand, has low sensitivity for case detection in populations with low healthcare-seeking rates. We also observed a high population-based bacteremia rate. With a detected rate of 912 cases per 100 000 child-years, almost 1% of children in our cohort suffered from culture-proven bacteremia during the study period. This rate is almost certainly an underestimate as study staff could not obtain consent for referral and blood culture in 59% of febrile episodes that were eligible for blood cultures according to study criteria. Nevertheless, approximately 20% of the entire cohort of children <5 years old had at least one blood culture performed during a febrile episode in the study period. Bacteremia rates between 1192 and 4110 per 100 000 child-years have been reported from other low-income countries, such as Bangladesh and Kenya (Brent et al. 2006; Brooks et al. 2007). In contrast, bacteremia rates in industrialized countries range from 80 cases per 100 000 child-years in infants under 1 year of age in Canada (Laupland et al. 2005) to 141 cases per 100 000 child-years in children <5 years in Finland (Saarinen et al. 1995). With pneumonia causing significant morbidity and mortality among Pakistani children, vaccines against pneumonia causing pathogens are critical for improving child survival in Pakistan. Pakistan has recently introduced the Hib vaccine in the expanded programme on immunization (EPI) schedule, which has been shown to reduce the burden of radiologically confirmed pneumonia by approximately 20%, in settings similar to that of Pakistan (Mulholland et al. 1997; Levine et al. 2006). The pneumococcal conjugate vaccine has also proven highly effective against radiologically proven pneumonia (Cutts et al. 2005; Hansen et al. 2006). With a national under-five mortality rate of 90 per 1000 live births, Pakistan should make the introduction of the pneumococcal conjugate vaccine in the national immunization programme a priority (WHO 2007). Given the 0.26 episodes per child-year estimated incidence of pneumonia, an estimated under-five population of 19.3 million (UNICEF 2009), vaccine efficacy of 27% against World Health Organization X-ray defined pneumonia (Lucero et al. 2009), and 70% vaccine coverage, the pneumococcal vaccine can potentially prevent almost 1 million radiologically confirmed pneumonia cases annually. This figure is almost assuredly an underestimate as herd immunity has the potential to prevent twice as many cases as the direct effects of immunization alone (Whitney et al. 2003, MMWR 2005). Limitations of this study include budgetary constraints that precluded a larger surveillance population, high prior antibiotic use in the study population despite weekly active surveillance, and a lower than expected rate of acceptance of referral to the local health centre for the evaluation and blood cultures of sick children identified through the surveillance system. Prior use of antimicrobials can significantly decrease yield of pneumococci, thereby underestimating true burden of IPD. Another PneumoADIP-supported study from Pakistan showed that the rate of detecting pneumococcal meningitis tripled when more sensitive antigen detection testing, using immunochromatographic tests, were used on CSF (Moisi et al. 2009). Despite study limitations cited earlier, we believe that the findings of this study provide sufficient evidence of the burden of pneumonia and pneumococcal disease in Pakistan. With the increasing resistance of S. pneumoniae strains to beta-lactam and other classes of antibiotics making treatment more complicated and expensive (Hsieh et al. 2008; Zaidi et al. 2009), vaccines present an effective protection against pneumococcal disease in both low-income and industrialized countries (Klugman et al. 2003; O’Brien et al. 2003; Cutts et al. 2005). Therefore, the introduction of pneumococcal vaccines in Pakistan’s EPI schedule should be carefully considered. We thank Dr. Abdullah Brooks of ICDDR,B for sharing data instruments from febrile illness surveillance in Bangladesh. We are grateful to the PneumoADIP Initiative at the Bloomberg School of Public Health, Johns Hopkins University, funded by the GAVI Alliance, and Wyeth Pharmaceuticals for providing support and funding for disease surveillance. A. Owais is supported by a grant from the Fogarty International Center, National Institute of Health, USA.