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Journal of Tropical Pediatrics Advance Access published online on April 28, 2009
Journal of Tropical Pediatrics, doi:10.1093/tropej/fmp030
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© The Author [2009]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Severe Pneumonia in Mozambican Young Children: Clinical and Radiological Characteristics and Risk Factors

Betuel Sigaúquea,b,c, Anna Rocaa,c, Quique Bassata,c, Luís Moraisa, Llorenç Quintóa,c, Anna Berengueraa, Sónia Machevoa,d, Azucena Bardajia,c, Manuel Corachanc, Josep Ribóe, Clara Menéndeza,c, Anne Schuchatf, Brendan Flanneryf, Montse Soriano-Gabarróf and Pedro L Alonsoa,c

aCentro de Investigação em Saúde da Manhiça, Maputo, Mozambique
bbInstituto Nacional de Saúde, Ministério de Saúde, Maputo, Mozambique
cBarcelona Centre for International Health Research (CRESIB), Hospital Clínic/IDIBAPS, University of Barcelona, Spain
dFaculdade de Medicina, Univerdade Eduardo Mondlane, Maputo, Mozambique
eHospital Universitari Sant Joan de Déu, Barcelona, Spain
fCenters for Disease Control and Prevention – CDC, Atlanta, USA

Correspondence: Betuel Lázaro Sigaúque, Centro de Investigação em Saúde da Manhiça (CISM), Instituto Nacional de Saude, Ministério de Saúde, Maputo, Moçambique, Rua N° 12 C. P 1929.

E-mail <betuel.sigauque{at}manhica.net> or <necy_sigauque{at}yahoo.com>.

Present address: Montse Soriano-Gabarró, GlaxoSmithKline Biologicals, Rue de l'Institut 89, B-1330 Rixensart, Belgium.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Funding
 References
 
Background: Pneumonia is a leading cause of hospitalization and death among children in Africa. We describe the clinical presentation of severe pneumonia among hospitalized children in a malaria endemic area with a high prevalence of HIV infection. Methods: As part of a 2-year prospective study of radiologically confirmed pneumonia, chest radiographs, malaria parasite counts and bacterial blood cultures were systematically performed for children 0–23 months admitted with severe pneumonia. Radiographs were interpreted according to WHO guidelines. HIV tests were performed during a 12-month period. Results: Severe pneumonia accounted for 16% of 4838 hospital admissions among children 0–23 months; 43% of episodes had endpoint consolidation, 15% were associated with bacteremia and 11% were fatal. Fever, cough >3 days, crepitations, hypoxemia and absence of malaria parasitemia were associated with radiologically confirmed pneumonia. Nineteen per cent of children with severe pneumonia and 27% with radiologically confirmed pneumonia had clinical malaria. HIV-prevalence was 26% among children hospitalized with severe pneumonia and HIV-testing results. HIV infection, anaemia, malnutrition, hypoxemia and bacteremia were associated with fatal episodes of severe pneumonia. Conclusion: Treatment of admitted children with severe pneumonia is complicated in settings with prevalent HIV and malaria. Children with severe pneumonia and clinical malaria require antibiotic and antimalarial treatment. In addition to vertical programs, integrated approaches may greatly contribute to reduction of pneumonia-related mortality.

Key Words: Mozambique • children • pneumonia • risk factors • mortality


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Funding
 References
 
Pneumonia is one of the most important causes of morbidity and mortality worldwide, especially in African children [1–4]. Each year, pneumonia accounts for approximately 1.9 million deaths in children under 5 years of age [5]. The highest risk of pneumonia and pneumonia-related mortality occurs among children under 2 years of age [6], with many cases attributable to bacteria, mainly Streptococcus pneumoniae and Haemophilus influenzae [7]. In recent years, the HIV pandemic has further increased both the burden [8] and the bacteriological spectrum of microorganisms [9] causing pneumonia, particularly throughout sub-Saharan Africa.

The diagnosis of pneumonia in resource-poor settings is challenging. The specificity of clinical presentation is poor with substantial overlap between pneumonia and malaria. In rural Africa, most hospital visits and admissions are attended by nurses or paramedics who use only signs and symptoms to guide diagnoses and management decisions. The aim of the widely used Integrated Management of Childhood Illness (IMCI) strategy, developed by the World Health Organization and UNICEF in the 1990s, was to create an algorithm that was sensitive, though not specific, to guide management and referral for life-threatening illnesses [10]. IMCI guidelines recommend prompt treatment and referral to hospital for children with clinical signs of severe pneumonia. IMCI guidelines may require revision for areas with high HIV prevalence [11].

Findings on chest radiograph, including consolidation and pleural effusion, improve the specificity of the diagnosis of bacterial pneumonia in children [12–14]. However, in resource-limited settings, availability of radiology is scarce, and chest radiographs are infrequently used to guide clinical management of severe pneumonia [15]. Therefore, better clinical markers of bacterial pneumonia are needed. During a 2-year prospective study of severe pneumonia among young children admitted to a rural district hospital in Mozambique, we assessed factors associated with radiologically confirmed and fatal episodes of pneumonia, including HIV and malaria infection.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Funding
 References
 
Study setting and population
This prospective study was conducted from 18 March 2004 to 17 March 2006 by the Centro de Investigação em Saúde da Manhiça (CISM) at the Manhiça District Hospital (MDH), the referral health facility (with 36 paediatric beds out of a total of 110) for Manhiça District, a rural area of Maputo Province in Southern Mozambique. Manhiça District has an estimated population of 143 000 inhabitants. Details of the study site have been described elsewhere [16]. There is perennial malaria transmission, mostly due to Plasmodium falciparum [17]. HIV prevalence was 24% among pregnant women attending the antenatal clinic of the MDH between August 2003 to April 2005 [18]. Antiretroviral therapy (single-dose nevirapine) has been available in the setting since 2003, and the mother-to-child vertical transmission rate of HIV was estimated as 15% during the study period [19].

During the study period, infant mortality was 90 per 1000 live births and under-5 mortality was 172 per 1000 [16, 20]. Hib and pneumococcal conjugate vaccines were not available through the Mozambican Expanded Programme on Immunization (EPI) [21].

The study was approved by the Mozambican National Bioethics Committee, the Institutional Review Board of the Clinic Hospital of Barcelona, the Human Subjects Protection Committee, U.S. Centres for Disease Control and Prevention, and the Human Subjects Board of the Program for Appropriate Technology in Health (PATH).

Hospital surveillance, clinical management and definitions
Since 1997, MDH and CISM have jointly operated round-the-clock surveillance of all paediatric outpatient visits and all ward admissions [22]. Clinical data are routinely assessed by a trained medical officer or physician using standard forms for all children under 15 years of age. Respiratory rates are counted for 60 s in awake, non-crying children using UNICEF chronometers.

The WHO/IMCI definition of clinical pneumonia includes history of cough or difficulty in breathing in the presence of increased respiratory rate according to age [23]. Severe pneumonia was defined by the presence of chest wall indrawing in a child with clinical pneumonia [24, 25]. Children with severe pneumonia were re-examined by a physician or a trained medical officer to confirm the initial diagnosis before hospitalization. A single blood culture (using 1–3 ml by venipuncture) was performed prior to hospital admission for all children <2 years of age.

For case ascertainment of bacterial pneumonia, an anterior-posterior chest X-ray was performed on admission for children <2 years of age with severe pneumonia. Children with evidence of asthma, congenital heart disease, neonatal asphyxia and chronic respiratory disorders were excluded. Children who were unconscious, presented convulsions or were critically ill were referred to radiology after their condition stabilized.

Blood glucose was measured on admission by finger prick using Accu-Check® Glucometer (Roche). Digital pulse oximetry (Nellcor®) was used to evaluate and monitor oxyhaemolobin saturation at admission. Nutritional status was defined using weight-for-height z-score, (threshold for severe malnutrition less than –3 SD from U.S. reference population) [26]. Clinical malaria was diagnosed in children who presented a history of fever or an axillary temperature ≥37.5°C and presence of any P. falciparum asexual parasitemia in infants or greater than 2500 parasites per µl in children ≥1 year of age [27, 28]. The WHO definition of anaemia in children >2 months of age is a haemoglobin (Hgb) level lower than 11 g/dl [29, 30], which is equivalent to a haematocrit lower than 33% [31]. Anaemia definitions and classification were based on WHO-proposed [29, 30] definitions and adapted to include newborns. Severe anaemia was defined as haematocrit <25% in neonates ≥28 days of age or <15% in infants older than 28 days; non-severe anaemia as haematocrit of 25–42% in neonates or 15–32% in children >28 days of age. Bacteremia was defined as isolation of pathogenic bacteria in blood [32].

Treatment
Following national and IMCI guidelines [10], non-severe pneumonia cases were treated as outpatients with oral amoxicillin or chloramphenicol or fenoximetil-penicilin when amoxicillin was not available. For children with severe pneumonia or suspected bacteremia/sepsis, empirical antimicrobial therapy with parenteral chloramphenicol or a combination of penicillin plus gentamicin was given. Infants <2 months of age and severely malnourished children were treated with ampicillin and gentamicin. Antibiotic therapy was re-assessed based on results of blood cultures. Ceftriaxone was used in cases of multi-resistant bacteria (defined as resistance to two or more antibiotic classes). Malaria infection was treated according to national guidelines. Blood transfusion was indicated when severe anaemia was detected. Patients requiring blood transfusion were transferred to Maputo Central Hospital when blood products were in short supply at MDH. Hypoxaemia was defined for study purposes as peripheral oxygen saturation (SPO2) <90%, but oxygen was administered with an oxygen concentrator (DeVibiss – 515 ADS) to children with SPO2 lower than 94%.

Laboratory methods
Bacterial blood cultures were performed using an automated blood culture system (Bactec 9050, Becton Dickinson, Temse, Belgium). Bacterial isolates were identified by colony morphology and growth requirements [33]. Malaria parasitemia was determined in thick blood smears [34].

HIV testing was performed from March 2005 through March 2006 using a sequential testing algorithm with two rapid HIV-1 antibody tests (Determine® and Unigold®). Filter paper blood samples were collected for subsequent confirmatory testing performed monthly using Amplicor HIV-1 DNA assay (version 1.5, Roche Molecular Systems, Inc., Branchburg, NJ) with dried blood spots. Children 18–23 months old were assumed to be infected with HIV if both rapid tests were positive. For seropositive children <18 months old and between 18–23 months old with discordant serologic tests, HIV infection was confirmed by a positive Amplicor test. Highly Active Antiretroviral Therapy (HAART), was available from the second year of study.

X-ray interpretation
Chest radiographs were interpreted by two primary readers and one external WHO radiologist following a WHO protocol for interpreting chest radiographs, developed by a group of clinical trialists to compare studies of bacterial pneumonia among children in different settings [14]. Episodes with evidence of consolidation or pleural effusion were defined as radiologically confirmed pneumonia (or endpoint pneumonia). Non-endpoint pneumonia was defined as interstitial infiltrates or normal radiographs.

Data management and statistical analysis
Data were double entered using Fox Pro software (version 2.6, Microsoft Corporation, Redmond, WA), and discrepancies were resolved by referring to original questionnaires. Analyses were performed in STATA (version 9.0, STATA Corporation, College Station, TX). Chi-squared tests or Fishers exact test were used to compare proportions. The non-parametric Wilcoxon Rank Sum test was used to compare continuous variables. P-value <0.05 was considered significant. Odds Ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. Case-fatality proportions (CFR) were calculated among children with known hospital outcome, excluding children transferred during admission or absconding from the hospital. Factors associated with radiologically confirmed episodes of pneumonia were analysed separately including all children, or restricted to children with known HIV status. Multivariate models included episodes with complete clinical data.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Funding
 References
 
During the 24-month study period, 4838 children, 0–23 months of age, were admitted to MDH; 757 (16%) met criteria for severe pneumonia diagnosis. Children admitted with severe pneumonia were younger, more likely to be male and admitted during the rainy season than admitted children without severe pneumonia (Table 1). Among children with blood culture results, bacteremia was present in 15% (90/613) of severe pneumonia episodes compared with 9% (290/3194) of other clinical syndromes (P < 0.001). The most frequently isolated bacteria from children with severe pneumonia were S. pneumoniae 24% (n = 22), non-typhi Salmonella (NTS) 22% (n = 20), H. influenzae 16% (n = 14) and Staphylococcus aureus 10% (n = 9), while S. aureus 18% (n = 56) was most prevalent among children without severe pneumonia, followed by NTS 17% (n = 51), E. coli 15% (n = 43) and S. pneumoniae 12% (n = 36). In-hospital mortality was higher (11%) among children admitted with severe pneumonia than other diagnoses (4%; Table 1).


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  		TABLE 1 Descriptive comparison of children 0–23 months of age admitted to district hospital in Mozambique over a 2-year period, with severe pneumonia versus all other causes of hospital admissions

 
Among children admitted with severe pneumonia, median oxygen saturation was 93% (IQR, 88–96%) and median temperature was 37.8°C (IQR, 37.0–38.8); 18% (132/715) were severely malnourished.

Severe pneumonia, clinical malaria and HIV
Among children hospitalized with severe pneumonia, 19% had clinical malaria (Table 2). Fever and severe anaemia were more often present in severe pneumonia episodes when clinical malaria was also present (P < 0.001). The prevalence of bacteremia and endpoint consolidation were higher when clinical malaria was absent. CFR was 14% among 112 episodes meeting criteria for both severe pneumonia and clinical malaria versus episodes meeting clinical malaria criteria alone (9%; P = 0.076).


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  		TABLE 2 Clinical findings among children admitted with severe pneumonia according to the coexistence of clinical malaria and HIV status

 
For 202 episodes with HIV-testing results, prevalence of HIV infection among children with severe pneumonia was 26%. HIV-infected children were younger (median, 7 months vs. 10 months), more frequently hypoxemic (P = 0.027), anaemic (P = 0.017) and severely malnourished (P = 0.017) than HIV-uninfected children admitted with severe pneumonia. Bacteremia tended to be more prevalent in HIV-infected children (P = 0.056) while malaria parasitemia was slightly lower (P = 0.074). There were four pneumococcal and one H. influenzae isolate from HIV-infected children; four H. influenzae and one pneumococcus were isolated from HIV-uninfected children. Oral candidiasis was present in 21% of 52 severe pneumonia episodes among HIV-infected children versus none among uninfected children (P < 0.001). Severe pneumonia episodes among HIV-infected children resulted in longer hospitalization (6 days vs. 4 days; P = 0.002) and higher case-fatality (27% vs. 2%; P < 0.001).

Radiologically confirmed pneumonia episodes
Among 634 (88% of 757) severe pneumonia episodes for which chest radiographs were interpreted, 43% were radiologically confirmed endpoint pneumonia. In the univariate analysis contrasting radiologically confirmed episodes with other infiltrates (17% of 634) or normal radiographs (40%), fever (P = 0.017), crepitations (P = 0.001), hypoxemia (P = 0.002), absence of malaria parasitemia (P = 0.001) and bacteremia (P = 0.023) were associated with endpoint consolidation (Table 3). Among all children regardless of HIV status, duration of cough (>3 days) (OR = 1.85; CI 1.12–3.07) and absence of malaria parasitemia (OR = 1.65; CI 1.37–1.80) were associated with radiologically confirmed pneumonia in multivariate analyses.


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  		TABLE 3 Risk factors associated with radiologically confirmed pneumoniaa among children 0–23 months of age presenting to district hospital in Mozambique with severe pneumonia

 
When analyses were restricted to children with known HIV status, severe malnutrition was associated with endpoint pneumonia (OR = 2.30; 95% CI 1.06–5.00) in addition to the factors identified in the unrestricted analyses. In the multivariate analysis performed in the subgroup with HIV test results, severe malnutrition (OR = 2.50; CI 95% 1.00–6.63) and duration of cough (>3 days) (OR = 2.78; 95% CI 1.34–5.76) were independently associated with radiologically confirmed pneumonia.

Mortality in children with severe pneumonia
Table 4 shows factors associated with death among children admitted with severe pneumonia and known hospital outcome. In the univariate analysis, severe anaemia, prostration, severe malnutrition, bacteremia, hypoxemia and HIV infection were associated with higher case-fatality. Among 16 fatal pneumonia episodes with HIV test results, 81% occurred in HIV-infected children.


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  		TABLE 4 Risk factors for death among children admitted with severe pneumonia

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Funding
 References
 
We describe clinical and radiological findings for a large number of severe pneumonia episodes among young children in a malaria endemic region of Mozambique with high HIV prevalence. The study used the WHO guidelines for chest radiography endpoints, designed to measure efficacy against pneumonia for Hib and pneumococcal conjugate vaccines [14]. Severe pneumonia was a major cause of hospital admission and in-hospital mortality among young children. The high prevalence of malaria and HIV infection among children with signs and symptoms of severe pneumonia complicates case management and treatment.

Children with immunosuppression caused by HIV infection, cancer or sickle cell disease are extremely susceptible to develop concomitant bacterial infections such as bacterial pneumonia [35]. Infections such as malaria may predispose to acquire bacterial infection [36], but may also clinically mimic severe pneumonia, being often indistinguishable from it despite very different pathophysiological pathways. For this reason, understanding the relevance of interaction between pneumonia and other infections such as HIV or malaria seems crucial to understand the real burden of pneumonia where these infections are highly prevalent.

Interestingly, in this study, as many as one in four children admitted with clinical criteria for severe pneumonia met the definition of clinical malaria. Among this group, prevalence of consolidation was lower than for other children. These results appear to support previous findings that suggest that, in malaria-endemic areas, the burden of severe pneumonia might be overestimated if only clinical findings are considered due to the clinical overlap between severe pneumonia and malaria [37, 38]. Almost half (44%) of children with clinical malaria and severe pneumonia also had abnormal chest X-rays (although lower than the 66% for other children). Therefore, pneumonia co-morbidity among children with clinical malaria was probably highly prevalent. Clinical differences between these two groups (i.e. children with severe pneumonia with and without clinical malaria) were mainly related to their chest findings, or the presence of concomitant anaemia or hypoxemia, despite those signs/symptoms being also highly prevalent among patients with severe pneumonia and malaria. Indeed, crepitations and wheezing/ronchi, were found in up to 27% of the patients with malaria and severe pneumonia, compared to 55% of the patients without parasites, and as many as one in four children were also hypoxemic. Given the clinical overlap between malaria and pneumonia, a significant proportion of children, meeting clinical criteria for severe pneumonia, need to be treated with both antibiotics and antimalarial in malaria-endemic regions. Clinical studies designed to improve the specificity of definition of these two infections and the relevance of their interaction are needed to improve treatment, and are currently underway in this setting.

In a setting with high HIV prevalence, HIV infection contributes disproportionately to severe pneumonia morbidity and mortality in young children. HIV-infected children tended to be younger than uninfected children with severe pneumonia, possibly in relation to an early predisposition to develop bacterial infections and a much higher CFR associated with the episodes (27% vs. 2%, P < 0.001). Factors associated with fatal pneumonia, including severe anaemia and severe malnutrition, were also associated with HIV infection. The higher proportion of hypoxemic cases among HIV-infected patients may be indirect indication of the prevalence of other comorbidities (pneumocystis jirovecii pneumonia or tuberculosis) among HIV infected children. Clinical malaria was not associated with severe pneumonia among HIV-infected children.

Hypoxemia was a predictor of poor outcome, as reported from other settings [39]. In many rural African hospitals, oxygen saturation is rarely measured, and supplemental oxygen is often not available. Young children may die prior to referral to hospitals where oxygen therapy is available. Use of oxygen concentrators in rural hospitals could reduce pneumonia mortality in young children [40].

Performing good quality radiographs in rural hospitals is difficult [15], particularly in severely ill children when portable X-ray machines are not available. More sensitive and specific clinical signs and laboratory tests for bacterial pneumonia are needed to improve treatment and measure the impact of interventions, such as introduction of bacterial conjugate vaccines. In this study, 43% of severe pneumonia episodes had endpoint consolidation on chest radiograph, and not all bacteremic episodes were associated with radiologically confirmed pneumonia. Clinical signs and symptoms were not good predictors of radiologically confirmed pneumonia. Unless chest radiographs can be shown to improve diagnosis and treatment of pneumonia episodes in hospitals throughout the developing world, their use will continue to be limited.

This study was limited by incomplete HIV information for children with severe pneumonia. Risk factors for fatal pneumonia could not be properly assessed because of the small proportion of fatal episodes with HIV-testing performed. In addition, multivariate analyses did not include all episodes due to missing clinical data. The sensitivity of blood cultures for invasive bacterial infection is low, resulting in a small percentage of episodes with proven aetiology [41, 42]. Laboratory testing for viral and fungal causes of pneumonia was not available.

Nonetheless, the results of this study give some insight into the IMCI strategy, designed as a non-specific but highly sensitive tool to avoid missing potentially life-threatening conditions in resource-limited settings. Additionally, our findings show the importance of malaria, HIV and bacteremia among children admitted to hospital with clinical criteria for severe pneumonia. These data suggest the value of prevention strategies including antiretroviral therapies for prevention of mother-to-child HIV transmission, promotion of insecticide-treated bed nets, and accelerated introduction of life-saving bacterial conjugate vaccines. While vertical programs for individual interventions can be effective, children in rural Mozambique will benefit greatly from integrated prevention programs.


   Funding
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Funding
References
 
CISM core funding is provided by the Spanish Agency for International Cooperation (Ministry of Foreign Affairs, Spain). The study was supported by funds from The Program for Appropriate Technology in Health (GAT.770-790-01350-LPS) and the World Health Organization (I8-181-1200). M Soriano-Gabarró currently works at GSK Biologicals, Belgium. Other authors declare no conflicts of interest. The study also received partial support from the U.S. Agency for International Development.


   Acknowledgements
 
We thank Jorge Uqueio for coordinating logistical aspects of the study, and our colleagues at the Manhiça District Hospital and the CISM for collecting and processing samples and completing questionnaires. We are grateful to Daniel Feikin, from CDC Atlanta, for his contributions to the surveillance protocol and Thomas Cherian and Harold Ostensen for radiology training and interpretation of chest radiographs.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 Funding
 References
 

  1. Mulholland K. Magnitude of the problem of childhood pneumonia. Lancet (1999) 354:590–92.[CrossRef][Web of Science][Medline]
  2. Williams BG, Gouws E, Boschi-Pinto C, et al. Estimates of world-wide distribution of child deaths from acute respiratory infections. Lancet Infect Dis (2002) 2:25–32.[CrossRef][Web of Science][Medline]
  3. Wardlaw T, Salama P, Johansson EW, et al. Pneumonia: the leading killer of children. Lancet (2006) 368:1048–50.[CrossRef][Web of Science][Medline]
  4. Lopez AD, Mathers CD, Ezzati M, et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet (2006) 367:1747–57.[CrossRef][Web of Science][Medline]
  5. Mulholland K. Global burden of acute respiratory infections in children: implications for interventions. Pediatr Pulmonol (2003) 36:469–74.[CrossRef][Web of Science][Medline]
  6. Hortal M, Estevan M, Iraola I, et al. A population-based assessment of the disease burden of consolidated pneumonia in hospitalised children under five years of age. Int J Infect Dis (2007) 11:273–7.[CrossRef][Web of Science][Medline]
  7. Wall RA, Corrah PT, Mabey DC, et al. The aetiology of lobar pneumonia in the Gambia. Bull World Health Organ (1986) 64:553–8.[Web of Science][Medline]
  8. Madhi SA, Petersen K, Madhi A, et al. Increased disease burden and antibiotic resistance of bacteria causing severe community-acquired lower respiratory tract infections in human immunodeficiency virus type 1-infected children. Clin Infect Dis (2000) 31:170–6.[CrossRef][Web of Science][Medline]
  9. Brent AJ, Oundo JO, Mwangi I, et al. Salmonella bacteremia in Kenyan children. Pediatr Infect Dis J (2006) 25:230–6.[CrossRef][Medline]
  10. Gove S. Integrated management of childhood illness by outpatient health workers: technical basis and overview. The WHO Working Group on Guidelines for Integrated Management of the Sick Child. Bull World Health Organ (1997) 75(Suppl 1):7–24.[Web of Science][Medline]
  11. McNally LM, Jeena PM, Gajee K, et al. Effect of age, polymicrobial disease, and maternal HIV status on treatment response and cause of severe pneumonia in South African children: a prospective descriptive study. Lancet (2007) 369:1440–51.[CrossRef][Web of Science][Medline]
  12. Forgie IM, Campbell H, Lloyd-Evans N, Leinonen M, O’Neill KP, Saikku P, et al. Etiology of acute lower respiratory tract infections in children in a rural community in The Gambia. Pediatr Infect, Dis J (1992) 11:466–73.[Web of Science][Medline]
  13. Obaro SK, Madhi SA. Bacterial pneumonia vaccines and childhood pneumonia: are we winning, refining, or redefining? Lancet Infect Dis (2006) 6:150–61.[CrossRef][Web of Science][Medline]
  14. Cherian T, Mulholland EK, Carlin JB, et al. Standardized interpretation of paediatric chest radiographs for the diagnosis of pneumonia in epidemiological studies. Bull World Health Organ (2005) 83:353–9.[Web of Science][Medline]
  15. Cutts FT, Enwere G, Zaman SM, et al. Operational challenges in large clinical trials: examples and lessons learned from the Gambia pneumococcal vaccine trial. PLoS Clin Trials (2006) 1:e16.[CrossRef][Medline]
  16. Alonso PL, Saúte F, Aponte JJ, et al. Manhiça DSS, Mozambique. In: Population Health in Developing Countries—Sankoh OA, Ngom P, Nyarko P, Mwageni E, Kahn K, eds. Vol. 1, 2002.
  17. Aranda C, Aponte JJ, Saute F, et al. Entomological characteristics of malaria transmission in Manhica, a rural area in southern Mozambique. J Med Entomol (2005) 42:180–6.[CrossRef][Web of Science][Medline]
  18. Menendez C, Bardaji A, Sigauque B, et al. A randomized placebo-controlled trial of intermittent preventive treatment in pregnant women in the context of insecticide treated nets delivered through the antenatal clinic. PLoS ONE (2008) 3:e1934.[CrossRef][Medline]
  19. Naniche D, Menendez C, Bardaji A, et al. Impact of maternal HIV infection on birth outcomes and infant survival in rural Mozambique. In: AJTMH (2009).
  20. Nhacolo AQ, Nhalungo DA, Sacoor CN, et al. Levels and trends of demographic indices in southern rural Mozambique: evidence from demographic surveillance in Manhica district. BMC Public Health (2006) 6:291.[CrossRef][Medline]
  21. World Health Organization. Immunization Surrveillance Assessment and Monitoring: Immunization Schedule – Mozambique. 11 April 2008, date last accessed. Available at: http://www.who.int/countries/moz/en.
  22. Loscertales MP, Roca A, Ventura PJ, et al. Epidemiology and clinical presentation of respiratory syncytial virus infection in a rural area of southern Mozambique. Pediatr Infect Dis J (2002) 21:148–55.[CrossRef][Web of Science][Medline]
  23. WHO young infants study group. Clinical prediction of serious bacterial infections in young infants in developing countries. Pediatr Infect Dis J (1999) 18:S23–S31.[CrossRef][Web of Science][Medline]
  24. Puumalainen T, Quiambao B, Abucejo-Ladesma E, et al. Clinical case review: a method to improve identification of true clinical and radiographic pneumonia in children meeting the World Health Organization definition for pneumonia. BMC Infect Dis (2008) 8:95.[CrossRef][Medline]
  25. Ayieko P, English M. Case management of childhood pneumonia in developing countries. Pediatr Infect Dis J (2007) 26:432–40.[CrossRef][Web of Science][Medline]
  26. Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, et al. CDC growth charts: United States. Adv.Data (2000) 00:1–27.
  27. Saute F, Aponte J, Almeda J, et al. Malaria in southern Mozambique: malariometric indicators and malaria case definition in Manhica district. Trans R Soc Trop Med Hyg (2003) 97:661–6.[CrossRef][Web of Science][Medline]
  28. Alonso PL, Sacarlal J, Aponte JJ, et al. Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Lancet (2004) 364:1411–20.[CrossRef][Web of Science][Medline]
  29. A review of Integrated Managemet of childhood illness – IMCI. 2 February 2009, date last accessed. http://www.safpj.co.za/index.php/safpj/article/viewFile/292/292.
  30. Nutritional anaemias. Report of a WHO scientific group. World Health Organ Tech Rep Ser (1968) 405:5–37.[Medline]
  31. Dreyfuss ML, Stoltzfus RJ, Shrestha JB, et al. Hookworms, malaria and vitamin A deficiency contribute to anemia and iron deficiency among pregnant women in the plains of Nepal. J Nutr (2000) 130:2527–36.[Abstract/Free Full Text]
  32. Sigauque B, Roca A, Mandomando I, et al. Community-acquired bacteremia among children admitted to a rural hospital in Mozambique. Pediatr Infect Dis J (2009) 28:108–13.[CrossRef][Web of Science][Medline]
  33. Roca A, Sigauque B, Quinto L, et al. Invasive pneumococcal disease in children <5 years of age in rural Mozambique. Trop Med Int Health (2006) 11:1422–31.[CrossRef][Web of Science][Medline]
  34. Guinovart C, Bassat Q, Sigauque B, et al. Malaria in rural Mozambique. Part I: children attending the outpatient clinic. Malar J (2008) 7:36.[CrossRef][Medline]
  35. Jaspan HB, Huang LC, Cotton MF, et al. Bacterial disease and antimicrobial susceptibility patterns in HIV-infected, hospitalized children: a retrospective cohort study. PloS ONE (2008) 3:e3260.[CrossRef][Medline]
  36. Ukaga CN, Orji CN, Orogwu S, et al. Concomitant bacteria in the blood of malaria patients in Owerri, southeastern Nigeria. Tanzan Health Res Bull (2006) 8:186–8.[Medline]
  37. O'Dempsey TJ, McArdle TF, Laurence BE, et al. Overlap in the clinical features of pneumonia and malaria in African children. Trans R Soc Trop Med Hyg (1993) 87:662–5.[CrossRef][Web of Science][Medline]
  38. English M, Punt J, Mwangi I, McHugh K, Marsh K. Clinical overlap between malaria and severe pneumonia in Africa children in hospital. Trans R Soc Trop Med Hyg (1996) 90:658–62.[CrossRef][Web of Science][Medline]
  39. Djelantik IG, Gessner BD, Sutanto A, et al. Case fatality proportions and predictive factors for mortality among children hospitalized with severe pneumonia in a rural developing country setting. J Trop Pediatr (2003) 49:327–32.[Abstract/Free Full Text]
  40. Duke T, Wandi F, Jonathan M, et al. Improved oxygen systems for childhood pneumonia: a multihospital effectiveness study in Papua New Guinea. Lancet (2008) 372:1328–33.[CrossRef][Web of Science][Medline]
  41. Bonadio WA. Bacteremia in febrile children with lobar pneumonia and leukocytosis. Pediatr Emerg Care (1988) 4:241–2.[Medline]
  42. Saez-Llorens X, Vargas S, Guerra F, et al. Application of new sepsis definitions to evaluate outcome of pediatric patients with severe systemic infections. Pediatr Infect Dis J (1995) 14:557–61.[Web of Science][Medline]

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