Respiratory infection diagnostics and the role of quality control testing

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Respiratory tract infections are common and can be asymptomatic or manifest as a mild illness with progression into serious complications, hospitalization,1,2 or death.4 Influenza and other viral pathogens such as adenovirus, human metapneumovirus, respiratory syncytial virus, and rhinovirus are common causes of respiratory infections.3 Early identification and diagnosis of the viral pathogen may allow for initiation of the appropriate treatment5 and serve as a confirmation of an outbreak to control and mitigate influenza spread.6

Current approaches to diagnosis and surveillance utilize the patient clinical presentation and a variety of diagnostic assays. However, this may present a challenge as overlapping symptoms make clinical presentation for respiratory infections inadequate for diagnosis.7,8 Laboratory diagnostics of respiratory infections have made immense strides over the last several years to provide timely and actionable results during a patient encounter.

Laboratory diagnostics

Laboratory diagnostic testing for respiratory assays has been rapidly evolving in recent years. A plethora of techniques and assays exist in the laboratory including traditional microbiological respiratory cultures, direct fluorescent antigen (DFA) testing, rapid serological assays, and pathogen-specific molecular assays. Each serve a unique purpose and play a vital role in the laboratory.

Several conventional testing methods including culture, DFA, and rapid testing are subjective and dependent on user technique and experience. In addition, DFA is subject to photobleaching and appropriate digestion of lower respiratory tract specimens. Another limitation of these conventional methods is turnaround time. Many conventional methods may take several hours to days or weeks to complete. On the other end of the spectrum are rapid serology-based assays. Whether point-of-care, or performed within the laboratory, these rapid assays allow for a quick screen to see if a particular pathogen is present. Positives are usually confirmed by conventional microbiology methods. Rapid tests provide a quick screen but lack in sensitivity compared to conventional microbiology.

Molecular testing, which typically provides a rapid turnaround time, has emerged as the contemporary method of laboratory diagnostics for respiratory viral infections. Most respiratory pathogen molecular test results are available within a couple hours with some platforms coming in under an hour. Early molecular assays were designed to target a single pathogen, but over time have evolved into multiplexed panels allowing laboratories to test a single specimen for multiple pathogens. There is wide variation from manufacturer to manufacturer on the respiratory targets chosen. Some all-encompassing panels test a large conglomerate of pathogens from a single specimen, while other mini panels test a handful of targets, and then there are single pathogen assays. However, this can be a double-edged sword. While results are available much quicker, there is an added cost for the convenience. This may be accounted for in the cost of the assay reagents and/or in reimbursement for the testing based on clinical presentation and diagnosis.

Impact of quality on patient results

While there are many considerations in determining which diagnostic test is right for an individual laboratory, it is important to remember the patient on the receiving end of the result. There are many options available in the market and not all choices are equal. One option may be particularly attractive from a cost and efficiency standpoint, but is it providing the best result for your patient population?

Recently there has been a change in the practice of quality control (QC) in clinical laboratories. Many labs are comfortable with QC in chemistry and hematology. Microbiology QC, however, is not as well defined, particularly for molecular methods. In 2014, the Centers for Medicaid & Medicare Services (CMS) updated its policy to replace Equivalent Quality Control (EQC) with an Individualized Quality Control Plan (IQCP). This change took effect at the start of 2016 and requires laboratories to perform routine quality control in accordance with Clinical Laboratory Improvement Amendments (CLIA), or establish their own risk-based ICQP plan demonstrating QC performance intervals out to 30 days if the manufacturer’s instructions allow it. There are also several exemptions to this for certain microbiology media.

In light of the requirements of IQCP, there are many questions a laboratory must address to determine its best course of action including:

  • Considering the amount of validation a laboratory must perform to validate an ICQP plan, to save a little up front on QC costs, is it costing more on the back end?
  • With tightening budgets, it may seem attractive to spend less on QC, but will this allow inaccurate results to creep out of your laboratory?

What is the patient impact of an inaccurate respiratory result? Can you ensure patients are always correctly diagnosed and treated? For example, a patient was treated improperly with an antibiotic instead of an antiviral and now they have developed a Clostridium difficile infection. In situations like this you must consider:

  • With a QC interval spanning several days to weeks, is there a group of inaccurate tests that went out undetected resulting in the recall of several patients?
  • Will the inaccuracies result in lost outreach laboratory testing?
  • Was the inaccurate result the cause of mistreatment and/or occurrence of a sentinel event leading to litigation? What is the cost of pending litigation against your facility or laboratory? How will this impact your organization’s reputation?

Quality and you

With the ever changing landscape of respiratory virus testing and migration from conventional subjective methods to contemporary molecular diagnostic methods, the quality of the patient result is just as important if not more important than the accelerated turnaround time. As these results are now actionable more quickly to the clinical provider, it is of the utmost importance that the result is accurate the first time. We all play a critical role in advocating for quality in our labs, and the choices we make may not seem cost-effective upfront, but may mean the difference between life and death for a patient and additional burdensome costs in reputation and litigation for the laboratory.

Learn more

Several organizations provide guidance for QC and implementing IQCP including the College of American Pathologists (CAP), CMS, and the Clinical and Laboratory Standards Institute (CLSI). CLSI’s EP23-A: Laboratory Quality Control Based on Risk Management document describes how to develop QC plans tailored to a laboratory’s measuring system, laboratory setting, and clinical application of the test. Visit the CAP, CMS, and CLSI websites to learn more.

REFERENCES
  1. Mistry R.D., Fischer J.B., Prasad P.A., Coffin S.E., Alpern E.R. Severe Complications in Influenza-like Illnesses. Pediatrics 134, e684–e690 (2014).
  2. Cate T.R. Impact of influenza and other community-acquired viruses. Semin. Respir. Infect. 13, 17–23 (1998).
  3. Hayden F.G. Respiratory viral threats. Curr. Opin. Infect. Dis. 19, 169–178 (2006).
    Ferkol T., Schraufnagel D. The global burden of respiratory disease. Ann. Am. Thorac. Soc. 11, 404–406 (2014).
  4. Sintchenko V., Gilbert G.L., Coiera E., Dwyer D. Treat or test first? Decision analysis of empirical antiviral treatment of influenza virus infection versus treatment based on rapid test results. J. Clin. Virol. 25, 15–21 (2002).
  5. Gaillat J., Dennetière G., Raffin-Bru E., Valette M., Blanc M.C. Summer influenza out-break in a home for the elderly: application of preventive measures. J. Hosp. Infect. 70, 272–277 (2008).
  6. Jiang L., et al. Performance of case definitions for influenza surveillance. Eurosurveillance 20, 21145 (2015).
  7. Campe H., Heinzinger S., Hartberger C., Sing A. Clinical symptoms cannot predict influenza infection during the 2013 influenza season in Bavaria, Germany. Epidemiol. Infect. 144, 1045–1051 (2016).
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