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Editorial Commentary: The Modern Quest for the "Holy Grail" of Pneumonia Etiology.

Defining the etiology of pneumonia is a messy business. Blood cultures are considered the “gold standard” for bacterial pneumonia but have low sensitivity, yielding a causative organism in only 5%–14% of adults with pneumonia, and even fewer in children [1, 2]. Urine antigen assays for Streptococcus pneumoniae and Legionella pneumophila have good specificity and improved sensitivity compared with culture but sensitivity is still only 70%–80%, and these assays cannot distinguish between colonization and infection in children [1-3]. Molecular assays for viruses and atypical bacteria represent important diagnostic advances. However, molecular detection of viruses that cause pneumonia from upper respiratory tract specimens may be due to milder infection confined to the upper airway or may represent remnants of past infections [4]. Potentially pathogenic bacteria can be part of the normal microbiome, and thus organisms detected in the nasopharynx may not represent the true etiology of infection in the lower respiratory tract. Furthermore, specimens from the site of infection in the lower respiratory tract are usually not available. When deep specimens are obtained, they are often contaminated with bacteria from the upper respiratory tract [3, 5]. Thus, sputum specimens are more likely to yield potential pathogens but have low specificity, making it hard to correlate detection with causation [3, 5]. Moreover, even the clinical diagnosis of pneumonia is fraught with difficulty. Radiographs are not always obtained. When radiographs are taken, variability between clinicians’ readings is common in the determination of pneumonia [6]. For decades, the high proportion of pneumonia due to S. pneumoniae and Haemophilus influenzae, coupled with a false sense of security about the risks of antibiotic overuse, has led to recommendations for empiric antibiotic therapy for virtually all patients with presumed pneumonia [1]. However, the changing epidemiology due to the impact of pneumococcal and H. influenzae type B vaccines in the United States