Tuesday, 18 July 2017 10:34

Multiplex White Paper: Clinical Utility of Multiplex Tests for Respiratory and Gastrointestinal Pathogens

Introduction

In spite of the continued utilization of conventional diagnostic methods in clinical microbiology laboratories, the expanded availability of molecular methods for detection of pathogens directly in clinical specimens is changing the paradigm for diagnosis and management of patients with infectious diseases. One of the recent reasons for these changes has been the development of syndromic-based multiplex molecular panels with the ability to simultaneously detect, differentiate, and even subtype bacterial, parasitic and viral pathogens in patient specimens. Some of these panels provide sample-to-answer results, using integrated nucleic acid extraction, amplification and detection with testing times of as little as 1 hour. Several test systems have received FDA-clearance for the detection of respiratory tract or gastrointestinal (GI) tract pathogens, which has facilitated their rapid integration into routine testing. Representative examples of these systems are shown in Table 1.

Benefits of Multiplex Molecular Diagnostic Panels

A variety of laboratory-centered factors have contributed to the increased utilization of multiplex molecular panels. Analytically, the molecular assays exhibit enhanced detection rates compared to conventional methods, which also results in an increased rate of diagnosis for affected patients (1, 2). In addition, the menu of analytes on several panels is for the first time providing access to routine testing for pathogens that have previously been difficult to detect, or for which testing was only available at reference laboratories (i.e. norovirus, coronaviruses, Chlamydophila pneumoniae, Mycoplasma pneumoniae). Operationally, multiplex molecular panels allow laboratories to consolidate testing for a broad range of pathogens from the same samples. This consolidation provides opportunities to eliminate conventional testing methodologies, including direct fluorescent antibody (DFA) and cell culture for the detection of respiratory viruses, as well as stool antigen testing for the detection of rotavirus, adenovirus, and shiga-like toxin. These types of workflow changes have been shown to enhance operational efficiency and improve cost-effectiveness of testing (3). Furthermore, utilization of GI panels, with testing for the most frequently detected parasites, offers the opportunity to redistribute how and when complete ova and parasite (O&P) exams are performed so that this resource-intensive procedure is utilized only when necessary, rather than as a first-line test. Since molecular device manufacturers have been able to develop much simpler platforms, it is now easier to train medical technologists to perform the testing and interpret objective results, as well as maintain their competency on these systems, compared to many conventional methods such as DFA, viral cell culture and O&P exams. Furthermore, the willingness of device manufacturers to invest in clinical trials and pursue FDA-clearance has standardized these technologies both within and between clinical laboratories. This allows laboratories of varying complexities to perform this testing while reducing reliance on laboratory-developed tests.

Implementation of syndromic-based multiplex molecular panels may also allow clinicians to provide a higher quality of care to their patients. A positive result obtained by a multiplex panel eliminates the need for additional diagnostic testing. In addition, respiratory panels detecting bacterial and viral pathogens, or GI panels detecting bacterial, viral and parasitic pathogens reduce the number of tests to be ordered, reduces the number of specimens to collect, and simplifies specimen transport. The increased sensitivity of these molecular multiplex tests relative to conventional methods allows laboratories to limit testing to one test per patient episode thereby decreasing laboratory and possibly overall healthcare costs. Furthermore, the rapid time to result provided by molecular multiplex tests allows clinicians to obtain results in a clinically relevant and actionable timeframe, compared to less sensitive, and often slower approaches utilizing conventional methods. For example, rapid detection of respiratory viruses has been shown to increase the rates of diagnosis of patients while still in the emergency department (4), as well as increase the ability to initiate influenza-specific antiviral therapy in a more timely manner (5).

Each of these factors can contribute to reductions in the complexity in managing the patient and allows the clinician to utilize a syndrome-specific approach to both developing a differential diagnosis as well as laboratory testing. The improved diagnostic yield and more targeted management approach have the additional opportunity to enhance patient and clinician satisfaction while reducing unnecessary or inappropriate testing or therapy.

Table 1. Examples of FDA-cleared multiplex molecular panels for detection of microbial pathogensa

Respiratory Pathogen Panels Detecting >5 Pathogens

     
FilmArray Respiratory Panel (RP and RP2) BioFire Diagnostics.  
xTAG Respiratory Viral Panel (RVP) and Respiratory Pathogen Panel (RPP) Luminex Corp.  
eSensor RVP and ePlex RPP GenMark Diagnostic  
Verigene Respiratory Virus Plus Nucleic Acid Test (RV+ and RP Flex) Luminex Corp. (Nanosphere)  
     

Gastrointestinal Pathogen Panels Detecting >5 Pathogens

     
xTAG Gastrointestinal Pathogen Panel (GPP) Luminex Corp.  
FilmArray Gastrointestinal Panel BioFire Diagnostics  
Verigene Enteric Pathogens Test (EP) Luminex Corp. (Nanosphere)  

awww.fda.gov

Clinical Value of Multiplex Molecular Diagnostic Panels

Multiplex molecular panels constitute a technological breakthrough that has revolutionized clinical microbiology. These technologies give healthcare providers unprecedented ability to test for a high number of pathogens in a single specimen with great accuracy and great speed. As a result, this revolutionary technology has been met with enthusiasm and widespread adoption across the industry. However, there is a paucity of outcome-based studies demonstrating the direct benefit to patient care. The field as a whole is aware of this shortcoming and has taken steps to produce data showing that multiplex PCR panels do in fact lead to better outcomes. As evidence of this, the Journal of Clinical Microbiology recently published a commentary outlining the need for such data and the steps that must be taken for its production (6).

In terms of viral respiratory tract infection, one of the primary impacts of improved diagnostic testing is the reduction in unnecessary antibiotic usage. Byington et al. evaluated this outcome in a pediatric population and found that hospitalized children with a diagnosis of viral respiratory tract infection did indeed receive fewer inappropriate antibiotics (7). These technologies can also improve the efficiency with which appropriate antimicrobials can be deployed. Xu et al. used the FilmArray respiratory pathogen panel to achieve a median turnaround time of 1.4 hours and showed that this allowed physicians to prescribe anti-influenza medication appropriately while the patient was still present in the Emergency Department or within 3 hours of discharge (5). This is a significant finding as there is a narrow window (48 hours from symptom onset) in which oseltamivir must be given to be optimally effective. In addition, clinical symptoms are not sufficient to differentiate influenza from other respiratory viral infections that commonly co-circulate and may prompt inappropriate anti-influenza treatment. These findings were supported by those of Rogers et al. who also found that multiplex testing improved antibiotic usage, but also shortened length of stay and reduced the amount of time patients spent in isolation (4).

Multiplex molecular panels for the diagnosis of gastrointestinal infection have more recently entered the market, thus fewer studies demonstrating their clinical benefit have been published. However, a study sponsored by the National Institute for Health Research (NIHS) recently asked whether these multiplex assays would have an impact on hospital infection control practices. In a retrospective analysis of nearly 1,000 clinical specimens they concluded that managing infectious diarrhea took up to 21% of infection control team’s time and identified improved diagnostics as an area that could significantly improve patient care (8).

Conclusion

There is no question that multiplex molecular panels provide superior diagnostic performance when compared to conventional methods and there is a small, but growing body of evidence that supports their positive impact on patient care and reduction in overall healthcare costs. Although the evidence demonstrating improved patient outcomes is sparse at this time, there are a number of intuitive reasons these tests improve patient care. In many cases, these tests provide definitive answers to clinicians in time frames that allow them act upon the results and have a real impact on patient care. As demonstrated by Xu et al. and Rogers et al., this leads to initiation of appropriate therapy as would be the case with pathogens such as influenza, Mycoplasma pneumoniae, Bordetella pertussis, Entamoeba histolytica, Salmonella, and many others. As has been shown in a variety of studies, timely initiation of antimicrobial therapy leads to shortened duration of symptoms, less transmission of disease, and reduction in unnecessary additional testing. In other cases, the detection of pathogens can lead to important non-medical interventions such as cohorting and isolation of patients. Additionally, for those patients that are diagnosed with infections that do not require any intervention, there is still great value in NOT administering antibiotics.

It is important to note that the absence of a large body of peer-reviewed, outcomes-based studies, demonstrating the clinical benefit of multiplex testing, does NOT mean that these tests have no impact on patient care.  The reality is, such studies are exceedingly difficult to perform and in their absence, we must rely on intuition and anecdotal experiences.  Nevertheless, these tests provide timely and definitive diagnoses which allow physicians to confidently treat, or withhold treatment, for their patients.

References

  1. Babady NE, Mead P, Stiles J, Brennan C, Li H, Shuptar S, Stratton CW, Tang YW, Kamboj M. 2012. Comparison of the Luminex xTAG RVP Fast assay and the Idaho Technology FilmArray RP assay for detection of respiratory viruses in pediatric patients at a cancer hospital. J Clin Microbiol 50:2282-2288.
  2. Rand KH, Rampersaud H, Houck HJ. 2011. Comparison of two multiplex methods for detection of respiratory viruses: FilmArray RP and xTAG RVP. J Clin Microbiol 49:2449-2453.
  3. Dundas NE, Ziadie MS, Revell PA, Brock E, Mitui M, Leos NK, Rogers BB. 2011. A lean laboratory: operational simplicity and cost effectiveness of the Luminex xTAG respiratory viral panel. J Mol Diagn 13:175-179.
  4. Rogers BB, Shankar P, Jerris RC, Kotzbauer D, Anderson EJ, Watson JR, O'Brien LA, Uwindatwa F, McNamara K, Bost JE. 2015. Impact of a rapid respiratory panel test on patient outcomes. Arch Pathol Lab Med 139:636-641.
  5. Xu M, Qin X, Astion ML, Rutledge JC, Simpson J, Jerome KR, Englund JA, Zerr DM, Migita RT, Rich S, Childs JC, Cent A, Del Beccaro MA. 2013. Implementation of filmarray respiratory viral panel in a core laboratory improves testing turnaround time and patient care. Am J Clin Pathol 139:118-123.
  6. Doern GV. 2014. The value of outcomes data in the practice of clinical microbiology. J Clin Microbiol 52:1314-1316.
  7. Byington CL, Castillo H, Gerber K, Daly JA, Brimley LA, Adams S, Christenson JC, Pavia AT. 2002. The effect of rapid respiratory viral diagnostic testing on antibiotic use in a children's hospital. Arch Pediatr Adolesc Med 156:1230-1234.
  8. Pankhurst L, Macfarlane-Smith L, Buchanan J, Anson L, Davies K, O'Connor L, Ashwin H, Pike G, Dingle KE, Peto TE, Wordsworth S, Walker AS, Wilcox MH, Crook DW. 2014. Can rapid integrated polymerase chain reaction-based diagnostics for gastrointestinal pathogens improve routine hospital infection control practice? A diagnostic study. Health Technol Assess 18:1-167.

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