Meeting the laboratory’s diagnostic needs for respiratory tract infections

The respiratory tract is far more prone to infection than other organ systems, as it frequently comes into contact with numerous pathogens present throughout the environment. Infections of the respiratory tract are caused by a wide range of viruses and bacteria that may vary seasonally and can impact the upper and lower respiratory tract, affecting different patient populations with varying degrees of severity. While influenza A and B and respiratory syncytial virus (RSV) receive much of the attention as virulent respiratory pathogens, the variety of other potential pathogens and similarities of clinical presentation create a challenge in diagnosing and managing patients with respiratory tract infections. 

Viral infections of the respiratory tract are far more common than bacterial infections. Each year, as many as 5% to 20% of the U.S. population contracts influenza.¹ The severity of flu is unpredictable from season to season and depends on such factors as the virulence of the circulating strains, how well-matched the flu vaccine is relative to the circulating strains, how many people get vaccinated, and when the vaccine was made available. Between 1976 and 2007, flu-associated deaths ranged between 3,000 and 49,000 deaths per year, which is a reflection of the varying severity of circulating influenza strains and the coverage of the flu vaccine.¹   

While anyone can get the flu, those at risk of serious complications associated with the infection include the very young and very old and those with chronic conditions such as heart disease or asthma. Similar to influenza, RSV is capable of causing severe infection in certain patient populations, with complications including bronchiolitis and pneumonia. Nearly 125,000 children under the age of one are hospitalized each year with RSV infections. Following initial exposure to the virus, 25% to 40% of children under of the age of one develop symptoms of bronchiolitis or pneumonia.² While RSV infections primarily occur in very young children, the elderly and adults with co-morbidities that are chronic or require immunosuppression are also at high risk of severe
infection with RSV.² 

In addition to influenza and RSV, other viruses and bacteria cause infection of the respiratory tract. Adenovirus, human metapneumovirus, parainfluenza, and rhinovirus are common viruses associated with significant morbidity and mortality.^3-6 In fact, rhinovirus causes nearly one billion cases of the common cold annually and is the most common cause of respiratory tract infections in hospitalized children.⁶ While less prevalent, bacterial infections of the respiratory tract, caused by such organisms as Bordetella spp., Mycoplasma pneumoniae, Chlamydophila pneumoniae, Haemophilus influenzae, and Streptococcus pneumoniae, are also associated with significant morbidity and mortality. Some of these bacteria even cause severe infections that can lead to pneumonia or possibly bacteremia.^7-11 

With the wide array of known respiratory pathogens, it can be difficult for physicians to determine optimal patient management based on clinical presentation alone. They must ask themselves: Does the patient have a true infection? Is that infection bacterial or viral? Is it appropriate to prescribe antimicrobials empirically, and if so, what is the best antibiotic to prescribe? Which diagnostic test or tests should I order to address these questions? And finally, will I get the necessary results in time to make the best treatment decision for my patient?

Given that these challenges can lead to the inappropriate or unnecessary use of antimicrobials for respiratory tract infections, it’s imperative that clinical laboratories equip themselves with the appropriate diagnostic tools to support the physician’s decision-making process. Unfortunately, the original gold standard test, viral cell culture, is plagued with many limitations, including slow turnaround times, a high cost of maintaining viral cell lines, and the need for specialized staff to perform this testing. As a result, many labs are moving away from this method in favor of more rapid diagnostic tests that offer reduced turnaround time while maintaining the necessary sensitivity and specificity. However, these tests are not without their limitations.

A majority of labs first moved from viral cell culture to the much quicker fluorescent antibody staining and enzyme immunoassays (EIA). These approaches provide the turnaround time necessary to better support the physician decision-making process, yet do not consistently provide the required sensitivity and specificity or cover the necessary range of respiratory pathogens. Recently, the emergence of multiplexed molecular tests has provided labs with the most complete diagnostic solution to date, providing the necessary turnaround time, sensitivity and specificity, and breadth of coverage of respiratory pathogens required to support the decision-making needs of the physician. However, these multiplexed molecular tests are one-size-fits-all, containing fixed panels of targets at fixed costs, and thereby do not fully address the needs of the clinical laboratory or physician. 

Unfortunately, there is no single test available that can meet both the physician’s need for coverage of the full continuum of respiratory infections and the lab’s workflow and cost needs. In many labs, the current solution is to choose between utilizing multiple platforms, selecting one abbreviated panel that does not provide the necessary coverage and then send the remaining samples to a reference laboratory, or running a one-size-fits-all panel for all patients, which may be too broad in some cases, yet not broad enough in others. The common theme of all of these approaches is that they are expensive. 

Use of multiple platforms is a costly solution, requiring, in many cases, capital purchase of multiple instruments, additional staff training, extra quality control testing, and extra proficiency testing. If labs choose one abbreviated panel for the primary respiratory pathogens of influenza and RSV, they are left with few alternatives, which can result in sending out the sample to a reference lab when clinicians order a more comprehensive respiratory infection work-up. This is very expensive and is associated with slow turnaround times. Using a broad all-or-nothing respiratory infection test does provide the necessary pathogen coverage a majority of the time; however, this approach either forces physicians to order a test with targets they do not need or forces labs to view and report results that physicians did not order. With a constant downward pressure on reimbursement, none of these options offer a sustainable, long-term solution.

We are now at the point where currently available respiratory infection tests can detect a majority of respiratory pathogens in a single, easy-to-use test. As great of a technological achievement as that is, these one-size-fit-all tests are out of touch with various pressures in our healthcare system. Labs are being pushed to be more efficient and cost-effective, while at the same time, healthcare is pushing for more personalized patient care. Is it possible for there to be one diagnostic test on one platform that can provide the turnaround time, sensitivity and specificity, and pathogen coverage required to accommodate the needs of the physician and still adapt to patient-specific and season-specific ordering patterns? Could this test also meet the workflow and cost needs of the laboratory? We think so. 

References

1. Centers for Disease Control and Prevention (CDC). Seasonal influenza Q & A. http://www.cdc.gov/flu/about/qa/disease.htm. Accessed August 8, 2014. 
2. Centers for Disease Control and Prevention (CDC). Respiratory syncytial virus infection (RSV): Frequently asked questions. Content source: National Center for Immunization and Respiratory diseases, Division of Viral Diseases. http://www.cdc.gov/rsv/about/faq.html. Accessed July 23, 2014.
3. Centers for Disease Control and Prevention (CDC). Adenovirus: clinical overview. Content source: National Center for Immunization and Respiratory diseases, Division of Viral Diseases. http://www.cdc.gov/adenovirus/hcp/clinical-overview.html. Accessed July 23, 2014. 
4. Kahn JS. Epidemiology of human metapneumovirus. Clin Microbiol Rev. 2006;19(3):546-547.
5. Counihan ME, Shay DK, Holman RC, et al. Human parainfluenza virus-associated hospitalizations among children less than five years of age in the United States. Pediatr Infect Dis J. 2001;20(7):646-653.
6. Miller EK, Lu X, Erdman DD, et al. Rhinovirus-associated hospitalizations in young children. J Infect Dis. 2007;195:773-781. 
7. Centers for Disease Control and Prevention (CDC). Pertussis —whooping cough: Frequently asked questions. Content source: National Center for Immunization and Respiratory diseases, Division of Bacterial diseases. http://www.cdc.gov/pertussis/about/faqs.html. Accessed July 23, 2014.
8. Centers for Disease Control and Prevention (CDC). Mycoplasma pneumoniae infection. Content source: National Center for Immunization and Respiratory diseases, Division of Bacterial diseases. http://www.cdc.gov/pneumonia/atypical/mycoplasma/index.html. Accessed July 23, 2014.
9. Centers for Disease Control and Prevention (CDC). Chlamydophila pneumoniae infection. Content source: National Center for Immunization and Respiratory diseases. http://www.cdc.gov/pneumonia/atypical/chlamydophila.html. Accessed July 23, 2014.
10. Centers for Disease Control and Prevention (CDC). Haemophilus influenzae disease (including Hib) Content source: National Center for Immunization and Respiratory diseases, Division of Bacterial disease. http://www.cdc.gov/hi-disease/clinicians.html Accessed July 23, 2014.
11. Centers for Disease Control and Prevention (CDC). Pneumococcal disease. Content source: National Center for Immunization and Respiratory diseases, Division of Bacterial disease. http://www.cdc.gov/pneumococcal/clinicians/clinical-features.html. Accessed July 23, 2014.