Paul C. Schreckenberger, Alexander J. McAdam Loyola University Medical Center, Maywood, Illinois, USA; Boston Children’s Hospital, Boston, Massachusetts, USA.
Point-Counterpoint: Large Multiplex PCR Panels Should Be First-Line Tests for Detection of Respiratory and Intestinal Pathogens
The ﬁrst FDA-approved multiplex PCR panel for a large number of respiratory pathogens was introduced in 2008. Since then, other PCR panels for detection of several respiratory and gastro intestinal pathogens have been approved by the FDA and are commercial available, and more such panels are likely to become available. These assays detect 12 to 20 pathogens, and some include pathogens that typically cause different manifestations of infection, although they infect the same organ system. Some of these tests are labor-intensive, while others require little labor, and all of the mare expensive, both for the laboratory and for the patient or insurer. They include a bundle of tests with limited or no options for selecting which tests will be performed. Laboratories and hospitals have adopted different strategies for offering these assays. Some have implemented strategies to limit the use of the tests, such as limiting the frequency with which patients can be tested, restricting testing to speciﬁc groups of patients (e.g., immunocompromised patients), or providing education to encourage the use of less expensive tests before using large multiplex panes. Others have offered these assays without limiting their use, either relying on the ordering provider to exercise good judgment or because such assays are thought to be appropriate for ﬁrst-line diagnostic testing. In this Point-Counterpoint, Paul Schreckenberger of Loyola University Medical Center explains why his laboratory offers these assays without restriction. Alex McAdam of Boston’s Children Hospital explains the concerns about the use of these assays as ﬁrst-line tests and why some limitations on their use might be appropriate.
With very few exceptions, infectious diseases present as a constellation of symptoms that collectively indicate or characterize a disease. Patients present with diarrhea or difﬁculty breathing, or they may have a fever accompanied by hypotension. The infectious causes are broad and diverse, and the infectious agents might be bacterial, viral, or fungal. The symptoms are rarely agent speciﬁc, and the empirical response is to treat for everything. Cocktails of antibiotics are given even when the cause may be viral or fungal. Gram-positive coverage is added even when the cause is Gram-negative bacteria or vice versa. It is called empirical therapy, but it is actually “guess” therapy because the causative agents are not symptom speciﬁc and the laboratory results will not be available for 2 to 3 days. In the clinical microbiology laboratory, we have always offered syndromic tests: i.e., stool culture, sputum culture, blood culture, urine culture, fungal culture, and viral culture, etc. Physicians are not asked to name the exact bacterium, fungus, or virus that should be tested for. The specimen is collected and submitted to the lab with the expectation that all pertinent pathogens will be isolated and identiﬁed. The development of molecular testing with agent-speciﬁc primers requires physicians to name which agents they want the laboratory to test for, and if they ask for too many, they get pushback from the lab.
Introduction of respiratory panels.
Our initial foray in to multiplex PCR testing came with the Prodesse ProFlu assay (Hologic), which detects inﬂuenza A and B viruses and respiratory syncytial virus. However, this was a batch assay that was run only once per day, so it did not satisfy our emergency department(ED) physicians, who wanted a rapid turnaround for patient management decisions. Next we implemented a rapid 1-h inﬂuenza A/B virus PCR assay(FLUPCR) that was hugely popular but limited in terms of etiologic agents detected. When the microarray respiratory panel (RESPAN) was implemented in our laboratory, our physicians could test for the 20 most common (17 viraland3bacterial)agents causing a cute respiratory infection, with results available in about 1 h at a total cost that was less than the cost of a single send-out PCR test. The test result provided the opportunity to limit the time in the ED, omit antibiotics if the agent was viral, and treat patients on an outpatient basis if the etiologic agent was known to cause a self limited type of infection, thus avoiding the cost of a hospital admission. After introducing the RESPAN, the most frequent question I received from physicians was “when are we going to have these types of panels for other syndromes, like sepsis, meningitis, pneumonia, and gastrointestinal symptoms?”
Do physicians practice good laboratory stewardship?
At Loyola University Medical Center, we continue to offer two testing options for acute respiratory illness, RESPAN and FLUPCR. We ask our physicians to choose which test they want, and we advise them not to order both tests. I send our physicians an annual email at the beginning of each inﬂuenza season detailing four things:(i) the names and order codes for the two tests offered,(ii) a statement that testing is performed on demand with a 1.5-h turnaround time, (iii) a list of agents detected in each assay, and (iv)t he cost to the laboratory and the patient charge for each assay. I remind them that they should not order FLUPCR as a screening test and then order RESPAN when the FLUPCR is negative, because this would drive up the cost of testing and third-party payers might consider the RESPAN to be a duplicate test and therefore deny payment. During our last ﬂu season, which lasted 4 months, from December 2013 through March 2014, a combined 1,761 viral respiratory tests were performed, with only 241 (13%) positive for inﬂuenza A/B (227 inﬂuenza A, 14 inﬂuenza B). That means that 87%of the patients will test negative if only the inﬂuenza A/B test is ordered. I ask our physicians to consider this fact when deciding whether to order FLUPCR or RESPAN. In the 12-month period from October 2013 to September 2014, 87% of the tests ordered were RESPAN and 13% were FLUPCR (Table 1). During the months of high ﬂu activity, physicians ordered more FLUPCR, and during the months of low ﬂu activity, they ordered mostly RESPAN, which is as it should be. Of great interest are the positivity rates for the two tests. When inﬂuenza A/B only testing is ordered in our laboratory, the positivity rate averages 28%, ranging from 0 to 42% depending on the prevalence of ﬂu in the area (Table 1). With our syndromic panel, the positivity rate is 39% (range, 28 to 48%) (Table 1). Inpatients and ED patients account for the majority of RESPAN orders, with 49% of orders coming from inpatients and 35% coming from ED patients (Table 1). I believe that our physicians are committed to laboratory stewardship and are prudent in making good choices about the use of syndromic test panels.
Cost of molecular multiplex respiratory virus panels.
When people talk about the cost of performing large multiplex PCR panels, what I refer to as “syndromic panels” for diagnosis of respiratory infections, they should consider that cost with respect to the overall cost of acute respiratory illness. Acute respiratory tract infections accounted for 219 per 10,000 ED visits from 1996 to 2010 in the United States (1). Moreover, there were 1,550 per 10,000 physician ofﬁce and hospital outpatient department visits from2002to2010(2).These visits are often associated with a total of 150 million days lost from work and more than $10 billion in costs for medical care (3). Viral pathogens are the most common cause of respiratory tract infections. Seasonal inﬂuenza contributes to substantial morbidity and mortality each year in the United States. In the 2012-13 inﬂuenza season, the CDC estimates that there were approximately 380,000 inﬂuenza-associated hospitalizations (4). Therefore, rapid diagnosis is important for timely intervention, especially when treatment exists for the pathogen identiﬁed, such as with inﬂuenza virus (5). In a large proportion of patients with respiratory tract infections, other viruses and non cultivable bacteria have been found to cause substantial morbidity and mortality. In the period October 2013 through September 2014, our laboratory identiﬁed1,528 positive specimens, of which only 242 (15.8%) were infections caused by inﬂuenza A virus (Fig. 1). An additional 1,286 respiratory pathogens were detected using our multiplex PCR assay. These known pathogens also contribute to the economic burden of health care; therefore, as for inﬂuenza virus, the rapid and accurate detection of these pathogens can greatly inﬂuence how physicians treat a respiratory infection. The difference in price between the two panels that we use at Loyola is $73.00. With our syndromic panel, the cost per analyte tested is $5.74. For our FLUPCR, the cost per analyte is $21.00. I would consider both of the se tests to be great bargains. The additional $73.00 cost for performing the syndromic panel should not be considered a deterrent, given the additional information obtained and the fact that there is a 39% positivity rate, compared to 28% for FLUPCR. During the 8 months per year when inﬂuenza prevalence is low, syndromic panels should be offered as the only choice when respiratory illness testing is desired.
Some will argue that detecting viruses other than inﬂuenza virus is not important because no treatment is available for the other viral agents. But a compelling reason for detecting other viruses is patient satisfaction. People do not go to the ED for a runny nose; they are usually sicker than they have ever been before from a respiratory illness, and to obtain a diagnosis in 1 to 2 h is a huge patient satisﬁer. Results of published satisfaction surveys can inﬂuence patients in the selection of a health care provider and can affect reimbursement from government and third-party payers. Providing continuity of care that is patient centered, efﬁcient, and timely are the new goals of our medical center, and we believe these will have a major inﬂuence on patients in choosing a medical care provider. I would argue that a rapid diagnosis of the patient’s illness goes a long way toward meeting our institution’s goal of providing quality outcomes that lead directly to patient satisfaction.
Additional beneﬁts of molecular multiplex respiratory virus panels.
Identifying non inﬂuenza respiratory viruses can provide epidemiologic tracking of local, regional, and national outbreaks. A recent example is the enterovirus D68 outbreak that occurred in late summer 2014. The increase in severe respiratory illness primarily in children could have been caused by many different viruses that are common during the late summer and fall. Hospitals in Missouri and Illinois were the ﬁrst to document this increase, which was later identiﬁed to be caused predominantly by enterovirus D68 infection (6). The ﬁnding of Enterovirus in respiratory specimens was possible only because the sentinel hospitals were using molecular multiplex respiratory virus panels for routine testing in the clinical microbiology laboratory. Once speciﬁc viruses are identiﬁed, appropriate infection control measures can be applied to admitted patients. Knowledge of the etiologic agent allows informed decisions about whether to use droplet and/or contact precautions and considerations for cohorting patients when isolation rooms become limited. As new pathogens emerge, the ability to exclude known viruses may help to more rapidly recognize and identify the presence of a new pathogen, such as Middle East respiratory syndrome coronavirus (MERS-CoV).
Cost analysis and silo mentality.
Decision-makers who are determining whether to allow or restrict the use of syndromic panels based on the individual test cost are thinking with a silo mentality. “Silo” refers to unit-based cost accounting and is the old way of managing hospital costs. If the business case for a new diagnostic test cannot be carved out of your department’s budget, then it is not likely to be approved. Fortunately, the federal government via the Affordable Care Act is forcing medical executives to use outcome-based decision trees. Beginning in 2016, the Centers for Medicare & Medicaid Services (CMS) will move 40% of medical cost reimbursement to outcome based payment. Outcome data will drive reimbursement in the future. The question to be asked is not how much does one test cost but rather how does the implementation of this test affect patient outcomes. When looking at patient outcomes in relationship to use of syndromic panels, several outcomes should be measured, as follows: 1. Quicker access to treatment 2. Shorter duration of symptoms 3. Less time out of work or school 4. Shorter emergency room times 5. Shorter hospital stay if admitted 6. Implementation of infection control measures, including cohorting of patients, the use or non use of isolation precautions based on the known etiologic agent 7. Reduction in pharmacy cost due to less antibiotic usage 8. Reduction in laboratory costs due to less need for additional follow-up tests, including additional diagnostic assays and determination of antibiotic peak and trough levels 9. Reduction in collateral side effects from antibiotics such as adverse drug reaction, Clostridium difﬁcile infection, and adverse effects on the human microbiome such as intestinal dysbiosis 10. Reduction in total medical cost for the particular medical encounter These types of outcome studies have not been done in the past and are difﬁcult to perform because hospitals do not typically track these metrics (7). Such a study is under way at our facility, and the results will certainly inﬂuence our institution’s decision going forward regarding the further implementation of syndrome-based molecular multiplex panels.
My discussion has focused primarily on multiplex PCR respiratory virus panels, because that has been my experience to date. Our laboratory is currently gearing up to implement syndromic panels for the identiﬁcation of bacteria and yeast species from positive blood culture bottles and panels for the identiﬁcation of agents of gastrointestinal illness performed directly from stool samples. A future application that we eagerly await is the detection of infectious agents directly from cerebrospinal ﬂuid (CSF). Syndromic, multiplex PCR panels offer the chance to have a deﬁnitive diagnosis in less than 2 h, allowing timely decisions about hospital admission, treatment, infection control, and patient return to work and family. They can be performed near the patient with minimal training and labor cost. Their use has the potential to reduce health care costs, and the rapidity of results is extremely satisfying to both patients and medical providers.