Time to Close Lariat’s Regulatory Loophole for LAA Closure in AF, Say Experts

A new review highlights a significant number of adverse events with the off-label use of the Lariat (SentreHEART) snare device for the exclusion of left atrial appendage (LAA) in patients with atrial fibrillation (AF)[1].

Investigators say the time has come for formal, randomized clinical trials to test the device specifically for this indication.
“The Lariat device didn’t undergo the full premarket approval [PMA] process where it was tested for that indication,” senior investigator Dr Jay Giri (Perelman School of Medicine at the University of Pennsylvania, Philadelphia) told heartwire from Medscape. “It was cleared for soft-tissue approximation, which is what you’d do to clear a suture device. Now one could argue that you’re suturing the left atrial appendage shut and that’s soft tissue, but it’s a little bit of a stretch from an indication standpoint.”

The Lariat for LAA exclusion emerged through a regulatory backdoor that saw the device receive class II (intermediate-risk) clearance by the Food and Drug Administration (FDA) via the 510(k) protocol. It did not require the more rigorous PMA pathway that all class I (high-risk) devices must undergo, and given that, there is an absence of data about how well and how safely Lariat works.

“The Lariat device is an absolutely ingenious piece of engineering for closing the left atrial appendage,” said Giri. “However, ingenuity does not guarantee safety and efficacy.”

Lariat Appears Designed for LAA Exclusion

Publishing their findings May 4, 2015 online in JAMA Internal Medicine, the researchers identified five reports of the Lariat device for LAA exclusion in 309 individuals. Of these, the procedure was successful in 90.3% of cases, but seven individuals (2.3%) required urgent cardiac surgery and one patient died in the hospital.
The group also reviewed the FDA Manufacturer and User Facility Device Experience (MAUDE) database to compile adverse-event reports from real-world clinical practice. In total, there were 35 adverse events documented with use of the Lariat device for LAA exclusion. Of these, five reports documented pericardial effusion and death and 23 reports noted the need for urgent cardiac surgery.

The 510(k) clearance protocol does not require clinical trials to approve a device for the indication under consideration. Instead, the only burden on companies is to show that the device is “substantially equivalent” to other devices. With the Lariat device, the company had to show only that the device was equivalent to existing devices used for suture placement during surgery.

To heartwire , Giri said that “when you get into the weeds of it,” the Lariat device appears to have been designed solely for the purpose of LAA exclusion. Upon 510(k) clearance, US and global patents were rapidly filed for closing the LAA with the device, he said, noting the company even emphasizes “heart” in its name. And while the design of the Lariat appears to be solely for LAA exclusion, the FDA did not have access to any data supporting that indication when the device was initially cleared.

In March, the FDA approved the Watchman (Boston Scientific) LAA closure device for the prevention of stroke in patients with AF. For the approval, the company and trial investigators took three trips before the FDA’s Circulatory System Device Panel, a process that took six years and involved two major clinical trials—PROTECT-AF and PREVAIL—and a large registry. Giri suspects use of the Lariat will decline now that physicians have an FDA-approved option for LAA closure.

“There is no question there is an unmet clinical need that existed and still exists because the Watchman has its own issues, with the problem of debilitating or even life-threatening strokes in people with atrial fibrillation,” said Giri. “The other problem is that the best proven way to treat them, anticoagulation, is not ideal for every single patient. Some patients can’t take blood thinners, and there are some patients that don’t want to take them. How do we address this unmet need? That’s why there is so much interest in these left atrial appendage devices—the market is very large.”

In an editorial[2], Dr Paul Varosy (University of Colorado, Denver) states that on behalf of patients, “we should expect for the Lariat the same rigorous evaluation by randomized trials and clinical device registries that is being undertaken for other left atrial appendage occlusion devices.”

In response to the JAMA paper, SentreHEART, the maker of the Lariat device, issued a statement saying it fully supports the 510(k) process and that it is committed to clinical trials with the device. It is currently engaged in talks with the FDA and will be submitting an investigational-device-exemption (IDE) application to the agency to conduct clinical trials with Lariat in LAA closure and will seek an indication for such use.

“It is important to note that it is not unusual for device manufacturers to obtain marketing authorization for one use and then subsequently seek additional indications for use,” according to SentreHEART.

Marketing Still Possible

LAA exclusion with devices such as the Lariat, Watchman, and Amplatzer Cardiac Plug (AGA Medical), which is currently undergoing testing in clinical trials, is intended to reduce stroke risk by eliminating the potential for thrombus from the left atrium. The PMA pathway, although onerous, does help the FDA verify safety and efficacy of devices before widespread utilization, according to the researchers.

Prior to their review, Giri said a rudimentary internet search of US hospitals turned up at least 60 programs promoting the utilization of the Lariat device for LAA exclusion in AF patients.

Given the way the approval process was subverted, Giri said there is no way to know if the device is safe or if it prevents stroke. Most important, there is no way to determine just how many patients have received the Lariat device for LAA exclusion. While companies are not allowed to market devices such as the Lariat for off-label uses, the message about its availability is reaching interventional cardiologists and electrophysiologists who perform the procedure.

“These are two subspecialties,” said Giri. “It’s not thousands and thousands of doctors around the country who need to know how to use the device. It’s a smaller group of people who need to be informed about it if you’re trying to get it out there. And those people can be reached in a lot of different ways that are not the classic ways the FDA considers marketing activity.”

Need for Trials and the Bigger Picture

The bottom line, said Giri said, is that he would like to see the Lariat tested in a clinical trial, one that might potentially test the device against the FDA-approved Watchman. Another test would be to compare the device with anticoagulant strategies, including novel oral anticoagulants. Finally, a third trial might be to test the Lariat in patients who are not candidates for anticoagulation.

In the editorial, Varosy said that until such data are available and until the Lariat is approved by the FDA for stroke prevention in patients with AF, the use of Lariat for LAA occlusion in clinical practice “should be questioned.” He believes this newest report suggests there is more than intermediate risk associated with the device.

“Because reporting to MAUDE is not mandatory and because the total number of procedures is unknown, event rates in real-world practice cannot be calculated,” writes Varosy. “Real-world adverse-event rates would, however, be calculable in a clinical registry, especially if enrollment in such a device registry were mandatory.”

Regarding the bigger approval picture, Giri told heartwire the 510(k) process makes sense if the device is truly low or intermediate risk. Still, once approved, such devices can be used however the physician sees fit. He said the FDA needs a better method to monitor use of an approved or cleared device so it can track how it is being used in clinical practice. He noted the agency is beginning to roll out use of a unique device identifier (UDI) that can be linked to various databases to determine how the device was used and what happened to the patient after implantation.

FDA OKs First Patient-Controlled Patch for Postop Pain

The US Food and Drug Administration has approved fentanyl iontophoretic transdermal system (Ionsys, The Medicines Co), the first needle-free, patient-controlled, preprogrammed fentanyl delivery system for management of acute postoperative pain in adults requiring opioid analgesia in the hospital, according to a company news release.

Ionsys is a “novel alternative” to traditional intravenous patient-controlled analgesia that uses a “credit-card-sized, self-adherent device employing an imperceptible electric current to deliver on-demand fentanyl,” Eugene R. Viscusi, MD, professor of anesthesiology and director of acute pain management at Thomas Jefferson University in Philadelphia, Pennsylvania, said in the release.
“Ionsys fits well in a multi-modal analgesic approach allowing opioid administration as a complement to other non-opioid based therapies. The simplicity of this device may make patient mobility and physical therapy easier while reducing the potential burdens associated with a programmable pump,” Dr Viscusi added.

“An important concern for nurses treating postoperative patients is the efficiency with which they are able to administer patient-controlled analgesia,” Cecile R. Pestano, RN, BSN, CCRP, nurse manager of clinical research, Beaumont Health System, Detroit, Michigan, commented in the release. “Ionsys has the potential to optimize nursing care for postoperative patients, resulting in a high degree of nurse satisfaction, while also improving patient mobility.”

The efficacy of Ionsys was established in three placebo-controlled trials, while safety was established in three placebo-controlled trials and four additional active-controlled randomized trials, the company said.

Ionsys is not intended for home use and will only be given to patients in hospitals enrolled in the Ionsys Risk Evaluation Mitigation Strategy (REMS) program. The goal of the Ionsys REMS is to mitigate the risk for respiratory depression resulting from accidental exposure to persons for whom it is not prescribed, the company said.

Smoking Cessation Linked to HbA1c Rise in Type 2 Diabetes

For people with type 2 diabetes, quitting smoking may lead to a worsening of glycemic control unrelated to weight gain, a new study suggests.

The findings, from a large UK primary-care database, were published online April 29 in Lancet Diabetes & Endocrinology by Deborah Lycett, PhD, RD, clinical dietitian and principal lecturer in nutrition and dietetics at Coventry University, United Kingdom, and colleagues.
Of 10,692 type 2 diabetes patients who were current smokers on January 1, 2005, the 29% (3131) who subsequently quit for at least a year had an average 0.21% increase in their HbA1c levels (7.9% vs 7.7%) that wasn’t associated with changes in body weight or prescribing practices and that lasted 3 years post–smoking cessation.

“We suspected we would find the rise in HbA1c would have been explained by the weight gain that accompanies smoking cessation, but when we investigated this we didn’t find the evidence to support the theory in our data — which was surprising,” Dr Lycett told Medscape Medical News.

Findings Should Not Deter People From Quitting Smoking

However, the authors of an accompanying editorial question whether the study findings imply causation.

“We cannot infer from these results that stopping smoking causes increases in HbA1c concentrations because, despite adjustment for a range of clinical and demographic factors, the observational data presented might still be biased by residual confounding, both by indications for treatment and by lifestyle factors other than smoking status,” write Amy E Taylor, PhD, and colleagues, of the MRC Integrative Epidemiology Unit at the University of Bristol, United Kingdom.

Furthermore, severity of diabetes might affect patients’ success in stopping smoking, “so reverse causality cannot be ruled out,” they add.

Moreover, both the authors and the editorialists strongly emphasize that the findings should not deter clinicians from encouraging patients to quit smoking.
According to Dr Lycett, “These findings are about supporting patients to make a successful quit attempt, not to deter people from quitting. Rather, being aware of a rise in HbA1c allows both patients and clinicians to prepare for this and respond to it in order to have optimal diabetes control.” Such measures include optimizing statin and blood-pressure treatment and adjusting diabetes medications, she said.

Indeed, Dr Taylor and colleagues observe, “Establishing causality is unlikely to alter clinical messages about smoking cessation, because the benefits of quitting clearly outweigh any potential negative effects on health.”

Independent Effect

The figures analyzed by Dr Lycett and colleagues came from the Health Improvement Network (THIN) database, which includes electronic medical records from over 3.5 million patients in 546 UK primary-care practices.

The data set is fairly complete, since general practitioners are paid in part for their performance in caring for diabetes patients, including assessing their smoking status and encouraging quitting, as well as recording HbA1c and targeting a level less than 7.5%.

Adjustment for age, sex, diabetes duration, baseline body weight, statin prescription, and other factors did not significantly change the 0.21% difference in HbA1c between those who quit smoking and those who didn’t, which disappeared after 3 years.

The patients who stopped smoking gained an average of 4.8 kg. But for every 1-kg increase in weight there was only a 0.008% rise in HbA1c, “which would have a clinically negligible effect on HbA1c for most quitters,” the authors say.

The investigators looked to see whether the rise in HbA1c might be due to more medication being prescribed to smokers, but instead found the opposite: more of those who stopped smoking than continual smokers were on additional glucose-lowering medications at the end of follow-up than at the beginning.

For example, at the start of the study, 34.6% of continual smokers vs 32.0% of quitters were on metformin monotherapy. By the end of follow-up, 29.5% of continual smokers vs 22.1% of quitters were on metformin alone. At study start, 13.2% of smokers and 15.9% of quitters had begun taking injectable glucose-lowering treatments, while by the end those proportions were 21.1% and 29.5%, respectively.

Dr Lycett told Medscape Medical News, “The deterioration in HbA1c we found was small and temporary, over a period of 3 years, but the follow-up of the study was not long enough to determine what the long-term impact of this would be on macrovascular and microvascular complications.”

Teasing Out Causality

The lack of association with weight gain leaves the explanation for the findings unclear.

Dr Lycett said, “Even if weight gain is not the explanation behind this, it is possible that dietary change is, as we know that the preference for sweet-tasting food increases when people stop smoking, so this could potentially raise the glycemic load of their diet and their HbA1c. However, we as yet have no data to support this.”

In their editorial, Dr Taylor and colleagues suggest the use of causal inference methods to “provide more robust evidence” about the effects of smoking and smoking cessation on diabetes. Such methods might include assessment within the THIN database of physicians’ prescribing preferences for varenicline (Champix [UK], Pfizer) or nicotine-replacement therapy, since quit rates would be expected to be higher with varenicline.

Alternatively, they say, Mendelian randomization analysis using genetic variants related to smoking behavior could also help illuminate the impact of smoking on glycemic control, as well as reduce bias associated with body-weight–measurement error.

In any case, Dr Lycett told Medscape Medical News that the data on the cardiovascular benefits of quitting smoking for people with type 2 diabetes are well-established.

“This would suggest that the long-term benefits of quitting smoking definitely outweigh the temporary problems associated with it. However, it stands to reason that the optimal outcome would be to both quit smoking and to have good blood glucose control.”

Peripheral Neuropathy Treatment Taps Into Quantum Theory

In the difficult challenge of treating peripheral neuropathy, a novel approach combining injections of local anesthesia with electronic signal treatment shows improved efficacy in managing pain.

Lead author Peter M. Carney, MD, a neurosurgeon based in Elkhart, Indiana, says the approach is based on the principles of quantum theory.
“What is unique about this is it doesn’t use pharmacology, it uses the principles of physics, and it follows the theory of Nobel Laureate and quantum theory founder Erwin Schrödinger,” he told Medscape Medical News, who first proposed in 1943 that “living matter at the cellular level can be thought of in terms of quantum mechanics — pure physics and chemistry.”

“If we understand that you can change how living cells function by changing their mechanics at a cellular level, you can heal them, and that is what this does,” Dr. Carney explained.

The approach, called combined electrochemical therapy (CET), involves the injection of 1 or 2 mL of 0.5% bupivacaine just above the ankle to the 5 nerves of the foot, followed immediately by application of the electronic signaling technique.

The electronic signaling delivers complex “specific parameters of electroanalgesia employing both varied amplitudes and frequencies of electronic signals,” he reports.

He presented preliminary findings with the approach here at the American Academy of Pain Management (AAPM) 25th Annual Clinical Meeting.

Combined Electrochemical Therapy

For the study, 98 patients with peripheral neuropathy were treated with CET up to 2 times per week. The treatments last 15 to 30 minutes.

After an average of 17.6 treatments, the patients showed an average reduction in visual analogue scale (VAS) score of 3.7 points, while their average peripheral neuropathy function index (PNFI) improvement was 49.4%.

As many as 82% of patients reduced their VAS score by at least 30%, and 63% had a reduction in pain of at least 50%.

Four patients stopped after just 4 treatments because their VAS score was reduced by 50% to 100%.

Dr. Carney said 2 patients had minor adverse effects, including a patient who developed a blister at the site of an electrode and a 91-year-old patient who felt faint while receiving an injection.
He noted that, unlike other studies that treated only diabetic peripheral neuropathy, the current study treated patients with 5 different diagnostic types, including chemotherapy-induced peripheral neuropathy, idiopathic peripheral neuropathy, traumatic neuropathy, and other mixed neuropathies.

The results well exceed those typically seen with pregabalin treatment, Dr. Carney said. Compared with findings in a previous report, in this study, CET decreased the average VAS score 54% more than did pregabalin (P = .00006), and it was 62% more effective than pregabalin in reducing the average pain score by 50% (P = .003).

Furthermore, adverse effects of pregabalin can be significant, with a randomized controlled trial showing at least 38% of patients having one or more adverse effects.

 “These results suggest CET therefore has at least 95% fewer adverse events than pregabalin,” Dr. Carney writes.

Dr. Carney gave the details of a patient who had success with the therapy. Before her treatments, the 34-year-old woman with ovarian dysgerminoma and chemotherapy-induced peripheral neuropathy described her pain as “On a daily basis I feel like I’m walking on glass.”

After 17 sessions with CET, the woman’s VAS score dropped from 7 to just 1.5 (a 79% decrease) and her PNFI decreased from 44 to 0. “The patient was able to run a marathon 3 months after CET.”

Dr. Carney noted that in a pilot group of 10 patients, biopsies performed 2 to 4 months after CET showed that 7 of the 10 patients had regrown their nerves by an average of 81%. “That is impressive,” he said.

He underscored that the study was not a randomized controlled trial, but he called on major organizations to continue the research with vigorous, double-blinded trials.

“If these results are replicated, then millions of people with neuropathy who are in agony may be able to lead fuller lives,” he said.

The study was awarded as one of the meeting’s “Best Posters.”

Tom Watson, DPT, a physical therapist based in Bend, Oregon, and chair of the AAPM’s Education Committee who moderated the session, commented that the study offered some intriguing insights.

“We really don’t fully understand exactly what peripheral neuropathy is, but if you use a technique to apply the anesthetic directly into the nerve electrically, that is intriguing,” he told Medscape Medical News.

“It could be that they are in some way altering the nerves. We don’t know, and we do need long-term follow-up studies to prove the efficacy, but I think it’s a great new theory and the results are promising.”

NSAIDs Raise Bleeding, Thromboembolic Risk in Treated AF

Patients with atrial fibrillation (AF) receiving antithrombotic treatment are at increased risk for bleeding if they also take a nonsteroidal anti-inflammatory drug (NSAID), even for a short period, a new nationwide Danish study has found.

The data suggest that a serious bleeding event occurs in up to 1 in 400 to 500 patients with AF exposed to an NSAID for 2 weeks and that the risk is elevated with both selective cyclooxygenase (COX)-2 inhibitors and nonselective NSAIDs.

The findings are important because NSAIDs are so widely available and commonly used, commented lead study author Morten Lamberts, MD, PhD, Department of Cardiology, Gentofte University Hospital, Hellerup, Denmark.

“Any safety issues are a major public health concern,” said Dr Lamberts. “Patients should know that it’s possible that even over-the-counter drugs might put them at increased bleeding and thromboembolic risk.”

The study is published in the November 18 issue of Annals of Internal Medicine.
The researchers used data from the Denmark’s National Patient Registry, which contains information on hospitalizations and on dosage, strength, and date of dispensed prescription drugs. The analysis included 150,900 patients, median age 75 years, who were hospitalized with a first-time diagnosis of AF between 1997 and 2011. During a median follow-up of 6.2 years, 35.6% of patients were prescribed an NSAID.
Study participants had a mean HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score of 1.5 and mean CHA2DS2VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke, vascular disease, sex) score of 2.8. Approximately 70% were being treated with an antiplatelet or oral anticoagulant.

Investigators categorized rofecoxib and celecoxib as selective COX-2 inhibitors and ibuprofen, diclofenac, and naproxen as nonselective NSAIDs. Since 2001, ibuprofen has been the only NSAID available in Denmark without a prescription, but only in low doses and in limited quantities. Since that time, this agent has accounted for 15% to 20% of all NSAID sales.

The study showed that serious bleeding events, including intracranial and gastrointestinal bleeding, occurred in 11.4% of the patients and thromboembolic events in 13.0%. The absolute risk for serious bleeding with 14 days of continuous NSAID exposure was 3.5 events per 1000 patients vs 1.5 events per 1000 patients without NSAID exposure, with an absolute risk difference of 1.9 events per 1000 patients. In patients selected for oral anticoagulant therapy, the absolute risk difference was 2.5 events per 1000 patients.

“This suggests a serious bleeding event in 1 of 400 to 500 patients exposed to an NSAID for 14 days,” the authors write.

Breast Radiotherapy Not Linked to Cardiac Conduction Problems

Women who undergo breast cancer radiotherapy do not face an increased risk for subsequent heart conduction problems requiring a pacemaker as a result of their treatment, according to new research reported here at the European Society for Radiotherapy and Oncology (ESTRO) 3rd Forum.

“If a woman receives a pacemaker after breast cancer we can assure her it was not due to her therapy,” said study investigator Jens Christian Rehammar, MD, from Odense University Hospital in Denmark.

“Our study is quite unique, as there are no corresponding large studies in breast cancer patients only — previous studies are often mixed with patients with Hodgkin’s lymphoma,” he told Medscape Medical News.
The findings are good news considering recent evidence that an increase in other types of cardiac problems is associated with breast radiotherapy, Dr Rehammar said. He was referring to a 2013 study that found that for every additional gray of radiation to the breast there is 7.4% increase in major coronary events (P < .001) including myocardial infarction, the need for coronary revascularization, and dying from ischemic heart disease ( N Engl J Med. 2013 Mar 14;368(11):987-998).

Analysis of Danish Data

Dr Rehammar’s study merged data from the Danish Breast Cancer Collaborative Group with data from the Danish Pacemaker and ICD Registry to compare women who did and did not receive breast radiotherapy and their likelihood of needing a subsequent pacemaker.

A total of 44,704 women were included in the analysis.

The study found that among 18,308 breast cancer patients who received radiotherapy, 179 (0.98%) received a pacemaker, 90 of whom had been treated for left-sided and 89 for right-sided breast cancers.

For comparison, 1.54% of the nonradiotherapy patients received a pacemaker.

After adjusting for year of treatment, age, and time since breast cancer diagnosis, the risk for cardiac conduction problems requiring a pacemaker was not significantly different between the two groups (relative risk, 1.06; P = .71), he said.
Asked by Medscape Medical News to comment on the findings, Ben Smith, MD, assistant professor of radiation oncology at The University of Texas MD Anderson Cancer Center in Houston, said, “Conduction problems have not really been studied before in breast patients, to my knowledge. I would have predicted this would be a negative study, but it is nice to have data to confirm that.”

Dr Smith, who wrote a recent review of cardiac effects of breast radiotherapy, added, “This study provides reassurance that the typical doses of radiation received by the heart during this era in Denmark did not produce clinically severe damage to the heart’s conduction system. When coupled with prior studies, this body of work suggests that the primary mechanism for cardiac damage following breast cancer radiation is vascular in origin. The conduction apparatus in the heart is fair away from the breast, whereas the blood vessels that feed the heart are closer to the breast.”

Herpes Zoster More Common Than Thought in Children

Herpes zoster (HZ) incidence among only children with past varicella infection is higher than previously reported, according to findings of a national population-based study published online February 23 in Pediatrics. Children contracting varicella at 2 years of age or younger have an even greater incidence of HZ.

“Studies regarding HZ among children are limited, and no previous population-based epidemiologic studies of pediatric HZ among only those infected with varicella have been published,” write Su-Ying Wen, MD, and Wen-Liang Liu, PhD, from Taipei City Hospital in Taiwan. “The aim of this study was to establish population-based pediatric HZ data from only those who had varicella infection and assess the early effect of routine varicella vaccinations on the incidence of pediatric zoster.”
The retrospective cohort included children younger than 12 years with varicella infections between 2000 and 2006. The investigators also included vaccinated children without medically attended varicella between 2004 (when a routine varicella vaccination program began) and 2006. Follow-up for a diagnosis of HZ occurred through December 2008.

Overall, 428 of 27,517 children with medically attended varicella developed HZ, for an incidence of HZ of 262.1 per 100,000 person-years. HZ also occurred in 106 of 25,132 vaccinated children without medically attended varicella, for an incidence of 93.3 per 100,000 person-years.

The mean time from varicella infection to HZ was 4.12 years. Compared with children diagnosed with varicella at age 2 years or older, those diagnosed with varicella at age younger than 2 years had a higher incidence of HZ (P < .001) and shorter time between varicella infection and HZ (P = .04).

Children diagnosed with varicella between 2 and 8 years of age had an 85% greater risk for HZ after the vaccination program began compared with before initiation of the vaccination program (relative risk, 1.85 at 3 years of follow-up; P = .03).

Risk for HZ was more than twice as high in children with varicella infections than in vaccinated children without a history of varicella (relative risk, 2.31 at 4 years of follow-up; P < .001).
“The HZ incidence increased for children contracting varicella aged <2 years,” the study authors write. “After a vaccination program, the HZ risk increased for those contracting varicella aged ≥2 years.”

The researchers also found that children given systemic antiviral treatment for varicella had a greater risk of developing HZ than those who did not receive antiviral treatment.

The authors note several study limitations, including unreported cases of HZ resulting in an underestimated incidence, reliance on physician diagnosis coding, and limited duration of follow-up.

“The results of the current study may serve as baseline data for the early effects of varicella vaccinations on pediatric HZ,” the study authors conclude. “Long-term studies are required to monitor the impact of a varicella vaccination program on pediatric HZ.”

MicroRNA Potential Biomarker for Esophagitis

In patients with eosinophilic esophagitis, microRNAs in the saliva might one day be used to diagnose and manage the disease, according to a pilot study.

“The technology we used to measure miRNAs is readily available and already inexpensive,” said senior investigator Faoud Ishmael, MD, from Pennsylvania State University College of Medicine in Hershey.

“It’s possible that a commercial assay could be available within the next 5 years or so,” he told Medscape Medical News.

The pilot study, presented here at the American Academy of Allergy, Asthma & Immunology 2015, is part of the ongoing search for noninvasive biomarkers of eosinophilic esophagitis, especially in children.

“The problem with eosinophilic esophagitis is that the only way to diagnose and monitor response is to perform invasive endoscopies to biopsy the esophagus, which can be difficult and possibly dangerous,” said Dr Ishmael.

But miRNAs, which are made by most cells in the body and are secreted into saliva and other body fluids, could serve as a “fingerprint” of the disease, he suggested.
“They are important regulators of inflammation, and their expression is altered in diseases such as eosinophilic esophagitis. About 2000 miRNAs have been discovered in humans so far, but only about 100 to 150 are easily detectable in biofluids, and the pattern of expression of these 100 or so varies across many diseases,” he explained.

Detectable in Biofluids

The study involved 15 adults with eosinophilic esophagitis. Each provided saliva samples at the time of diagnostic esophageal biopsy and after 2 months of swallowed fluticasone therapy.

Expression profiles from untreated eosinophilic esophagitis patients were compared with those from healthy control subjects. There was a significant relation between eosinophil count and the expression of miR-3613-3p (P = .005), but not the expression of miR-4668 (P = .06) or miR-570-3p, reported investigator Theodore Kelbel, MD, from the Penn State Hershey Medical Center.

After treatment, there was a significant reduction in the expression of miR-3613-3p and miR-4668 (P < .05) in eosinophilic esophagitis patients, but the expression of miR-570-3p did not change.

The expression of miR-3613-3p and miR-4668, however, did not reach the levels seen in the control group.

“Perhaps this is just a function of patients only being 2 months on therapy. If they’d been on therapy longer, maybe levels would have continued to go down,” said Dr Kelbel.

“We are now performing these studies in larger numbers of patients to confirm that our findings are valid and clinically useful,” Dr Ishmael reported.

The investigators found that miRNAs might be involved in asthma, and might have similar diagnostic potential in that disease. Dr Ishmael said they are hopeful that, in the future, “these miRNAs could be manipulated for a generation of new anti-inflammatory therapies.”
These findings suggest that “noninvasive diagnosis and/or eosinophilic esophagitis status monitoring may be possible in the near future,” said Ting Wen, PhD, from Cincinnati Children’s Hospital.

However, “whether this noninvasive approach will replace the current conventional method depends on the reproducibility and the to-be-proven specificity of the test,” he told Medscape Medical News. “There is still a long way to go.”

Dr Wen and his colleagues recently developed the eosinophilic esophagitis diagnostic panel, a molecular test that is currently used on biopsied tissue when the initial esophageal biopsy results are ambiguous.

A reliable noninvasive biomarker for the disease could “save patients the time, cost, and suffering of obtaining at least five esophageal biopsies,” he pointed out.

Other approaches currently being developed include blood miRNA, exhaled breath condensate miRNA, and esophageal lavage cytokine levels, Dr Wen reported. “All of these hold strong potential,” he said.

New Strain of Acinetobacter Identified in Fatal Outbreak

A clade B strain of Acinetobacter baumannii (AB) was tied to a healthcare-associated outbreak that led to six patient deaths. Clade B is characterized by extensive drug resistance. It is also hypervirulent, and experts warn it warrants continued investigation and increased surveillance.

Crystal L. Jones, MD, from the Walter Reed Army Institute of Research in Silver Spring, Maryland, and colleagues published their outbreak report online March 29 in Clinical Infectious Diseases. The outbreak investigation included clinical and microbiological data as well as comparative genomics and animal models of virulence.
Instead of using the more common multilocus sequence typing (MLST) assay, the investigators used a polymerase chain reaction (PCR) assay for clade B strains. “The [MLST] assay is useful for epidemiologic surveillance, especially if all that they have available is MLST for genetic fingerprinting… but it can’t distinguish this strain/clade from other closely related strains,” explained senior author Emil P. Lesho, MD, also from Walter Reed Army Institute, in an email to Medscape Medical News.

AB is a known cause of healthcare-associated infections. There have been previous reports of higher-virulence healthcare-associated AB isolates. The clade B strain is noteworthy because it is not only highly virulent but also very resistant to antibiotics.

“[Acinetobacter] is usually not a high-virulence pathogen, in that it mainly affects patients who are substantially immune compromised and very sick. It is unusual to see a strain that is very resistant and very virulent,” explained Dr Lesho.

“A key finding of our work was that AB strains that are genetically closely related may show significant differences in virulence, suggesting that small genomic changes can profoundly affect virulence. To our knowledge, this is the first report leveraging comparative genomics, animal models, and a surveillance network with isolate repository to characterize an emerging clade of [extensively drug-resistant]-AB associated with a fatal outbreak in patients not severely immunocompromised,” the authors write.

In an accompanying editorial, David L. Paterson, MD, PhD, and Patrick N.A. Harris, MD, from the University of Queensland Centre for Clinical Research in Brisbane, Australia, agree that the significance of the outbreak report lies in the fact that AB infection killed patients who had relatively minor underlying disease. The study also suggests that assumptions about AB pathogenicity may be misplaced.
“Our current understanding of A. baumannii pathogenicity is primarily based on mutagenesis studies using reference strains ATCC 19606 and ATCC 17978, which were isolated over 50 years ago. Considering the ease with which A. baumannii can alter its genetic structure and acquire resistance or virulence determinants, these models of AB pathogenesis may have limited clinical relevance,” write Dr Jones and colleagues.

The investigators propose that the potential virulence gene structures may provide insights into path-adaptation and evolutionary relationship of the clade B strain. They also report that the host response to the pathogen is a driver of virulence and outcomes.

Bourbon Virus Case History Released

Late last year, the Kansas Department of Health and Environment announced the discovery of a previously unknown virus that has been linked to the death of a Kansas man in late spring 2014. Now researchers have published the details of the man’s illness and describe the so-called Bourbon virus.

Olga I Kosoy, MS, from the Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, and colleagues report their findings online February 20 and in the May issue of Emerging Infectious Diseases.
The Bourbon virus, named after the county in which the man lived, belongs to a group of viruses called thogotoviruses, which have not been known to cause illness in the United States until now. Worldwide, thogotoviruses are known to have caused illness in only eight patients, including the Kansas man.

A Tick Bite Preceded Illness

The Kansas man had been working outside when he noticed several tick bites. He removed an engorged tick from his shoulder several days before becoming ill with nausea, weakness, and diarrhea. The following day, he developed a fever, anorexia, chills, headache, myalgia, and arthralgia. He went to his primary care physician on the third day of illness, who empirically prescribed doxycycline for a presumed tickborne illness because of patient’s history and the fact that he had not traveled outside his immediate area. The man’s wife found him obtunded but able to be aroused the following day.

He was admitted to the hospital, where he developed thrombocytopenia and leukopenia. He was given intravenous fluids for dehydration and placed on intravenous doxycycline.

He continued to complain of malaise and anorexia and developed periodic fevers to a maximum temperature of 38.8°C. On the eighth day after illness onset, he was transferred to a tertiary care center. Blood samples taken before his transfer showed no serologic evidence of Rocky Mountain spotted fever, Lyme disease, or ehrlichiosis.
The patient developed a temperature of 39.4°C and a nontender left axillary lymphadenopathy; a diffuse maculopapular rash on his chest, abdomen, and back; petechiae on his soft palate and lower extremities; and bibasilar crackles in the lung fields. He continued to have mild leukopenia (3600 cells/μL), as well as worsening thrombocytopenia (34,000 cells/μL).

He had a chest, abdomen, and pelvis computed tomography scan, which showed trace pleural effusions, bibasilar atelectasis, and multiple prominent abdominal lymph nodes. He developed progressive dyspnea, for which he required oxygen, pulmonary venous congestion, and interstitial edema, and an echocardiogram revealed global hypokinesis.

His condition continued to worsen, and on the tenth day of illness, he was transferred to the intensive care unit and intubated for acute respiratory distress syndrome. He continued to deteriorate, developed refractory shock, and then died from cardiopulmonary arrest on the eleventh day.

Virus Discovery

Serologic and molecular tests were negative for Rocky Mountain spotted fever, tularemia, brucella, babesiosis, Q fever, Ehrlichia species, Anaplasma phagocytophilum, and Babesia species. Fungal pathogen tests (Aspergillus spp. galactomannan, antibodies against Histoplasma species, and Histoplasma species antigen in serum and urine) were also negative.

Testing showed he had previously been infected with cytomegalovirus, Epstein-Barr virus, and parvovirus. Test results for hepatitis B and C viruses, West Nile virus, and HIV were negative, as were blood, sputum, and urine bacterial cultures.

Using a whole-blood specimen that was collected 9 days after the patient became ill, scientists at the Centers for Disease Control and Prevention in Fort Collins, Colorado, conducted testing for Heartland virus antibodies using plaque reduction neutralization. This test was negative for Heartland virus but showed the presence of another virus, and next-generation sequencing and phylogenetic analysis showed that the virus was a novel virus of the genus Thogotovirus.

High levels of viremia in blood taken 2 days before the patient died suggest the virus may have contributed to the man’s death.

Phylogenetic analyses showed that the virus is most closely related to the Dhori and Batken viruses, which have only been seen in the Eastern Hemisphere. Dhori, Batken, and Thogoto viruses have been seen in various hard tick species, but Batken virus has also been seen in mosquitos; therefore, the current mode of transmission to humans is unknown. For this reason, experts recommend wearing long sleeves and pants, using an insect repellent that is effective against ticks, avoiding wooded or bushy areas, and checking for ticks after being outdoors.

“It is currently not known how many human infections and disease cases might be attributable to this novel pathogen. On the basis of limited information for our case-patient, health care providers might consider Bourbon virus as a potential infectious etiology in patients in whom fever, leukopenia, and thrombocytopenia develop without a more likely explanation and who have shown negative results for other tickborne diseases (e.g., ehrlichiosis, anaplasmosis, or Heartland virus disease) or have not responded to doxycycline therapy,” the authors write.

Given the possibility that the Bourbon virus, similar to the recently described Heartland virus, is a tick-borne pathogen, the authors caution that “the public health burden of these pathogens has been underestimated. As nonselective molecular methods of pathogen identification (i.e., [next generation] sequencing) become more widely used, ideally in combination with classical microbiologic techniques, it is anticipated that similar discoveries will be made in the future.”