Testing for viral infections in severe lower respiratory tract infections; the unpredictable effects of diagnostic certainty
Authors: L.M. Vos, J.J. Oosterheert
Journal: Clinical Microbiology and Infection (2019)

In this issue, Sengchen et al. [[1]Shengchen D Gu Xiaoying Fan Guohui Sun Ruihua Wang Yeming Yu Donghao et al.Evaluation of a molecular point of care testing for viral and atypical pathogens on intravenous antibiotic duration in hospitalized adults with lower respiratory tract infection: a randomized clinical trial.Clin Microbiol Infect. 2019; 25: 1415-1421https://doi.org/10.1016/j.cmi.2019.06.012Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar] describe an important single-centre randomized study among immunocompetent hosts presenting with severe lower respiratory tract infections to the emergency department of a large teaching hospital. The study evaluates the clinical effects and potential improvements in efficiency after the use of a rapid test for viral pathogens. The intervention consisted of a molecular ‘point-of-care’ test for 17 respiratory pathogens and three atypical bacteria, and was compared with usual care. In the control group, 48% of patients were tested using routine real-time PCR. The point-of-care test was executed not directly at the bedside—which is indeed hardly feasible due to the time constraints, complexity of the procedure, contamination issues and less specific training of emergency room personnel compared with specialized analysts—but within 4 hours of admission in the microbiological laboratory by a dedicated study team. The primary outcome was the duration of intravenous antibiotic therapy, which was reduced by 1 day in the intervention group. In general, the justification of studies that evaluate the introduction of point-of-care tests lies in the contribution of these tests to increased diagnostic certainty, within a short time, leading to positive clinical effects. Translated to respiratory infections: when a pathogen is detected, this may lead to more targeted and efficient use of available resources such as intravenous antibiotics, antivirals and hospital (isolation) beds. As a result, these point-of-care tests may lead not only to a reduction in health-care cost, but also to more targeted antibiotic prescribing and lower selection pressure, which eventually has a positive effect on the prevalence of infections with antibiotic-resistant microorganisms. Although this is an attractive hypothesis on how diagnostic certainty leads to positive effects, the question remains whether this chain of events holds true for respiratory infections. Importantly, there is the issue of the safety. The authors are to be complimented for incorporating safety end points in their analysis, but the study was neither designed nor powered to provide definitive answers on whether it is safe to withhold antibiotics in patients—especially severely ill patients—in whom a viral pathogen is detected. Yes, there is some evidence for the safety of such an approach in less severely ill patients [2Ladd E. The use of antibiotics for viral upper respiratory tract infections: an analysis of nurse practitioner and physician prescribing practices in ambulatory care, 1997–2001.J Am Acad Nurse Pract. 2005; 17: 416-424Crossref PubMed Scopus (59) Google Scholar, 3Little P. Stuart B. Moore M. Coenen S. Butler C.C. Godycki-Cwirko M. et al.Amoxicillin for acute lower-respiratory-tract infection in primary care when pneumonia is not suspected: a 12-country, randomised, placebo-controlled trial.Lancet Infect Dis. 2013; 13: 123-129Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar] and in patients with a low risk of complications with specific biomarker levels that indicate a mild host inflammatory response [4Kapasi A.J. Dittrich S. González I.J. Rodwell T.C. Host biomarkers for distinguishing bacterial from non-bacterial causes of acute febrile illness: a comprehensive review.PLoS One. 2016; 11: 1-29Crossref Scopus (88) Google Scholar, 5Hakami F.H.A. Serum procalcitonin and C-reactive protein level as markers of bacterial infection.Egypt J Hosp Med. 2018; 71: 2214-2216Crossref Google Scholar, 6Branche A.R. Walsh E.E. Vargas R. Hulbert B. Formica M.A. Baran A. et al.Serum procalcitonin measurement and viral testing to guide antibiotic use for respiratory infections in hospitalized adults: a randomized controlled trial.J Infect Dis. 2015; 212: 1692-1700Crossref PubMed Scopus (91) Google Scholar, 7Ramilo O. Mejías A. Shifting the paradigm: host gene signatures for diagnosis of infectious diseases.Cell Host Microbe. 2009; 6: 199-200Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 8Oved K. Cohen A. Boico O. Navon R. Friedman T. Etshtein L. et al.A novel host-proteome signature for distinguishing between acute bacterial and viral infections.PLoS One. 2015; 10Crossref PubMed Scopus (115) Google Scholar], but specific evidence to safely withhold antibiotics-based point-of-care tests in severely ill patients is still lacking. As a result, physicians have been reluctant to withhold antibiotics in this category of patients, even if viral pathogens are detected, since the introduction of a molecular test to detect viral pathogens [[9]Oosterheert J.J. van Loon A.M. Schuurman R. Hoepelman A.I. Hak E. Thijsen S. et al.Impact of rapid detection of viral and atypical bacterial pathogens by real-time polymerase chain reaction for patients with lower respiratory tract infection.Clin Infect Dis. 2005; 41: 1438-1444Crossref PubMed Scopus (168) Google Scholar]. This reluctance can also be observed in the study of Sengchen et al., in which physicians did not immediately respond to readily available results: although the turnaround time of the molecular test results was impressively low (results available within 100 minutes after sampling), until 72 hours after admission the effect on de-escalation of antibiotics (defined as reduction in the number, spectrum and/or administration route of antibiotics) compared with the control group was only small. Within 72 hours, only 7.9% of patients in the intervention group had been de-escalated, despite a high detection rate of viral pathogens in this group. This suggests reluctance of physicians to solely base their (antibiotic) treatment decisions on microbiological test results. This study illustrates that a diagnostic intervention may lead to increased diagnostic certainty, but that these interventions do not necessarily lead to improved clinical effects. Indeed, compared with conventional diagnostic methods, point-of-care methods to detect respiratory viruses have comparable diagnostic accuracy and have already shown benefits such as a reduced length of hospital stay and an increase in the appropriate use of oseltamivir in influenza virus-positive patients [[10]Vos L.M. Bruning A.H.L. Reitsma J.B. Schuurman R. Riezebos-Brilman A. Hoepelman A.I.M. et al.Rapid molecular tests for influenza, respiratory syncytial virus, and other respiratory viruses: a systematic review of diagnostic accuracy and clinical impact studies.Clin Infect Dis. 2019; (Epub ahead of print)Crossref Scopus (64) Google Scholar]. However, these effects have not been so evident for antibiotic prescribing. Antibiotic prescribing is not an exact science, but the result of multiple considerations in the mind of a physician. In primary care, considerations to prescribe or withhold antibiotics are driven by prognostic rather than diagnostic (un)certainty [[11]Horwood J. Cabral C. Hay A.D. Ingram J. Primary care clinician antibiotic prescribing decisions in consultations for children with RTIs: a qualitative interview study.Br J Gen Pract. 2016; 66: e207-e213Crossref PubMed Scopus (69) Google Scholar]. Although doctors in the hospital have more diagnostics at their disposal, for these physicians the risk of complications is probably also the main driver for antibiotic prescriptions. Subsequently, hospital physicians build up their confidence to stop or withhold antibiotic treatment based on the severity of presentation, the clinical response and the definitive microbiological results. In addition, education, training and experience, as well as the physical and mental state of the physician—being tired or when working under pressure—are also important factors when it comes to antibiotic prescribing [12Silverman M. Povitz M. Sontrop J.M. Li L. Richard L. Cejic S. et al.Antibiotic prescribing for nonbacterial acute upper respiratory infections in elderly persons.Ann Intern Med. 2017; 166: 765-774Crossref PubMed Scopus (66) Google Scholar, 13Linder J.A. Doctor J.N. Friedberg M.W. Nieva H.R. Birks C. Meeker D. et al.Time of day and the decision to prescribe antibiotics.JAMA Intern Med. 2014; 174: 2029-2031Crossref PubMed Scopus (146) Google Scholar]. So what should be the next step to improve targeted antibiotic treatment in patients with severe respiratory tract infections? First, more studies are required on what information physicians at the emergency department require in order to act on the results of point-of-care tests for viral pathogens. Above all, evidence on the safety of a strategy of withholding antibiotics if a viral pathogen is detected is needed. Ideally, this evidence should come from randomized non-inferiority trials adequately powered to assess safety. Additionally, implementation studies that properly evaluate the psychological factors that determine treatment decisions of physicians could help to optimize adherence to guidelines. Furthermore, there is a responsibility for acute-care physicians to critically evaluate, educate and provide feedback on how antibiotics are prescribed. A practical approach for the prescription of antibiotics—in which the first consideration is ‘does this patient have an infection that needs antibiotics?’—was published recently [[14]Tamma P.D. Miller M.A. Cosgrove S.E. Incorporating the 4 moments of antibiotic decision making into clinical practice.JAMA. 2019; 321: 139-140Crossref PubMed Scopus (56) Google Scholar]. In this publication, the potential benefit of identification of the causative pathogen by means of point-of-care testing and practical information on the implementation of such tests are also discussed. In conclusion, given the diagnostic accuracy, benefits on more targeted use of oseltamivir and effects on management we feel that point-of-care tests for respiratory viruses should be incorporated in hospital care settings. However we also think that for a successful contribution to patient care, implementation strategies should be based on safety studies and studies evaluating factors that determine the treatment decisions of physicians. If safety is not at stake, the introduction of such point-of-care tests should be accompanied by the recommendation to adhere to evidence-based guidelines to optimize antibiotic prescribing for severe respiratory infections in the emergency department. All authors have stated that there are no conflicts of interest. No external funding was used.