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Fighting flu: adopting routine molecular multiplex testing of respiratory pathogens during flu season.

As public health authorities around the world continue to work to contain the 2014 Ebola epidemic, the largest Ebola outbreak in history, concern over the spread of infectious diseases is a matter of intense public concern. Despite the Centers for Disease Control and Prevention's (CDC) assurances earlier this year that Ebola is not an imminent threat to the Western world, (1) the re-emergence of other contagious diseases that have been considered to be "eradicated" tends to trigger public alarm, particularly when the disease is not well understood or is unfamiliar.

Infectious diseases by their very nature remain a constant threat to public health. As we enter peak winter flu season, health experts are reminding us that the greatest threat we face to our health is one much closer to home than Ebola virus disease.

Significant vaccination and surveillance efforts have kept influenza in check in recent years. As our defenses against diseases have become increasingly sophisticated, however, so do the diseases we are trying to protect ourselves against. As the influenza pathogen mutates, antigenic shifts can cause a very severe flu epidemic such as the 2009 H1N1 influenza pandemic which infected approximately 60.8 million people in the United States, resulting in more than a quarter of a million hospitalizations and nearly 12,500 deaths. (2)

But the threat of an evolved, mutated strain of influenza this flu season should not be the only infection we guard against; commonly circulating flu strains can prove equally fatal to at-risk individuals.

The familiar face of flu

Influenza is a common infectious disease which typically affects 5 percent to 10 percent of adults and 20 percent to 30 percent of children globally each year, resulting annually in a quarter to half a million deaths. (3) In the U.S., the CDC estimates that the average number of annual deaths from influenza can fall anywhere between 3,000 and 49,000. (4)

Aside from being potentially fatal, the influenza virus is often the underlying cause of associated respiratory tract infections (RTIs), which are present in approximately 5 percent and 15 percent of the population. (5) RTIs can occur in the lower and upper respiratory tracts, with the World Health Organization (WHO) declaring lower respiratory tract infections the leading infectious cause of death and the third biggest killer globally (3.1 million deaths per year), behind only heart disease and stroke. (6)

The most common upper respiratory tract conditions seen worldwide include rhinitis, pharyngitis, and laryngitis. These infections occur more frequently in younger children, potentially leading to acute asthma exacerbations and lower respiratory tract infections, such as bronchitis and pneumonia. (7)

Pathogens most commonly implicated in cases of RTIs include influenza A&B, parainfluenza virus (PIV) type 1 (PIV1), PIV2, PIV3, respiratory syncytial virus (RSV), adenovirus, and rhinovirus. Other viruses, such as coronavirus, PIV4, bocavirus, and enterovirus also commonly occur, albeit less frequently. (7) Indeed, in a study by Lepiller et al., human coronavirus (HuCoV) was shown to contribute to 52% of upper respiratory tract infections in immunosuppressed patients and was closely associated with multiple infections. (8)

Respiratory tract infections can be complex and multifaceted with underlying co-infections, often missed or overlooked once initial diagnosis is made, exacerbating serious illness. Since many respiratory viruses can present with similar signs and symptoms to influenza, differentiation between virus infection and accurate first-time diagnosis can be difficult to achieve clinically.

Multiplex molecular testing for respiratory tract infections

Molecular laboratory testing is the key to identifying causal infection, along with any underlying secondary or co-infections, to provide comprehensive diagnoses and improve understanding of the infection in individual patients. Understanding the exact drivers of disease will ensure that optimum clinical management outcomes are achieved and contribute to more accurate monitoring and surveillance of respiratory pathogens throughout peak flu season.

Multiplex molecular diagnostic tests to rapidly identify respiratory pathogens provide a quicker and more specific and sensitive approach compared to culture tests, which are characterized by relatively poor sensitivity and specificity; indeed, up to 30% of cultures are unable to identify the primary cause. (9) In particular, at times when a patient may be shedding low levels of the virus, the causal infection is often missed due to such poor sensitivity. (7)

Highly sensitive and specific molecular assays offer a reliable solution to the challenges posed by current testing methods and provide substantial benefits not only to the individual patient, but to the wider public, health authorities conducting surveillance, and the molecular laboratory performing the test. Through such assays, patients can be diagnosed more accurately and rapidly, with appropriate therapeutics administered in a timely manner for optimal treatment of infection, reducing the need for hospitalization and avoiding unnecessarily long and costly recovery times.

Utilizing molecular assays to detect respiratory infections can provide substantial time and cost savings to the laboratory and ease the burden on the payer. Moreover, in a surveillance setting, it will allow us to understand how respiratory pathogens are adapting, spreading, and reacting to current treatment.

Each year in the United States, at least two million people acquire serious bacterial infections that are resistant to one or more of typically prescribed antibiotics, and at least 23,000 people die as a direct result of these antibiotic-resistant infections. (10) For both the patient and the wider public, the appropriate use of antibiotics will help curb the current problem of antimicrobial resistance, which the world now faces as a result of overprescribing and misuse of antibiotics in both humans and animals.

Through molecular testing, accurate diagnoses and recording of all infections present will assist in surveillance of infection, allowing public health authorities to accurately monitor what viruses and bacteria are circulating in the community and adjust public health policy accordingly. Improved infection control measures, based on response to circulating pathogens, can also be relied upon to identify agents and track outbreaks.

Molecular testing applies equally, of course, to the detection of bacterial respiratory infections. Each year in the United States, at least two million people acquire serious bacterial infections that are resistant to one or more of typically prescribed antibiotics, and at least 23.000 people die as a direct result of these antibiotic-resistant infections. (10) For both the patient and the wider public, the appropriate use of antibiotics will help curb the current problem of antimicrobial resistance, which the world now faces as a result of overprescribing and misuse of antibiotics in both humans and animals.

Adopting routine use of molecular assays to test for respiratory infections at first presentation is a protective strategy to ensure appropriate treatment and control of infection in the community. In particular, a multiplex diagnostic assay which simultaneously tests for a wide range of viral and bacterial pathogens affecting both the upper and lower respiratory tracts is the optimal method for diagnosis and management of disease. Not only will the test results contribute to our understanding of the epidemiology of RTIs. but they will empower us with a wealth of new information on seasonality, geographical distribution, and risk groups to help better arm us against the threat of respiratory diseases, both old and new.

By Martin Crockard, PhD

Martin Crockard, PhD, Molecular Diagnostics Manager for Randox Laboratories, leads a team of 20 molecular biologists in the company's Molecular Diagnostics group. He has more than 20 years' experience leading molecular biology projects, 13 at Randox. Dr. Crockard works closely with the company's engineering, regulatory affairs, marketing, and manufacturing departments to develop both multiplex arrays and complementary analyzers.


(1.) Centers for Disease Control and Prevention (CDC). 2014 Ebola outbreak in West Africa, http://www. Accessed November 11, 2014.

(2.) Shrestha S, Swerdlow D, Borse R, et al. Estimating the burden of 2009 pandemic influenza A (H1N1) in the United States (April 2009--April 2010). Clinical Infectious Diseases. 2011;52(S1):S75-S82.

(3.) World Health Organization. Influenza (Seasonal). Fact sheet No 211. March 2014. http://www.who. int/mediacentre/factsheets/fs211/en/. Accessed November 11, 2014.

(4.) Centers for Disease Control and Prevention (CDC). Key facts about influenza (flu) & flu vaccine. Accessed November 11, 2014.

(5.) Forum of International Respiratory Societies. Respiratory diseases in the world realities of today--opportunities for tomorrow. 2013. -respiratory-diseases-in-the-world/ resources/firs-report-for-web.pdf. Accessed November 11, 2014.

(6.) World Health Organization (WHO). The top 10 causes of death. Fact sheet No 310. May 2014. fs310/en/. Accessed November 11, 2014.

(7.) Mahony JB. Detection of respiratory viruses by molecular methods. Clinical Microbiology Reviews. 2008;21 (4):716-747.

(8.) Lepiller Q, Barth H, Lefebvre F, et al. High incidence but low burden of coronaviruses and preferential associations between respiratory viruses. Journal of Clinical Microbiology. 2013;51 (9):3039-3046.

(9.) Zumla A, Tawfiq J, Enne V, et al. Rapid point of care diagnostic tests for viral and bacterial respiratory tract infections--needs, advances and future prospects. Lancet Infectious Diseases. 2014. Accessed November 11, 2014.

(10.) Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. port-2013/pdf/arthreats-2013-508.pdf#page=13. Accessed November 11, 2014.
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Title Annotation:Clinical issues: Flu/respiratory
Author:Crockard, Martin
Publication:Medical Laboratory Observer
Geographic Code:1USA
Date:Dec 1, 2014
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