Thinking beyond flu: the importance of other respiratory viruses in routine testing

It is widely recognized that respiratory viral illnesses are one of the most common infections worldwide and that they place a heavy burden on the healthcare system, with seasonal influenza outbreaks costing the United States economy alone between $71 and $167 billion annually.¹ Annual influenza epidemics result in three to five million cases of severe illness and 250,000 to 500,000 deaths globally, with an estimated infection rate of five percent to ten percent in adults and 20 percent to 30 percent in children.¹National and global influenza surveillance programs are well developed and serve as a valuable tool for tracking influenza epidemiology.

However, there are many other viruses in addition to influenza that commonly cause respiratory illness.² Pathogens such as rhinovirus, enterovirus, human metapnuemovirus, and parainfluenza virus are often underreported by hospitals because they lack the methods for testing of respiratory pathogens beyond influenza. Comprehensive molecular respiratory panels are enabling accessible testing for these pathogens, and each year more institutions concerned about non-influenza viruses are implementing these panels into routine clinical diagnostics. An increasing number of studies have investigated the clinical significance of the additional information these comprehensive respiratory panels provide and the clinical outcomes that demonstrate their value.^3-5

Circulation of non-influenza respiratory viruses

It has been estimated that more than 500 million non-influenza respiratory tract infections occur annually in the United States,⁶ affecting a range of individuals regardless of age, immunocompromised status, or other traditionally accepted risk factors. Similar to influenza, these viruses cause a significant burden to the healthcare system and economy.^2,6 Non-influenza viruses have different patterns of seasonality, which make infection possible year round.

Respiratory syncytial virus (RSV), human metapneumovirus, parainfluenza viruses, and coronaviruses co-circulate with influenza during the fall and winter, while adenovirus and rhinovirus circulate throughout the year.^7,8 Symptoms of infection from these non-influenza respiratory viruses also vary from mild ailments like the common cold to more severe disease such as bronchitis or pneumonia, making it difficult to differentiate them from influenza.

Recently, the importance of non-influenza viruses in respiratory illness has been elevated within the medical community. Institutions are finding that other respiratory viruses are often more common causative agents of illness than influenza, citing high rates of RSV, rhinovirus, enterovirus (EV), and adenovirus.^7,9,10 Human rhinovirus is the most common respiratory virus identified in patients with respiratory infection and has been shown to result in increased symptoms and longer hospital stays.^6,11 Coinfections with rhinovirus and other respiratory viruses have also been shown to increase morbidity and be a significant predictor of disease outcome.^12,13

The clinical significance of human EV infection was seen in the 2014 outbreak of EV-D68, which led to serious illness and even death of infected children.¹⁴ During the course of this outbreak, more than 1000 EV-D68 respiratory infections were confirmed by the CDC or by public health laboratories; most of these infections occurred in children with asthma or a history of wheezing.¹⁵ RSV has been shown to be an important pathogen in children and has also been implicated as a serious cause of morbidity and mortality in immunocompromised adults.^16,17

Adenovirus is also a well known cause of respiratory infections in children and immunocompromised populations and has been associated with adult outbreaks in crowded environments such as military barracks.^18,19 The clinical impact of comprehensive testing for these non-influenza respiratory viruses has been demonstrated in recent studies, paving the way for adoption of technologies that easily detect these organisms.

Adoption of multiplex respiratory testing

The first expanded multiplex molecular respiratory panel received Food and Drug Administration (FDA) clearance in 2008.²⁰ Since that time, multiplex respiratory panels have shown good sensitivity and performance compared to their low-plex counterparts.^10,21 The rise in available study and surveillance data showing the prevalence of non-influenza viruses involved in respiratory infections has contributed to an increase in panel adoption into mainstream hospital respiratory testing algorithms. Institutions that have implemented this strategy include Geisinger Medical Laboratories, Beaumont Health Systems, and Loyola University Medical Center (LUMC).^9,22,23

While it is widely recognized that comprehensive molecular methods have the ability to detect non-influenza pathogens quickly and easily, questions have been raised about their effect on patient outcomes. A recent article by Dr. Paul Schreckenberger, Clinical Microbiology Laboratory Director at LUMC, corroborates the value of syndromic-based multiplex panels as the first-line test for respiratory illness.⁹ LUMC has chosen to offer a comprehensive respiratory panel without restricted use (e.g., patient population), in addition to an influenza PCR test.⁹ Dr. Schreckenberger suggests that when influenza prevalence is low, syndromic panels should be offered as the only choice if respiratory illness is suspected.⁹ From October 2013 through September 2014, testing at LUMC with the comprehensive respiratory panel found 15.8 percent of samples positive for Flu A and 5.7 percent positive for Flu B, while other respiratory virus prevalence included rhinovirus/enterovirus at 43 percent, RSV at 13.6 percent, coronavirus at 8.4 percent, human metapneumovirus at 7.8 percent, parainfluenza at 6.4 percent, and adenovirus at 4.3 percent.⁹ This article also emphasizes that the laboratory has traditionally offered syndromic- based testing through methods such as culture, where physicians were not expected to specify respiratory pathogens for testing.⁹ Numerous studies have demonstrated that patients often present with similar symptoms upon infection with influenza or another respiratory virus, and it is difficult to efficiently detect the causative agent through a pick-and-choose testing approach, also demonstrating the need for comprehensive, syndrome-based testing.^7,9

Outcomes-based testing

Even when the benefits associated with comprehensive panel testing for respiratory pathogens are pointed out, institutions are asking for additional outcomes-based evidence to help justify costs of implementation. In an era of growing scrutiny of hospital budgets, institutions are turning to health economics and outcome study data before implementing new technologies that may result in higher costs to the laboratory but a decrease in overall institutional expenses.^3-5

Under the Affordable Care Act, about 30 percent of medical cost reimbursement will be outcome-driven in 2015.^24,25 There has been a change in how payers are reimbursing, moving away from paying for individual tests performed toward improved patient outcomes in the most cost-effective manner, in an effort to create more efficient care.^9,24 Institutions are increasingly focused on outcomes such as time to implementation of appropriate therapy, length of stay, days in isolation, mortality, time out of work and school, and patient satisfaction.^4,5,9 As reimbursement continues to shift toward improved patient outcomes, institutions will likely re-evaluate testing algorithms along with new diagnostic technology that may help decrease the overall cost of care. In the future, outcome data will help drive reimbursement and the focus will be on overall costs, rather than individual departmental costs. As data become available showing the impact on patient care, this may encourage the adoption of more comprehensive testing techniques like multiplex respiratory panels.

Where do we go from here?

While each institution must decide which respiratory testing algorithm to incorporate into clinical practice to best impact patient care, it is clear that comprehensive respiratory pathogen detection can help optimize patient treatment and outcomes. Although syndromic-based panels may have a higher cost than low-plex tests, they detect many viruses beyond influenza that cause respiratory illness and burden the healthcare system. It’s likely that the benefits of syndromic respiratory panel testing can positively impact patient outcomes, and contribute to  overall reduction in patient management costs.

References

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