Respiratory diagnostics tested as pandemic evolves

Rapid diagnostic testing is an evolving area of medicine that enables physicians to diagnose within hours, sometimes minutes, the condition of their patients.

Several rapid diagnostic tests are already available to patients and health care providers. Blood-glucose rapid test devices help guide diabetes treatment. Gastric and fecal tests can determine the presence of occult blood in about a minute. There are rapid tests that deliver HIV test results in about 20 minutes.

Rapid tests for respiratory illnesses have taken center-stage in recent weeks, as several studies examined their role in the diagnosis of the 2009 influenza A H1N1 virus. Another meta-analysis was published that examined these tests’ role in clinical practice.

“Rapid diagnostics are very important, and new technologies are going to make their use even more widespread,” said Janet Englund, MD, a professor in the department of pediatrics, at the University of Washington/Seattle Children’s Hospital. She said many of the viral diagnostic tests that are available are sensitive, and they have an important role in guiding infection control policies and in conducting infectious disease surveillance.

Clementine Tang, MD, a general pediatrician and a clinical instructor at Children’s Hospital in Vancouver, said these tests could play a role in potentially reducing unnecessary antibiotic use and assist in counseling parents of patients, but cost prohibits routine use in practice.

Tang said knowing what type of virus is causing an illness is important in cases like respiratory syncytial virus (RSV).

She said data have shown wheezing occurs after RSV infection, so knowing which type of virus a child has could potentially assist with counseling patients about wheezing management post-hospital discharge.

But limitations of the tests, specifically that they are expensive and are not always specific or sensitive, make their routine use impractical, Tang said.

Study results

Several recently published studies examined the use of rapid diagnostic tests for the detection of respiratory illnesses.

One CDC study indicated rapid diagnostic tests for influenza may not be able to detect the novel influenza A H1N1. The results of a CDC analysis indicated that although the rapid tests were capable of detecting influenza A H1N1 virus from respiratory specimens that contained high levels of virus, the overall sensitivity rate was only 40% to 69% when compared with polymerase chain reaction (PCR). Furthermore, the results showed that the sensitivity rate declined significantly among specimens with lower virus levels.

Quidel Corporation recently received Special 510(k) clearance for an update to the company’s QuickVue Influenza A+B test package insert to include reactivity with culture isolates of the 2009 H1N1 influenza A virus.

In an interview with Infectious Diseases in Children, Quidel President Douglas Bryant said that he was not surprised that the CDC study showed QuickVue detected clinical specimens positive for the novel influenza, but he said performance characteristics for this test have not been established. He added he was not surprised to see that the rapid tests were lower in sensitivity than PCR.

“PCR tests are sensitive, but our test has a specific place at front end, where speed is important. It takes 10 minutes, it is not very costly, and while it is not perfect in terms of sensitivity, it does provide an important aid in terms of diagnosis of flu,” Bryant said.

Earlier in the year, Luminex Molecular Diagnostics also received Special 510(k) clearance for a package insert update for its PCR based test, xTAG RVP, which is an FDA-cleared diagnostic test for detecting 12 viral strains and subtypes in a single patient sample. The Luminex product was designed to subtype influenza A, and thus, generates different results for seasonal strains compared with influenza A H1N1.

Both Bryant and Luminex Molecular Vice President Nancy Krunic, PhD, said their companies are watching the novel strain of influenza closely to determine whether changes to their diagnostics’ configuration would be needed to ensure the tests continue performing well. At this point, neither said they have seen a need to do that. Luminex manufactures the xTag RVP.

A meta-analysis published last month by Quynh Doan, MD, and colleagues from the British Columbia Children’s Hospital in Vancouver, noted that rapid viral diagnostic testing did not reduce the amount of antibiotics used or other outcomes such as length of ED stay. The study did note a reduction in the use of chest radiography, but the reduction fell short of the 25% deemed clinically meaningful by the study researchers.

Other studies have shown benefit in terms of reducing testing and or/unnecessary antibiotics. And even those studies with negative outcomes hold important lessons for the future of rapid diagnostics, Doan said. Although current evidence is insufficient to support routine rapid viral testing as a means to reduce antibiotic use in pediatric EDs, Doan said that their results may have been limited by size, and that their data are “promising” and may show more benefits with larger sample sizes.

Current technologies

Newer diagnostics offer the advantages of speed, reliability, reproducibility and the ability to type many viruses — including influenza A, B, RSV, parainfluenza, rhinovirus, adenovirus and metapneumovirus — simultaneously. However, extreme sensitivity of these tests may lead to false positives. This high sensitivity may also detect latent viruses even if they are not making the patient sick, according to Rosalyn Singleton, MD, of the Alaska Native Tribal Health Consortium.

Singleton’s group has used PCR data to show variations from year to year in seasonality and incidence of major respiratory viruses.

She said that the commonly used RSV rapid antigen tests are quite specific, as high as 97% to 98% when compared with PCR, but she said the sensitivities of these tests are less, more in the range of 70% when compared with PCR.

“On one end of the spectrum is the antigen tests, which are highly specific but not as sensitive, and then on the other end, you have the PCR, which is highly sensitive and highly specific but you run into this question of whether or not you are picking up coinfections that are with not necessarily causing illness,” Singleton said.

On the horizon

Doan said more studies exploring the sensitivity of different approaches to collect testing samples are needed. A big problem with these tests, Doan said, has been the traditional way that physicians get the sample, via nasopharyngeal wash.

“The kids hate it; they often kick and scream through the whole thing, the nurses hate it because the children are uncomfortable and it takes so long to set up,” Doan said. “So really, looking at other ways to collect samples are needed too.”

Currently, the government is providing research support for numerous rapid tests, particularly in the influenza area. Jose Romero, MD, chief of the pediatric infectious diseases section at Arkansas Children’s Hospital/University of Arkansas for Medical Sciences, said rapid tests for dengue virus and other illnesses that are global threats are also in the works.

He said there have been significant advances in PCR technology, noting that GeneXpert System, which combines on-board sample preparation with real-time PCR amplification and detection functions for fully integrated and automated nucleic acid.

The problem with these PCR tests, Romero said, still is cost. Singleton concurred.

Singleton said in the hospital setting, there is definitely a movement toward more use of PCRs and rapid tests that look at multiple viruses.

While PCR may have an increasing role in large university hospitals, antigen testing would likely still be used in smaller facilities, Singleton said.

“The issue is having trained personnel to do molecular testing,” she said, adding that she continues to see a role for antigen testing, particularly for RSV. She said she would like to see more tests developed for metapneumovirus and parainfluenza as well, and she would like to see more cost-effective rapid tests.

Bryant said Quidel is moving toward improving sensitivities of its assays and is exploring more molecular diagnostics. Quidel last month announced it has entered into a joint development and commercialization agreement with BioHelix Corporation. The agreement with BioHelix focuses on the development and commercialization of in vitro molecular diagnostic tests using BioHelix’s novel isothermal amplification technology, according to a Quidel press release. Bryant said newer technologies are enabling many companies to develop more sensitive tests that will be less expensive.

Englund said a less expensive, easy-to-use rapid test would be ideal.

“There are limitations with these rapid tests, but that does not mean we shouldn’t pursue them,” she said. – by Colleen Zacharyczuk

For more information:

• CDC.MMWR. 2009;58:826-829.
• Doan Q. Rapid viral diagnosis for acute febrile respiratory illness in children in the emergency department. Cochrane Rev. 2009; DOI: 10.1002/14651858.CD006452.pub2.

• J Clin Microbiol. 2009; 2347-2348.

• www.xtagrvp.com/physicians