The role of microbiological testing to assist the management of lower respiratory tract infection continues to be debated. Few physicians would deny that therapeutic decisions are aided with rapidly provided accurate information about causative pathogens. Unfortunately, the ability of microbiology laboratories to perform this service is constrained by the limitations of conventional diagnostic tests. Culture-based methods can be slow, are often insensitive, may not distinguish colonization from infection, and may be influenced by previous antimicrobial use. Serological testing is slow and often poorly sensitive and poorly specific. Furthermore, in most cases, an etiological diagnosis is not made, despite the best efforts. As a consequence, many authoritative guidelines on the management of community-acquired pneumonia in adults do not support routine comprehensive microbiological testing except in certain situations or in patients with severe disease [1–3]. The situation is changing. Recently, there have been promising advances with antigen and nucleic acid detection assays for respiratory pathogens. New immunochromatographic urinary antigen detection assays for Legionella pneumophila and Streptococcus pneumoniae are easy and quick to perform and have relatively high sensitivities and specificities [4, 5]. A variety of rapid antigen-detection assays are also available for influenza A and B viruses and respiratory syncytial virus [6, 7], although the sensitivities of these assays still have room for improvement. There has also been considerable development of nucleic acid amplification techniques as diagnostic tools for lower respiratory tract infection [8]. Despite development over many years, none of these assays are yet readily available or in widespread routine use. This situation is likely to change soon with the introduction of commercial nucleic acid amplification assays specifically for the diagnosis of respiratory tract infections [9, 10]. For detection of viruses in the respiratory tract, PCR is more sensitive than conventional diagnostic techniques and is the only practical tool for detecting some viruses [11, 12]. Will these recent developments in diagnostic testing have a beneficial impact on the management of patients with lower respiratory tract infections? The study by Oosterheert et al. [13] in this issue of Clinical Infectious Diseases was designed to address this issue. The authors conducted a randomized controlled trial involving 107 adults with lower respiratory tract infections at 2 Dutch hospitals. All patients had upper respiratory tract samples tested by real-time PCR for common respiratory viruses, Mycoplasma pneumoniae, Chlamydia pneumoniae, and L. pneumophila, but only the results from patients in the intervention group were immediately reported to attending clinicians. PCR results from patients in the control group were unavailable during the study period. All patients were followed up for up to 4 weeks, and the main outcome measures were change in antibiotic therapy, clinical outcome, and treatment costs. The main findings of this study were that real-time PCR significantly increased the diagnostic yield, compared with conventional diagnostic tests alone, but did not reduce antibiotic use, duration of hospital stay, or treatment costs. Indeed, treatment costs were much higher in the intervention group, and reporting of real-time PCR results led to partial or total cessation of antibiotic therapy for only 6 of 55 patients. Were these findings surprising? Do the findings argue against the utility of molecular diagnostic techniques to assist with the management of lower respiratory tract infections? I would answer no to both questions. The increase in diagnostic yield with PCR, particularly for viral pathogens, is certainly consistent with results of other studies [11, 12]. The lack of a change in antibiotic use is also not unexpected, given the study design. In the study by Oosterheert and colleagues, the majority of additional diagnoses in the intervention group were of infection to due viral pathogens. Many clinicians would not be brave enough to stop antibacterial agents solely on the basis of discovery of a viral pathogen, especially given the high rate of documented bacterial copathogens in adult viral pneumonia [14]. This may be particularly so for some viruses, such as rhinovirus, whose role in adult pneumonia is still being established [15]. For adults with lower respiratory tract infections, clinicians are more likely to modify antibiotic therapy (possibly to an agent with a narrower spectrum) after the rapid identification of bacterial pathogens, especially S. pneumoniae (particularly penicillin-resistant strains), M. pneumoniae, C. pneumoniae, or L. pneumophila. This view is supported by the observation in the study by Oosterheert and colleagues that antibiotic therapy for 4 of the 6 patients was changed because PCR results were negative for M. pneumoniae, C. pneumoniae, and L. pneumophila. This is an interesting observation in itself, because the negative predictive values of these tests in the analysis of upper respiratory tract samples are poorly characterized. The study design could have been strengthened in several ways, including the use of a larger sample size that is based on the expected detection of M. pneumoniae, C. pneumoniae, and L. pneumophila in the intervention group and the expansion of the diagnostic tools in the intervention arm to include other tests for bacterial pathogens, such as the Now Streptococcus pneumoniae Urinary Antigen Test (Binax). Incorporation of these changes may have demonstrated more-profound changes in antimicrobial use in the intervention arm. Moreover, the findings may be quite different in children in whom the impact of viral infections is greater. The rapid detection of respiratory viruses by immunofluorescence has lead to reductions in the duration of hospital stay and antibiotic use among children [16]. Future similar studies should also aim to provide PCR results within a shorter period, to have the opportunity to better influence early therapeutic decisions. Providing results within 24 h after sample collection (at least during the working week) should be achievable. Without changes in antibiotic therapy, it is not surprising that, because of the increased expense of the additional diagnostic testing, the cost per patient was higher in the intervention group. Furthermore, the identification of influenza virus infection may be more likely to prompt the addition of an antiviral agent, such as oseltamivir, and the initiation of infection-control measures. Although these are important interventions, they will lead to increased costs per individual. Despite the limitations of their study, Oosterheert et al. [13] should be commended for undertaking this project, because relatively few randomized trials are performed to assess the benefits and harms of introducing new diagnostic tests [17]. Although such studies can be problematic with respect to control of potential confounders, allocation concealment, and blinding, this approach should be used more often. Before progressing to randomized trials, however, it is essential that newer diagnostic tests are fully evaluated for diagnostic accuracy. Sensitivity, specificity, and predictive values should be determined for each sample type. For lower respiratory tract infections, the predictive values of PCR testing of nasopharyngeal or throat swab samples for some pneumonia pathogens (e.g., C. pneumoniae and Legionella species) are not yet sufficiently characterized for progression to randomized trials. Only with this information can clinicians make well-informed decisions about altering therapy on the basis of test results. In addition to being evaluated for diagnostic accuracy and benefits in terms of improved patient outcomes and reduced cost, newer microbiological tests also need to be assessed for their role in infection control and public health responses to certain infections. Recent experiences with severe acute respiratory syndrome, avian influenza, Legionella infection, and inhalational anthrax highlight the critical role of good microbiological studies to help direct epidemiological investigation and therapy. As recently indicated by John Bartlett [18], we may now be entering an era when the priority of microbiological examinations for diagnosis of respiratory tract infections substantially increases. Ongoing developments in diagnostic testing will provide further momentum. Potential conflicts of interest. D.R.M.: no conflicts.
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David R. Murdoch (2005) studied this question.