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MLO201705_AD CompuGroup.indd 1 4/11/2017 8:54:21 AM The Peer Reviewed Management Source for Lab Professionals since 1969 MAY 2017 | Vol. 49, No. 5 8

FEATURES CONTINUING EDUCATION

SPECIAL FEATURE 8 Clinical and diagnostic challenges of antimicrobial resistance in 16 Latest lab diagnostics for seasonal allergies Mycoplasma genitalium By Anthony Horner, MD By Litty Tan, BSc, PhD 14 CE Test LAB MANAGEMENT Tests can be taken online or by mail. See page 14 for 18 Pediatric thyroid testing plays an essential role in disease testing and payment details. management By Linda C. Rogers, PhD, DABCC, FACB DEPARTMENTS 20 Detection methods for prevention of early-onset neonatal group B strep infections 4 From the editor By Diane Kawa, PhD 6 The observatory 22 Testing gaps remain in addressing GBS infections among infants 42 Washington report By Anjana Bhattacharya, PhD, and Sherry Dunbar, PhD Medicare’s new Quality Payment Group B strep: questions and answers Program 23 By Kim Futrell, BS, MT(ASCP) By Jennifer W. Sayers, MHA, MT(ASCP) 43 Having my say MANAGEMENT MATTERS Who am I? By Elizabeth Dahlgren, MT(ASCP) 24 Building an effective PPE program By John Ross PRODUCTS EDUCATION 28 Microbiology, molecular, MALDI-TOF, or all of the above? 44 Product focus: LIS By Richard Cleveland and Amanda Schmidt MARKETPLACE THE PRIMER 32 Back to Basics: RNA molecular diagnostics 46 Advertiser index By John Brunstein, PhD 47 Spotlights CLINICAL ISSUES EXECUTIVE SNAPSHOT 34 Flow cytometry advances in the clinical and military arenas By MSgt Samantha Kunzelman, MT(ASCP), and SSgt Jillian A.N. Salazar 48 Providing educational and consultative services to help labs FUTURE BUZZ succeed James Liggins 38 The future state of informatics and the clinical lab By Wido Menhardt, PhD CEO COLA Resources, Inc. 40 Looking ahead: the future bioinformatics of genetic testing and precision medicine By Ramon M. Felciano, PhD

2 MLO-ONLINE.COM MAY 2017

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A new chapter begins for MEDICAL LABORATORY OBSERVER Vol.49, No.5 Publisher/Executive Editor/President Kristine Russell 23andMe [email protected] Editor Alan Lenhoff e now have authorization to tell you about your [email protected] Managing Editor personal risk,” said Anne Wojcicki, chief execu- Lisa Moynihan “W tive at 23andMe. Indeed, the action taken by the [email protected] U.S. Food and Drug Administration (FDA) on April 6 was a Ad Contracts Manager Laura Moulton momentous one for the California-based direct-to-consumer [email protected] (DTC) genetic testing company, and perhaps a turning point Ad Traffi c Manager Kathleen Shook for the DTC industry. [email protected] In a way, it was a triumphant return to prominence for Subscriptions 23andMe. In 2013, the FDA had ordered the company to stop [email protected] presenting its product as a method for assessing disease risk. LABline/eProduct Insider Mary Haberstroh After that, 23andMe continued to sell a personal genome test, [email protected] but without a health component. Reprints Evelyn Dodge In 2015, the agency approved the company’s test for a ge- [email protected] netic variant linked to Blood syndrome, a rare autosomal dis- ADVERTISING order. But 23andMe was not cleared to give information related to Alzheimer’s East Coast/Midwest Sales (except IL) Classifi ed/Recruitment Advertising disease or other conditions, as it did before the 2013 FDA ruling. Carol Vovcsko (941) 321-2873 Until now. With last month’s ruling, the FDA allowed marketing of 23andMe [email protected] Personal Genome Service Genetic Health Risk (GHR) tests for 10 diseases or con- South/West Coast/Illinois Sales ditions. As the agency’s news release noted, these represent the fi rst direct-to- Lora Harrell (941) 328-3707 consumer (DTC) tests authorized by the FDA that provide information on an [email protected] individual’s genetic predisposition to certain medical diseases or conditions. MLO EDITORIAL ADVISORY BOARD The 23andMe GHR tests work by isolating DNA from a saliva sample, which is John Brunstein, PhD, Biochemistry (Molecular Virology) then tested for more than 500,000 genetic variants. The presence or absence of some President & CSO of these variants is associated with an increased risk for developing any one of the PathoID, Inc., British Columbia, Canada following 10 diseases or conditions: Parkinson’s disease, late-onset Alzheimer’s John A. Gerlach, PhD, D(ABHI) Laboratory Director disease; celiac disease, alpha-1 antitrypsin defi ciency; early-onset primary dysto- Michigan State University, East Lansing, MI nia; factor XI defi ciency; Gaucher disease type 1; glucose-6-phosphate dehydro- Barbara Strain, MA Director, Supply Chain Analytics genase defi ciency; hereditary hemochromatosis; and hereditary thrombophilia. University of Virginia Health System, Charlottesville, VA Authorization of the 23andMe GHR tests was supported by data from peer- Jeffrey D. Klausner, MD, MPH Associate Clinical Professor of Medicine reviewed scientifi c literature that demonstrated a link between specifi c genetic Divisions of AIDS and Infectious Diseases variants and each of the 10. University of California, San Francisco, CA The FDA was quick to add cautionary words for consumers who might misun- Susan McQuiston, JD, MT(ASCP) Instructor, Biomedical Laboratory Diagnostics Program derstand the results of such genetic testing, or the implications of the results for Michigan State University, East Lansing, MI their health: “Consumers can now have direct access to certain genetic risk infor- Donna Beasley, DLM(ASCP) Manager mation,” said Jeffrey Shuren, MD, director of the FDA’s Center for Devices and Huron Healthcare, Chicago, IL Radiological Health. “But it is important that people understand that genetic risk Anthony Kurec, MS, H(ASCP)DLM Clinical Associate Professor is just one piece of the bigger puzzle; it does not mean they will or won’t ultimately SUNY Upstate Medical University, Syracuse, NY develop a disease.” Suzanne Butch, MLS(ASCP)CM, SBBCM, DLMCM The news release spells out that the GHR tests cannot determine a person’s over- Administrative Manager, Blood Bank and Transfusion Service, University of Michigan Health System Department all risk of developing a disease or condition. It makes the point that in addition of Pathology, Ann Arbor, MI to genetic variants, environmental and lifestyle factors play a role in whether an Paul R. Eden, Jr., MT(ASCP), PhD Lt. Col., United States Air Force individual will develop a disease or condition. Chief, Laboratory Services 88th Diagnostics/Therapeutics Squadron It is signifi cant to note that the FDA reviewed data for the 23andMe GHR tests Wright-Patterson AFB, OH through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already NP Communications, LLC. legally marketed device. In addition, the agency plans to exempt additional 2477 Stickney Point Rd., Suite 221B Sarasota, FL 34231 23andMe GHR tests from its premarket review, and GHR tests from other makers Phone: (941) 388-7050 Fax: (941) 388-7490 may be exempt after submitting their fi rst premarket notifi cation. Such a proposed www.mlo-online.com exemption would allow other, similar tests to enter the market quickly and in the least burdensome way, after a one-time FDA review. That means 23andMe may MLO - MEDICAL LABORATORY OBSERVER soon have plenty of competition. (ISSN: 0580-7247). Published monthly, with an additional issue in August, by NP Communications, LLC., 2477 Stickney Point Rd, Suite 221B, The FDA excluded from its marketing authorization and any future exemption Sarasota, FL 34231 (941) 388-7050. Subscription rates: $127.60/ GHR tests that function as diagnostic tests—that is, tests that are often used as the year in the U.S.; $154.88 Canada/Mexico; Intl. subscriptions are $221.43/year. All issues of MLO are available on microfilm from basis for major treatment decisions. University Microfi lms International, Box 78, 300 N. Zeeb Rd., Ann Arbor, MI 48106. Current single copies (if available) $15.40 each (U.S); and Nevertheless, this is a big win for 23andMe and direct-to-consumer genetic test- $19.80 each (Intl.). Back issues (if available) $17.60 each (U.S.); $22.00 each (Intl.). Payment must be made in U.S. funds on a U.S. bank/ ing. Whether it is a win or loss for the clinical lab industry remains to be seen. It branch within the continental U.S. and accompany request. Subscrip- could increase business, in the context of follow-up testing. Whether it is a win or tion inquiries: [email protected]. MLO is indexed in the Cumulative Index for Nursing and Allied Health Literature and Lexis-Nexis. loss for consumer health also remains to be seen; the American College of Medical MLO Cover/CE, Clinical Issues, and Lab Management features are peer reviewed. Title® registered U.S. Patent Offi ce. Copyright© 2017 Genetics and Genomics, among others, has expressed concerns that DTC genetic by NP Communications, LLC. All rights reserved. No part of this testing could lead to unnecessary follow-up. It seems to be an idea whose time has publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any come. Time will tell if it is a good idea. information storage-and-retrieval system, without written permission from the publisher. Offi ce of publication: Periodicals Postage Paid at Sarasota, FL 34276 and at additional mailing offi ces. Postmaster: Send address changes to MLO MEDICAL LABORATORY OBSERVER, 2477 Stickney Point Rd, Suite 221B, Sarasota, FL 34231. Printed in U.S.A. 4 MLO-ONLINE.COM MAY 2017

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MLO201705_AD BD_Diagnostics.indd 5 4/11/2017 8:51:34 AM NEWS TRENDS ANALYSIS

sclerosis (ALS), offering a much-needed Allergies in America Zika Virus tool to measure disease outcomes in clinical trials, a new study reports. The study Almost one in 10 pregnant women in the was published in Science Translational United States with ZIKV had a baby with Medicine. 30 percent birth defects. Of the 250 pregnant wom- No effective treatments currently exist Is the proportion of adults estimated en who had confi rmed Zika virus (ZIKV) for ALS (Lou Gehrig’s disease), a neuro- to suffer from allergies in the U.S. infection in 2016, 24—or almost one in degenerative disorder that rapidly pro- 10—had a fetus or baby with Zika-related gresses from symptoms of weakness and birth defects, according to a new Vital muscle atrophy to complete paralysis and 40 percent Signs report from the U.S. Centers for death within 30 months of the initial diag- Is the proportion of children estimated Disease Control and Prevention (CDC). nosis in almost half of all cases. Despite to suffer from allergies in the U.S. This report is the fi rst to provide the analy- more than 30 clinical trials since 1995, sis of a subgroup of pregnant women only one ALS treatment has been brought in the U.S. with clear, confi rmed test to market, and that compound, Riluzole, 50 million results of ZIKV infection. extends survival by only two to three Testing for Zika remains complex be- months. Is the estimated number of people cause there is a narrow timeframe for who have nasal allergies in the U.S. In this study Tania Gendron, PhD, of the obtaining a positive laboratory result, and Mayo Clinic, and colleagues demonstrat- many infected people do not have symp- ed that a genetic change associated with 17.6 million toms that might motivate testing. For this the most common form of ALS—known reason, the CDC is monitoring all pregnant as C9ORF72—also caused an abnormal Is the number of adults in the U.S. women with any evidence of recent Zika protein called polyGP to accumulate in with hayfever. (2012) infection. In 2016, nearly 1,000 pregnant the cerebrospinal fl uid (CSF) and blood women from 44 states who completed cells of patients. The researchers detected their pregnancies had some evidence of polyGP in CSF from 134 individuals with 6.6 million a recent Zika infection and were at risk of the C9ORF72 form of ALS, including from Is the number of children in the U.S. having a fetus or baby with Zika-related 83 ALS patients, 24 people with diseases with hayfever. (2012) birth defects. Most of these women ac- other than ALS, and 27 asymptomatic quired Zika infection during travel to an carriers. area where Zika was known to be present. Interestingly, polyGP was not found in 11.1 million The fi ndings from this report confi rm CSF from 120 people lacking the C9ORF72 the serious threat posed by ZIKV infection Is the number of people diagnosed mutation, including 57 patients with a dif- during pregnancy and the critical need for with allergic rhinitis. (2012) ferent form of ALS. What’s more, when the pregnant women to continue taking steps scientists administered a therapy targeting to prevent ZIKV exposure through mos- the C9ORF72 mutation in mouse models 200,000 quito bites and sexual transmission. The of C9ORF72 ALS, they observed reduced report also emphasizes the importance of polyGP levels in the animals’ CSF. Is the number of annual Emergency healthcare providers screening all preg- The authors say that with further devel- Room visits linked to food allergies. nant women for possible ZIKV exposure opment, polyGP may prove to be a useful and testing and evaluating all infants born pharmacodynamic marker for therapeutic to women with evidence of Zika infection. responses in clinical trials, especially for 10,000 This report updates previously pub- those patients who carry the mutation but Is the number of annual hospital lished estimates of the proportion of fe- are not yet symptomatic. admissions linked to food allergies. tuses or babies with birth defects among pregnant women with possible Zika infection reported to the U.S. Zika Pregnancy Diabetes 4 million Registry from January 15, 2016, to De- Children at risk of diabetes should be cember 27, 2016, in the 50 U.S. states and Is the number of children in the U.S. screened by HbA1C, OGTT. Doctors Washington D.C. The Registry includes with food allergies. (2014) should add an oral glucose tolerance data from all U.S. states, DC, and all U.S. test (OGTT) to their hemoglobin A1C territories except Puerto Rico; pregnancies (HbA1C) when they screen high-risk chil- in Puerto Rico are monitored separately 8.8 million dren for prediabetes and diabetes, new by the Zika Active Pregnancy Surveil- Is the number of children in the U.S. South Korean research suggests. lance System. This report also highlights with skin allergies. (2012) “We recommend the combined use possible gaps in clinical evaluation and of fasting and two-hour glucose lev- management of infants with possible els, in addition to HbA1C, for the di- congenital ZIKV infection. 40 agnosis of childhood prediabetes and Is the number of people who die in diabetes,” says fi rst author Hyo-Kyoung the U.S. each year from insect sting Genetics/Genomics Nam, MD, PhD. “Traditionally, plasma reactions. glucose levels obtained from oral glu- A new marker is proposed for the most cose tolerance tests have been used • Source: Asthma and Allergy Foundation of America common form of ALS. A molecule to diagnose prediabetes and diabe- Allergy Facts and Figures: http://www.aafa.org/page/ found in blood and cerebrospinal fl uid tes. Hemoglobin A1C, which is easy to allergy-facts.aspx could serve as an indicator for the most use and does not require fasting, has common form of amyotrophic lateral recently been recommended as an

6 MLO-ONLINE.COM MAY 2017

MLO201705_Observatory_MECH_AL.indd 6 4/13/2017 1:39:45 PM NEWS TRENDS ANALYSIS THE OBSERVATORY

In attendance by alphabetical order: TSgt Caso, Mary Ann; SrA Crandell, Eric; 1st Lt Giambanco, Amanda; SrA Greco, Dominic; Maj Griffi n, Edward; Lt Col Labit, Jimmey; SrA Muscato, Chanel; CMSgt Quicanopalacios, Margie; MSgt Romero, MLO Publisher/Executive Editor/President, Kristine Russell and David Grant USAF Medical Center Laboratory’s proud team Tina; SrA Stainiger, team members of David Grant USAF Medical Center Laboratory members celebrate their MLO 2017 Lab of the Year Award at the Adam; A1C Sto accept MLO’s 2017 Lab of the Year Award at CLMA in Nashville, TN. MLO booth at CLMA in Nashville, TN. Domingo, EJ Kevin; 2nd Lt Tate, Lindsay

alternative diagnostic method in adults. including lung, colorectal, female breast, the requirement for days spent in the However, using HbA1C to diagnose pre- and prostate cancers. hospital, and the use of antibiotics. diabetes and diabetes in children and Meanwhile, death rates increased for In this study, the team identifi ed two adolescents is controversial.” cancers of the liver, pancreas, and brain patients with bronchiectasis who suffered The research team evaluated the abili- in men and for liver and uterine cancer with chronic Pseudomonas aeruginosa ty of HbA1C to diagnose prediabetes and in women. The report fi nds overall cancer infections that were resistant to many anti- diabetes and they established the optimal incidence rates, or rates of new cancers, biotics: a 64-year-old male, diagnosed with HbA1C cutoff points for detecting pre- decreased in men but stabilized in women bronchiectasis aged fi fteen, and a 69-year- diabetes and diabetes in youth. They re- during the period 1999-2013. old female who had bronchiectasis from viewed the medical records of 217 obese The Report to the Nation is released childhood. boys and 172 obese girls who had under- each year in a collaborative effort by the Co-author Ian Henderson, PhD, ex- gone OGTT and HbA1C testing simulta- American Cancer Society; the Centers for plains: “These patients had an excess of a neously between January 2010 and June Disease Control and Prevention (CDC) particular antibody in the bloodstream. In 2016 in six hospitals. The children were and National Cancer Institute (NCI), both contrast to the protective effect normally diagnosed with prediabetes (fasting glu- parts of the Department of Health and Hu- associated with antibodies, in these pa- cose 5.6 to 6.9 mmol/L; 2-hour glucose man Services; and the North American tients the antibody stopped the immune 7.8 to 11.0 mmol/L) or with diabetes (fast- Association of Central Cancer Registries system from killing the Pseudomonas ing glucose 7.0 mmol/L or higher; 2-hour (NAACCR). aeruginosa bacterium, and this wors- glucose 11.1 mmol/L or higher). Compared to cases diagnosed in ened the patients’ lung disease. Perhaps All children with diabetes were de- 1975-1977, fi ve-year survival for cancers counter-intuitively, we decided to remove tected using the combined OGTT and diagnosed in 2006-2012 increased sig- this antibody from the bloodstream, and HbA1C tests. Roughly half of overweight nifi cantly for all but two types of cancer: the outcomes were wholly positive.” children at risk had prediabetes or dia- cervix and uterus. The greatest abso- The researchers used a process known betes based on OGTT results, and the lute increases in survival (25 percent as plasmapheresis, which, according to agreement between OGTT and HbA1C or greater) were seen in prostate and co-author Tony De Souza, MD, “involves results was moderate. kidney cancers as well as non-Hodgkin “the removal, treatment, and return of The authors found that the optimal lymphoma, myeloma, and leukemia. blood plasma from circulation. We then HbA1C cutoff points were 40 mmol/ Cancers with the lowest fi ve-year replaced antibodies with those from blood mol (5.8 percent) for prediabetes and 44 relative survival for cases diagnosed in donations. This treatment restored the mmol/mol (6.2 percent) for diabetes. 2006-2012 were pancreas (8.5 percent), ability of the patients’ blood to kill their “The usefulness of adult criteria of liver (18.1 percent), lung (18.7 percent), infecting Pseudomonas.” HbA1C for the diagnosis of prediabetes esophagus (20.5 percent), stomach (31.1 Both patients reported a rapid improve- and diabetes in children and adolescents percent) and brain (35 percent). Those with ment in health and wellbeing, greater remains to be clarifi ed due to dispari- the highest were prostate (99.3 percent), independence, and improved mobility ties between the results of OGTT- and thyroid (98.3 percent), melanoma (93.2 compared to any point in the previous two HbA1C-based tests,” Nam says. percent), and female breast (90.8 percent). years. This is the fi rst description of antibody- Infectious Diseases dependent enhancement of bacterial dis- Cancer ease. It may be widely applicable to other Study suggests a new treatment for bacterial infections and offers hope for Cancer death rates continue to decline. antibiotic-resistant bacteria and in- the treatment of some antibiotic-resistant Overall cancer death rates continue to de- fectious disease. A recent study, pub- infections. crease in men, women, and children for all lished in the American Journal of major racial and ethnic groups, according Respiratory and Critical Care Medicine, Clarifi cation: In the April 2017 MLO article to the latest Annual Report to the Nation describes a new treatment pathway for “Transforming the microbiology laboratory on the Status of Cancer, 1975-2014. antibiotic-resistant bacteria and infectious to address the Triple Aim in healthcare,” con- The report fi nds that death rates dur- diseases. Researchers from the University tributor Irene K. Dusich describes how North- ing the period 2010-2014 decreased of Birmingham and Newcastle University Shore University HealthSystem Evanston for 11 of the 16 most common types of found that the unusual approach of re- (Illinois) implemented an automation system cancer in men and for 13 of the 18 most moving antibodies from the bloodstream in its microbiology lab. The system they use common types of cancer in women, reduced the effects of chronic infections, is the BD Kiestra Total Lab Automation.

MAY 2017 MLO-ONLINE.COM 7

MLO201705_Observatory_FINAL.indd 7 4/13/2017 1:57:10 PM STIs

Clinical and diagnostic challenges of antimicrobial resistance in Mycoplasma genitalium By Litty Tan, BSc, PhD

ycoplasma genitalium is a small bacterium from the Mycoplasma genitalium infections.9 M. genitalium infection is Mollicute class that was fi rst isolated from the hu- also strongly correlated with persistent or recurrent NGU, M man urogenital tract in the 1980s.1 It has taken some found in 19 percent to 41 percent of men with persistent time to gain traction as an accepted sexually transmitted in- or recurrent disease.4,10,11 These high levels may be a conse- fection (STI); however, the U.S. Centers for Disease Control quence of current treatment practices resulting in inadequate and Prevention’s (CDC) most recent guidelines for sexually syndromic treatment of NGU. transmitted diseases (STDs)2 have highlighted M. genitalium as an emerging issue. M. genitalium has been strongly Disease in women and consistently associated with non-gonococcal urethri- Mucopurulent cervicitis has also been described as the fe- tis (NGU) and cervicitis, and is also implicated in pelvic male counterpart of NGU in men,8 and non-gonococcal mu- infl ammatory disease in women.3-6 copurulent cervicitis is caused by similar etiologic agents. Table 1 summarizes the diseases associated with M. genita- C. trachomatis is responsible for 20 percent to 40 percent of lium and the level of evidence for this association, as published cases, and M. genitalium is responsible for fi ve percent to 20 in the World Health Organization (WHO) manual, Laboratory percent of cases.8 Diagnosis of Sexually Transmitted Infections, Including Human Immunodefi ciency Virus.5 Disease Level of disease association* Disease in men Urethritis ++++ M. genitalium was fi rst discovered in men with NGU, and most of the subsequent studies focus in the same manner.4 Urethritis is an infl ammation of the urethra and may be char- Cervicitis +++ acterized by symptoms such as dysuria, urethral pruritus, and purulent or non-purulent urethral discharge. Urethritis Bacterial vaginosis - can have many infectious etiologies. When it is not caused Endometritis and/or by a gonorrheal infection it is known as non-gonococcal ure- +++ thritis or NGU. C. trachomatis is the primary cause of NGU, Pelvic Infl ammatory Disease (PID) responsible for 15 percent to 40 percent of cases,7 and M. gen- Preterm birth +/- italium is now recognized as the second most common cause, responsible for 15 percent to 25 percent of cases in men with symptomatic NGU.4 U.S. studies on M. genitalium preva- Infertility (women) + lence in men with NGU range from 13 percent to 31 percent. * ++++ strong association, +++ association in most studies, + association from a (Table 2) few studies, +/- confl icting results (adapted from WHO 2013) The strong association of M. genitalium with NGU has led to its inclusion in diagnostic considerations by the Centers Table 1. Disease associations of Mycoplasma genitalium.5 for Disease Control and Prevention's Sexually Transmit- ted Diseases Treatment Guidelines,2 European guidelines Meta-analysis studies on the disease association of M. gen- for management of NGU,8 and the European guideline on italium infection and female reproductive tract syndromes have shown signifi cant association with increased risk of cervicitis, pelvic infl ammatory disease (PID), pre-term birth, spontaneous abortion, and risk of infertility.1,6 U.S. studies Continuing Education on M. genitalium prevalence in women with cervicitis range from 11.2 percent to 28.6 percent. (Table 3) To earn CEUs, see test on page 14 or online at www.mlo-online.com under the CE Tests tab. Prevalence of M. genitalium From the limited data available, the prevalence of M. geni- LEARNING OBJECTIVES talium in the general population is reported at between Upon completion of these articles, the reader will be able to: 1.1 percent and 3.3 percent (Table 4, pg. 10). In compari- 1. Discuss the history, progression, symptoms, and disease son to other causes of sexually transmitted infections, this states of M. genitalium. is higher than the prevalence of Neisseria gonorrhoeae at 0.4 percent, but lower than Chlamydia trachomatis at 4.2 2. Identify risk factors for M. genitalium and describe the 4,2 concerns with current treatment regimens. percent and Trichomonas vaginalis at 2.3 percent. Simi- lar to C. trachomatis, M. genitalium can also be found in as- 3. Discuss current testing methods for M. genitalium and ymptomatic infection12,13; thus the true prevalence may be describe the limitations associated with each one. underestimated. 4. List and describe alternative testing methods and treatment A recent multicenter clinical study cohort in the U.S. options for M. genitalium infection. investigated the prevalence of M. genitalium infections in

8 MLO-ONLINE.COM MAY 2017

MLO201705_CEStory_MECH_AL.indd 8 4/13/2017 9:28:23 AM STIs CE

urogenital specimens collected Population MG from 946 male and female sub- Study cohort Study period size (N) prevalence jects.14 M. genitalium prevalence rates were 16.1 percent for females STD clinic (Baltimore, MD) no info 286 13.9%44 and 17.2 percent for males. Signifi - cant risk factors for M. genitalium STD clinic (New Orleans, LA) Feb 2001 - Apr 2004 398 20%15 infections were African descent, younger age, non-Hispanic ethnic- 2 STD clinics (Baltimore, MD) 2004 290 22.2%45 ity, and female symptomatic status. 4 STD clinics (Birmingham, AL; New Orleans, Nov 2006 - Apr 2009 305 31%16 Management of NGU and LA; Durham, NC; Baltimore, MD) cervicitis Different etiologic agents, such as STD clinic (Seattle, WA) May 2007 - Oct 2009 370 12.5%46 C. trachomatis and M. genitalium, can have similar clinical presen- STD clinic (Seattle, WA) Jan 2007 – Jul 2011 606 13%31 tations, as seen in urethritis and cervicitis. Therefore these STIs are Table 3. Prevalence of MG in women with cervicitis in the U.S. commonly managed as syndromes grouped by similar symptoms. In syndromic management, thus, testing patterns vary widely throughout the U.S. and treatment is targeted at the most common causes at the time globally. Whereas both chlamydia and gonorrhea are widely of diagnosis and before the etiologic agent is identifi ed. tested and reported on, there are no offi cial guidelines on Urethritis in symptomatic men is fi rst determined to screening for M. genitalium in sexually active individuals, be gonococcal or non-gonococcal using microscopy. In the and many clinics do not currently request testing for this U.S., the Sexually Transmitted Diseases Treatment Guide- pathogen in initial consultations. More recent publica- lines, 2015, recommend presumptive treatment of NGU tions and discussions are now calling for the monitoring of with doxycycline, a tetracycline antibiotic, or azithromy- M. genitalium in high-risk populations.14, 27-29 cin, a macrolide antibiotic.2 Doxycycline and azithromycin When testing does occur, laboratories have limited op- are highly effective against C. trachomatis (67 percent to 87 tions. M. genitalium is a fastidious organism and grows very percent for men with NGU); however, doxycycline regimens slowly in culture, taking up to six months to detect.1 Only have poor cure rates for M. genitalium (30 percent to 45 per- a few labs globally have been able to isolate M. genitalium cent).15,16 Therefore, if doxycycline was given as the fi rst line from clinical samples. Additionally, due to closely related therapy for NGU where M. genitalium was the causative species, serology lacks adequate specifi city.30 Therefore, agent, treatment is more likely to fail. Of further concern is culture and serology, which are the traditional diagnos- the high rate of M. genitalium macrolide resistance appear- tic methods for bacteria, are not suitable for routine testing in studies world-wide.14,17-29, 31 The most recent and com- ing of M. genitalium. The only viable diagnostic option is prehensive U.S. study found macrolide-resistant M. geni- detection using a nucleic acid amplifi cation test (NAAT). talium phenotypes in 51 percent of females and 42 percent There are currently no U.S. Food and Drug Administration of males,14 indicating that a signifi cant portion of the tested (FDA)-cleared tests for detection of M. genitalium. For that population would not respond to current frontline treatment reason, in-house NAATs have been extensively used along recommendations. with available CE-marked or research use only (RUO) assays. The practice of syndromic treatment and subsequent use The majority of in-use tests allow only for detection of M. of doxycycline and/or azithromycin without appropri- genitalium, providing no information on potential resistance ate and targeted diagnostics is likely contributing to the status of an infection.29 The rise in prevalence of antibiotic- high prevalence of M. genitalium in persistent or recurrent resistant strains, however, has infl uenced the latest European urethritis. guidelines for the management of M. genitalium infection, recommending the addition of resistance testing for effective Currently available tests for M. genitalium management of NGU and other M. genitalium infections.8,9 Although M. genitalium has been in the literature for several decades, it has only recently been more broadly recognized Mutations associated with azithromycin resistance as an STI1 and is currently not listed as a notifi able disease; Macrolide resistance in M. genitalium has been strongly and consistently associated with Study cohort Study period Population size (N) MG prevalence mutations occurring at posi- tions 2058 and 2059 (Escherichia coli numbering) of region V of STD clinic (Baltimore, MD) no info 286 13.9%44 the 23S rRNA gene.4,32 The fi ve most common mutations are STD clinic (New Orleans, LA) Feb 2001 - Apr 2004 398 20%15 A2058G (adenine transition to guanine base at position 2058), 2 STD clinics (Baltimore, MD) 2004 290 22.2%45 A2059G, A2058T, A2058C, and A2059C,32 and those are 4 STD clinics (Birmingham, AL; New Orleans, Nov 2006 - Apr 2009 305 31%16 the only mutations found in LA; Durham, NC; Baltimore, MD) the majority of studies.14,17-27 Isolated M. genitalium strains 46 STD clinic (Seattle, WA) May 2007 - Oct 2009 370 12.5% with four of the most common mutations have been shown to STD clinic (Seattle, WA) Jan 2007 - Jul 2011 606 13%31 confer high-level azithromycin resistance in vitro,33 and all fi ve Table 2. Prevalence of MG in men with NGU in the U.S. mutations have been found in

MAY 2017 MLO-ONLINE.COM 9

MLO201705_CEStory_MECH_AL.indd 9 4/13/2017 9:28:33 AM STIs

M. genitalium and resistance MG prevalence Population markers incorporates a novel Country of study Age size (N) Men % (CI%) Women % (CI%) priming technology to overcome these diagnostic challenges. 47 Denmark 21-23 1652 1.1% (0.3-1.9%) 2.3% (1.3-3.2%) This technology introduces an insert sequence during amplifi - N.America 18-27 2932 1.1% (0.5-2.4%) 0.8% (0.4-1.6%)48 cation, creating amplicons that are distinctly different from the Australia 16-25 1116 n/a 1.6% (0.7-2.6%)49 original sequence.36 Advantages to this approach may include UK 15-27 2378 n/a 3.3% (2.6-4.1%)42 increased stringency and subsequent selective amplifi cation of mutant alleles, as well as the 43 UK 16-44 4507 1.2% (0.7-1.8%) 1.3% (0.9-1.9%) ability to multiplex a number of different SNP targets.36 The CI – Confi dence interval assay combines detection of M. genitalium with fi ve azithromy- Table 4. Prevalence of MG in the general population cin-associated mutations, multiplexing the detection of multiple samples from patients exhibiting azithromycin treatment resistance markers within a single-well reaction.37 Tested on failure.4 400 stored clinical samples of positive M. genitalium patients, There have been limited U.S. studies investigating 23S M. genitalium detection sensitivity was 99.1 percent, specifi c- rRNA mutation prevalence. One study investigating M. geni- ity 98.5 percent, while sensitivity and specifi city of mutation talium prevalence also analyzed a subset of subjects for mac- detection was 97.4 percent and 100 percent respectively.37 rolide-resistant mutations and found rates of 50.8 percent [95 percent CI, 42.2 percent to 59.3 percent] in females (65 of 128) Treatment of M. genitalium and 42 percent [95 percent CI, 29.4 percent to 55.8 percent] in Mycoplasma lack a cell wall and thus are unaffected by many males (21 of 50), with an overall prevalence of 48.3 percent.14 common antibiotics, leaving limited treatment options. Al- though the CDC STD guidelines recommend either doxy- Testing for antibiotic resistance in M. genitalium cycline or azithromycin for the presumptive treatment of Given the high failure rates of the now standard azithromy- NGU,2 due to the rising recognition of M. genitalium in NGU, cin treatment, a detection-only assay for M. genitalium may and the known ineffectiveness of doxycycline, many coun- have limited use in informing effective patient management. tries (Australia, New Zealand, United Kingdom, Denmark, The European guidelines for management of NGU8 now Japan) use only azithromycin.21 The European guidelines on recommend screening of male patients with urethritis for Mycoplasma genitalium infections9 specifi cally recommend macrolide resistance mutations in order to improve clinical azithromycin for treatment of uncomplicated M. genitalium outcomes. infections. There are currently no FDA-cleared tests for detection of While azithromycin is more effective than doxycycline in M. genitalium or for the determination of resistance status. the treatment of M. genitalium, cure rates have been declin- With resistance linked to multiple mutations in the 23S rRNA ing. Three clinical trials across a decade in the U.S. showed gene, many studies rely on sequencing methods to deter- declining cure rates from 77 percent in 2002-200415 to 67 per- mine resistant phenotypes14,27 This approach is not readily cent in 2006-200916 to 40 percent in 2007-2011.31 Lau et al38 re- conducive to clinical practice due to high cost and increased cently published a meta-analysis of 21 studies on the effi cacy sample processing times. Some alternative in-house ap- of azithromycin for M. genitalium treatment, demonstrating proaches include the use of high resolution melting (HRM)34 declining cure rates since 2009. The pooled microbial cure for or qPCR based on fl uorescence resonance emission transfer the 12 studies conducted prior to 2009 was 85.3 percent (95 (FRET) coupled with melting curve analysis.20 Clinical prac- percent confi dence interval [CI], 82.3 percent to 88.3 percent). tices rarely incorporate HRM methodologies, as results may For the nine studies conducted since the beginning of 2009, vary due to DNA concentration and can be diffi cult to repro- the pooled microbial cure was 67.0 percent (CI, 57.0 percent duce in other labs, and melt curve analysis requires skilled to 76.9 percent).38 interpretation. The example of the FRET assay is also not M. genitalium treatment failures can be addressed with suitable for clinical purposes, as researchers only achieved a moxifl oxacin. Initial reports showed moxifl oxacin to be sensitivity of 76.7 percent.20 highly effective,1,11 yet its use is limited due to cost, side ef- NAAT diagnostics for allelic discrimination typically uti- fects, availability, and potential for development of resis- lize qPCR with allele-specifi c primers or detection with al- tance. Resistance to moxifl oxacin has been observed over the lele-specifi c fl uorescent probes.35 This approach works well last decade, often in conjunction with macrolide resistance, for conditions involving a single nucleotide polymorphism resulting in persistent infection that is very challenging to (SNP); however, design costs and complexity increase when manage.29 multiple SNPs are involved. Often there are multiple varia- M. genitalium is exhibiting alarming capabilities of de- tions within the same location, and/or SNPs are clustered veloping antimicrobial resistance (AMR), and the wide- within areas associated with specifi c structural or functional spread use of azithromycin as front-line treatment ap- importance, leading to diffi culties with cross priming or pears to be driving even higher rates of resistance.28,29,38 primer competition that affects specifi city and sensitivity There is a real clinical need to accompany M. genitalium of the assay.36 The mutations associated with azithromycin testing with surveillance of macrolide resistance-mediat- resistance in M. genitalium represent such complexity. ing mutations to enhance patient management and con- The one available CE marked test for both detection of trol the spread of AMR.8,29,37,39,40 Dr. Margaret Chan, the

continued on page 12 10 MLO-ONLINE.COM MAY 2017

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continued from page 10 WHO director, summarized perfectly the larger AMR issue 27. Anagrius C, Lore B, Jensen JS. Treatment of Mycoplasma genitalium. Observations facing us when she said, “Today, antibiotics are rarely pre- from a Swedish STD clinic. PloS One. 2013 8(4):e61481. scribed based on a defi nitive diagnosis. Having rapid, low- 28. Jensen JS, Bradshaw C. Management of Mycoplasma genitalium infections—can we hit a moving target? BMC Infectious Diseases. 2015;15(1):343. cost, and readily available diagnostics is an essential part of 29. Unemo M, Jensen JS. Antimicrobial-resistant sexually transmitted infections: gonor- 50 the solution to this urgent problem.” rhoea and Mycoplasma genitalium. Nature Reviews Urology. 2017;14(3):139-152. 30. Lind K, Lindhardt BO, Schütten HJ, Blom J, Christiansen C. Serological cross-reactions between Mycoplasma genitalium and Mycoplasma pneumoniae. J Clin Microbiol. REFERENCES 1984; 20(6):1036–1043. 1. Tully JG, Taylor-Robinson D, Cole RM, Rose DL. A newly discovered mycoplasma in 31. Manhart LE, Gillespie CW, Lowens MS, et al. Standard treatment regimens for non- the human urogenital tract. Lancet. 1981;I:1288–1291. gonococcal urethritis have similar but declining cure rates: A randomized controlled trial. Clin Infect Dis. 2013;56(7):934–942. 2. Workowski K, Bolan G. Sexually Transmitted Diseases Treatment Guidelines, 2015. MMWR Recomm Rep 2015;64(3):1-135. 32. Couldwell DL, Tagg KA, Jeoffreys NJ, Gilbert GL. Failure of moxifl oxacin treatment in Mycoplasma genitalium infections due to macrolide and fl uoroquinolone resistance. 2015; 3. Jensen JS, Bjornelius E, Dohn B, Lidbrink P. Use of TaqMan 5’ nuclease real-time doi.org/10.1177/0956462413502008. PCR for quantitative detection of Mycoplasma genitalium DNA in males with and without urethritis who were attendees at a sexually transmitted disease clinic. J Clin Microbiol. 33. Jensen JS., Bradshaw CS., Tabrizi SN, Fairley CK, Hamasuna R. Azithromycin treat- 2004;42(2): 683-692. ment failure in Mycoplasma genitalium-positive patients with nongonococcal urethritis is associated with induced macrolide resistance. Clin Infect Dis. 2008;47(12):1546–1553. 4. Taylor-Robinson D, Jensen JS. Mycoplasma genitalium: from chrysalis to multicol- ored butterfl y. Clin Microbiol Rev. 2011;24(3):498–514. 34. Twin J, Jensen JS, Bradshaw CS, et al. Transmission and selection of macrolide resistant Mycoplasma genitalium infections detected by rapid high resolution melt analysis. 5. World Health Organization (WHO). Laboratory diagnosis of sexually transmitted infec- PLoS ONE. 2012;7(4): e35593. doi:10.1371/journal.pone.0035593. tions, including human immunodefi ciency virus. Switzerland: World Health Organization 2013. 35. Chen X, Sullivan PF. Single nucleotide polymorphism genotyping: biochemistry, protocol, cost and throughput. The Pharmacogenomics Journal. 2003;3(2):77–96. 6. Lis R, Rowhani-Rahbar A, Manhart LE. Mycoplasma genitalium infection and female reproductive tract disease: a meta-analysis. Clin Infect Dis. 2015;61(3):418-426. 36. Tan LY, Walker SM Lonergan T, et al. Superior multiplexing capacity of plexprimers enables sensitive and specifi c detection of SNPs and clustered mutations in qPCR. Plos 7. Centers for Disease Control and Prevention (CDC). Diseases characterized by urethri- One. 2017;12(1):e0170087. tis and cervicitis in Sexually Transmitted Diseases Guidelines. 2015. http://www.cdc.gov/ std/tg2015/urethritis-and-cervicitis.htm. 37. Tabrizi SN, Tan LY, Walker S Twin, et al. Multiplex assay for simultaneous detection of Mycoplasma genitalium and macrolide resistance using Plexzyme and Plexprime tech- 8. Horner PJ, Blee K, Falk L, vander Meijden W, Moi H. 2016 European Guideline on the nology. Plos One. 2016;11(6):he0156740. management of non-gonococcal urethritis. Int J STD AIDS. 2016;27(11):928-937. 38. Lau A, Bradshaw CS, Lewis D, et al. The effi cacy of azithromycin for the treatment of 9. Jensen JS, Cusini M, Gomberg M, Moi H. 2016 European guideline on Mycoplasma genital Mycoplasma genitalium : a systematic review and meta-analysis. Clin Infect Dis. genitalium infections. J Eur Acad Dermatol Venereol. 2016;30(10):1650-1656. 2015;61(9):1389–1399. 10. Wikstrom A, Jensen JS. Mycoplasma genitalium: a common cause of persistent ure- 39. Manhart LE. Diagnostic and resistance testing for Mycoplasma genitalium: what will thritis among men treated with doxycycline. Sex Transm Infect. 2006; 82(4):276–279. it take? Clin Infect Dis. 2014;59(1):31–33. 11. Manhart LE, Broad JM, Golden MR. Mycoplasma genitalium: should we treat and 40. Nijhuis, RHT, Severs TT, Van der Vegt, DS. J. M., Van Zwet AA, Kusters JG. High levels how? Clinical Infectious Diseases. 2011;53(Suppl 3):S129-S142. of macrolide resistance-associated mutations in Mycoplasma genitalium warrant antibi- 12. Falk L, Fredlund H, Jensen, JS. Signs and symptoms of urethritis and cervicitis among otic susceptibility-guided treatment. J Antimicrob Chemother. 2015;70(9):2515-2518. women with or without Mycoplasma genitalium or Chlamydia trachomatis infection. Sex- 41. Manhart LE, Critchlow CW, Holmes KK, Dutro SM, et al. Mucopurulent cervicitis and ually Transmitted Infections. 2005;81(1):73–78. Mycoplasma genitalium. J Infect Dis. 2003;187(4):650–657. 13. Ross JD, C., Brown L, Saunders P, Alexander S. Mycoplasma genitalium in asymp- 42. Oakeshott P, Aghaizu A, Hay P, et al. Is Mycoplasma genitalium in women the “new tomatic patients: implications for screening. Sexually Transmitted Infections. 2009; chlamydia”? a community‐based prospective cohort study. Clin Infect Dis. 2010;51(10): 85(6):436–437. 1160–1166. 14. Getman D, Jiang A, O’Donnell M, Cohen S. Mycoplasma genitalium prevalence, coin- 43. Sonnenberg P, Ison CA, Clifton S, et al. Epidemiology of Mycoplasma genitalium in fection, and macrolide antibiotic resistance frequency in a multicenter clinical study Co- British men and women aged 16–44 years: evidence from the third National Survey of Sex- hort in the United States. (R. Patel, Ed.). J Clin Microbiol. 2016;54(9):2278–83. ual Attitudes and Lifestyles (Natsal-3). International Journal of Epidemiology. 2015; dyv194. 15. Mena LA, Mroczkowski TF, Nsuami M, Martin DH. A randomized comparison of 44. Hardick J, Giles J, Hardick A, et al. Performance of the gen-probe transmission-me- azithromycin and doxycycline for the treatment of Mycoplasma genitalium-positive ure- diated amplifi cation research assay compared to that of a multitarget real-time PCR for thritis in men. Clin Infect Dis. 2009;48(12):1649–1654. Mycoplasma genitalium detection. J Clin Microbiol. 2006;44:1236–1240. 16. Schwebke JR, Rompalo A, Taylor S, et al. Re-evaluating the treatment of nongonococ- 45. Gaydos C, Maldeis NE, Hardick A, Hardick J Quinn TC. Mycoplasma genitalium as a cal urethritis: Emphasizing emerging pathogens - A randomized clinical trial. Clin Infect contributor to the multiple etiologies of cervicitis in women attending sexually transmitted Dis. 2011;52(2):163–170. disease clinic . Sex Transm Dis. 2009; 36(10):598–606. 17. Tagg KA, Jeoffreys NJ, Couldwell DL., Donald JA, Gilbert GL. Fluoroquinolone and 46. Wetmore CM, Manhart LE, Lowens MS, et al. Demographic, behavioral, and macrolide resistance-associated mutations in Mycoplasma genitalium. J Clin Microbiol. clinical characteristics of men with nongonococcal urethritis differ by etiology: a case- 2013;51(7):2245–2249. comparison study. Sex Transm Dis. 2011;38(3):180-186. 18. Gesink DC, Mulvad G, Montgomery-Andersen R. Presence, resistance and epidemiol- 47. Yew HS, Anderson T, Coughlan E, Werno A. Induced macrolide resistance in Myco- ogy in Greenland. International Journal of Circumpolar Health. 2012;71(0):1–8. plasma genitalium isolates from patients with recurrent nongonococcal urethritis. J Clin 19. Pond MJ, Nori AV Witney AA, et al. High prevalence of antibiotic-resistant Myco- Microbiol. 2011; 49(4):1695–1696. plasma genitalium in nongonococcal urethritis: the need for routine testing and the inad- 48. Manhart LE, Holmes KK, Hughes JP, Houston LS, Totten PA. Mycoplasma genitalium equacy of current treatment options. Clin Infect Dis. 2014;58(5):631–637. among young adults in the United States: an emerging sexually transmitted infection. Am 20. Touati A, Peuchant O, Jensen JS, Bébéar C, Pereyrea S. Direct detection of macrolide J Public Health. 2007;97(6):1118-1125. resistance in Mycoplasma genitalium isolates from clinical specimens from France by 49. Walker J, Fairley CK, Bradshaw CS, et al. The difference in determinants of Chla- use of real-time PCR and melting curve analysis. J Clin Microbiol. 2014;52(5):1529–1555. mydia trachomatis and Mycoplasma genitalium in a sample of young Australian 21. Bissessor M, Tabrizi SN, Twin J, et al. Macrolide resistance and azithromycin failure women. BMC Infect Dis. 2011 Feb 1;11:35. http://bmcinfectdis.biomedcentral.com/ar- in a Mycoplasma genitalium-infected cohort and response of azithromycin failures to al- ticles/10.1186/1471-2334-11-35. ternative antibiotic regimens. Clin Infect Dis. 2015;60(8):1228–1236. 50. O'Neill J. Tackling drug-resistant infections globally: fi nal report and recommenda- 22. Kikuchi M, Ito S, Yasuda M, et al. Remarkable increase in fl uoroquinolone-resistant tions. The Review on Antimicrobial Resistance. May 2016:35. Mycoplasma genitalium in Japan. J Antimicrob Chemother. 2014;69(9):2376–2382. 23. Gossé M, Nordbø SA, Pukstad B. Bacterial load in daily urine samples of atients infected with Mycoplasma genitalium, mutation analysis, and response to treatment. Infec- Litty Tan, BSc, PhD, has more than 10 tious Diseases in Obstetrics and Gynecology. 2016;.doi.org/10.1155/2016/8382469. years’ experience in medical research, 24. Kristiansen GQ, Lisby JG, Schønning K. A 5’ nuclease genotyping assay for identifi ca- and she has extensive expertise in mo- tion of macrolide-resistant Mycoplasma genitalium in clinical specimens. J Clin Microbiol. lecular assay development for cancer 2016;54(6):1593-1597. and infectious disease diagnostics. 25. Dumke R, Thürmer A, Jacobs E. Emergence of Mycoplasma genitalium strains show- She serves as the Director of Research ing mutations associated with macrolide and fl uoroquinolone resistance in the region and Development at SpeeDx Pty. Ltd. Dresden, Germany. Diagn Microbiol Infect Dis. 2016;86(2):221–223. In this role she manages research proj- 26. Chernesky M, Jang D, Gilchrist J, et al. Mycoplasma Genitalium (MG) Infections in ects and coordinates product development and product Canadian Women with Chlamydia Trachomatis (CT) and/or Neisseria Gonorrhoeae (NG). evaluations to ensure quality and regulatory compliance. Poster presented at 2016 CDC STD Prevention Conference.

12 MLO-ONLINE.COM MAY 2017

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MLO201705_AD BD_Diagnostics_20654.indd 13 4/11/2017 8:51:57 AM CONTINUING EDUCATION TEST CLINICAL AND DIAGNOSTIC CHALLENGES OF ANTIMICROBIAL RESISTANCE IN MYCOPLASMA GENITALIUM May 2017 [This form may be photocopied. It is no longer valid for CEUs after November 30, 2018.)

TEST QUESTIONS Circles must be fi lled in, or test will not be graded. Shade circles like this:O Not like this: O

1. In which decade was M. genitalium fi rst 8. Which antibiotic has poor effectiveness in 15. Clinical testing that identifi es resistant isolated from the human urogenital tract? treating M. genitalium? phenotypes of M. genitalium is lacking  a. 1970s  a. augmentin because of  b. 1980s  b. doxycycline  a. varying degrees of reproducibility due to  c. 1990s  c. azithromycin DNA concentration.  d. 2000s  d. amoxicillin  b. skilled interpretation of test results.  c. low sensitivity. 2. Which condition(s) is M. genitalium 9. Which class of antibiotics shows a high d. all of the above strongly and consistently associated rate of resistance, according to global  with? studies? 16. The one available test that detects  a. non-gonococcal urethritis (NGU)  a. macroclide M. genitalium and identifi es resistance  b. cervicitis  b. tetracycline markers has shown promise by using a  c. pelvic infl ammatory disease  c. penicillin higher level of priming technology and  d. all of the above  d. cephalosporin testing against fi ve mutations.  a. True 3. What is the etiology of the primary and 10. There are currently no screening  b. False secondary causes of NGU? guidelines for M. genitalium, and many  a. M. genitalium and N. gonorrhoeae clinics do not order testing for this 17. M. genitalium detection sensitivity  b. N. gonorrhoeae and C. trachomatis pathogen in initial consultations. and specifi city for the test described in  c. C. trachomatis and M. genitalium  a. True question 16 was found to be  d. none of the above  b. False  a. 91.9 percent and 98.8 percent.  b. 99.1 percent and 98.5 percent. 4. What disease state is described as the 11. What factors make culture and serology  c. 99.9 percent and 99.8 percent. female counterpart of NGU in men? testing of M. genitalium unsuitable?  d. 91.5 percent and 98.2 percent.  a. gastritis  a. It’s a fastidious organism.  b. mucopurulent cervicitis  b. It grows very slowly. 18. M. genitalium mutation detection c. urethritis c. It lacks specifi city. sensitivity and specifi city for the test   described in question 16 was found to be  d. all of the above  d. all of the above  a. 97.4 percent and 100 percent. 5. Studies estimate that the prevalence for 12. The tests that are currently available for  b. 99.1 percent and 98.5 percent. M. genitalium causing NGU in men is M. genitalium offer both identifi cation  c. 99.9 percent and 99.8 percent. 13-31 percent, and the prevalence for and potential resistance status of the  d. 91.5 percent and 98.2 percent. M. genitalium causing mucropurulent organism. cervicitis is 11.2-28.6 percent.  a. True 19. What is the alternative antibiotic of choice  a. True  b. False for resistant strains of M. genitalium?  b. False  a. penicillin 13. A study investigating M. genitalium  b. ciprofl oxacin 6. Why might the true prevalence rates for resistance prevalence concluded that the  c. moxifl oxacin M. genitalium be underestimated? overall prevalence of resistance was  d. cephalexin  a. The reporting of the etiological organism  a. 15.6 percent. has not been consistent.  b. 33.7 percent. 20. While there is an alternative antibiotic of  b. Patients frequently resist treatment.  c. 48.3 percent. choice for the treatment of resistant strains  c. The organism can be found in  d. 63.2 percent. of M. genitalium, its use is limited due to asymptomatic infection. costs, side effects, availability, and concern 14. Sequencing methods to determine for potential resistance development.  d. all of the above resistant phenotypes of M. genitalium  a. True 7. Signifi cant risk factors for M. genitalium include  b. False infections include African descent,  a. HRM. younger age, non-Hispanic ethnicity, and  b. qPCR. female symptomatic status.  c. both a and b.  a. True  d. neither a nor b.  b. False Tests can be taken online or by mail. Easy registration and payment options are available through NIU by following the links found at www.mlo-online.com/ce. PLEASE PRINT CLEARLY

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Send your $20 check payable to Northern Illinois University with this form to: University Outreach Services, Northern Illinois University, DeKalb, IL 60115-2860 Phone: 815-753-0031 FEE NOT REFUNDABLE OR TRANSFERABLE P = Poor; E = Excellent CE Licensure Information for FL and CA: 1. To what extent did the article focus 2. To what extent was the article 3. How will you use the CE units? FL: Your FL license number:______(required for CE credit) on or clarify the objectives? well-organized and readable? state license employment CA: Accrediting Agency: 0001 P E P E recertifi cation other (for use in submitting your CE credits to CA)

MLO and Northern Illinois University (NIU), DeKalb, IL, are co-sponsors in offering continuing education units (CEUs) for this issue’s CE article. CEUs or contact hours are granted by the College of Health and Human Sciences at Northern Illinois University, which has been approved as a provider of continuing education programs in the clinical laboratory sciences by the ASCLS P.A.C.E.® program. Approval as a provider of continuing education programs has been granted by the state of Florida (Provider No. JP0000496). Continuing education credits awarded for successful completion of this test are acceptable for the ASCP Board of Registry Continuing Competence Recognition Program. Readers who pass the test successfully (scoring 70% or higher) will receive a certifi cate for 1 contact hour of P.A.C.E.® credit. Participants should allow three to fi ve weeks for receipt of certifi cate. The fee for this continuing education test is $20.This test was prepared by Amanda Voelker, MPH, MT(ASCP), MLS, Clinical Education Coordinator, School of HealthStudies, Northern Illinois University, DeKalb, IL.

14 MLO-ONLINE.COM MAY 2017

MLO201705_CETest_FINAL.indd 14 4/13/2017 1:42:24 PM EL CAMINOEL CAMINO HOSPITAL HOSPITAL CASE CASE STUDY STUDY AUTOMATIONAUTOMATION + +INFORMATICS: INFORMATICS: KEYSKEYS FOR FOR QUALITY-BASED QUALITY-BASED HEALTHCARE HEALTHCARE HowHow El ElCamino Camino Hospital Hospital Is MeetingIs Meeting Today’s Today’s Healthcare Healthcare Challenges Challenges Head-On Head-On

TheThe shift shift from from a fee-for-service a fee-for-service (FFS) (FFS) reimbursement reimbursement system system to to AddingAdding Extended Extended Quality Quality Control Control (EQC) (EQC) a value-baseda value-based system system is here—and is here—and the thetransition transition continues continues to to In 2013,In 2013, the thelaboratory’s laboratory’s quality quality and and efficiency efficiency took took another another step step affectaffect healthcare healthcare institutions institutions everywhere. everywhere. Now Now more more than than ever, ever, forwardforward when when it addedit added the theoptional optional Extended Extended Quality Quality Control Control today’stoday’s hospitals hospitals need need to measureto measure quality quality and and performance performance (EQC)(EQC) module module to its to REMISOLits REMISOL Advance Advance systems. systems. on ona continuous a continuous basis. basis. And And if they if they aren’t aren’t meeting meeting their their quality quality standards,standards, they they need need to pinpointto pinpoint the thecause. cause. Here’s Here’s the thestory story of of “Prior“Prior to addingto adding EQC, EQC, we wehad had to delayto delay placing placing patient patient samples samples howhow one one facility facility recently recently tackled tackled the thechallenge. challenge. on theon theinstruments instruments every every morning morning until until quality quality control, control, for forall theall the tests,tests, could could be beverified. verified. This This often often added added 15-20 15-20 minutes minutes to ourto our El CaminoEl Camino Hospital’s Hospital’s Mission: Mission: Streamline Streamline Workflow Workflow to to overalloverall turnaround turnaround time,” time,” said said Abbott. Abbott. “With “With EQC, EQC, however, however, we we ImproveImprove Patient Patient Care Care don’tdon’t have have to waitto wait for forall QCall QCto finishto finish before before loading loading specimens. specimens. NowNow our ouroperators operators have have full full ForFor more more than than a decade, a decade, El Camino El Camino Hospital Hospital (Mountain (Mountain View, View, Calif.) Calif.) Pre- Pre-Post- Post- confidenceconfidence that that if anyif any single single test’s test’s EQC EQCEQC EQC hashas been been a leader a leader in laboratoryin laboratory process process improvement. improvement. During During QC QCvalue value is out,is out, the thepatient patient results results Quality Quality thatthat time, time, they they have have achieved achieved a 95% a 95% autoverification autoverification rate rate and and for forthat that test test will willbe beblocked blocked from from Time Time eliminatedeliminated unnecessary unnecessary draws draws through through the theimplementation implementation and and autovalidation,autovalidation, so sonothing nothing gets gets 20 min. 20reduction min. reduction useuse of integrated of integrated automation, automation, LEAN LEAN processes processes and, and, most most recently, recently, in overallin TAToverall TAT reportedreported erroneously. erroneously. This This enables enables trulytruly advanced advanced healthcare healthcare informatics informatics solutions. solutions. El ElCamino Camino us tous bringto bring patient patient specimens specimens onto onto Hospital’sHospital’s two two campuses campuses continually continually enrich enrich their their experiences experiences and and the theinstruments instruments sooner, sooner, reduce reduce TAT TAT contributionscontributions to their to their network network by incrementalby incremental improvements. improvements. 0 0 andand increase increase workflow.” workflow.” TheThe EQC EQC patient patient protocols protocols also also feature feature exponentially exponentially weighted weighted movingmoving averages averages (EWMA), (EWMA), which which add add another another layer layer of assurance. of assurance.

AutomationAutomation REMISOLREMISOL › › Streamlined workflow with Power Processor ThisThis feature feature continuously continuously monitors monitors patient patient results results between between QC QC AdvanceAdvance › › TAT reduction through autoverification by runs.runs. If QC If QCvalues values start start to drift,to drift, it alerts it alerts the thereviewing reviewing technician technician BeckmanBeckman CoulterCoulter Extended Quality Control (EQC) in realin real time, time, stopping stopping autoverification autoverification of those of those affected affected results. results. expertiseexpertise › › Improved operational efficiencies with “In “Inthe thepast, past, we wewould would occasionally occasionally turn turn out outresults results for forfive five or or CPI CPI IntelligenceIntelligence process improvement engagements softwaresoftware six sixhours hours before before we werealized realized the theQC QCwas was out,” out,” explained explained Abbott. Abbott. “That“That meant meant we wehad had to rerunto rerun all thoseall those patient patient samples samples and and re- re- reportreport the theresults results to theto thephysicians. physicians. Having Having EWMA EWMA catch catch any any QC QC issuesissues right right away away saves saves us time us time and and means means more more efficiency efficiency for forthe the InitialInitial Gains Gains Through Through Automation Automation and and entireentire laboratory.” laboratory.” InformationInformation Technology Technology Pre-EQCPre-EQC InstrumentInstrument drifts drifts WorkingWorking in inpartnership partnership with with Beckman Beckman Coulter, Coulter, El ElCamino Camino › 5-6 hours› 5-6 to hoursidentify to QC identify shift QC shift › Corrrective› Corrrective actions to actions resolve to resolve › Added ›work Added work HospitalHospital first first automated automated its coreits core laboratory laboratory in 2003. in 2003. Since Since then, then, › Poor physician› Poor physician satisfaction satisfaction the theorganizations organizations have have continued continued to topartner, partner, implementing implementing › Potential› Potentialpatient harm patient harm multiplemultiple workflow workflow optimizations optimizations and and solution solution upgrades, upgrades, building building a progressivelya progressively stronger, stronger, more more profitable profitable and and more more efficient efficient Post-EQCPost-EQC ImmediateImmediate action action › Drifts caught› Drifts immediately caught immediately laboratorylaboratory operation operation at every at every step step of the of theway. way. › Autoverification› Autoverification stopped stopped › Prevented› Prevented release of release of erroneous erroneous results results › Improved› Improved physician physician In termsIn terms of information of information technology, technology, the thelaboratory’s laboratory’s transformation transformation confidenceconfidence beganbegan in 2009,in 2009, when when it upgradedit upgraded from from the theDL2000 DL2000 Data Data ManagerManager to theto theREMISOL REMISOL Advance Advance data data management management system system withwith Command Command Central. Central. First, First, they they implemented implemented standardized standardized DeliveringDelivering Continuous Continuous Process Process Improvement Improvement verificationverification rules—thus rules—thus eliminating eliminating subjective subjective interpretation interpretation of of ThanksThanks to data-driven to data-driven software software and and valuable valuable new new process process insights, insights, results—andresults—and added added the theability ability to viewto view information information from from multiple multiple El CaminoEl Camino Hospital Hospital is focusingis focusing on onbold, bold, new new LEAN LEAN initiatives initiatives analyzersanalyzers remotely remotely from from a centrala central location. location. The The REMISOL REMISOL thatthat help help bolster bolster system-wide system-wide efficiency efficiency and andimprove improve patient patient AdvanceAdvance servers servers are areconfigured configured with with data data redundancy redundancy features features satisfaction.satisfaction. The The core core laboratory laboratory has has also also received received a lot a lotof helpof help andand automatic automatic backup backup functions functions to ensure to ensure data data integrity. integrity. fromfrom Beckman Beckman Coulter’s Coulter’s Continuous Continuous Process Process Improvement Improvement (CPI) (CPI) “Because“Because of REMISOLof REMISOL Advance Advance and and autoverification autoverification rules, rules, we we Team,Team, who who has has been been instrumental instrumental in providingin providing LEAN LEAN training training werewere freed freed up toup justto just look look at results at results that that need need our ourattention, attention, and and andand guidance. guidance. thatthat makes makes a big a bigdifference,” difference,” said said Kelly Kelly Abbott, Abbott, chemistry chemistry lead. lead. “Over“Over the theyears, years, Beckman Beckman Coulter Coulter has has proven proven its excellenceits excellence in all in all In fact,In fact, with with autoverification, autoverification, 90% 90% of theof thelaboratory’s laboratory’s chemistry chemistry areasareas from from sales sales to service,” to service,” said said Abbott, Abbott, “but “but these these value-added value-added resultsresults and and 95% 95% of ofits itsimmunoassay immunoassay results results are arereleased released resourcesresources like likethe thebusiness business intelligence intelligence software software and and the theLEAN LEAN automatically,automatically, requiring requiring no reviewno review from from the thelaboratory laboratory staff. staff. This This expertiseexpertise we’ve we’ve received received in recentin recent years years really really put put our ourhospital hospital savessaves time, time, optimizes optimizes labor labor and and decreases decreases TAT TAT for thefor thetest test results. results. wayway ahead.” ahead.”

REMISOLREMISOL Advance Advance is a istrademark a trademark of Normand-Info of Normand-Info SAS. SAS. © 2017© 2017 Beckman Beckman Coulter, Coulter, Inc. Inc.All rightsAll rights reserved. reserved. Beckman Beckman Coulter, Coulter, the thestylized stylized logo, logo, and and the theBeckman Beckman Coulter Coulter product product and and service service marks marks mentioned mentioned hereinherein are trademarksare trademarks or registered or registered trademarks trademarks of Beckman of Beckman Coulter, Coulter, Inc. Inc.in the in theUnited United States States and and other other countries. countries. For ForBeckman Beckman Coulter’s Coulter’s worldwide worldwide office office locations locations and andphone phone numbers, numbers, please please visit www.beckmancoulter.com/contactvisit www.beckmancoulter.com/contact AD-52401AD-52401

MLO201705_AD BeckmanCoulter.indd 15 4/11/2017 8:53:19 AM SPECIAL FEATURE ALLERGIES

Latest lab diagnostics for seasonal allergies By Anthony Horner, MD

think it’s just an allergy.” Almost every clinician health conditions for some patients including the very hears that from patients, especially during allergy young, the elderly, and patients with weakened immune “I season. Many people believe that allergies explain systems. Moreover, some respiratory infections are easily their upper respiratory tract symptoms, such as cough, spread, so proper diagnosis is vital to protect others from congestion, and runny nose. In fact, studies suggest that infection. about 30 percent of Americans have allergies based on serum or skin test allergy results, and higher rates have Asthma and allergies been reported. However, it is important to recognize that Asthma is a lung disease sometimes confused with al- many people with positive allergy tests do not have per- lergic upper airway disease (also known as allergic rhi- sistent respiratory symptoms and the true prevalence nitis or allergic rhino-sinusitis), and these conditions of allergic respiratory disease is less than commonly often coexist in the same patient. One study,1 based on perceived. analyses of 14 million IgE laboratory test results, found Because many allergy symptoms mimic other health that people with positive IgE results for respiratory al- concerns, it is important for treating clinicians to under- lergens are more likely to have asthma than those with stand the cause of these symptoms and whether or not negative results. Moreover, the study confi rmed previous their patient has true allergies or is suffering from some observations in noting that young children with food al- other condition. Colds and sinus disease, for example, lergies commonly go on to develop respiratory allergies share many clinical features with allergic rhinitis. While and asthma more often than young children who do not the symptoms can be similar, clinical details often identi- develop food allergies. fy patients with allergies. For instance, compared to other Because allergies are common and readily treatable, conditions, allergies far more commonly cause eye symp- medical evaluation of patients with presumed respiratory toms and an itchy, as well as runny, nose. Also worth allergy symptoms is important. In many cases, a medi- noting, allergies do not cause fever. cal evaluation will include the use of allergy testing to The time of year can also be a clue: In many areas of the help confi rm or exclude the allergy diagnosis. Positive United States, pollen allergies begin in early spring and results help physician and patient develop an effective last until fall due to the pollination from trees, grasses, allergy treatment plan, which may include environmen- and weeds. However, wet but mild winter temperatures tal controls to reduce allergen exposure and/or medi- can cause plants to pollinate early in the spring or mold cations. However, negative allergy results are equally spores to be a problem during the winter months. useful, because they will lead to additional diagnostic It is also important to note that some allergy sufferers investigation and an alternative diagnosis. may present with symptoms all year long, which may be the result of indoor allergens, such as mold, dust mites, or Laboratory allergy testing pet dander. Generally, these patients will have their worst Physicians may use skin prick tests or immunoglobulin symptoms when indoors at home or work, and in particu- E (IgE) blood tests to aid in the diagnosis of respiratory lar upon waking. If not pollen-sensitized, they may also allergies, and these two approaches are generally consid- report that their symptoms are less severe when outside. ered to be equally reliable. However, only allergy specialists are trained to conduct allergy skin tests, while serum The problem of self-diagnosis IgE tests are available to all healthcare providers through Because allergies and upper respiratory infections (URIs) laboratory diagnostics. Moreover, while allergy skin test- are prevalent, share symptoms, and are generally non- ing takes about 20 to 30 minutes to complete, serum IgE life threatening, it is not surprising that patients may be testing only requires a small volume of blood. inclined to self-diagnose and over-diagnose one or both Immunoglobulin E (IgE) is an antibody that binds to of these conditions. That’s a potential concern, because the surface of mast cells and basophils through a special the treatments for allergies and URIs differ, and a patient receptor called the high affi nity IgE receptor. When these may spend precious time and money on over-the-counter IgE armed cells encounter their allergen in the airways, treatments that are appropriate for one condition but not they immediately release histamine and other substances the other. that give rise to patient symptoms, including sneezing, Of greater concern than that: sometimes symptoms congestion, and watery and itchy nose and eyes. How- suggestive of allergic upper respiratory disease (or a ever, while serum IgE tests help determine what aller- simple cold) are actually due to more serious lower re- gens people are sensitized to, it is important to point out spiratory tract conditions such as asthma, infl uenza, or that many sensitized individuals will not develop symp- bacterial pneumonia. These can be particularly serious toms after appropriate allergen exposure. For this and

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several other reasons, it is important that serum IgE aller- symptoms. These include environmental controls to gy testing be evaluated in the context of a comprehensive reduce exposure to relevant aeroallergens based on al- medical evaluation by a practitioner well versed in the lergy test results, antihistamines to control intermittent diagnosis and management of allergic diseases. eye and/or nose symptoms, nasal steroids for chronic IgE technology is available for hundreds of individu- symptoms, and immunotherapy, which involves a series al respiratory allergens. Respiratory allergen panels are of injections with allergens to which a patient is known also customized, as it were, for multiple regions in the to be allergic. However, only with a good history, physi- United States. Each includes allergens most prevalent cal exam, and respiratory allergen testing results can a in that region, making those panels ideal for diagnosing medical provider make a fully informed decision about respiratory allergies. how best to manage patients with allergic upper-airway disease. Treatment steps post-diagnosis REFERENCE While over-the-counter allergy medications are read- 1. Kaufman HW, Odeh MA, Bost WH, Ragothama P. Allergies across America: the larg- ily available, they are often misused by people suffering est study of allergy testing in the United States. Quest Diagnostics, Madison, NJ: 2011. from respiratory symptoms not caused by allergies, as well as by allergic patients who are unaware of the best therapeutic strategies for their condition. Therefore, the Anthony Horner, MD, certifi ed by the most important fi rst step in the management of allergies American Board of Allergy and remains the clinical evaluation. This evaluation is likely Immunology, serves as Associate to include allergy testing. Medical Director, Immunology for The good news for patients suffering from allergic Quest Diagnostics. Quest provides a range of testing services to aid the upper airway diseases (allergic rhinitis, allergic rhino- diagnosis of allergies based on sinusitis, and allergic rhino-conjunctivitis): many safe ImmunoCAP and other technologies. and effective therapies are available for the control of

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MLO201705_SpecFeature_Quest_MECH_AL.indd 17 4/13/2017 9:30:40 AM LAB MANAGEMENT NEONATAL/PEDIATRIC DIAGNOSTICS

Pediatric thyroid testing plays an essential role in disease management By Linda C. Rogers, PhD, DABCC, FACB

hen it comes to laboratory testing, children are not functioning properly. It is ordered primarily to help diagnose just small adults. Clinical interpretation of many lab- a form of hyperthyroidism called T3 thyrotoxicosis, in which Woratory tests requires age-specifi c data. This is partic- only T3 is elevated. It may also be ordered to help monitor ularly important with thyroid function testing, as specifi c thy- the progress of a patient with this disorder. Free T3 is usually roid tests change with age, organ growth, and development. ordered following abnormal TSH and T4 tests. Thyroid function abnormalities are among the most com- Like T3, T4 is a hormone synthesized and secreted by the mon endocrine problems in children. Because proper thyroid thyroid gland. In the circulation, 99.95 percent of T4 is revers- function is essential for brain and bone growth, detection of ibly bound to transport proteins. The remaining T4 is not any issues is especially critical in children. bound to transport proteins but is free in circulation. This un- The thyroid gland is an important endocrine gland located bound fraction, free T4, is the metabolically active hormone. at the front of the neck, just below the Adam’s apple. The thy- Free T4 is used as a follow-up test to an abnormal TSH. roid produces hormones that are responsible for the rate of Patients with hypothyroidism have decreased levels of free T4 all metabolic and chemical processes affecting every cell, tis- and elevated levels of TSH. In contrast, patients with hyper- sue, and organ in the body. The thyroid gland is, therefore, thyroidism have increased levels of free T4 and low levels of essential for life, growth, and development. TSH. Signs and symptoms of thyroid disease are general and Less-common thyroid function tests include thyroglobu- nonspecifi c and may be silent or diffi cult to detect. Although lin antibodies (anti-TG), antibodies to thyroid peroxidase the prevalence of thyroid disorders is most common in adults, (anti-TPO), thyroid receptor antibodies (TRAb), and thyroid- diseases of the thyroid can occur at any age, from newborn stimulating immunoglobulins (TSI). These antibody assays through adolescence and adulthood. are used for the diagnosis of various autoimmune diseases Pediatric-specifi c reference intervals (See sidebar, pg. 19) affecting the thyroid gland. for thyroid tests enable proper interpretation of test results for optimal patient care for the smallest patients. However, few Thyroid disease in the neonate studies have been published to provide this information, and Congenital hypothyroidism affects one in 1,500 to 3,000 hospital laboratories may fi nd establishing their own pediat- newborns in the U.S. each year. The condition most often ric reference intervals challenging due to resourcing issues; occurs for no known reason, due to the thyroid gland fail- lack of suffi cient, well-characterized samples; and blood-vol- ing to develop normally, but 10 percent to 20 percent of the ume constraints. Further, general published intervals are not time, it is inherited.1 If the diagnosis is delayed and imme- always accurate for each instrument and assay. Instrument- diate treatment is not given, congenital hypothyroidism can and assay-specifi c pediatric reference intervals are preferred lead to growth and developmental defects and severe mental for the accurate interpretation of thyroid results. retardation. Because most newborns show no signs of it, the condition Thyroid function assays is usually detected during routine newborn screening. At When the thyroid gland produces too much thyroid hormone U.S. hospitals, routine testing for thyroid function in new- (overactive), the condition is called hyperthyroidism. When borns has been mandatory since 1976. Within the fi rst week the thyroid gland produces too little thyroid hormone (un- of life, a heel-stick blood sample is taken to assess an infant’s deractive), the condition is called hypothyroidism. Diagno- thyroid (most commonly with a TSH test). If any abnormal- sis and management of hyper- and hypothyroidism require ity is found, confi rmatory thyroid testing is performed. If test accurate laboratory testing. Tests used to aid in the clinical results show elevated levels of TSH and decreased levels of assessment of thyroid status include thyroid-stimulating hor- free T4, the infant is immediately given thyroid hormone- mone (TSH), free and total thyroxine (T4), and free and total replacement therapy. There is usually no cure for congeni- triiodothyronine (T3). tal hypothyroidism, but replacement therapy and continued TSH is a hormone produced by the anterior pituitary gland monitoring will ensure proper growth and development of that stimulates the thyroid gland to synthesize and secrete the infant. thyroid hormones T4 and T3. Measurement of TSH is the best Congenital hyperthyroidism is less common in neonates initial screening test for the presence of primary hyper- or hy- but is critical to detect early, as consequences can be very pothyroidism. The capability of a TSH assay to distinguish serious and complex. While thyroid hormones produced between normal and subnormal concentrations is essential by or given to the mother cross the placenta in only limit- for thyroid testing strategy. Quantifi cation of TSH at a lower ed amounts, both thyroid antibodies and antithyroid drugs value of 0.01 mlU/L yields information that is useful to clini- (ATDs) readily cross the placenta and affect fetal thyroid cians referring patients with subnormal TSH concentrations. function. If the mother has the autoimmune disease Graves’ An abnormal TSH measurement leads to additional testing, disease (GD), the thyroid-stimulating antibodies or immu- which may include free or total T3 and/or free or total T4. noglobulin in maternal blood can cross the placenta and Both T3 and T4 play an important role in regulating metab- stimulate the unborn child’s thyroid gland, resulting in olism. In the circulation, 99.7 percent of T3 is reversibly bound hyperthyroidism in the neonate. to transport proteins. Unbound T3 (free T3) is metabolically Because neonatal Graves’ disease is caused by maternal active. The free T3 test helps determine whether the thyroid is antibodies, it is self-limited and usually resolves when the

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child is aged three to four months. However, symptoms of Thyroid disorders in pregnancy, neonates, and childhood hyperthyroidism can persist longer, depending on the clear- can be complex. Patients require frequent laboratory testing ance of the stimulating antibodies. In rare circumstances, the and follow-up treatment, often throughout their lives. Along levels of stimulating antibodies are high enough to cause with endocrinologists, the lab plays a vital role in managing severe hyperthyroidism in the newborn. This can be a po- their challenging conditions. tentially life-threatening medical condition, and immediate treatment with antithyroid medication is necessary to lower REFERENCES thyroid hormone levels. 1. Bahn RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyro- If the levels of stimulating antibodies are low, newborns toxicosis: management guidelines of the ATA and AACE. Endocr Pract. 2011;17(3)457- may hardly be affected and no treatment may be necessary, as 520. the mother’s antibodies will soon clear from the baby’s blood- 2. Zori RT, Schatz DA, Ostrer H, Williams CA, Spillar R, Riley WJ. Relationship of auto- stream. If the mother is taking antithyroid drugs, infants are immunity to thyroid dysfunction in children and adults with Down syndrome. American usually born asymptomatic. Signs and symptoms of hyper- Journal of Medical Genetics—Supplement. 1990;7:238-241. thyroidism may develop when the antithyroid medications 3. Raymond J, LaFranchi SH. Fetal and neonatal thyroid function: review and summary of signifi cant new ndings.fi Curr Opin Endocrinol Diabetes Obes. 2010;17(1):1-7. that have crossed the placenta are cleared from the infant’s 4. CLSI. Defi ning, Establishing and Verifying Reference Intervals in the Clinical Labo- bloodstream and the thyroid-stimulating antibodies have not ratory; Approved Guideline—Third Edition. Volume 28, Number 30, Guideline C28-A3c, yet cleared. The hyperthyroidism, although transient, can be 2010. serious. Neonates born to mothers with GD must be carefully 5. Horn PS, Pesce AJ. Reference Intervals: A User’s Guide. Washington, DC: AACC monitored with both thyroid function tests and TSI or TRAb Press; 2005. assays and managed with medication if needed. In childhood and adolescence Both hypothyroidism and hyperthyroidism can develop Linda C. Rogers, PhD, DABCC, FACB, serves as Senior during childhood. Children with Down syndrome are at Clinical Consultant, Scientifi c & Clinical Affairs, increased risk of thyroid disorders, including congenital Siemens Healthineers. hypothyroidism, GD, and another autoimmune disease, Hashimoto’s thyroiditis.2 Hypothyroidism in childhood and adolescence is more common in females and in those with a family history of autoimmune disorders. They usually undergo testing because of the detection of a goiter (enlarged thyroid gland) on routine examination or because of poor growth rate present for Pediatric reference intervals several years. In adolescence, these children may experience delayed puberty if not diagnosed and treated. Worldwide, To ease the challenges presented by a lack of age-specifi c refer- iodine defi ciency continues to be an important cause of hy- ence intervals for infants and pediatrics, a study was designed pothyroidism in children and adults, but it is a less common and conducted to establish such intervals for thyroid hormones cause in North America. for four instrument systems. The study included FT4, FT3, T4, The most common cause of hypothyroidism in children and T3 (on four systems) and the third-generation TSH (on two and adolescents is Hashimoto’s thyroiditis. The treatment systems) for three age groups: infants (1–23 months), children for Hashimoto’s thyroiditis in children and adolescents is (2–12 years), and adolescents (13–20 years). Stringent inclusion the same as in adults. Thyroid hormone replacement is taken criteria were used to ensure a well-characterized subject selec- daily for life. The dosage of thyroid hormone must be age- tion and a signifi cant sample size. Statistical analysis used to appropriate, as the body’s demands for thyroid hormone derive the thyroid reference intervals for these subgroups were vary with age. Regular thyroid function tests must be as- based on the CLSI C28-A3 and Horn and Pesce’s Reference sessed by a doctor to ensure that normal hormone levels are Intervals: A User’s Guide. maintained and adjusted as needed.3 Eight collection sites across the United States were used to Hyperthyroidism, like hypothyroidism, can produce collect samples, which were aliquoted and shipped frozen to symptoms that are often vague and nonspecifi c and can one laboratory for testing. Testing was conducted using assay- mimic other conditions. These symptoms include goiter, specifi c runs on the instruments, and samples were tested with anxiety and irritability, heat sensitivity and increased perspi- the handling conditions recommended for each assay in its ration, weight loss (despite normal eating habits), rapid or Instructions for Use (IFU). irregular heartbeat, and ophthalmopathy. The most common For the infant group, the lower and upper reference limits cause of hyperthyroidism is GD, and although it is much less were estimated as the 2.5th and 97.5th percentiles of the dis- common in childhood than in adults, it can occur at any age. tribution produced by the robust method. For the children and The clinical diagnosis of hyperthyroidism is made by the adolescents groups, the lower and upper reference limits were fi nding of decreased TSH and increased concentrations of established as the 2.5th and 97.5th percentiles of the test result circulating thyroid hormones (T4, or preferably free T4, and distribution. free T3). In hyperthyroidism, the circulating T3 concentra- The sample size totals (391, 421, 407, and 435) for each of the tion may be elevated out of proportion to the T4 because TSH four analyzers included in the study were signifi cant, and strin- receptor antibodies stimulate increased conversion of T4 to gent inclusion criteria were used for well-characterized subject T3. The diagnosis of GD is confi rmed by the demonstration selection as well as a statistical package recommended by CLSI of TSH receptor antibodies in serum. Treatment of GD is and Horn and Pesce.4,5 with antithyroid drugs (ATDs) or by removal of the thyroid The pediatric reference ranges thus established are refl ected gland by surgery or radioablation. Following either medical in the IFUs for the respective assays. For more information and treatment or thyroid gland removal, child patients become study details, please visit usa.siemens.com/pediatricthyroid. hypothyroid and require lifelong thyroid replacement therapy and thyroid hormone monitoring.

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Detection methods for prevention of early-onset neonatal group B strep infections By Diane Kawa, PhD

roup B Streptococcus (GBS) remains a leading cause of antiserum).7 The downside is that culture methods have a neonatal infections, with very severe outcomes. Infec- long turnaround time (TAT) of 24 to 72 hours, which could Gtions are acquired through vertical transmission from result in delayed prophylaxis or unnecessary treatment of a GBS-colonized mother before delivery, during prolonged the infant. This precludes use of culture for intrapartum GBS labor or premature rupture of membranes, during passage screening, and it is typically performed during prenatal or through the birth canal, or by post-partum exposure. Neo- antepartum screening at 35 to 37 weeks gestation. nates exposed to GBS may develop symptoms of rapidly in- Chromogenic media which depend on the ability of vasive disease including sepsis, pneumonia, and meningitis ß-hemolytic GBS to produce a visible orange carotenoid within the fi rst week after birth (early-onset disease) or after pigment (granadaene) offer good options for GBS cul- a week and up to three months of life (late-onset disease). In- ture in clinical laboratories.8,9 However, ~fi ve percent trapartum antibiotic prophylaxis for GBS-colonized women to eight percent of GBS isolates are non-hemolytic, and during labor reduces transmission and the risk of early onset some also do not produce granadaene, making detec- neonatal disease 1,2 tion by culture diffi cult.10 Consequently, women colonized with these strains may be missed and, in the ab- Prevention strategies sence of appropriate prophylaxis, pose signifi cant risk for Prevention efforts for early-onset neonatal GBS disease development of neonatal sepsis. focus on identifying women for whom prophylaxis during labor is appropriate. Risk factors include maternal Molecular testing intrapartum GBS colonization, a previous GBS-infected Molecular methods have raised the bar for accurate and baby, positive for GBS in urine (bacteruria) in any trimes- defi nitive results for detection of GBS in less time than ter of current pregnancy, delivering at <37 weeks’ gesta- culture, but they also raise important questions about tion, having an intrapartum temperature ≥38.0°, or mem- their use for timely intervention and intrapartum prophy- brane rupture for ≥18 hours, and intrapartum women laxis for colonized women. DNA hybridization probe as- with any of these are given antibiotic prophylaxis.1,2 In the says were the earliest methods developed for detection United States, universal culture-based screening for GBS of GBS in vaginal/rectal swabs11 but were gradually re- colonization is also done for all pregnant women between placed by nucleic acid amplifi cation tests (NAATs), which 35 and 37 weeks of gestation, and prophylaxis is given to are more sensitive, simplifi ed, and based on polymerase colonized women.1 chain reaction (PCR) or novel technologies such as loop- Prevention strategies have led to an appreciable decline mediated isothermal amplifi cation (LAMP) and helicase- in the incidence of early-onset GBS disease.3-5 However, de- dependent amplifi cation (HDA). spite their positive impact, neonatal GBS infections still oc- Most commercial GBS NAATs are performed with 18-to- cur, which highlights signifi cant gaps in identifying those at 24-hour broth-enriched specimens, which is consistent with risk of early-onset infection. In a recent analysis, only 58 per- GBS screening recommendations for prevention of neonatal cent of mothers with infants who developed early onset GBS disease. These assays have excellent sensitivities, from 95 disease were screened for GBS (63 percent full term and 44 percent to 99 percent, compared to broth-enriched culture percent pre-term), and 81 percent of term mothers who were methods,12,13 and demonstrate similar performance with screened had a negative GBS culture result. This suggests 97 percent to 98 percent overall agreement.14,15 The perfor- that a change in colonization status of women at the time of mance of NAATs with non-enriched specimens is variable, birth or a less-than-optimal GBS detection method may have with sensitivities from ~63 percent to 99 percent compared to contributed to these cases.6 broth enriched culture.1 A more recent study of a GBS NAAT designed for direct testing of vaginal/rectal swab speci- Traditional detection methods mens showed an inferior performance (86 percent sensitiv- Accurate and timely identifi cation of GBS carriage is es- ity) compared to two broth-enriched molecular PCR tests, sential for appropriate prophylactic treatment during labor. with 97 percent and 99 percent sensitivities, respectively.13 The current standard for GBS detection in pregnant wom- A summary of studies assessing NAAT’s performance at an- en is broth enrichment culture of a vaginal/rectal swab, tepartum or intrapartum, with antepartum enriched broth which is central to the universal culture-based GBS screen- enriched culture as the reference, shows mixed results, but ing strategy.1 Direct culture is unreliable as it misses many mostly supports the conclusion that NAAT sensitivity is women who are GBS carriers. Selective enrichment broths signifi cantly improved with broth enrichment culture.1 for GBS are variations of Todd-Hewitt broth, with either 8 A roadblock to widespread adoption of NAATs for de- μg/mL gentamicin and 15 μl/mL nalidixic acid (TransVag tection of GBS carriage is that, despite their simplicity and broth) or 10 μg/mL colistin and 15 μl/mL nalidixic acid (Lim rapid assay turnaround time (one to four hours), the need broth).1,7 The enriched broth is sub-cultured on blood agar for a pre-enrichment step to maximize sensitivity prevents plates, and presumptive isolated GBS colonies are identifi ed their use in identifying GBS carriers for prophylaxis dur- by a characteristic narrow zone of ß-hemolysis, followed ing labor. Furthermore, laboratories contend that with by confi rmation by standard phenotypic methods (e.g., NAATs, an isolate may not be recoverable for antimicro- CAMP test ) or serological tests (e.g., agglutination with GBS bial susceptibility testing, which is required to guide the

20 MLO-ONLINE.COM MAY 2017

MLO201705_LabMgmt_BD_MECH_AL.indd 20 4/13/2017 7:59:46 AM LAB MANAGEMENT Simplexa® C. difﬁcile Direct Kit

treatment of penicillin-allergic women at high risk for ana- phylaxis. Despite these limitations, however, rapid GBS FLEXIBLE NAATs with a TAT of at least one hour are increasingly con- Now sidered for use in emergent cases where the GBS coloniza- AVAILABLE tion status of a pregnant woman is unknown or other risk factors such as pre-term labor exist, and allow for selective C. DIFFICILE intrapartum antibiotic prophylaxis for individuals identifi ed as GBS carriers. As molecular technologies continue to evolve, it is reason- TESTING. able to expect that NAATs or more sophisticated methods will emerge as the standard for detection of GBS carriage at intrapartum in the near future. They may even replace culture for diagnosis of suspected cases of neonatal GBS sepsis as test Direct detection of C. difficile sensitivity improves. using real-time PCR. REFERENCES 1. Verani JR, McGee L, Schrag SJ. Prevention of perinatal group B streptococcal disease: revised guidelines from CDC, 2010. MMWR Recomm Rep. 2010;59(RR-10):1-36. Flexible Molecular 2. Royal College of Obstetricians & Gynaecologists. 2012 Guideline No. 36. The Pre- vention of Early-Onset Neonatal Group B Streptococcal Disease. https://www.rcog.org. uk/en/guidelines-research-services/guidelines/gtg36/. Solutions with 3. Lukacs SL, Schrag SJ. Clinical sepsis in neonates and young infants, United States, ® 1988–2006. J Pediatr. 2012;160(6):960-5 e1. Simplexa 4. Van Dyke MK, Phares CR, Lynfi eld R, et al. Evaluation of universal antenatal screening for group B Streptococcus. NEJM. 2009;360(25):2626-36. Direct Assays 5. Darlow B, Voss L, Lennon D, Grimwood K. Early-onset neonatal group B Strep- tococcus sepsis following national risk-based prevention guidelines. ANZ Obs Gyn. 2016;56:69-74. • Detection of 6. Stoll BJ, Hansen NI, Sanchez PJ, et al. Early onset neonatal sepsis: the burden of group B Streptococcal and E. coli disease continues. Pediatrics. 2011;127(5):817-826. Epi Strain(s) 7. Manual of Clinical Microbiology, 11th Edition. K.C. Carroll, G. Funke, J.H. Jorgen- son, M.L. Landry, S.S. Richter and D.W. Warnock. Editors In Chief: J.H Jorgensen, M.P. • Simple Pfaller. American Society for Microbiology Press. Washington DC, 2015. Sample Prep 8. Church D, Baxter H, Lloyd T, Miller B, Elsayed S. Evaluation of Strep B Carrot broth versus Lim broth for detection of group B Streptococcus colonization status of near- term pregnant women. J Clin Microbiol. 2008:46:2780-2782. • Flexible – 9. Tazi A, Reglier-Poupet H, Dautezac F, Raymond J, Poyart C. Comparative evaluation Test from 1 to 8 of Strepto B ID chromogenic medium and Granada media for the detection of group B Streptococcus from vaginal samples of pregnant women. J Microbiol Methods. samples per run 2008;73:263-265. 10. Nickmans S, Verhoye E, Boel A, Van Vaerenbergh K, De Beenhouwer H. Possible • Sample Prep Kit solution to the problem of nonhemolytic group B Streptococcus on Granada medium. J included Clin Microbiol. 2012;50:1132–1133. 11. Bourbeau P, Heiter B, Figdore M. Use of Gen-Probe Accuprobe Group B Strep- tococcus test to detect group B streptococci in broth cultures of Vaginal-Anorectal • Results in about specimens from pregnant women: Comparison with traditional culture method. J Clin an hour Microbiol. 1997;35:144-147. 12. Riedlinger J, Beqaj SH, Milish MA, et al. Multicenter evaluation of the BD Max GBS • CLIA Moderate assay for detection of group B streptococci in prenatal vaginal and rectal screening swab specimens from pregnant women. J Clin Microbiol. 2010;48:4239-4241. Complexity 13. Buchan, B, Faron M, Fuller D, Davis T, Mayne D, Ledeboer N. Multicenter clinical evaluation of the Xpert GBS LB assay for detection of group B Streptococcus in prena- • Easy to perform tal screening specimens. J Clin Microbiol. 2015;53:443-448. 14. Couturier BA, Weight T, Elmer H, Schlaberg R. Antepartum screening for group B • Direct Amplification Disc Streptococcus by three FDA-cleared molecular tests and effect of shortened enrichment culture on molecular detection rates. J Clin Microbiol. 2014 52(9):3429 –3432. 15. Miller S, Deak E, Humphries R. Comparison of the AmpliVue, BD Max System, Find out how we can help and illumigene molecular assays for detection of Group B Streptococcus in antenatal screening specimens. J Clin Microbiol. 2015;53(6):1938-1941. streamline your lab’s workflow and improve patient management.

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MLO201705_LabMgmt_BD_MECH_AL.indd 21 4/13/2017 7:59:55 AM LAB MANAGEMENT NEONATAL/PEDIATRIC DIAGNOSTICS Testing gaps remain in addressing GBS infections among infants By Anjana Bhattacharya, PhD, and Sherry Dunbar, PhD

ne of the biggest threats to neonatal health comes from Advocates of nucleic acid-based assays point to other benefi ts. group B Streptococcus (GBS), which is responsible for more Molecular tests also offer faster turnaround time than cultures do, Ocases of meningitis and sepsis during the fi rst week of an getting results back to physicians more quickly. While it is widely infant’s life than any other agent. In cases where mortality can be accepted that generating results is not urgent for antenatal GBS prevented, GBS can still lead to profound disabilities later in life. detection, it’s worth considering the peace of mind that faster re- The bacterium is commonly carried by healthy adults and can be sults can bring to anxious expectant mothers. Also, the workfl ows passed to newborns from their mothers during delivery. In some for these assays tend to be simpler to perform, with less room for countries, as many as four in 1,000 live births are affected by GBS.1 error and minimal hands-on time for laboratorians. For all these Improvements in detection—including better guidelines and reasons, more and more laboratories are transitioning their GBS the adoption of nucleic acid-based tests—have led to a signifi cant cultures to molecular assays. decrease in the incidence of GBS infections among newborns. In the United States, for example, routine screening of women Improvement needed around the 36th week of pregnancy has made it possible to de- Despite the success of screening programs, there are still many ar- tect the mother’s GBS colonization status ahead of time and treat eas where GBS detection can be improved—with many infants’ GBS-positive mothers with prophylactic antibiotics during labor lives to save along the way. The consistency of screening guide- and delivery. While this has dramatically reduced the number of lines is one such area. Recommendations vary by country or re- infants affected, statistics from the Centers for Disease Control and gion, and some countries have opted for no guidelines at all. In the Prevention (CDC) indicate that GBS remains the leading infectious United Kingdom, some experts believe the recent increase in the cause of morbidity and mortality in infants born in the U.S.2 incidence of GBS among infants can be attributed to the country’s There is still much room for improvement in GBS detection, na- lack of screening guidelines. Statistics from Public Health England tionally and globally. Many labs use culture tests rather than new- show a 12 percent increase in the number of babies affected by er, more accurate molecular tests. Guidelines for routine screening, GBS between 2011 and 2015.6 A recent clinical trial there screened such as the ones that have been successful in the U.S. and Can- 5,000 women; preliminary results indicated an 80 percent decrease ada, are still not used in some countries. Even where screening in neonatal GBS infections when this approach was used.7 guidelines are available, pregnant women without regular access Even in places where screening is routine, successful outcomes to healthcare are unlikely to get the benefi t of screening. Address- have not been evenly distributed. Racial disparities persist, and ing these gaps in GBS detection would have a signifi cant positive women without access to standard prenatal medical care typi- impact on the health of infants around the world. cally miss being screened.8 One recent study in the U.S. found that just 67 percent of mothers who delivered full-term babies and Screening guidelines 58 percent of mothers with preterm deliveries had been screened The effects of GBS infections among infants were not discovered for GBS.9 This suggests a real opportunity to improve education until fairly recently. In the 1970s and 1980s, researchers and clini- among patients and physicians about the importance of getting cians began showing that this bacterial strain was associated with tested during pregnancy. symptoms seen in affected babies. By the mid-1990s, enough re- Better testing could also make a difference in reducing the in- search and clinical studies had been conducted to convince major cidence of GBS among newborns. While CDC guidelines include medical groups that treating pregnant mothers and infants exhib- both culture and molecular assays for detecting GBS after initial iting early signs of sepsis with a preventive course of antibiotics enrichment, a lot of labs still use culture for that step despite strong for GBS would lead to better health outcomes. The American Col- evidence that molecular assays generate more reliable tests in less lege of Obstetricians and Gynecologists, the American Academy time. There is a lingering perception that culture-based tests are of Pediatrics, and the CDC all issued recommendations for this less expensive, but many lab directors who factor in the value of approach. their staff time have concluded that these laborious tests are more Within the past 15 years, these groups have updated their costly than they appear. If we could eliminate the false negatives guidelines to include universal screening for women at 35 to 37 associated with culture tests, we could get antibiotic treatment weeks of pregnancy. This program has been credited with the to mothers and babies in greatest need and lessen the number of dramatic reduction in infants suffering GBS infections in the deaths and disabilities caused by GBS infections. U.S., down 27 percent during just the few years following the introduction of universal screening.3 Moving forward Although GBS remains a signifi cant threat to newborn health, the Molecular tests good news is that there are still many levers to pull that can drive When screening programs were fi rst launched, culture-based test- infection rates down. With a renewed commitment to universal ing was considered the gold standard. More recently, however, screening and better education to get the word out to the medical several laboratories and diagnostic companies have developed community, lab directors, and the public, there is reason to hope nucleic acid-based tests, which offer a number of advantages. that early detection can make a real difference. And as labs adopt Repeated studies have shown that nucleic acid amplifi cation modern testing methods with increased sensitivity and specifi c- tests using enrichment protocols are far more sensitive than cul- ity, it will be possible to ensure that treatment is available for the ture-based tests, with at least one report demonstrating sensitivi- infants who are most likely to need it. ties greater than 90 percent for multiple commercially available REFERENCES GBS diagnostics, compared to less than 54 percent for culture test- 1. Marió MJS, Valenzuela I, Vásquez AE, Illanes SE. Prevention of early-onset neona- ing.4,5 In a high-stakes diagnosis such as GBS, getting a false nega- tal group B streptococcal disease. Rev Obstet Gynecol. 2013;6(2):63-68. tive could have dire consequences for the newborn, while a false 2. Verani J, McGee L, Schrag S. Prevention of perinatal group B streptococcal positive could lead to unnecessary antibiotic treatment. Clearly, it disease – revised guidelines from CDC, 2010. MMWR. 2010;59(RR10);1-32. 3. Phares CR, Lynfi eld R, Farley MM, et al. Epidemiology of invasive group B strep- is critical to get an accurate answer to provide optimal healthcare tococcal disease in the United States, 1999-2005. JAMA. 2008;299(17):2056-2065. for mother and child. doi:10.1001/jama.299.17.2056.

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4. Brown HL, Ahmadzia HK, Heine RP. GBS screening: an update on guidelines and Anjana Bhattacharya, PhD, serves as methods. Contemporary OB/GYN. July 1, 2013. Global Product Manager for Women’s 5. Miller SA, Deak E, Humphries R. Comparison of the AmpliVue, BD Max System, and illumigene molecular assays for detection of group B Streptococcus in antenatal Health at Luminex, which recently screening specimens. J Clin Microbiol. 2015;53(6):1938-1941. received FDA clearance for its new 6. Mortimer C. One baby dies every two weeks from a preventable infection in ARIES GBS assay. England. Independent. March 5, 2017. http://www.independent.co.uk/life-style/health- and-families/health-news/baby-health-nhs-infection-group-b-streptococcus-neonatal-care-sepsis-testing-a7611951.html. 7. London North West Healthcare NHS Trust. Pilot shows that screening mothers for Sherry Dunbar, PhD, serves as Senior group B strep (GBS) saves babies. London North West Healthcare NHS Trust. March Director of Global Scientifi c Affairs at 11, 2015. http://www.lnwh.nhs.uk/about-us/news-and-media/latest-news/pilot-shows- that-screening-mothers-for-group-b-strep-gbs-saves-babies/. Luminex. 8. Centers for Disease Control and Prevention. Trends in perinatal group B streptococcal disease — United States, 2000—2006. MMWR. 2009;58(05);109-112. 9. Stoll BJ, Hansen NI, Sánchez PJ, et al. Early onset neonatal sepsis: the burden of group B streptococcal and E. coli disease continues. Pediatrics. 2011;127(5):817-826. doi:10.1542/peds.2010-2217. Group B strep: questions and answers By Jennifer W. Sayers, MHA, MT(ASCP)

aising awareness of group B streptococcal disease (GBS) percent.2 Specimens that are enhanced in chromogenic broth or among pregnant women and women who are of child-bear- plated to chromogenic media present a similar challenge with re- Ring age is an important component in the effort to prevent gard to detection of non-hemolytic strains of GBS. Approximately a potentially fatal infection in neonates. Clinical laboratorians fi ve percent of human-colonizing GBS isolates are reported non- play an important role in educating patients about current testing hemolytic and non-pigmented.3 According to a 2009 study pub- methods—the centerpiece of the GBS awareness puzzle. lished in the New England Journal of Medicine,4 61.4 percent of term infants with GBS disease were born to women who tested nega- What is GBS? tive for GBS before delivery, and 99.5 percent of these mothers S. agalactiae or group B Streptococcus is a gram-positive bacteria were tested with traditional culture. commonly found in the gastrointestinal, genital, and urinary tract of healthy adults. Approximately 25 percent of all pregnant What role can NAAT play? women are colonized with GBS. While colonized mothers typi- The limitation of culture is but one aspect of the problem. In addi- cally show no symptoms or adverse health effects, the bacteria can tion, suboptimal specimen collection methods and/or lower levels be passed to their children during labor and delivery. The fatality of colonization may be contributing to false negative results. For rate for infants with early-onset GBS disease is currently estimated this reason, the most sensitive assay should be used to optimize re- at four percent to six percent. Surviving infants may experience sults. Nucleic acid amplifi cation testing (NAAT) may be benefi cial long-term disabilities including hearing loss, vision loss, or mental in confi rming true positives in women with lower levels of GBS in retardation. If detected, transmission of GBS can be prevented by the collected specimen. Testing via NAAT removes the subjectivity administration of antibiotic prophylaxis prior to delivery. from culture testing and provides a greater level of confi dence in test reports. What do the guidelines say about testing? The ramifi cations of not detecting group B Streptococcus in a The Centers for Disease Control and Prevention (CDC) recom- pregnant mother can be devastating. Testing with a molecular mends that all pregnant women between 35 and 37 weeks gesta- assay can protect newborns from suffering serious GBS-related tion be tested for GBS.1 Women who test positive should be given complications. Early-onset GBS infection in neonates is a grave, prophylactic antibiotics during labor, which will usually prevent yet preventable, disease. NAAT can serve a crucial role as a con- transmission to the infant. GBS colonization status should be defi rmatory test for positive cultures. Many laboratory leaders are termined by collecting both vaginal and rectal specimens at 35 currently reviewing their current testing protocols and making to 37 weeks. A single combined vaginal-rectal specimen can be changes as necessary. collected if preferred. By the way, Group B Streptococcus Awareness Month is just around the corner—it’s July. Why not plan an awareness event for What is the traditional way to detect GBS? lab staff, the larger institution, or the community! Detection of GBS may be accomplished using various testing algorithms, media, and methodologies. Direct plating has a lower REFERENCES sensitivity than enriched culture and should not be used as a sole 1. Department of Health and Human Services, Centers for Disease Control and Pre- means of isolation and identifi cation. To maximize the recovery of vention. Prevention of perinatal group B streptococcal disease, revised guidelines from GBS, all specimens should undergo an 18-to-24-hour incubation at CDC, 2010. MMWR. 2010:59. 35° to 37°C in an appropriate enrichment broth medium, such as 2. Rallu F, Barriga P, Scrivo C, Martel-Laferrière V, Laferrière C. Sensitivities of antigen detection and PCR assays greatly increased compared to that of the standard culture carrot or Lim broth. method for screening for group B Streptococcus carriage in pregnant woman. J Clin The traditional method of testing is to inoculate an enrichment Microbiol. 44(3) 725-728. broth with the vaginal-rectal swab sample and plate the incubated 3. Rodriguez-Granger J, Spellerberg B, Asam D, Rosa-Fraile M. Non-haemolytic and enriched broth on a blood agar plate (BAP). The BAP is incubated non-pigmented group B Streptococcus, an infrequent cause of early onset neonatal and examined for growth of beta-hemolytic colonies. Suspicious sepsis. FEMS Pathogens and Disease. 2015;73(9);1-3. 4. Van Dyke M, Phares C, Lynfi eld R, et al. Evaluation of universal antenatal screening colonies are sub-cultured and tested by latex agglutination for for group B Streptoccoccus. NEJM. 2009;360:2626-2636. identifi cation. This method presents challenges. There are strains of GBS that are non-hemolytic. These strains mimic the appearance of Jennifer W. Sayers, MHA, MT(ASCP), serves as a product enterococcus and can be easily overlooked when reading plates. manager for Cincinnati, Ohio-based Meridian Bioscience. Studies have shown that sensitivity of culture can be as low as 42

MAY 2017 MLO-ONLINE.COM 23

MLO201705_LabMgmt_Luminex_Meridian-COMBO_MECH_AL.indd 23 4/13/2017 11:19:14 AM MANAGEMENT MATTERS

Building an effective PPE program By John Ross

n the public mind, fed by disaster movies and paper- Administration (OSHA) and Clinical Laboratory back techno-thrillers I suppose, the idea of dangerous Improvement Amendments (CLIA). The insight and con- I “lab accidents” is probably still most associated with clusions drawn from this research will contribute to de- research labs—and indeed, the possibility of contamina- termining the specifi c items appropriate for inclusion in tion by infectious agents involved in research is a con- the program, such as lab coats, masks, gloves, and safety tinuous concern for leaders of such labs. But clinical lab goggles. directors have always known that the issue is highly rel- An essential component of PPE that should not be evant to their operations as well. It has ever been thus, overlooked is the fi t and feel of each product. This is es- even before Ebola and Zika, even before HIV. Laboratori- pecially important because PPE that fi ts poorly can con- ans have always needed to take precautions against being tribute to additional safety hazards. Uncomfortable or ill- exposed to dangerous organisms via the serum samples fi tting protective clothing can become neglected, unused they collect and analyze. protection that wearers opt to alter or forgo. Even roll- Despite all of those efforts, ing up the sleeves of a lab coat each year hundreds of accidents or temporarily removing a mask occur in laboratories across the can have signifi cant safety con- world. It would be wrong to sequences, so it is essential for say that all incidents can be pre- PPE to be comfortable enough vented if proper precautions are that it is worn properly. Addi- taken. However, implementing tionally, PPE that doesn’t fi t well appropriate safety measures and can contribute additional safety adhering to a well-structured hazards to the lab environment. personal protective equipment For instance, a lab coat that is too (PPE) program can reduce expo- large can easily get caught on or sures to infectious material and dragged through something, in- improve overall safety condi- creasing the likelihood of spills, tions in clinical laboratories. trips, and falls. To ensure the No laboratory is immune to proper fi t, PPE that is available the risk of an accident occur- in multiple sizes or styles should ring. In clinical laboratories, be assigned and fi tted on an laboratory-acquired infections individual basis. (LAIs) are a particularly signifi - cant concern. LAIs can happen Implementation and training as a result of inhalation or inges- It is also necessary for PPE pro- tion, percutaneous inoculation, grams to be built with imple- and direct contact with samples mentation and long-term ef- or with contaminated surfaces— fectiveness in mind. Programs all of which can be minimized must be developed to facilitate through the use of proper PPE. consistency and longevity, while providing staff—both new em- Components of an effective Photo courtesy of Halyard Health ployees and veterans—the op- program portunity to be properly and An effective PPE program takes into account the follow- effi ciently trained. Training procedures should be estab- ing considerations: compliance with standards, appro- lished to properly implement the program and ensure priate types of protection to address potential hazards, that each individual understands the importance of PPE, the comfort and fi t of each (wearable) item, quality of as well as how to use it correctly. A variety of training products, convenience and ease of ordering the necessary resources can be made available. Examples include video equipment, proper training procedures for wearers, and tutorials, pamphlets and brochures, and hands-on prac- long-term effectiveness of the program. tice with various protective products. Ongoing, regularly In order to best assess the types of protection a PPE scheduled meetings and training sessions can also be program should provide, a thorough analysis of the very benefi cial in reinforcing the importance and proper potential hazards should be performed. Additionally, use of PPE. it is important to review and adhere to the safety re- To provide long-lasting PPE, laboratories need to prior- quirements provided by regulatory agencies and docu- itize investing in high-quality items that are built for du- mentation, such as the Occupational Safety & Health rability and guaranteed to retain their protective qualities continued on page 26 24 MLO-ONLINE.COM MAY 2017

MLO201705_MgmtMatters_MECH_AL.indd 24 4/13/2017 9:21:35 AM Untitled-4 25 4/13/2017 9:54:26 AM MANAGEMENT MATTERS

continued from page 24

over time. Inspections A culture of safety should be conducted A laboratory accident can happen in an instant, but the regularly to assess effects may last forever. PPE programs are an important damage and autho- component in laboratory safety that—when properly de- rize repairs or replace- veloped and implemented—help prevent unnecessary ments as needed. tragedies. The effectiveness of a PPE program can be One game-changing optimized through a thorough hazard assessment, com- factor in the landscape pliance with all applicable regulations, prioritization of of PPE programs is the comfort and fi t, and consideration of long-term sustain- ever-evolving technol- ability. With a responsible PPE program in place, labora- ogy that many laboratory administrators are helping to create an environment tories are starting to that fosters effi ciency as well as optimal patient care. utilize for implementation. For example, the option to work with PPE suppliers to John Ross is president and CEO of Photo courtesy of Key Surgical develop customized Mission Linen Supply, a single-source provider of rental and direct-sale online stores has streamlined and simplifi ed the order- uniforms, linens, and other essentials ing process, creating a convenience not associated with for laboratories, industrial businesses, PPE program implementation in the past. The stores can corporations, and the healthcare and be populated with preselected products that meet each hospitality industries. With more than organization’s specifi c preferences and safety require- 16 years of experience in uniform program implementation and workplace health and ments. This technology also allows fl exibility and fast safety, John’s expertise helps ensure the success of turnaround in response to ongoing needs and changes, PPE programs that Mission develops. allowing lab leaders to update equipment as needed.

26 MLO-ONLINE.COM MAY 2017

MLO201705_MgmtMatters_MECH_AL.indd 26 4/13/2017 9:21:50 AM TAP INTO BIO-RAD MOLECULAR CONTROLS. IMPROVE ANALYTICAL PERFORMANCE AND PATIENT CARE.

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MLO201705_AD BioRad_220281.indd 27 4/11/2017 8:53:51 AM EDUCATION MOLECULAR/MICROBIOLOGY

Microbiology, molecular, MALDI-TOF or all of the above? By Richard Cleveland and Amanda Schmidt

hile hematology and clinical Automated blood culturing, anti- cultured organisms, although less chemistry labs were automated microbial susceptibility testing (AST), growth is often acceptable for identi- Wmany years ago, the microbiol- and MALDI-TOF systems lead to more fi cation by mass spectrometry than ogy lab is still largely a hands-on pro- accurate and faster results, with less is required for standard biochemical cess. In part, this refl ects the complex- wasted materials and tech time. Mass techniques. ity of microbiology. There are hundreds spectrometry has a simple sample of infectious pathogens, including preparation process and generally re- A holistic approach bacteria, viruses, fungi, and parasites. quires a smaller amount of culture A new generation of pre-analytical sys- In order to properly diagnose these growth for identifi cation. MALDI-TOF tems that require very little interaction pathogens, they have to be cultured, so generates high throughput of dozens of and improve error rates and ineffi cien- the lab has enough of the pathogen to pathogens per run. Automated ID/AST cies holds the promise of maximizing identify it via a litany of biochemical provides a broad range of Gram- the benefi ts of the new analytical sys- tests. Because all of these bugs are so negative AST cards, and, in some cases, tems and creating a new holistic sys- different, some take just hours to grow, three-drug yeast susceptibility testing tem—from sample collection to results while certain fungal infections can take on a single card with results in under reporting— that is more than the sum weeks. Some bacteria are aerobic, while eight hours. Multiplexing PCR systems of its many parts. others are anaerobic. All have ideal have evolved from identifying a single Sometimes called “walk-away” growth media to foster optimal growth. organism to identifying groups of bac- specimen pre-analytical processing These “pre-analytical” considerations teria, viruses, and yeast that often lead systems, these new tools include a new are vital to rapid identifi cation. In to certain conditions such as sepsis, all generation of automated plate streak- other words, the microbiology lab is as in one run lasting less than 60 minutes. ers, Gram slide preparation, enrich- complex as microbiology. No two cases Some systems can also identify se- ment broth inoculation, and newer are exactly the same, so automating quences of nucleotides that are unique tools including the digital imaging and the microbiology lab is a much more to dominant types of antibiotic resis- magnifi cation of growth colonies that diffi cult challenge. tance, such as methicillin, vancomycin, reduce the time required to identify and carbapenem resistance. Such fea- bacterial growth. This feature, in par- Molecular and MALDI-TOF tures can speed up treatment decisions ticular, could prove to be very synergis- The newest technologies in the mi- and may be able to facilitate targeted tic with MALDI-TOF systems, which crobiology lab hold the potential to therapy sooner. generally require less growth for posi- solve many of these problems. Mo- However, molecular and MALDI-TOF tive identifi cation. The microbiology lecular techniques can generate results are still held hostage to the pre-analyti- lab is on the brink of complete auto- and positive identifi cations remark- cal steps and delays. PCR techniques— mation that encompasses all aspects of ably quickly; so can Matrix-Assisted even multiplexing techniques that specimen processing and management, Laser Desorption Ionization-Time of search for likely pathogenic suspects incubation, digital colony selection, Flight (MALDI-TOF) mass spectrom- based on the “syndromic” symptoms and software to assist laboratorians in etry, which is having a signifi cant of the patient—still must wait for cul- analysis and results reporting. Some impact on clinical microbiology. turing. Likewise, MALDI-TOF requires full lab automation systems include algorithms and artifi cial intelligence that automatically read, interpret, and segregate bacterial cultures. Rapid and robust pre-analytics are vital to maximizing the benefi ts of the new identifi cation systems that have changed the face of the microbiology lab over the last decade. These benefi ts can be lost if the culture process is slow, ineffi cient, or prone to errors. Think of it this way: a best-in-class automobile designed for luxury, speed, and fuel effi ciency is useless on a road riddled with sink holes, water damage, and debris. So it’s vital to pair cutting-edge diagnostic technology with cutting- edge pre-analytical processes and Figure 1 technologies. continued on page 30 28 MLO-ONLINE.COM MAY 2017

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continued from page 28

New tools are also helping to bring For example, the manual streaking thickness. In Figure 1 (page 28), for ex- new effi ciencies to the identifi cation and incubation processes should be ample, the resulting usable image of process by assisting in the steps re- automated and standardized by auto- this plate is 27 megapixels, which al- quired for identifi cation. For example, mated plate streaking systems and an lows for the visualization of colonies a laser trace tool can help lab staff se- innovative incubation which includes even smaller than 0.1. This larger-than- lect the precise growth cluster identi- a growing list of automated features. life image can help techs detect growth fi ed on a digital image. This cluster Digital imaging and analysis can re- invisible to the naked eye on the actual may be so small that fi nding and select- duce the time needed to identify bac- plate. After a set time, fi le images are ing it manually is a major challenge. terial growth. These instruments can compressed for storage. However, by using a laser trace, pin- integrate with a lab’s automated blood Lab imaging systems should capture pointing the optimal clusters should culturing and antibiotic susceptibil- high resolution images of plates be- be much easier, which, in turn, allows ity testing. And algorithms and arti- fore incubation to automatically iden- for optimal MALDI-TOF identifi cation. fi cial intelligence automatically read, tify and eliminate any existing artifact. Artifi cial intelligence and reading algo- interpret, and segregate plates. Such This high-resolution image approach rithms can integrate with chromogenic systems hold the potential to move for differential image analysis is a re- culture media to automatically detect current laboratories to the digital mi- liable warranty for accurate pathogen the color change that indicates positive crobiology era through high-resolu- growth detection. Other key features growth. Plates that are negative can tion culture plate imaging, improving should include high-throughput read- be automatically discarded by the sys- speed, interpretation, reliability, and ing and the ability to quickly discard tem, while those that are positive are accessibility of results. negative plates. This allows staff to expedited for susceptibility testing. The ideal image acquisition technol- focus on critical positive samples ogy should provide highly sophisti- quickly and frees highly experienced Creating synergies cated lighting and a camera system to laboratorians to do high-value work. The ideal marriage between pre-analyt- make each plate image clear and accu- No two microbiology labs are the ic automation and new identifi cation rate—just like using a plate microscope same. Ultimately, each must make techniques should enable the automat- with every plate, so lab staff can reli- choices that signifi cantly enhance its ic processing of a sample during many ably make accurate work-up decisions. operational effi ciency, compensate for of the steps inherent to microbiological The lab camera optics should provide the growing shortage of specialized analysis. clear colony views, no matter the agar staff, and obtain the accreditation it needs to operate. This can be accomplished by streamlining workfl ows while delivering faster and more standardized results and improving traceability of analyses. The key for all labs is to fi nd open, fully automated, modular and fl exible diagnostic solutions that fi t the unique needs of the lab and its patient population.

Richard Cleveland serves as Sr. Marketing Manager, U.S. Clinical Laboratory Optimiza- tion, for bioMerieux, Inc., provider of the VIRTUO and VITEK automated microbial identifi cation systems.

Amanda Schmidt serves as Marketing Manager, COPAN Diagnostics, provider of the WASP DT and WASPLab microbiology specimen processors.

In 2015, bioMerieux and COPAN began a partnership for integrating pre-analytic automation with various culturing and identifi cation technologies. In January 2017, the COPAN-bioMerieux offering became available in the U.S.

30 MLO-ONLINE.COM MAY 2017

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Sources: 1. Faron, M. L., Buchan, B. W., Coon, C., Liebregts, T., Bree, A. V., Jansz, A. R., . . . Ledeboer, N. A. (2016). Automatic Digital Analysis of Chromogenic Media for Vancomycin-Resistant-Enterococcus Screens Using Copan WASPLab. Journal of Clinical Microbiology, 54(10), 2464-2469. doi:10.1128/jcm.01040-16 2. Faron ML, Buchan BW, Vismara C, Lacchini C, Bielli A, Gesu G, Liebregts T, van Bree A, Jansz A, Soucy G, Korver J, Ledeboer NA. 2016. Automated scoring of chromogenic media for detection of methicillin- resistant Staphylococcus aureus by use of WASPLab image analysis software. J Clin Microbiol 54:620 –624. doi:10.1128/JCM.02778-15. 3. Kirn TJ. 2016. Automatic digital plate reading for surveillance cultures. J Clin Microbiol 54:2424-2426. doi:10.1128/JCM.01279-16. 4. Three scientific studies to be presented at ASM Microbe 2017.

MLO201705_AD Copan.indd 31 4/11/2017 8:54:53 AM A GUIDE TO MOLECULAR DIAGNOSTICS

Back to Basics: RNA molecular diagnostics By John Brunstein, PhD

hile much of molecular diagnos- independent of any informational content gene expression. A shortcoming of DNA- tics (MDx) deals with deoxy- carried purely on a nucleotide-sequence based MDx in ID can be that it doesn’t Wribonucleic acid (DNA) as its basis. differentiate between viable organisms target material, this month’s “Back to Ba- and leftover unviable remnants; because sics” Primer topic will pause to consider Why do RNA MDx? of RNA’s much lower stability (discussed “the other nucleic acid,” ribonucleic acid If all living organisms use DNA as their ge- further below), RNA-based assays can be (RNA): why it can be the target of choice netic storage material, it’s tempting to ask a more direct indication of ongoing infec- or even necessity for some MDx methods, why would we be interested in looking at tion than their DNA counterparts. This and what some of the general challenges RNA at all? A fi rst answer is that it’s some- data may even directly relate to probable are in handling RNA in the lab. what disingenuous to only consider strictly pathogenicity, such as in the example of First, a quick refresher on the chemical living organisms as being clinically signifi - HPV; evidence suggests that even among difference between RNA and DNA. In ei- cant. Viruses do not count as living, yet it is infections with known high-risk geno- ther case, a nucleotide—the building block an understatement to say that many are of types, active expression of the E6 and for a nucleic acid strand—consists of a ni- clinical importance—and many viruses are E7 genes is a more likely indicator of trogenous base, a sugar, and phosphate(s). not only RN-based but never go through a progression to signifi cant disease than is The critical difference is in the sugar, DNA stage in their replication cycle. A fi rst mere presence of intact but transcription- where RNA has a 2’ –OH group not found key reason for RNA-based MDx methods, ally inactive virus. in DNA (Figure 1). It is this missing piece then, is to detect these types of pathogens. This concept of examining RNA as a that leads to the “D” in DNA’s name— If we stay within the infectious diseases window into transcriptional activity is Deoxyribonucleic acid. There’s also a dif- (ID) context for the moment, there can also how RNA-based diagnostics comes ference in that, while the bases adenine, also be benefi ts to choosing RNA as our into use outside of the ID fi eld. Genetic guanine, and cytosine are common to both target material even in living, DNA-based diseases arising through dysregulation RNA and DNA, the DNA base thymine is organisms. One such reason is that by na- (over- or under-expression) of a gene substituted by uracil in RNA. Base pairing ture, with a single DNA gene copy being aren’t distinguishable by traditional rules, however, are the same, and this base potentially transcribed hundreds or even DNA-based MDx, particularly in ex- difference isn’t generally a conceptually thousands of times, we may be able to ef- amples where no variation in gene copy signifi cant concept. fectively increase our detection thresholds has occurred but may be readily dis- On a macrostructural level, a more sig- by an equivalent amount; that is, testing tinguished by RNA-based quantitative nifi cant difference between DNA and RNA for the expressed RNA of a characteris- methods such as real-time quantitative is that RNA is generally a single-stranded tic gene marker may allow for the use of reverse transcription polymerase chain macromolecule, while DNA is double- smaller samples and/or the detection of an reaction (qRT-PCR) or RNA gene expres- stranded. This allows much more strand organism at much lower levels than direct sion arrays. In addition to permanent fl exibility than DNA has, and lRNA will DNA-based MDx. genetic changes such as promoter activa- take advantage of this to frequently fold A second reason is an extension of this, tion or inactivation, these methods can back on itself and pair self-complementary in which we consider that RNA is a mark- also be employed to capture information regions in various stem-loop confi gura- er for not just gene (and thus organism) on transient variations in gene expres- tions. These structures can have specifi c presence but more specifi cally for its bio- sion related to pathologic processes such functional purposes in an RNA molecule, logical activity as evidenced by ongoing as immunological responses. O O

O O CH3 NH NH HrO - P - O lllO - P - O N O N O O O OH OH

OH OH OH

Uridylate RNA Thymidilate DNA

Figure 1. Differences between DNA and RNA are loss of the sugar 2’ -OH in DNA, and the use of the bases uracil in RNA in place of thymine in DNA. Differences are circled.

32 MLO-ONLINE.COM MAY 2017

MLO201705_Primer_FINAL.indd 32 4/13/2017 11:47:03 AM A GUIDE TO MOLECULAR DIAGNOSTICS THE PRIMER

Why not do only RNA MDx? so prepared. Use of personal protective option is pre-treatment of the RT step We have established above that in some equipment (PPE), already essential for template material with DNase enzymes. cases RNA is the only possible MDx target, protection of staff from materials being If this approach is taken, it is important while in others it offers advantages in sen- handled, gains an additional level of ur- that the DNase be of high purity (no sitivity or insight to gene/organism activ- gency in handling of RNA samples, where RNase contaminant) and that it be used ity over DNA targets. With all of these fea- it must also protect the specimen from the under conditions which do not lend tures in its favor, our question now is not staff. Similarly, many labs will enact prac- themselves to side RNA-degrading ac- “Why do RNA MDx?”—but rather, “Why tices such as keeping designated pipettor tivity. In the case where the target RNA do DNA MDx when we could do RNA?” sets for RNA work. With these mitigations is from a eukaryotic organism, a simpler Much of the answer to that comes back in place to ensure template stability, we solution may sometimes be available by to the existence of that 2’ –OH group in can now consider some of the mechanistic selecting PCR primers from different ex- RNA and its impacts on molecular stabil- changes needed in performing MDx work ons, such that they are close together in ity. In the simplest summary, this “extra” on RNA templates. an RNA transcript and readily amplifi ed hydroxyl group relative to DNA makes but separated by large intron(s) on the RNA much less chemically stable than MDx on RNA templates genomic DNA. The genomic DNA target DNA by virtue of its being prone to hydro- To a fi rst approximation, any PCR-based will then fail to amplify, and only spliced lytic cleavage events along the sugar-phos- assay intended for use on a specifi c DNA RNA will yield product. phate backbone. This intrinsic lower chem- target can be modifi ed to work on its RNA In conclusion, I hope the reader will ical stability of RNA is vastly accentuated transcript by addition of a single prelimi- appreciate how RNA can be a valuable by the pervasive prevalence of RNases— nary stage to the existing PCR protocol. or even essential target for MDx applica- enzymes dedicated to the degradation of This fi rst stage utilizes a retrovirally de- tions, but its use requires additional steps RNA molecules. In fact, from a biological rived enzyme known as a reverse tran- and complexities. This ensures that it perspective this enforced instability of scriptase (RT), which as the name suggests won’t supplant DNA as target of choice in RNA is, as people in the software world takes an RNA transcript and converts it all applications. would say, “a feature, not a bug!” back to a single conjugate DNA strand. One fi nal bit of interesting related in- Consider that a cell reacting to local en- This reverse transcription activity initi- formation: recall from above that one base vironmental cues wants to alter its activi- ates at a section of the RNA hybridized in RNA (uracil) is functionally replaced ties in response, and in many cases does so to a primer, allowing, for example, one of by another in DNA (thymine). The dif- by altering (up- or down-regulating) tran- the pre-existing PCR primers to perform ference between these bases is a single scription of one or more relevant genes. this function and direct reverse transcrip- methyl (-CH3) group present on thymine For this sort of environmental response tase activity to region of interest. but absent in uracil. This methyl group is to be dynamic, a rapid turnover of RNA While it is possible to perform a stand- not signifi cant from a chemical reactivity transcripts is essential so that increases or alone reverse transcription reaction and standpoint, so what is its biological use? decreases in RNA transcription actually then manually use the products of this as The answer to this comes in realizing that relate within a reasonable time period to a template for a second PCR reaction, the uracil is also structurally similar to the increases or decreases of the steady-state additional handling steps and potential other DNA pyridine, cytosine, having an level of the transcript (and thus either its for contamination inherent in such a two- exocyclic oxygen where cytosine has an direct function or its capacity to drive step process make it undesirable in a clini- amine (-NH2). It turns out that a very com- protein translation, for a coding mRNA). cal lab setting. While it is less likely to be mon form of DNA mutation can arise due RNA, then, is a great template when you ideally optimized for maximal sensitivity, to spontaneous hydrolytic deamination of can get it intact, but ensuring that this is a combined reaction mixture containing cytosine, where its amine is displaced by done is quite a lot more challenging than both PCR and RT reagents is more prac- an oxygen—in fact turning it into a uracil. in obtaining intact DNA. tical. In this context, the most common If this were not detected, during the next In order to be able to handle RNA in the approach involves an initial lower-tem- DNA replication cycle the base added to laboratory, it is important to take steps to perature reaction phase generally around the nascent strand at this point would be mitigate these stability issues. Intrinsic 42°C for 15 to 30 minutes that provides an adenine (A-U base pair, equivalent to an chemical instability is addressed through the RT step, followed by a high-temper- A-T base pair) instead of the correct gua- use of carefully pH-adjusted sample buf- ature step for a few minutes to deactivate nine (originally pre-mutation paired to the fers (readily done, and usually done for the RT enzyme and trigger function of a cytosine). By having thymine residues car- DNA as well, although it’s not quite as heat-activated PCR polymerase, followed ry a methy group “fl ag,” as it were, DNA essential). Where sample handling and by regular PCR thermocycling. Within repair machinery in the cell can detect any storage needs begin to diverge from those this outline, PCR variations such as real- uracils present as being “wrong” and trig- of DNA are in long-term storage, where time techniques, touchdown or thermal ger a DNA repair mechanism which excis- -80°C is recommended for RNA while gradient steps, and the like can all be per- es the uracil and replaces it with a correct -20°C is often suffi cient for DNA. (Lest formed as they would be on a plain DNA cytosine before the mutation can be fi xed anyone panic, short-term storage of RNA template. in the genome. samples at -20°C is generally fi ne). In some contexts, additional consider- More important are steps taken to inac- ations of the underlying biology remain tivate RNases that are lurking everywhere. useful—particularly if the goal is to spe- John Brunstein, PhD, is This involves steps such as ensuring all cifi cally detect RNA such as an actively a member of the MLO reagents are RNase activity-free but, as produced transcript distinct from its Editorial Advisory Board. He serves as RNase enzymes are remarkably robust, DNA gene of origin. From the description President and Chief simple autoclaving of reagents will not of an RT-PCR assay above, it’s possible to Science Offi cer for suffi ce, and this is generally done in-house imagine how either an RNA or DNA copy British Columbia-based through use of specifi c chemical inactiva- of the region fl anked by the PCR primers PathoID, Inc., which tors and/or inhibitors of RNases. Many could be amplifi ed. If it’s critical to know provides consulting for development and reagents can also be purchased (at a pre- that a resulting positive signal (ampli- validation of molecular assays. mium) as intended for RNA use and arrive con) can only be RNA-derived, then one

MAY 2017 MLO-ONLINE.COM 33

MLO201705_Primer_MECH_AL.indd 33 4/12/2017 4:30:52 PM CLINICAL ISSUES FLOW CYTOMETRY

Flow cytometry advances in the clinical and military arenas By MSgt Samantha Kunzelman, MT(ASCP), and SSgt Jillian A. N. Salazar

low cytometry is so widely used nowadays for particle, tissue, and cellular research/analysis that F we can almost take it for granted. We may also take for granted how much fl ow cytometry has improved over the years. Clinical laboratorians can analyze almost anything about generations of cells provided that they have the proper kits and reagents to do so. And the military has taken notice of this “analyze almost anything” aspect of fl ow cytometry, and has applied its use in military bio-detection and medicine models. Flow cytometry was originally known as pulse cyto- photometry.1 The name was introduced in 1976, about eight years after the patent was issued on this new kind of technology. In fl ow cytometry, particles are measured utilizing liquid and lasers on all types of cellular samples. The measured data found from particles passes through a liquid solution, and then impedance, along with fl uores- Basic fl ow cytometer cence, stains the different components of the cells. The particles are suspended in a liquid and pass through a funnel, Additionally, leukocytes include neutrophils, lympho- where a laser tags them for identifi cation purposes. The cytes, eosinophils, and basophils, among other compo- light that passes through the particle is detected and deter- nents. These leukocytes sometimes are detected in earlier mines the identifying factors for each particle measured.2 stages of development, depending on the medical criteria These identifi ed components help to identify characteris- and patient status. Flow cytometry is an excellent tool tics which are then used to diagnose specifi c diseases and in identifying those earlier cells within the patient blood disorders. (The beginnings of this methodology actually sample. Microscopic examination enables the laboratorian go back further; they originated with Wallace H. Coulter’s to view and catalog the earlier cells. However, the use of patented “Means for counting particles suspended in a fl ow cytometry both as a standalone and as a component fl uid,” back in 1953.) of a more comprehensive laboratory analyzer allows laboratory staff to identify underdeveloped cells within a pa- Clinical and research applications tient’s bloodstream. This enables clinicians to rule out or in Thanks to fl ow cytometry, we have been able to diagnosis multiple medical conditions. In addition, if a patient has a more than 300 genetic disorders. Genetic disorders affect bone marrow disease that generates more promyelocytes different components of the immune system and are patho- or other earlier-stage cells, fl ow cytometry has proven to logically, clinically, and immunologically heterogeneous. be benefi cial in measurement of these cells due to their size The advancement of genomics has enabled the discovery and constituents. of 10 to 15 new genetic defects every year. The procedure Flow cytometry is also used frequently in medical re- is essential to analyze the immune system, quantitatively search, as it enables tracking of cell generations depend- and functionally, to validate new genetic fi ndings and pro- ing on the study and research focus. It is increasingly be- vide accurate laboratory data to immunologists. Patients’ ing used to further specifi c research goals and projects, clinical symptoms do not always follow the textbooks to among them stem cell research. Stem cell monitoring is fre- direct doctors to a single genetic defect, and fl ow cytom- quently used in modeling of therapeutic drugs, and fl ow etry is key in providing this vital information. It is used to cytometry is also used for tracking stem cells. assess protein expression, cell viability, apoptosis, cellular interactions, and cell enrichment. All that analytical data Military applications aids immunologists in diagnosing genetic disorders and Within the last decade, fl ow cytometry has been utilized in making feasible prognoses. bio-detection for the military, in response to a threat whose Blood cells, both red cells and leukocytes, are traced true magnitude may have come to be broadly understood back to a lineage, or early developmental stages. For exam- only during the Gulf War era and since. Flow cytome- ple, monocytes are “bone marrow-derived leukocytes.”3 try is utilized in the U.S. Department of Defense’s BIDS

continued on page 36 34 MLO-ONLINE.COM MAY 2017

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(Biological Integrated Detection System), its standardized REFERENCES bio-agent threat matrix. This system uses a one to 10 um 1. Barlogie B, Drewinko B, Johnston DA, Buchner T, Hauss WH, Freireich EJ. Pulse collection sample size, which is the typical size of most cytophotometric analysis of synchronized cells in vitro. Cancer Research. 1976;36:1176- 1181. bio-warfare agents. With the addition of fl ow cytometry 2. Kachel V, Messerschmidt R, Hummel P. Eight-parameter PC-AT based fl ow cytomet- to BIDS, soldiers, sailors and airmen are able to detect and ric data system. Cytometry. 1990;11:805-812. possibly identify a bio-warfare attack before it develops 3. Ziegler-Heitbrock L. Blood monocytes and their subsets: established features and into a potentially serious situation. open questions. Frontiers in Immunology. 2015;Aug 17. doi: 10.3389/fi mmu.2015.00423. Military personnel have been sent to almost every corner 4. Portable fl ow cytometer by Handyem. BioOptics World. 7.16.12. http://www.bioop- ticsworld.com/articles/2012/07/portable-fl ow-cytometer-by-handyem.html. of the Earth, and a variety of medical conditions can occur as a result of those deployments. The use of fl ow cytometry in these cases may alleviate issues specifi c to military members in modern combat due to its regenerative and supportive roles. Advances in fl ow cytometry have included portable and hand-held fl ow cytometers4 utilized by MSgt Samantha Kunzelman, both civilian and military laboratories. These fl ow cytom- MT(ASCP), serves at the 88th eters are starting to make their way into clinical settings, Diagnostics & Therapeutics Squadron, 88th Medical Group, Wright Patterson enabling the laboratory to increase its footprint within the AFB, OH. clinics in addition to its typical laboratory space. That is a good example of the cross-pollination that is going on between clinical and military applications of fl ow cytometry. What is being learned in the military context is SSgt Jillian A.N. Salazar serves at the 88th Diagnostics & Therapeutics making its way back to the clinical laboratory. By enabling Squadron, 88th Medical Group, 88th tracking of cell development within patient bloodstreams Air Base Wing, Wright Patterson AFB, as well as its position in military research, fl ow cytometry OH. has become a critical addition to the laboratory arsenal. As that arsenal increases, fl ow cytometry is an increasingly important piece of the diagnostic puzzle.

36 MLO-ONLINE.COM MAY 2017

MLO201705_ClinicalIssues_MECH_AL.indd 36 4/13/2017 9:25:05 AM MLO201705_AD MichiganState.indd 37 4/11/2017 8:56:31 AM FUTURE BUZZ BIOINFORMATICS The future state of informatics and the clinical lab Changing the utility of information through cloud-based innovation and remote access By Wido Menhardt, PhD

aboratory professionals at all lev- that use advanced cloud-based innova- minimum. Offering laboratory work- els face a growing number of pres- tion and remote-access capabilities to ers the ability to monitor multiple net- Lsures, as the healthcare landscape connect laboratory professionals to the worked instruments remotely in real continues to evolve. The shift from fee- right data at the right time. These new time from a single workstation may to value-based services, for example, clinical information management tools provide a more robust view of labora- leaves decision-makers asking how best are intended not only to make infor- tory activities, facilitate fast decision- to support the increasing need for care mation more actionable and empower making, and save time. Laboratory staff that is proactive, patient-oriented and more confi dent decision-making for the members gain a big-picture perspective outcome-focused. Laboratory consoli- laboratory professional, clinician, and of what is happening throughout the dations place added burden on manag- patient, but also to yield laboratory effi - lab, using a single view. This remote-ac- ers to track consistency and maintain ciencies, improve customer service, and cess capability is intended to help labo- operations for individual laboratories promote better patient care. ratories increase productivity and better and networks, at large. These, along manage personnel shortages. with the drive to produce more timely Streamlining inventory results with fewer resources in highly management Proactive system service cost-conscious environments, push per- One highly time-consuming function Potential system issues threaten labo- sonnel to search for solutions that may of any laboratory is inventory man- ratory performance and can result in help them to: agement. Ineffi ciencies in controlling downtime. Finding possible disruptions • Improve laboratory effi ciencies inventory can cause disruptions to before they become threats is key to • Provide insights into operations across operations, jeopardizing the labora- keeping laboratory operations running networks tory’s ability to produce results in a smoothly and consistently. This is driv- • Produce a more robust understanding of timely manner and causing unplanned ing providers to offer a proactive service business performance. costs. This is exacerbated when mul- approach through both remote and on- Propelled by the desire to address tiple sites within a network are affected. site troubleshooting. The ability to ac- these mounting challenges, clinical Advanced cloud-based systems can cess analyzers remotely enables support laboratory professionals are turning streamline inventory management func- staff to gain insight into system perfor- their attention to information manage- tions and automate routine tasks to help mance to proactively manage any po- ment. This, in turn, is spurring in vitro laboratories save money, maintain tight tential operational interference, which diagnostic (IVD) product providers to turnaround times, track trends, and de- is believed to improve uptime. create a new wave of integrated sys- vote more time to patient care, instead tems, designed to harness the power of of administrative duties. Providing insights into operations information into usable solutions that Managing inventory is vitally impor- across the network meet the most pressing needs of today’s tant in the laboratory; not having the Managing network operations across laboratories. right inventory items on hand could multiple sites can be challenging due to slow a laboratory’s ability to perform a non-standardized reporting methods, Finding laboratory solutions specifi c test when a physician and pa- overwhelming amounts of data, and a Healthcare’s age of enlightenment tient need it. Automatic reorder prompts lack of access to needed information. It brought an increased demand for a enable laboratory professionals to make is not enough to have access to informa- more comprehensive picture of both sure they have what they need and help tion anymore. Today, information has to the patient and laboratory operations. reduce staff workload, so workers can be easy to access, easy to understand, Today’s shift from an age of enlighten- focus on the most important entity—the and easy to use. ment to an age of healthcare value has patient. New cloud-based information man- produced the desire not for more data, Beyond individual laboratory op- agement systems have the ability to but for rich data—information that is erations, these inventory management connect instruments throughout an en- not just plentiful, but usable and effec- systems give managers greater vis- tire network to provide access to action- tive. This has paved the way for innova- ibility into supply usage throughout a able cloud-based analytics, including a tors to fi nd practical means by which to network, offering them added insight blend of instrument data and service in- help healthcare professionals handle big into testing, supply usage, and costs formation. Actionable data is coalesced data. Laboratory personnel need access throughout the network. into a central repository. This provides a to information, and they need a stream- detailed view of patient, quality control, lined process for sifting through mas- Centralizing instrumentation and calibration information by site. The sive amounts of data to gain the impor- monitoring information also helps managers under- tant insights that will drive decisions Busy laboratories often require op- stand instrument workload balance and and improve effi ciencies within their erators or managers to monitor several daily test volumes, and, because it is all laboratories, hospitals, and networks. instruments at the same time. This is cloud-based, there is no need for addi- Many are fi nding their solutions in particularly true during night shift and tional hardware and a reduced need for new information management systems other times when staffi ng may be at a IT support.

continued on page 41 38 MLO-ONLINE.COM MAY 2017

MLO201705_FutureBuzz_Beckman_Qiagen-COMBO_MECH_AL.indd 38 4/13/2017 11:17:03 AM PSaveP More Lives. P by screening for colorectal cancer. P® Automated FIT Blood Test for Colorectal (Fecal Immunochemical Test) Cancer Screening

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MLO201705_AD Polymedco.indd 39 4/11/2017 8:57:02 AM FUTURE BUZZ BIOINFORMATICS

Looking ahead: the future bioinformatics of genetic testing and precision medicine By Ramon M. Felciano, PhD

ne of the most effective ways to We need electronic medical records that too expensive to be done routinely for reach an audacious goal is to en- can manage genomic datasets, integrate the broad patient population. Instead, Ovision, in detail, exactly what you them with other large- and small-scale these hybrid assays will be validated for aspire to achieve. In that spirit, I’ve been clinical data, and enable integrative specifi c indications where single assay thinking about what the genetic testing querying of the comprehensive patient modalities show limited clinical util- landscape could look like ten years from record. Simple representation of clini- ity, and from there will gain traction in now so that we as a community can be- cal test reports as PDF documents is not mainstream healthcare. gin reverse-engineering solutions to enough; our clinical tools must support overcome the obstacles facing us today. the richness and complexity of genomic IA will lead AI in clinical Let’s imagine that it’s May 2027. and other molecular test results as well applications Precision medicine is standard practice, as their associated clinical metadata. That is, intelligence augmentation (IA) and genetic testing is routine and es- Data privacy will be another key will come before artifi cial intelligence sentially ubiquitous. Clinical labs run component of our future IT landscape. (AI). With this abundance of data, it will genetic tests of varying sizes and com- We must address concerns about the be more important than ever for clinical plexities, and genome-wide testing is privacy of patient data to take full ad- labs and physicians to have high-quali- far more affordable and broadly used vantage of large-scale analysis of ag- ty, sophisticated tools for accelerated, for a range of indications. Genome se- gregated patient datasets, and to allow evidence-based interpretation of test re- quencing is no longer a one-time test for the healthcare industry to fully realize sults and other information used to drive each patient; physicians have patients’ the economic benefi ts of cloud comput- clinical decisions. While such tools will genomes sequenced repeatedly over ing. Techniques like differential privacy undoubtedly leverage algorithm innova- time to monitor for changes and answer and other privacy-preserving comput- tion from computer science—and artifi - new clinical questions. Clinical labs and ing and data transfer methods require cial intelligence and machine learning patients themselves contribute a great broader adoption in order to address in particular—we are unlikely to see AI deal to secure, cloud-based personal legal and regulatory concerns around drive a radical shift in medical practice data repositories, both as active par- sharing and transfer of molecular data. for some time. In ten years, the bulk of ticipants in their and their loved ones’ Addressing privacy concerns effectively healthcare and precision medicine will care, and as contributors to global R&D will be critical to allow patients to share still be operating with trained physi- efforts that extract new medical insights their data for research studies easily and cians, oncologists, and primary care giv- from large-scale, privacy-compliant, re- safely. ers—but with improved effectiveness search-accessible genome repositories. thanks to these algorithmic techniques. Finally, since genetic and genomic test- Integration of genetic insights Well-designed software systems with ing is routine, molecular data specialists with new sources of health data powerful embedded computational en- are more directly involved in patient Insights from genetic testing will be gines will enable doctors to acquire, fi l- care. integrated with increasingly available ter, integrate, and make sense of all in- Now, let’s take this future apart, piece patient data from consumer devices and formation relevant to a patient and his or by piece, and pinpoint the challenges novel assay platforms. With the prolif- her clinical context. These decision-sup- we must overcome to make it a reality. eration of health-related mobile apps port systems will give clinical geneticists, and wearable devices, in a decade’s pathologists, and physicians the right in- Molecular data must infuse time we should expect that clinical information at the right time to drive the healthcare IT terpretation of patient test results will right decision. We will not fully embrace the era of occur within the context of multiple pa- Technologies that aim to improve hu- genomic medicine without signifi cant tient-generated streams of health data. man decision making must be radically improvements to the computational Whether that’s from sleep sensors mea- transparent, evidence-based, and cus- infrastructure and policies that govern suring a range of physiological param- tomizable in their function. Systems that healthcare data. Today’s labs and hos- eters or smart toilets with built-in urine aim to improve decision making must pitals lack shared data standards and antigen screening assays, there will be provide full access to every data point, technical integration capabilities robust plenty of data feeds that, if properly every reasoning step, and every calcu- enough to share, manage, manipulate, quality-controlled and integrated, can lation that supports a certain clinical and make effective use of rich molecu- help make diagnoses more accurate and conclusion—and provide clear mecha- lar datasets. Medical record systems personalized. In addition, as molecular nisms that allow expert human insight are increasingly electronic in nature, assay costs continue to drop, genome- to guide the system performance. This and show great promise for managing based testing will expand to include mi- design philosophy will make it possible patient data from a variety of sources, crobiome, metabolome, proteome, and to generate not only a simple one-page but today’s systems still lack broad sup- transcriptome data. While such multi- report for people who need a concise, port for storage, representation, and omics studies will likely be common in high-quality clinical insight, but also useful querying of molecular test data. research, in ten years they may still be a 100-page report with supporting

40 MLO-ONLINE.COM MAY 2017

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Informatics continued from page 38

evidence which illustrates the reasoning Implementing solutions to stream- targeted information enable closer moni- behind each summary result. Clinicians line workfl ow is an ongoing focus of toring of key performance indicators. will review these details as needed and clinical laboratory professionals. A Today’s clinical information man- be confi dent in system correctness and next-generation middleware system agement tools enable healthcare per- performance. Well-designed systems provides a single solution for access- sonnel to make informed decisions will further enable customization by ing and managing laboratory infor- about operations through the use of allowing users to adjust analytic work- mation system (LIS) data. Workfl ow is rich data. The ability to access and ana- fl ows on a case-by-case basis, change fi l- optimized through cloud-based tech- lyze this vital information on-demand tering assumptions and decision logic, nology. This technology minimizes is an important part of quality control adjust computer-based diagnostic and the hardware footprint, and multi- and continuous improvement efforts. treatment guidelines, and introduce site, multi-time-zone technology helps These tools allow professionals to tar- new sources of evidence. reduce training and rework for staff get specifi c areas of interest more close- members. Advancements also include ly, helping to ensure laboratories are Molecular expertise across the roles-based access to ensure the secu- performing effi ciently and effectively. care continuum rity of protected health information, Ultimately, optimal laboratory per- Greater involvement of clinical lab per- simplifi ed rule building, and increased formance leads to enhanced customer sonnel across the patient care continuum throughput of resulted tests through service and improved patient care. will also be key. As molecular testing be- auto-verifi cation. comes routine, clinical lab professionals will play a greater role in the direct care A better understanding of Wido Menhardt, PhD, and treatment of patients. This transi- business performance serves as Vice tion is already happening in oncology, Healthcare changes are putting extra President, R&D Clinical Informatics, for where tumor boards have created part- pressure on laboratories, hospitals, and Beckman Coulter, Inc. nerships among oncologists, patholo- networks. To maintain quality and effi - gists, lab specialists, and other care pro- ciency in the clinical laboratory, person- viders to foster a holistic perspective on nel at all levels must be able to track per- patient care. To apply this team-based formance. Solutions that ease access to approach in other indications that can benefi t from deep molecular insights, we need better organizational integration between clinical lab specialists and medical practitioners. We also need IT systems with robust support for molecular testing data. The fundamental thing to note about this vision of genetic testing just ten years from now is that there is no “insert miracle here” step. While the goals are ambitious, every aspect involved is realistic and achievable. Technological improvements are feasible; many are already underway. Policy changes are certainly achievable if we come together as a community with clinical and patient advocacy groups. I believe that if we join forces and push for change, we can usher in a new era of clinical testing and signifi cantly improved healthcare for patients around the world.

Ramon M. Felciano, PhD, serves as QIAGEN Bioinformatics’ Chief Technology Offi cer and was a founder of Ingenuity Systems, a QIAGEN Company. He leads strategy for the QIAGEN Clinical Insight (QCI) solutions, a clinical decision support platform designed to help labs streamline and accelerate the interpretation of genetic test results.

MAY 2017 MLO-ONLINE.COM 41

MLO201705_FutureBuzz_Beckman_Qiagen-COMBO_FINAL.indd 41 4/13/2017 11:36:41 AM WASHINGTON REPORT Medicare’s new Quality Payment Program How the lab can support organization-wide quality initiatives By Kim Futrell, BS, MT(ASCP)

n October of 2016, the Department of four categories (based on 2017 data) that utilization management to ensure best use Health and Human Services (DHHS) will determine their payment adjustment of resources. And last, laboratories are an Ireleased the fi nal Medicare Qual- for 2019 (Figure 1): integral part of the precision medicine plus ity Payment Program (QPP) rule, which • Quality (50 percent) companion diagnostics equation. is a part of the Medicare Access and CHIP • Advancing care information (25 percent) Reauthorization Act of 2015 (MACRA). • Clinical practice improvement activities Effi ciency & TAT MACRA repealed the sustainable growth (15 percent) In today’s healthcare environment, partic- rate (SGR) formula that was used to de- • Resource use/cost (0 percent in 2017, ularly with Protecting Access to Medicare termine Medicare reimbursements for 10 percent in 2018).1 Act (PAMA) reimbursement cuts looming physicians, and replaced it with the QPP PQRS, VM, and the Medicare EHR In- over labs, it is vital for labs to perform at framework, changing the way physicians centive Program or MU have each played top effi ciency, producing fast, yet accurate, are paid. an important role in the beginning stages test results that can be used to diagnose of quality measurement and reporting and treat patients quickly. Today’s top LISs Value-based care and for Medicare. By aligning these programs have perfected the integration of advanced interoperability within MACRA, CMS is consolidating re- decision support result evaluation rules While there is disagreement about repeal- quirements to reduce the reporting burden that streamline nearly every aspect of testing or replacing the Affordable Care Act on clinicians. ing. Decision-support rules automate and (ACA), the Republican and Democratic standardize tasks to increase effi ciency, parties both appear committed to patient- Quality domains productivity, and error-proofi ng through- centered care with a strong focus on value Continued development and reporting of out the total testing process, and free staff and positive patient outcomes. As such, quality measures is important in the transi- for other complex duties. Two effective MACRA’s QPP rule passed with a strong tion to value-based reimbursement models ways to improve a lab’s effi ciency and val- bipartisan majority. Additionally, in line and patient-centered care. Several of the ue using decision-support rules are auto- with other federal regulations, the Medi- quality domains offer opportunities for verifi cation of results and set-up of refl ex care QPP is a driving force for interop- laboratories to contribute. Included with- testing cascades that allow it to provide the erability and a bigger push away from in the category of quality are outcomes most appropriate testing and readily sup- fee-for-service (FFS) toward value-based measures for: port utilization management efforts. payment models. The QPP defi nes how • Clinical care providers will be reimbursed for qual- • Safety Population health and preventive ity and gives providers two options: the • Care coordination services Merit-based Incentive Payment System • Patient and caregiver experience Laboratories can also use their LIS to col- (MIPS) or Advanced Alternative Payment • Population health and prevention lect population-level data that can support Models (APMs). Only those who are al- • Affordable care (overuse of clinical tests).1 the organization’s efforts toward popu- ready well into value-based reimburse- lation health management. Population ments will qualify for APMS; therefore, the Four ways labs can contribute health involves impacting the health and majority of providers will fall under MIPS. The laboratory information system (LIS) outcomes of a lab’s specifi c group of pa- is part of an interoperable network of elec- tients to promote better health. Measures Reimbursements for quality care tronic data sources that feeds the EHR, re- in this quality domain involve determin- Intended to be implemented in stages, the sulting in a rich set of clinical data to use ing if clinical services (such as lab testing) QPP incentivizes providers to focus on for quality measures. As a fi rst step, labs and preventive services are used in such population health management, preven- can use their LIS to improve internal ef- a way that improvements in population tive care, and quality. MIPS consolidates fi ciency and promote rapid expedition of health occur. Included in this domain are Meaningful Use (MU), the Physician results that can impact quality scores. Sec- process measures that focus on prevention Quality Reporting System (PQRS), and ond, LIS data can be tapped to help iden- of disease by screening for early detection. the Value-based Payment Modifi er (VM). tify patients who, based on their lab re- Laboratories can use LIS data to deter- While hospitals will still be subject to MU sults, are candidates for further preventive mine patients for whom preventive testing Stage 3 in 2018, January 2017 marked the testing, and to provide data that supports would be benefi cial based on evidence- start date for MACRA reporting for eligi- population health measures. Third, and based guidelines (e.g., identifying women ble clinicians. MIPS-eligible clinicians will more important for today’s laboratory, eligible for HPV screening by age groups). receive a composite performance score for the LIS can be used to track and support Utilization management 10% Quality (previously PQRS) Tracking laboratory utilization management falls within the quality domains of af- 15% Advancing care information fordable care and safety. Quality measures (previously MU) focus on lowering costs, reducing errors, 50% Clinical practice improvement and improving outcomes. The Centers for Medicare & Medicaid Services (CMS) activities 25% considers utilization management a high Resource use/cost priority within the QPP, and are collabo- (previously VM) rating with various stakeholders to adopt evidence-based practices for appropriate Figure 1. MIPS Categories use.1 One such resource is the Choosing

42 MLO-ONLINE.COM MAY 2017

MLO201705_WashReport_Letters-COMBO_MECH_AL.indd 42 4/13/2017 2:10:53 PM WASHINGTON REPORT HAVING MY SAY

Wisely initiative of the American Board of Internal Medicine (ABIM) Foundation, Who am I? which publishes evidence-based recommendations for the appropriate use of By Elizabeth Dahlgren, MT(ASCP) tests and procedures to reduce inappro- priate use. Labs can use LIS data to track test utilization and identify unnecessary ho am I? I am your phleboto- that what they are doing is helping, that testing combinations. This can be part of mist, your processor, your lab you are getting better and that nothing ongoing feedback to providers to promote W tech. else is going on. I hope that it will work. improved quality scores. What is my job? I draw your blood, I process your samples because each process your samples, run your tests. one represents you. I work with the doc- The Cures law What do I do? I see you. I talk with tor, with the nurses. I offer advice if they Another area of bipartisan agreement in you. I ask about your life, your children, need help ordering tests or knowing Congress was the passage last December, your parents. what to collect or how to transport it. I by large majorities in both Houses, of the You tell me about your vacation. You make sure that the tests they ordered are 21st Century Cures Act. The Cures law tell me about your hospital stay. I come correct and meaningful. I see if there is builds on the Precision Medicine Initia- into your home if you can’t leave so you any way to avoid another draw. I work tive and targets approximately $5 billion still get the tests done that are needed. with reference labs to make sure that toward National Institutes of Health proj- I worry about you if you don’t come in we are sending the tests correctly and ects. Laboratories that serve a patient pop- as usual. I hope everything is all right. I that the results will be returned in time. ulation that can benefi t from companion hope you are all right. I hold your treatment, your future, in diagnostic testing—testing to determine I see you at your best. I celebrate your my hands. I make sure that there are no drug treatment effi cacy—should consider new grandchild, your new job, your re- errors due to me. I can affect your out- the feasibility of including companion cent engagement. I watch you grow up. I come if I don’t do my job right. I know if diagnostic testing on their menu. watch your children grow up. We laugh I make a mistake it could kill you. I take together. We share stories. I see you get pride in my work. Every sample is a life. To sum up better with treatment. We celebrate the It is your life. Medicare’s new QPP speaks to a continued victories. I run your tests. I see your results. I focus on quality, preventive care, better uti- I see you at your worst. I hold your help the doctor piece together what is lization of services, and population health hand when you tell me that you lost going on. I am a silent partner in your management. While much of the data and your job, that your child is sick, that treatment. I went to school and trained metrics used to support quality measures you lost a loved one. You tell me about for years so that I am an expert at my comes from the EHR, the LIS plays an im- your diagnosis, you tell me about your job. I make sure that all the analyzers portant role as an information system that prognosis. I understand your feelings. are running properly, that everything feeds the EHR and as an essential tool to You don’t like the needles. You don’t is under control. I do maintenance help laboratories increase effi ciency and want me there. You don’t want to be and troubleshoot anything that seems monitor their internal utilization and pro- there. You are afraid of the outcome of wrong. I want your results to be correct. ductivity as it relates to quality measures. the tests. I am the fi rst to see your results. I Overall, there is a feeling of uncertainty I wake you up in the middle of the see your positive pregnancy test after as laboratories wait for the PAMA gavel to night in your hospital bed to get blood. I you have been trying for years. I see fall, and it is vital for labs to be part of mak- want to tell you it is doctor’s orders, that your hormone levels normalize because ing improvements in our healthcare sys- I do this because it is needed. I want to treatment is working and hopefully you tem. Quality is being measured with clini- tell you that because you haven’t been can come in less frequently. I see your cal data, and labs handle a tremendous able to drink anything for days your undiagnosed leukemia that may ex- amount of that data. They can leverage veins collapse as soon as I try to take plain your headaches and weakness. I the tools in their LIS to be part of promot- blood from them. I want to say phlebot- see these results and they affect me too. ing safety, population health, and preven- omy is an art, not a science—that I can’t I know I may see you on your last nor- tive measures to support providers in make a vein appear and work. That mal day. I know that these answers can improving patient outcomes. there are a lot of things that can cause is- give you a lot of relief or can crush your sues during a blood draw. That I always family. I would rather think that I did REFERENCE try my best to get a sample the fi rst time something wrong than fi nd something 1. Centers for Medicare & Medicaid Health Services and to cause the least amount of pain. wrong with you. But I make sure every Advisory Group, Inc. (2016, May 2). CMS quality measure development plan: Supporting the transition to I don’t say any of this. Instead I smile. result is accurate so you are treated and the merit-based incentive payment system (MIPS) and I listen, even when you yell at me, when so you have the best possible outcome. alternative payment models (APMs). https://www.cms. you tell me that I don’t know how to I see you. I hear you. I understand. I gov/Medicare/Quality-Initiatives-Patient-Assessment- do my job, when you get so frustrated come to work every day because of you. Instruments/Value-Based-Programs/MACRA-MIPS- and-APMs/Final-MDP.pdf. with me, with your treatment, with the The ability to help you is what makes my entire process. I want to tell you that I job worthwhile. I do this because I care. Kim Futrell, BS, see you. I see you in pain. I cause you I am your lab tech, your processor, your MT(ASCP), currently pain. I know this. I wish there was an- phlebotomist. I am your caregiver. serves as Products other way, but there isn’t. There is no Marketing Manager for other way. Elizabeth Dahlgren, Orchard Software. Kim I do this for you. I want you to get MT (ASCP), serves as has more than 20 years better. I want you to not need this any- Supervisor of Ambula- of laboratory manage- more. The doctor needs this to deter- tory Laboratory Services ment experience. Prior mine what is wrong, to see if what he with ACL Laboratories to joining Orchard in 2012, her role was as and Aurora Healthcare in prescribed is working, to make sure you Operations Manager of a multispecialty Milwaukee, WI. physician’s offi ce in North Carolina. are getting better. I am helping to monitor your treatment. This is to make sure

MAY 2017 MLO-ONLINE.COM 43

MLO201705_WashReport_Letters-COMBO_MECH_AL.indd 43 4/13/2017 2:11:04 PM PRODUCT FOCUS LIS

zero-downtime solution built on advanced industry technol- Integration and interfacing ogy; and 4) live human support to keep labs running smoothly. xLAB LIS is a state-of-the art Visit Comp Pro Med: www.rsleads.com/705ml-153 laboratory information system (LIS). Using the MySQL data- base and Crystal reports, it is Inventory tracking user-friendly and accommo- The InvMan software dates multiple instrument inte- system streamlines re- gration, and interfacing for an agent inventory tracking EMR and billing system. Cou- by scanning vendor re- pled with the xLAB reporting agent barcodes, tracking package, it accommodates re- lot numbers and expira- porting needs for moderately complex to highly complex lab re- tion dates, and prompting quirements like pain management. The add-on xPortal Outreach when and what to order. gives the lab the ability to handle any number of remote loca- Features include: reagent tions for entering orders and obtaining results over the internet. package inserts, SOPs, SDS, and vendor contracts saved online Visit AP Visions: www.rsleads.com/705ml-150 for immediate access; instrument service with storage of fi eld service report and life cycle tracking; and comprehensive management reports for reagent status, inventory, purchasing, off-site dis- Manage orders within network tribution, budgeting, and expense analysis. InvMan is accessed from multiple PCs on the network with no additional per user fee. The Multi-Lab Network enables labs to manage orders within a Visit Cove Lab: www.rsleads.com/705ml-154 lab network after a merger, acquisition, or alliance without the need to replace existing LIS or other IT infrastructure. ATLAS solutions address order management challenges that healthcare organizations face today. The solution supports test rout- Dashboard added ing/sharing, consolidated reporting, customized workfl ow, and The NovoPath Dashboard rules management capabilities with centralized administration has been added to NovoPath, for an entire network of labs and physician customers, including Inc.’s NovoPath Anatomic Pa- those using EMRs and other third-party middleware solutions, thology Software Platform. and enables labs to get the complete order information where Having the ability to monitor it needs to be so they can perform the work and can get paid. operational effi ciency “real- Visit ATLAS Medical: www.rsleads.com/705ml-151 time” is crucial to a lab’s success in today’s time-pressed anatomic pathology environment. NovoPath’s dashboard Optimize revenue, workfl ow displays real-time informa- CGM LABDAQ from Compu- tion such as the number of Group Medical (CGM) is an cases accessioned, grossed, pending, resulted, and released. evolved laboratory information The dashboard can be customized to provide each user with system (LIS). CGM LABDAQ em- the information that matters most to them, allowing the us- powers labs of all sizes to optimize ers to monitor processes impacting their functional activity. revenue and improve customer Visit NovoPath: www.rsleads.com/705ml-155 retention by increasing effi ciency, streamlining workfl ow, reducing turnaround times, and promoting POCT management patient safety. Rules-based tech- The Orchard Trellis offers nology supports compliance with POCT management and in- best practices. Order routing rules tegration tools to address can automatically order reference lab vs. in-house tests based on the complexities and di- patient insurance to ensure reimbursement and minimize deni- versity of POCT situations als. Instrument data and quality control metrics are electronically and ease the workload for captured and reviewed, and CGM LABDAQ integrates with bill- POC coordinators. In addi- ing systems and provides business decision support analytics. tion to capturing results Visit CGM: www.rsleads.com/705ml-152 in real-time into the EHR, Trellis can track training and competency assess- Easy-to-use system ments for a multitude of operators, devices, and locations Comp Pro Med developed the Polytech LIS in to help ensure quality of testing and meet inspection require- 1983. Polytech LIS is a robust, scalable, and ments. Trellis supports remote handling of POCT QC, automates affordable system with constantly updating billing, and provides a full menu of reports. Depending on the features and functions based on customer in- POCT devices, Orchard offers options for users to access the put and industry requirements. Key benefi ts POCT software alongside the test device, or the device can be include: 1) The ability to implement a new LIS “docked” to directly load results into the LIS and EHR. Orchard in days, not months; 2) An easy-to-use sys- Trellis can handle the POCT connectivity and management needs tem that’s intuitive and straightforward; 3) A of today’s integrated healthcare facilities and organizations. Visit Orchard Software, www.rsleads.com/705ml-156 continued on page 46 44 MLO-ONLINE.COM MAY 2017

MLO201705_ProductFocus_MECH_AL.indd 44 4/13/2017 1:46:29 PM 69TH AACC ANNUAL SCIENTIFIC MEETING & CLINICAL LAB EXPO JULY 30 - AUGUST 3, 2017 SAN DIEGO, CA USA

WELCOME TO A NEW DIMENSION IN LABORATORY MEDICINE This year, 20,000 of the sharpest minds in clinical laboratory medicine will come together for ﬁve science packed days in San Diego. Envision your future: Hear from the foremost experts sharing their inventive ideas that are transforming the state of the clinical lab Examine new technology: Explore the vision for clinical testing and patient care through the lenses of 750 exhibitors shaping the future of the lab Connect with colleagues: Network and collaborate with this international community of change makers Register today. www.aacc.org/2017am

MLO201705_AD AACC.indd 45 4/11/2017 8:51:06 AM PRODUCT FOCUS LIS continued from page 44 deadlines; submit data in real time using one of the Unity software End-to-end solution solutions; get reports, product information and more on QCNet. GeneInsight is a software platform that deliv- Visit Bio-Rad Laboratories: www.rsleads.com/705ml-158 ers an end-to-end solution—from sample receipt to fi nal report, encompassing both the wet (LIMS), and dry (Analysis) lab operations for molecular and genetic testing. Specializ- Anatomic path lab solution ing in molecular lab automation, GeneInsight WinSURGE is a sophisticated, easy-to-use, effi cient Anatomic simplifi es complex workfl ow, sample, and Pathology Laboratory System. WinSURGE is in use at many resource management and provides a com- of the nation’s hospitals and commercial labs, including some plete chain-of-custody audit trail with interac- multi-site lab corporations. It includes the easy-to-use, user- tive dashboards to monitor lab operations. The platform also driven rules engine WinsRULES, Executive Dashboard Win- streamlines the analysis, interpretation, and management of sALERTS, point-to-point tracking module WinsTRACK, and more. genetic data and facilitates actionable report creation and de- Visit Computer Trust Corp.: www.rsleads.com/705ml-159 livery so that physicians can leverage the power of precision medicine in their everyday diagnosis and treatment of patients. Visit GeneInsight: www.rsleads.com/705ml-157 Enhance path utilization Sunquest PowerPath is a highly innovative AP LIS designed to Interlaboratory program help accurately and effi ciently Participation in an interlaboratory program manage and communicate is important for laboratories to help ensure anatomic pathology diagnoses. the reliability and precision of test systems. The solution offers a proven The Unity Interlaboratory Program provides workfl ow to help manage ana- information and helps to improve laborato- tomic pathology laboratories ry analytical performance. The Program en- in hospitals, medical centers, reference laboratories, and aca- ables users to: unite with more than 25,000 demic facilities. It features new functionality to streamline ac- peers with data generated from more than 46,000 instruments in cessioning, manage pathologist scheduling, automatically 92 countries; recognize analytical process improvement opportu- allocate cases to pathologists, automate tasks with rules, and nities; increase confi dence in profi ciency survey outcomes; iden- simplify structured data capture. The new capabilities work in tify unrecognized trends or shifts that may occur between profi - concert to enhance pathologist utilization and improve pro- ciency surveys; receive on-demand interlaboratory comparison cess standardization throughout the anatomic pathology lab. reports; receive monthly reports with regular data submission Visit Sunquest: www.rsleads.com/705ml-160

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This index is provided as a service. The publisher does not assume liability for errors or omissions.

46 MLO-ONLINE.COM MAY 2017

MLO201705_ProductFocus_MECH_AL.indd 46 4/13/2017 1:46:40 PM CLINICAL SPOTLIGHTS

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MAY 2017 MLO-ONLINE.COM 47

MLO201705_Spotlights_FINAL.indd 47 4/13/2017 7:40:15 AM EXECUTIVE SNAPSHOT By Alan Lenhoff, Editor Providing educational and consultative services to help labs succeed How would you characterize the tity was based on the confi dence that our What do you see as signifi cant mission of COLA Resources, Inc. services, which had been specifi cally for trends in the clinical lab industry? (CRI), in a few words, for people COLA-only laboratories, would provide How is CRI staying “ahead of the who may not be aware of it? The value for all laboratories. CRI has a wealth curve”? The laboratory industry is submission of CRI is to “provide educational of knowledge and experience that we want ject to the same technological, regulatory, and consultative services aimed at im- to make available to the entire laboratory demographic, cultural, and political forc- proving laboratory medicine and patient profession. With more than 20 years of ex- es as all other components of the healthcare.” Between the changing healthcare perience developing educational products care industry. CRI, through its webinars, environment, the depth of regulatory de- and with expert knowledge of the fi eld of videos, written blogs, and continuously mands placed upon laboratories, and the laboratory medicine including regulatory, updated product information on regula- demand for continuing education, CRI operational and quality requirements, we tory requirements, is aggressively keep- recognizes the value and impact that con- are confi dent that CRI is a superb resource ing our fellow professionals current with tinuing education has on driving quality for quality achievement. all these changes. The most signifi cant laboratory medicine. CRI is positioned to We decided in 2012 to separate CRI as trends can be characterized under the fol- focus on the educational needs of this ever- a COLA subsidiary, with the goals of pro- lowing categories: changing environment. viding an educational platform to assist Technical: Trends include point-of-care laboratory and other healthcare profes- testing; mobile (including wearable) tech- What is the history of CRI? When and sionals, and to assist these profession- nology; digital storage and transmission of why did it separate from COLA itself? als in establishing Continuous Quality data (including electronic health records); The decision to develop CRI as a separate standards through consultative services. molecular diagnostics and genomic test- educational and consultative services en- ing, enabling the development of person- What types of educational resources alized medicine; and computerized, virtu- does CRI provide for the laboratory? al offi ce visits between patients and their For the lab director? For brand new physicians. labs that are yet to be surveyed? Demographic: Aging baby boom- Through CRI’s LabUniversity distance ers require more frequent medical ser- learning program, healthcare profession- vices, including management of chronic als can access a wide array of education diseases. Millennials, who are much resources through a single, convenient less likely to have designated personal online learning management system. In physicians, and are quite comfort- addition to an extensive series of online able with as-needed medical visits, educational courses, the educational plat- are also more likely to utilize and pro- form addresses important industry issues, mote the newest technological innova- enables physicians to meet CME education tions. They feel more at ease access- JAMES LIGGINS requirements to qualify as a laboratory ing walk-in and retail clinics staffed by CEO director of a moderate complexity labora- non-physician professionals such as COLA Resources, Inc. tory, and assists laboratory professionals in nurse practitioners. earning P.A.C.E. credits to meet state licen- Cultural: The opioid epidemic has had Professional sure requirements. CRI also provides an a signifi cant effect on laboratory technol- I have been in my present position as CEO extensive series of webinars, training and ogy—for example, enormous growth of of CRI for over two years. I transitioned into review videos, and educational manuals Mass Spectroscopy laboratories and the this role from the position of Chief Market- and guides, plus live presentations at our resources needed to regulate them. Also, ing Offi cer at COLA. I have been in the annual Symposium. the growth of retail medicine and mobile healthcare arena for more than 25 years, For brand-new labs, we offer a Qual- technology has led to the decentraliza- starting in a direct-care environment and assuming greater responsibilities through ity Improvement Program led by our CRI tion of how medical care is provided. the years. Prior to COLA, I worked for 10 Educational Surveyors. These surveyors Political: An additional 20 million years at Magellan Behavioral Health. are tasked with on-site visits to these new people are now covered through the Af- (start-up) laboratories that have chosen fordable Care Act (ACA), resulting in an Education COLA as their accreditation organization. overloaded healthcare delivery system I received a BA degree from Tuskegee Uni- They visit the laboratory for a full day and and exacerbating the physician shortage, versity, which has been an amazing foun- review all essential aspects of a quality as well as shortages in allied healthcare dation to support our work in laboratory laboratory operation (on-site pre-assess- professionals, including laboratorians. medicine. I will complete my MBA from ments). These visits occur prior to an offi - Future changes to the ACA will affect in- the University of Maryland in the summer cial COLA survey, and are designed to re- of 2017. surance coverage and access to medical view, assess, and advise those laboratories, care. I also would include in this catego- Personal many of which do not have experienced ry PAMA (Protecting Access to Medicare I am a member of Leadership Howard personnel. This service is provided at no Act) and how its payment/reimburse- County (Maryland) and I serve as a Trustee cost to these labs. After almost two years of ment requirements will affect the future on the board of the Maryland 10th Cavalry this service to COLA labs, studies have in- survival of smaller hospital, reference, Association. My family and I participate in dicated a signifi cant reduction in first-time and physician offi ce laboratories, and all events that support youth mentoring, How- survey citations. Our plans are to expand the activities of professional organiza- ard County Police Foundation, Rebuilding this pre-assessment initiative to any labo- tions around this issue. Howard County, and the Howard County ratory. We think labs will consider the cost This interview continues online at Hospital Association, among others. to be an investment in quality. www.mlo-online.com

48 MLO-ONLINE.COM MAY 2017

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