Syndromic panels or ‘panel syndrome’? A perspective through the lens of respiratory tract infections
Authors: M.-C. Zanella, P. Meylan, L. Kaiser
Journal: Clinical Microbiology and Infection (2020)

"In seeking continued 'laboratory improvement' there is a great danger of establishing exhaustive microbiology as an end in itself …. This trend is discouraging to many microbiologists who recognize that the quality of their services will be more effectively improved through careful integration of what is technically feasible with what is clinically important." Raymond C. Bartlett (1974) [[1]Bartlett R.C. Medical microbiology: quality, cost and clinical relevance. Wiley, New York1974Google Scholar]. In past decades, molecular testing and PCR-based identification of viral infections have changed the face of clinical virology. More recently, panels have allowed the screening of dozens of viruses and other pathogens in the same analysis, with sometimes short turn-around times and minimal technical expertise, using a so-called 'syndromic approach' of testing marked by the use of panel assays designed with predefined targets for specific infectious syndromes (e.g. respiratory, gastrointestinal syndromes). Respiratory panels comprise diverse assays that differ in their number and type of pathogens (up to dozens), their qualitative or semi-quantitative approach, their manufacture (in-house versus commercial), and their technique (some are point-of-care diagnostic tests). They screen pathogens that infect the upper and/or lower respiratory tract and vary widely in their clinical manifestations (Table 1). Furthermore, there is no single generic specimen for respiratory infections: nasopharyngeal swab, sputum and bronchoalveolar lavage samples are not equivalent. None of these panels have been constructed according to specimen type.Table 1Diverse epidemiological and clinical manifestations of a selection of viruses and bacteria targeted in some currently available panels described as 'syndromic respiratory panels' [20Jacobs S.E. Lamson D.M. St George K. Walsh T.J. Human rhinoviruses.Clin Microbiol Rev. 2013; 26: 135-162Crossref PubMed Scopus (437) Google Scholar, 21de Crom S.C. Rossen J.W. van Furth A.M. Obihara C.C. Enterovirus and parechovirus infection in children: a brief overview.Eur J Pediatr. 2016; 175: 1023-1029Crossref PubMed Scopus (110) Google Scholar, 22Zheng X.Y. Xu Y.J. Guan W.J. Lin L.F. Regional, age and respiratory-secretion-specific prevalence of respiratory viruses associated with asthma exacerbation: a literature review.Arch Virol. 2018; 163: 845-853Crossref PubMed Scopus (101) Google Scholar, 23Griffiths C. Drews S.J. Marchant D.J. Respiratory syncytial virus: infection, detection, and new options for prevention and treatment.Clin Microbiol Rev. 2017; 30: 277-319Crossref PubMed Scopus (274) Google Scholar, 24Paules C. Subbarao K. Influenza.Lancet. 2017; 390: 697-708Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar, 25von Konig C.H. Halperin S. Riffelmann M. Guiso N. Pertussis of adults and infants.Lancet Infect Dis. 2002; 2: 744-750Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar, 26Cunha B.A. Burillo A. Bouza E. Legionnaires' disease.Lancet. 2016; 387: 376-385Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 27Hu Y.L. Chang L.Y. Current status of enterovirus D68 worldwide and in Taiwan.Pediatr Neonatol. 2019 Sept 13; (pii: S1875-9572(19)30503-0. [Epub ahead of print])Abstract Full Text Full Text PDF Scopus (4) Google Scholar, 28Hoyle E. Erez J.C. Kirk-Granger H.R. Collins E. Tang J.W. An adenovirus 4 outbreak amongst staff in a pediatric ward manifesting as keratoconjunctivitis-a possible failure of contact and aerosol infection control.Am J Infect Contr. 2016; 44: 602-604Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 29Lion T. Adenovirus infections in immunocompetent and immunocompromised patients.Clin Microbiol Rev. 2014; 27: 441-462Crossref PubMed Scopus (467) Google Scholar]RhinovirusEnterovirusRSVAdenovirusInfluenza virusBordetella pertussisLegionella pneumophilaEpidemiologyAll yearSpring/summerWinterWinter/outbreaksWinterAll year/outbreaksAll year/outbreaksAffected populationPaediatric and adult patientsEnterovirus 68: paediatric and adult patientsParechovirus: paediatric patients <3 years oldPaediatric patients, especially infants (Adult patients)Paediatric and adult patientsPaediatric and adult patientsNon-vaccinated paediatric and adult patientsPaediatric and adult patientsClinical manifestationsURTI (common cold)Asthma exacerbationsMeningitisBronchiolitisLRTI in elderly and IC hosts (pneumonia)URTILRTI (IC hosts)Influenza-like illnessLRTI (pneumonia)Whooping coughLRTI (pneumonia)Abbreviations: IC, immunocompromised; LRTI, lower respiratory tract infections; RSV, human respiratory syncytial virus; URTI, upper respiratory tract infections. Open table in a new tab Abbreviations: IC, immunocompromised; LRTI, lower respiratory tract infections; RSV, human respiratory syncytial virus; URTI, upper respiratory tract infections. Many consider these panels an ideal solution given their capacity to target numerous pathogens and so relieve the clinician from pre-test clinical thinking. Here we consider whether panel assays, through the lens of respiratory panels, are compatible with a Bayesian approach [[2]Mohan A. Srihasam K. Sharma S.K. Diagnostic reasoning: approach to clinical diagnosis based on Bayes' theorem.in: Bichile S.K. Medicine update. 18. Association of Physicians of India, Mumbai2008: 563-569Google Scholar]. In 2020, evidence-based algorithms and the judicious use of resources should remain the cornerstone of any medical decision. New technologies should serve to support a logical and clinically adapted decision process and should be validated by clinical studies, not vice versa. Clinicians are facing a choice: should testing drive clinical management or should medical needs stay in the driver seat, with decisions to test and treat target(s) remaining secondary to a stepwise clinical strategy that includes consideration of epidemiological factors. The development and implementation of new technologies with the sole aim of producing more microbiological data only because it is technologically feasible, irrespective of predefined clinical hypotheses, is at best a waste of resources and at worst a cause of unnecessary treatment. The interpretation of a test's results requires the integration of the pre-test probability that the disease is present with the test's accuracy. The pre-test probability of the diverse aetiological agents included in a panel needs to be estimated to compute the positive and negative predictive values of the test: this has to be performed separately for each target of the panel assay. For very rare pathogens, a positive result will have to be considered as a potential false-positive, depending on the test's performance. The larger the panel, the greater the need for cautious clinical interpretation of positive results for unusual or unexpected pathogens. Conversely, it means that panels should not be designed simply to include all pathogens potentially found in a given specimen (sample-designed panel), but rather pathogens with similar clinical manifestations, host type and epidemiological context. Some tests consider too many different conditions under the umbrella of the so-called 'respiratory syndrome', with respiratory infections ranging from upper-respiratory-tract infection to severe pneumonia and acute respiratory distress syndrome. Gathering all these conditions under the same 'syndrome' without considering specific clinical features, host susceptibility and epidemiology is turning our back on clinical science and moving toward an 'all-you-can-screen world' by ignoring an evidence-based approach and personalized testing. For instance, we could consider that agents of atypical pneumonia (e.g. Mycoplasma spp., Chlamydia spp. or mycobacterial targets) should not be included in respiratory virus panels, as they practically never present in a similar manner. Likewise, panels including opportunistic pathogens should not be used in 'normal' hosts. Rhinovirus testing should not be at the forefront of screening in immunocompetent adults with pneumonia. We should not promote testing by chance. Laboratory stewardship needs to meet antimicrobial stewardship. Algorithmic strategies integrating clinical assessment, risk factors and therapeutic options would allow more appropriate use of available technologies. A 'less-is-more' approach with judicious selection of tests affecting clinical management should be promoted. By contrast, it must be recognized that screening for multiple agents rarely at the foreground of differential diagnoses could bring new information and influence clinical decisions. However, the decision to screen so widely should be restricted to specific situations and should be downstream in a stepwise approach. At present, given the uncertainty regarding the role of co-infections and of certain viruses 'orphaned' of any clear clinical impact (e.g. human bocavirus, parainfluenza virus 4 and influenza C virus), a one-step 'all-you-can-screen' approach should be restricted to clinical research. Such studies will provide novel information on the epidemiology of certain respiratory viruses and co-infection and so inform clinicians' interpretation of the myriad results with which they are now confronted [[1]Bartlett R.C. Medical microbiology: quality, cost and clinical relevance. Wiley, New York1974Google Scholar,[2]Mohan A. Srihasam K. Sharma S.K. Diagnostic reasoning: approach to clinical diagnosis based on Bayes' theorem.in: Bichile S.K. Medicine update. 18. Association of Physicians of India, Mumbai2008: 563-569Google Scholar]. One argument in favour of the new panels is their rapidity in producing an array of results with, for some point-of-care tests, turnaround times <2 hours. Although rapid pathogen identification can lead to tailored therapeutic interventions in some circumstances, empirical therapy and isolation measures should be driven by clinical features rather than delayed while tests are pending [[3]Metlay J.P. Waterer G.W. Long A.C. Anzueto A. Brozek J. Crothers K. et al.Diagnosis and treatment of adults with community-acquired pneumonia. an official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America.Am J Respir Crit Care Med. 2019; 200: e45-e67Crossref PubMed Scopus (1293) Google Scholar,[4]Vos L. Oosterheert J.J. Testing for viral infections in severe lower respiratory tract infections; the unpredictable effects of diagnostic certainty.Clin Microbiol Infect. 2019; 11: 1302-1303Abstract Full Text Full Text PDF Scopus (2) Google Scholar]. A short turnaround time could be a key parameter for pathogens for which therapeutic measures are relevant, targeted treatments exist, or specific infection-control measures are required. Specific and rapid diagnostic tests for some of these pathogens already exist (e.g. influenza virus, respiratory syncytial virus). Another key element to consider is clinical validity. Testing for human immunodeficiency virus, hepatitis C virus and other viruses has been subject to numerous comparisons among assays using different specimen types, so providing clear information on the reproducibility, variability and performance of a given assay. This is clearly lacking for many respiratory panels, with the disadvantage that multiplexing dramatically affects validation. Assessing the performance of a new microbiological diagnostic assay typically involves the comparison of its analytical performance to that of a reference assay, using clinical samples harvested prospectively to avoid bias. The assessment requires a sample number that is inversely proportional to the pathogen's prevalence in the sample set. When testing more than one parameter, as in a panel assay, the number of samples needed for prospective validation increases proportionately to the number of pathogens included in the assay. Hence, for a 15-plexed assay, tens of thousands of specimens are theoretically needed. As a result, suboptimal approaches have been employed, with the use of small, retrospectively selected sample sets enriched in positive ones for the different pathogens included, or sets of negative samples spiked with nucleic acid targets from both viruses and bacteria. By introducing some panel assays into clinical practice, we are tolerating a departure from the quality standards that we have promoted for decades. For these reasons, there is a need to raise standards and the reference standard must be defined for panel assays. Regarding respiratory diseases, published clinical validation studies have been historical comparisons where the introduction of a panel assay offered the opportunity to evaluate the impact of end points such as diagnostic yield, hospitalization rates and antibiotic prescriptions compared with those of previous periods [5Barenfanger J. Drake C. Leon N. Mueller T. Troutt T. Clinical and financial benefits of rapid detection of respiratory viruses: an outcomes study.J Clin Microbiol. 2000; 38: 2824-2828Crossref PubMed Google Scholar, 6Rappo U. Schuetz A.N. Jenkins S.G. Calfee D.P. Walsh T.J. Wells M.T. et al.Impact of early detection of respiratory viruses by multiplex PCR assay on clinical outcomes in adult patients.J Clin Microbiol. 2016; 54: 2096-2103Crossref PubMed Scopus (104) Google Scholar, 7Rogers B.B. Shankar P. Jerris R.C. Kotzbauer D. Anderson E.J. Watson J.R. et al.Impact of a rapid respiratory panel test on patient outcomes.Arch Pathol Lab Med. 2015; 139: 636-641Crossref PubMed Scopus (170) Google Scholar, 8Semret M. Schiller I. Jardin B.A. Frenette C. Loo V.G. Papenburg J. et al.Multiplex respiratory virus testing for antimicrobial stewardship: a prospective assessment of antimicrobial use and clinical outcomes among hospitalized adults.J Infect Dis. 2017; 216: 936-944Crossref PubMed Scopus (42) Google Scholar]. However, these comparisons are likely to be confounded by epidemiological changes, because different winter seasons marked by differing incidences of various respiratory viruses were included. Some molecular assays for respiratory viruses have demonstrated reduced sensitivity for some important pathogens compared with reference assays, such as adenovirus [[9]Schreckenberger P.C. McAdam A.J. Point-counterpoint: large multiplex PCR panels should be first-line tests for detection of respiratory and intestinal pathogens.J Clin Microbiol. 2015; 53: 3110-3115Crossref PubMed Scopus (71) Google Scholar,[10]Song E. Wang H. Salamon D. Jaggi P. Leber A. Performance characteristics of filmarray respiratory panel v1.7 for detection of adenovirus in a large cohort of pediatric nasopharyngeal samples: one test may not fit all.J Clin Microbiol. 2016; 54: 1479-1486Crossref PubMed Scopus (20) Google Scholar]. For other assays, clinical validation studies were performed in populations with very low prevalences of some targeted infections [11Leber A.L. Everhart K. Daly J.A. Hopper A. Harrington A. Schreckenberger P. et al.Multicenter evaluation of BioFire FilmArray Respiratory Panel 2 for detection of viruses and bacteria in nasopharyngeal swab samples.J Clin Microbiol. 2018; 56 (pii: e01945-17)Crossref Scopus (84) Google Scholar, 12Loeffelholz M.J. Pong D.L. Pyles R.B. Xiong Y. Miller A.L. Bufton K.K. et al.Comparison of the FilmArray Respiratory Panel and Prodesse real-time PCR assays for detection of respiratory pathogens.J Clin Microbiol. 2011; 49: 4083-4088Crossref PubMed Scopus (109) Google Scholar, 13Pierce V.M. Elkan M. Leet M. McGowan K.L. Hodinka R.L. Comparison of the Idaho Technology FilmArray system to real-time PCR for detection of respiratory pathogens in children.J Clin Microbiol. 2012; 50: 364-371Crossref PubMed Scopus (100) Google Scholar, 14Nijhuis R.H.T. Guerendiain D. Claas E.C.J. Templeton K.E. Comparison of ePlex Respiratory Pathogen Panel with laboratory-developed real-time PCR assays for detection of respiratory pathogens.J Clin Microbiol. 2017; 55: 1938-1945Crossref PubMed Scopus (37) Google Scholar, 15Babady N.E. England M.R. Jurcic Smith K.L. He T. Wijetunge D.S. Tang Y.W. et al.Multicenter evaluation of the ePlex Respiratory Pathogen Panel for the detection of viral and bacterial respiratory tract pathogens in nasopharyngeal swabs.J Clin Microbiol. 2018; 56 (pii: e01658-17)Crossref Scopus (58) Google Scholar]. These aspects need to be considered in the interpretation of negative results, because they may result in additional testing and delays in clinical management. Panel results, then, need to be interpreted with more caution than ever. What is the clinical meaning of a positive result? Does the requesting clinician or laboratory staff have the appropriate training and availability to validate and interpret results? Results from a bronchoalveolar lavage analysis do not have the same predictive value as those from a nasopharyngeal swab, because contamination of the lower respiratory tract by viruses or bacteria that colonize/infect the upper respiratory tract can occur. Moreover, panels provide qualitative or at best semi-quantitative results, whose clinical significance is lower than those of quantitative assays in specific situations, such as viral co-infections or follow up during therapy. The impact in terms of antimicrobial prescribing, isolation and additional work up has only recently been better assessed. A recent meta-analysis evaluated the potential clinical impact of rapid molecular tests for respiratory viruses, including respiratory syndromic panels, by analysing 56 diagnostic-test accuracy studies and 15 impact studies [[16]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; 69: 1243-1253Crossref PubMed Scopus (62) Google Scholar]. Compared with conventional molecular assays, use of these rapid molecular tests was associated with more appropriate oseltamivir use, reduced length of hospital stay by about 1 day (due to shortened turnaround times), fewer chest X-rays, and (potentially) lower costs. They did not, however, demonstrate any effect on antibiotic use and duration, isolation measures, or hospital admission [[16]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; 69: 1243-1253Crossref PubMed Scopus (62) Google Scholar]. The cost-effectiveness of syndromic respiratory panel testing remains poorly studied and controversial [[17]Pinsky B.A. Hayden R.T. Cost-effective respiratory virus testing.J Clin Microbiol. 2019; 57 (pii: e00373-19)Crossref Scopus (28) Google Scholar], and randomized non-inferiority trials are needed to determine the safety of delayed antibiotic prescription when a virus is detected [[4]Vos L. Oosterheert J.J. Testing for viral infections in severe lower respiratory tract infections; the unpredictable effects of diagnostic certainty.Clin Microbiol Infect. 2019; 11: 1302-1303Abstract Full Text Full Text PDF Scopus (2) Google Scholar]. Clinicians should question the added value of such a diversity of pathogen screening in the same assay, particularly when testing for pathogens with a specific epidemiology. Systematic biological testing is certainly a reality of modern medicine. Nevertheless, it should not preclude pre-test clinical thinking. 'Systematic' should not be synonymous with 'broad' testing. Besides multistep approaches, in-house panels can represent an intelligent and adaptive strategy that can be adjusted according to novel circulating variants or specific epidemiology (e.g. seasonality, patient's immune status). The influence of panels on clinical management is probably not the consequence of the multiplicity of the pathogens tested, but rather the rapid identification of key pathogens (e.g. influenza virus or respiratory syncytial virus) leading to actionable results and an impact on therapeutic interventions [[18]Kuypers J. Impact of rapid molecular detection of respiratory viruses on clinical outcomes and patient management.J Clin Microbiol. 2019; 57 (pii: e01890-18)Crossref PubMed Scopus (4) Google Scholar,[19]Rogan D.T. Kochar M.S. Yang S. Quinn J.V. Impact of rapid molecular respiratory virus testing on real-time decision making in a pediatric emergency department.J Mol Diagn. 2017; 19: 460-467Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar]. Apart from specific patient populations, such as immunocompromised patients, the need for screening of some viruses included in respiratory molecular panels remains marginal. Among solid-organ and haematopoietic-stem cell transplant recipients, in-house or commercial panels may contribute to the detection of clinically relevant viruses other than influenza virus and respiratory syncytial virus (e.g. human metapneumovirus or parainfluenza virus) that may benefit from specific management although no specific antivirals are available yet. In conclusion, testing for a broad range of pathogens that are neither clinically nor epidemiologically suspected will not have any impact on clinical end points, such as admission rate, length of stay, additional microbiological testing and antibiotic use. We should employ smaller, more targeted panels, and only when they can actually impact clinical management. In an era of resource constraints and increasing health-care costs, and in a context of persuasive marketing, the introduction of new assays should rely more than ever on high-quality evidence supporting their clinical validation and impact. A scientific approach with evidence-based decisions for diagnostic and therapeutic strategies needs to be kept at the forefront of medical practice. As microbiologists and clinicians, we have a responsibility to promote diagnostic stewardship and design and conduct appropriate studies for the judicious integration of these new technologies into daily care, increasing their clinical relevance and decreasing their current ambiguity. The authors have no conflicts of interest to declare. No funding was received for this review. The authors would like to thank Rosemary Sudan (Geneva University Hospitals, Switzerland) for editorial assistance. Re: 'Syndromic panels or "panel syndrome"? A perspective through the lens of respiratory-tract infections' by Zanella et alClinical Microbiology and InfectionVol. 26Issue 8PreviewWe read with interest the article by Zanella et al. [1]. The authors suggest that the increasing use of rapid, automated, syndromic molecular panels for respiratory viruses (RVs) should be abandoned in favour of more limited PCR testing for RVs (e.g. testing for influenza alone or influenza and RSV combined) due to the high cost and uncertain clinical impact of detecting non-influenza viruses. Full-Text PDF Open Archive