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Microbiology’s shifting role in war on sepsis

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Anne Paxton

August 2018—If you were casting about for the severest test of a laboratory’s capabilities, day in and day out, sepsis admissions at a pediatric hospital might fit the bill.

At Children’s Hospital of Philadelphia, and at other hospitals, waging war on sepsis requires battles on multiple fronts and clinical pathways that rely on an agile and highly equipped microbiology laboratory.

Three main categories of patients ensure there is no shortage of sepsis cases at CHOP, says Erin H. Graf, PhD, D(ABMM), director of the infectious disease diagnostics laboratory. “We’re a very large oncology center with a lot of children with hematologic malignancies as patients, who are certainly at high risk for sepsis.”

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The hospitals treating adults see much more carba­penem-resistant Enterobacteriaceae than the pediatric hospitals, “and it’s just a matter of time before they become more common in our community,” says Dr. Erin Graf of Children’s Hospital of Philadelphia. [Bob Williams]

A large neonatal population makes up the second category, since the 546-bed hospital is also the major center to which other hospitals send their most premature babies. “Low-birthweight infants are at increased risk for sepsis, and we see that fairly often,” Dr. Graf notes. The third population consists of patients with community-acquired sepsis, including, among others, infants with group B strep or E. coli acquired from the mother.

Community-acquired infections have gradually declined, thanks to vaccination and successful group B strep screening programs, but the populations of low-birthweight neonates and the immunocompromised continue to grow and help keep the roughly 40 FTEs of the CHOP microbiology laboratory busy. Performing more than 200,000 tests a year, the lab is constantly looking for ways to identify bacteria in the bloodstream faster.

The laboratory uses BD Bactec instruments to run blood cultures, and when a blood culture is positive, there are two mechanisms by which to rapidly identify the organisms, Dr. Graf says. “We run the Luminex Verigene for Gram-positive organisms and find within a couple of hours whether it’s Staph aureus that might be resistant, or MRSA or coagulase-negative staphylococci versus a group A or B strep.” A new Accelerate Pheno instrument, soon to go live, will provide rapid identification within an hour and susceptibility testing within eight hours. “That will speed up the process significantly,” she says.

Also on deck, though still in a research phase, is next-generation sequencing. “The beauty of NGS is you can look for everything, so we don’t have to bias what we’re looking for.” That is one reason her lab has not been as excited about the T2 Biosystems bacteria panel, which the FDA approved this spring, and Candida panel. “They only cover five bacteria and Candida, but we do not see a lot of Candida bacteremia here.”

She would be pleased to see NGS testing become more cost-effective. “Right now it’s not fast enough and not cheap enough, but I think we’ll get there. There is newer technology on its way that is promising at picking up bacteria in the bloodstream. And we can start asking questions about genetic resistance determinants that are present.” She is optimistic, for example, that Oxford Nanopore Technologies instruments will soon bring speed at lower cost.

Pathologists at CHOP have expressed interest in total lab automation, but Dr. Graf is a bit wary. “There’s a large validation that goes along with that because pediatric samples can be so different from adults’. Considering our volume and collection and sample types, that would mean devoting brainpower that we’re currently using on other important projects.”

The laboratory testing that goes along with the several clinical pathways for sepsis includes blood culture and testing of isolates on a MALDI-TOF mass spectrometer, although with the Accelerate Pheno, she notes, it’s not necessary to confirm the identification. Then the lab may run flu or other viral PCRs if there is a need to rule out a viral cause. “The PCRs could include herpes virus, CMV, and EBV, in addition to the standard respiratory viruses that can cause fever and other sepsis-like symptoms,” all of which are laboratory-developed assays, she notes.

“Our chemistry lab runs the standard biomarker tests you’d expect for sepsis, although the clinical staff don’t necessarily use all of those values to decide whether to treat. Treatment is largely based on clinical presentation and meeting SIRS criteria.” The laboratory does run procalcitonin, but there’s uncertainty about predictive use to guide therapy in pediatrics, Dr. Graf says, because the test’s use is not well established and interpretation is hospital- and age-dependent. “So our groups will order it and it is part of the clinical pathway, but they’re not necessarily using that result to make a decision about treatment. It’s more like supportive supplemental information.”

Turnaround time is a constant concern, the great limiting step, she says. “If there is anything we can do to speed up the process from the perspective of whether the child is on the right antibiotic—are we adequately treating organisms they might have, can we narrow the therapy as quickly as possible to be good stewards—we are continuously trying to find ways to get that answer faster.”

Luckily, the hospital is strongly supportive of the laboratory. “We are very well clinically integrated at CHOP—and that’s not necessarily true at every hospital.” For the influenza or meningitis or sepsis pathways, “we are brought to the table to discuss what we can do from the lab’s perspective, what the turnaround time is, what the right specimen type is. And that’s before decisions are made. The lab also has a strong role and strong presence on the hospital’s quality and safety committees. If there’s an instrument the laboratory wants and we can show the clinical value, we usually get it,” Dr. Graf says.

Specimen collection, of course, presents unique problems in the pediatric population and requires the different labs to work together. Clinical protocols require that microbiology receive a specimen first. “Then we will sterilely manipulate it and give it to chemistry; it can go on their nonsterile analyzer there.”

A lot of dialogue takes place between Dr. Graf and the infectious disease clinicians about what should be performed first, when to wait for a positive or negative result, or whether to reflex to other series of tests. “Sometimes it’s a question of sample volume, where we only have enough to do a certain set of tests. Should we save some for downstream testing we may need later? And sometimes it’s a stewardship question. We don’t want to charge patients a ton of money for useless testing, so sometimes we do try to triage testing.”

Sepsis is a clinical diagnosis and does not always include a microbiologic diagnosis, Dr. Graf points out. “So sometimes you’re sending kids home and you don’t really know what you’re treating, because nothing ever grew in culture. That’s why we’re looking at NGS, hoping it might prove to be more sensitive than blood culture.”

Not that NGS will be the be-all and end-all of testing. It has its own limitations, she cautions. In theory, though, it could be more sensitive than culture, particularly in cases in which the child was pretreated with antibiotics and nothing grows in culture. “You could still potentially pick up the DNA of the bacteria floating in the bloodstream.”

With the Accelerate Pheno, Dr. Graf says the laboratory is hoping that by getting results faster, clinicians can say, “‘OK, we need to put in a PICC and we can send you home on x antibiotic.’ And if we can make that happen a day or two earlier, it would be wonderful for our patients and families. Other groups are already starting to present data on these types of outcomes, and we hope there is a similar benefit for our population.”

A continuum of care at Geisinger

The approach to sepsis at Geisinger’s Diagnostic Medicine Institute in Danville, Pa., involves a continuum of care, starting with predictive analytics aimed at prevention through rapid diagnosis and efforts to reduce readmissions after discharge, says Donna Wolk, PhD, D(ABMM). As division director for molecular and microbial diagnostics, Dr. Wolk leads a clinical program that combines traditional and molecular testing with her translational research.

The Janet Weis Children’s Hospital at Geisinger was the first rural acute-care pediatric hospital in the U.S. and is unique for its location in rural central Pennsylvania, where it serves 44 counties. “But I think we’re also unique in the U.S. in that we place actionable testing, including rapid diagnostic testing with multiplex PCR, at all of our hospital sites large and small. We function as one system in terms of our microbiology diagnostic service.” Systemwide, Geisinger performs about 45,000 blood cultures a year, a subset of which is collected from pediatric patients.

When adopting new technology, such as morphokinetic cellular analysis (MCA) on the new Accelerate Pheno instrument, “we tend to perform pilot testing at our larger hospital sites. After assessing clinical utility and economic benefit, we may expand testing to all 10 hospitals.”

Sepsis diagnostic testing begins with the collection of a traditional blood culture, then a rapid Gram stain, followed by a bacterial or fungal subculture.

Laboratory instrumentation is selected with this in mind: “We believe that microbiology, in terms of bacteremia and sepsis, is a 24/7/365 operation. As such, we deploy rapid molecular testing that is classified as moderate complexity or waived testing so it can be performed anytime by cross-trained second- and third-shift employees who may or may not be microbiologists.” The same is true for performance of their Gram stains, although those are categorized as high-complexity testing. “We consider all positive Gram stains from blood cultures to be stat, and we deployed quality improvement programs that aim to deliver the Gram stain within 30 minutes of the positive blood culture flag at all of our sites around the clock.”

To maintain accuracy for Gram stains, which can be difficult to interpret, the core laboratory offers telemicroscopy consults. All community hospital sites in the system can phone the core laboratory and share electronic images with microbiology staff or submit an image to the doctoral directors via photo sharing. Errors for Gram stains have decreased by about 40 percent since telemicroscopy measures were deployed in 2014, Dr. Wolk reports. Telemicroscopy gives greater confidence to off-campus and alternate-shift staff who may not get to see many positives. “It helps us maintain competency across 10 different hospitals.”

“Unfortunately,” she says, “despite the knowledge that time is of the essence, some hospitals still don’t perform Gram stains on second and third shift or don’t have blood cultures on site. Historically, when turnaround time was measured in weeks, maybe that practice was accepted, but with newer, faster blood culture instruments and rapid molecular testing, we don’t feel that transport to a core laboratory is an acceptable practice anymore.” Geisinger supported research funding to assess the impact of delays in specimen transport, Gram staining, and reporting of results to providers.

Dr. Wolk

Dr. Wolk

Dr. Wolk expresses concern that with more laboratory consolidations in which smaller hospitals are being taken over by larger core laboratories, shipping of blood cultures across the state or even the country is delaying actionable results for bacteremic patients. “If one only examines laboratory costs, consolidation might seem appealing, but there are downstream human and financial costs associated with delays in blood culture processing that lead to delays in adjusting antibiotics. Also, the CMS star ratings and associated reimbursements can suffer if the system’s mortality rate is too high.”

To date, Geisinger has collected evidence of the impact of deploying blood cultures and rapid detection Gram stains at its core hospital sites. But armed with a new research grant, “we’ll be examining the impact of reporting rapid results in all inpatients and pediatric patients as we expand our studies. For instance, if we’re only saving lives in our ICU but not saving extra lives or resources in our general inpatient or pediatric population, then the evidence will tell us how to proceed with deployment of rapid PCR and rapid susceptibility testing. We’ll ask, what patient population is going to benefit from the new technology?”

At Geisinger, pediatric and adult testing are performed with equal speed. “Approximately 60 percent of our sepsis patients are admitted through our emergency rooms, and we focus on every step of the process. Our phlebotomists provide sepsis patients in the ER with an average order-to-collect time for blood cultures of 1.2 minutes. Then, those blood cultures are transported by pneumatic tube system directly to our microbiology laboratory, where they are loaded immediately into our blood culture incubators.” The system maintains quality metrics to document speed at each step of the process. “Gram stains and multiplex PCR results from the BioFire BCID assay are reported as critical values by our phone center within 10 minutes of the laboratory report,” Dr. Wolk says.

In a study performed with an adult ICU sepsis population, results showed a decrease in mortality and total costs per visit. Study of the pediatric population was launched in June and is incomplete. “But our pediatric physicians appear thankful for the improvements in turnaround time for culture, Gram stain results, and multiplex PCR. Anecdotally, they say the faster results help them provide better care on a daily basis.”

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