Diagnosing the etiologic agent of pneumonia has an essential role in ensuring the most appropriate and effective therapy for individual patients and is critical to guiding the development of treatment and prevention strategies. However, establishing the etiology of pneumonia remains challenging because of the relative inaccessibility of the infected tissue and the difficulty in obtaining samples without contamination by upper respiratory tract secretions. Here, we review the published and unpublished literature on various specimens available for the diagnosis of pediatric pneumonia. We discuss the advantages and limitations of each specimen, and discuss the rationale for the specimens to be collected for the Pneumonia Etiology Research for Child Health study.
We investigated the performance of polymerase chain reaction (PCR) on blood in the diagnosis of pneumococcal pneumonia among children from 7 low- and middle-income countries. We tested blood by PCR for the pneumococcal autolysin gene in children aged 1–59 months in the Pneumonia Etiology Research for Child Health (PERCH) study. Children had World Health Organization–defined severe or very severe pneumonia or were age-frequency–matched community controls. Additionally, we tested blood from general pediatric admissions in Kilifi, Kenya, a PERCH site. The proportion PCR-positive was compared among cases with microbiologically confirmed pneumococcal pneumonia (MCPP), cases without a confirmed bacterial infection (nonconfirmed), cases confirmed for nonpneumococcal bacteria, and controls. In PERCH, 7.3% (n = 291/3995) of cases and 5.5% (n = 273/4987) of controls were blood pneumococcal PCR-positive (P < .001), compared with 64.3% (n = 36/56) of MCPP cases and 6.3% (n = 243/3832) of nonconfirmed cases (P < .001). Blood pneumococcal PCR positivity was higher in children from the 5 African countries (5.5%–11.5% among cases and 5.3%–10.2% among controls) than from the 2 Asian countries (1.3% and 1.0% among cases and 0.8% and 0.8% among controls). Among Kilifi general pediatric admissions, 3.9% (n = 274/6968) were PCR-positive, including 61.7% (n = 37/60) of those with positive blood cultures for pneumococcus. The utility of pneumococcal PCR on blood for diagnosing childhood pneumococcal pneumonia in the 7 low- and middle-income countries studied is limited by poor specificity and by poor sensitivity among MCPP cases.
Detection of pneumococcus by lytA polymerase chain reaction (PCR) in blood had poor diagnostic accuracy for diagnosing pneumococcal pneumonia in children in 9 African and Asian sites. We assessed the value of blood lytA quantification in diagnosing pneumococcal pneumonia.The Pneumonia Etiology Research for Child Health (PERCH) case-control study tested whole blood by PCR for pneumococcus in children aged 1-59 months hospitalized with signs of pneumonia and in age-frequency matched community controls. The distribution of load among PCR-positive participants was compared between microbiologically confirmed pneumococcal pneumonia (MCPP) cases, cases confirmed for nonpneumococcal pathogens, nonconfirmed cases, and controls. Receiver operating characteristic analyses determined the "optimal threshold" that distinguished MCPP cases from controls.Load was available for 290 of 291 cases with pneumococcal PCR detected in blood and 273 of 273 controls. Load was higher in MCPP cases than controls (median, 4.0 × 103 vs 0.19 × 103 copies/mL), but overlapped substantially (range, 0.16-989.9 × 103 copies/mL and 0.01-551.9 × 103 copies/mL, respectively). The proportion with high load (≥2.2 log10 copies/mL) was 62.5% among MCPP cases, 4.3% among nonconfirmed cases, 9.3% among cases confirmed for a nonpneumococcal pathogen, and 3.1% among controls. Pneumococcal load in blood was not associated with respiratory tract illness in controls (P = .32). High blood pneumococcal load was associated with alveolar consolidation on chest radiograph in nonconfirmed cases, and with high (>6.9 log10 copies/mL) nasopharyngeal/oropharyngeal load and C-reactive protein ≥40 mg/L (both P < .01) in nonconfirmed cases but not controls.Quantitative pneumococcal PCR in blood has limited diagnostic utility for identifying pneumococcal pneumonia in individual children, but may be informative in epidemiological studies.
The date 2 November 2009 marked the first World Pneumonia Day, launched by a coalition of child health organizations to support global efforts to prioritize pneumonia treatment and prevention. Despite recent medical advances, pneumonia takes the lives of up to 2 million children under age 5 each year—more than AIDS, malaria, and measles combined (15). As with many other illnesses, the disease burden is greatest among the world's most vulnerable population: children living in developing nations. For every child who dies of pneumonia in a developed country, more than 2,000 die in developing countries (16).
With safe and effective vaccines against Haemophilus influenzae type b (Hib), Streptococcus pneumoniae, and measles virus and with improvements in environment and nutrition and in case management standards, we now have several strategies to both prevent and treat pneumonia. The challenge is to ensure universal access to these life-saving interventions.
Laboratory diagnostics and clinical microbiologists should play an important part in global efforts to prevent and treat pneumonia. Diagnostic testing has an essential role in ensuring the most appropriate and effective therapy for individual patients. It also plays a role in disease surveillance in defining the etiologic spectrum of pneumonia cases and deaths. This in turn forms the evidence base for strategic decisions by global decision makers (such as the World Health Organization, UNICEF, and the GAVI Alliance), vaccine manufacturers, and funders to develop and support treatment algorithms, vaccine products and programs, and other effective prevention strategies. World Pneumonia Day also reminds us that much work remains to be done in pneumonia diagnostics and that historically, even with the best of methods, we have been unable to define the microbial etiology of a significant proportion of pneumonia episodes, particularly in children. The conditions under which pneumonia mortality is greatest are also the conditions under which adequate diagnosis is least possible. Even in settings with access to state-of-the-art microbiological diagnosis, establishing the etiology of a pneumonia case is fundamentally vexed by the limited ability to obtain specimens from the site of infection without contamination by upper respiratory secretions. Lack of sensitive laboratory diagnostic tools has probably played a direct role in the delayed introduction of effective vaccines to prevent pneumonia. Vaccines against Hib and S. pneumoniae alone may prevent >50% of severe childhood pneumonia, but poor diagnostics contribute to substantial underdiagnosis, and thus, substantial efforts need to be put into place to build awareness about the potential impact of these interventions. In spite of these limitations, significant advances have been made in diagnostic technology. However, technology alone is not a panacea for pneumonia diagnostic needs: assessment of performance within clinical and epidemiologic contexts is essential.
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