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■ Antiemetics: a guideline ■ Hypertension in diabetes ■ HRT safe in menopause FEATURE

Preventing sudden death in young athletes LEGAL ADVISOR

Violating a patient’s privacy

■ Dermatologic Look-Alikes




■ Feature







Co-prescribing opioids and naloxone for pain in primary care.

Editor Colby Stong Associate editor Lauren Grygotis Assistant editor Madeline Morr Contributing editors Mark P. Brady, PA-C; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP; Sharon Dudley-Brown, PhD, FNP; ­Abimbola Farinde, PharmD; Laura A. Foster, CRNP, FNP; Abby A. Jacobson, PA; Maria Kidner, DNP, FNP; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Mary Newberry, CNM, MSN; Claire Babcock O’Connell, MPH, PA; Kathy Pereira, DNP, FNP; Sherril Sego, DNP, FNP; Ann Walsh, PA-C, SCT(ASCP); Kim Zuber, PA-C Production editor Kim Daigneau Group art director, Haymarket Medical Jennifer Dvoretz Production manager Krassi Varbanov Circulation manager Paul Silver National accounts manager Alison McCauley, 973.224.6414 alison.mccauley @

Editorial director Kathleen Walsh Tulley General manager, medical communications Jim Burke, RPh CEO, Haymarket Media, Inc. Lee Maniscalco

“She’s had work.”

All correspondence to: The Clinical Advisor 275 7th Avenue, 10th Floor, New York, NY 10001 For advertising sales, call 646.638.6085. For reprints, contact Wright’s Reprints at 877.652.5295. Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Clinical Challenge” are not the actual individuals ­mentioned in the articles.They appear for illustrative purposes only. The Clinical Advisor ® (USPS 017-546, ISSN 1524-7317), Volume 20, Number 10, is published 12 times a year, monthly, for $75.00 per year in the United States; $85.00 in Canada; $110.00 for all other foreign, in U.S. dollars, by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. Single copy: $20 U.S.; $30 foreign. To order or update your paid subscription, call 800.436.9269. Periodicals postage rate paid at New York, NY, and additional mailing offices. POSTMASTER: Send address change to DMD Data Inc., 10255 W. Higgins Rd, Suite 280, Rosemont, IL 60018. ­Subscription inquiries: call 800.430.5450 to change your ­address or make other subscription inquiries. Requests for subscriptions from outside the United States must be accompanied by payment. All rights reserved. Reproduction in whole or in part without permission is prohibited. Copyright © 2017

“And would it kill you to put some pizzazz into it?” • THE CLINICAL ADVISOR • OCTOBER 2017 1

Top: © Harley Schwadron, 2017. Middle, bottom: © The New Yorker Collection 2017 from All Rights Reserved.

Publisher Kathleen Hiltz, 201.774.1078



Newsline ■■Antiemetics: a clinical practice guideline update from the American Society of Clinical Oncology ■■Managing hypertension in diabetes: an updated position statement from the American Diabetes Association ■■Anti-inflammatory drug may reduce the risk of cardiovascular events ■■Hormone replacement therapy for menopause is not associated with an increased mortality risk. ■■The CDC releases its updated influenza vaccine recommendations for 2017-2018. ■■Vitamin D supplements reduce depressive symptoms and cardiac events in patients with moderate to severe depression.


Antiemetics: a clinical practice guideline 9

12 Opioids and naloxone for pain management Co-prescribing naloxone and opioids in primary care may be recommended for patients who have a high risk for opioid overdose.


Follow us on Twitter @ClinicalAdvisor

CME The spectrum of molecular


CME Feature posttest

testing protocols for HCV Strategies to monitor hepatitis C virus progression and treatment efficacy are key to averting therapy resistance.


Sudden death in young athletes 19

9 Preventing sudden death 1 in young athletes Hypertrophic cardiomyopathy, myocarditis, valvular heart disease, and dilated cardiomyopathy are among the most common causes.

4 2


Web Roundup A summary of our most recent opinion, news, and multimedia content from


Commentary Opioid use in middle-aged adults. Healthcare professionals have the responsibility of providing safe and cost-effective pain management

39 Dermatology Clinic n A pruritic rash and rippled plaques on a woman’s shin n Red bumps on a young boy’s fingers 45

Dermatologic Look-Alikes A brown macule on the arm and face

Continues on page 6

Kefir is considered a natural probiotic 50

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Legal Advisor Fired after violating a patient’s privacy. A nurse notifies other clinicians that a patient is positive for hepatitis C.


Alternative Meds Update Kefir is generally included in the category of natural probiotics, with the added benefits of vitamins, minerals, and some proteins.


Your Comments ■ Immunization in healthcare providers: comments from our readers


My Most Memorable Patient ■ Transcending the emotional barriers between provider and patient

© Harley Schwadron, 2017.






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USPSTF recommends screening for amblyopia in all children who are aged 3 to 5 years old The USPSTF recommends that children aged 3 to 5 years undergo vision screening to detect amblyopia or its risk factors.

FDA approves labeling change for peanut products The US Food and Drug Administration has announced that labels of peanut products will include the National Institute of Health recommendation that food containing peanuts should be introduced in the diet between the ages of 4 and 6 months. Watch the video here:

2017-2018 recommendations for pediatric influenza vaccination The guidelines include a recommendation for annual seasonal flu immunization for everyone 6 months and older.

The Waiting Room

GERD may be associated with longterm risk of pneumonia Incidence of pneumonia was higher among patients with GERD compared with matched controls. Many avoidable emergency department visits include mental health and dental conditions A significant number of avoidable visits to the emergency department are related to mental health and dental conditions.

Official Blog of The Clinical Advisor Sean Grambart, DPM, FACFAS Treating patients with a fracture: Engage and expert It is essential for healthcare professionals to collaborate with other experts from all specialty areas. Jillian Knowles, MMS, PA-C Please stop filming me: Smartphones in the emergency department A hospital policy to prevent video recording in the emergency department helps to prevent patients from recording clinicians without their permission.

Breastfeeding is associated with a lower risk of endometriosis Duration of total and exclusive breastfeeding is significantly associated with a decreased risk of endometriosis. Natriuretic peptide-guided therapy does not improve outcomes in highrisk heart failure patients NT-proBNP-guided treatment strategy did not improve outcomes compared with a usual care strategy in high-risk patients with heart failure.


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Sharon O’Brien, MPAS, PA-C Binge watching television and its effects on sleep Recent evidence has shown that binge watching television could lead to poor sleep quality and higher fatigue.

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Go mobile with us • THE CLINICAL ADVISOR • OCTOBER 2017 7

• Grade • Grade

Advisor Dx


INTERACT WITH YOUR PEERS by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

Ortho Dx

In partnership with

Elbow pain in an athlete A 17-year-old male presents with right elbow pain for several months. His pain is made worse when throwing, and he has lost velocity on his fastball. Ice and nonsteroidal anti-inflammatory drugs provide little relief. He tried taking a few months off from pitching, but the pain returned as he started throwing again. WHAT IS THE LIKELY DIAGNOSIS?

• Osteochondritis dissecans of the capitellum • Ulnar collateral ligament tear • Panner disease • Lateral epicondylitis ● See the full case at

Derm Dx A growing lesion first observed in early childhood An 18-year-old Caucasian male presents for examination with a growth on his leg that he first noted in early childhood. During the past several years, the lesion has increased in size and has darkened in color. He denies both personal and family history of skin cancer. CAN YOU DIAGNOSE THIS CONDITION?

• Verrucas • Verrucous epidermal nevus • Basal cell nevus syndrome • Xanthoma ● See the full case at


Journal of Orthopedics for Physician Assistants

Newsline O C T O B E R 2 017

Hypertension in diabetes: an ADA statement page 10

HRT may be safe for women postmenopause page 11

CDC updates influenza vaccine availability page 11

THE AMERICAN Society of Clinical Oncology (ASCO) has updated its guidelines to prevent and manage nausea and vomiting caused by antineoplastic agents or radiation therapy in patients with cancer. An expert panel conducted a systematic review that included evidence from 41 publications between November 2009 and June 2016. The panel found evidence from a phase III randomized controlled trial that showed that adding olanzapine to antiemetic prophylaxis reduces the risk of nausea among adult patients treated with high emetic-risk antineoplastic agents. Additional data also support expanded use of neurokinin 1 receptor antagonists in patients who undergo chemotherapy. A summary of the updated guidelines, which were published in the Journal of Clinical Oncology, includes the following: • Adult patients treated with cisplatin and other high-emeticrisk single agents should be offered a 4-drug combination, including neurokinin 1 (NK1) receptor antagonist, a serotonin (5-HT3) receptor antagonist, dexamethasone, and olanzapine. Dexamethasone and olanzapine should be continued on days 2 to 4 (high quality of evidence; strong recommendation).

• Patients treated with an anthracycline combined with cyclophosphamide should be offered a 4-drug combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, dexamethasone, and olanzapine. Olanzapine should be continued on days 2 to 4 (high quality of evidence; strong recommendation). • Patients treated with carboplatin area under the curve (AUC) ≥4 mg/mL per minute should be offered a 3-drug combination of an NK 1 receptor antagonist, a 5-HT3 receptor antagonist, and dexamethasone (high quality of evidence; strong recommendation). • Patients treated with moderate-emetic-risk antineoplastic agents should be offered a 2-drug combination of a 5-HT3 receptor antagonist and dexamethasone (high quality of evidence; strong recommendation). • Patients treated with moderateemetic-risk antineoplastic agents that are known to cause delayed nausea and vomiting may be offered dexamethasone on days 2 to 3 (low quality of evidence; moderate recommendation). • Patients treated with lowemetic-risk antineoplastic agents should be offered a single dose of a 5-HT receptor antagonist or a single 8-mg


Antiemetics: a clinical practice guideline update from ASCO dose of dexamethasone before The practice antineoplastic treatment (low guideline quality of evidence; moderate addresses recommendation). nausea and • Patients treated with minimalvomiting emetic-risk antineoplastic caused by agents should not be offered antineoplastic routine antiemetic prophylaxis agents or (low quality of evidence; modradiation erate recommendation). therapy • Patients treated with antineoin patients plastic combinations should be offered antiemetics that are with cancer. appropriate for the component antineoplastic agent of greatest emetic risk (intermediate quality of evidence; moderate recommendation). • Lorazepam is a useful adjunct to antiemetic drugs, but ASCO does not recommend this as a single-agent antiemetic (low quality of evidence; moderate recommendation). • There is insufficient evidence for a recommendation regarding treatment with medical marijuana for the prevention of nausea and vomiting. Evidence is also insufficient for a recommendation regarding the use of medical marijuana in place of cannabinoids, dronabinol and nabilone. • THE CLINICAL ADVISOR • OCTOBER 2017 9

Newsline Managing hypertension in diabetes: an ADA statement THE AMERICAN DIABETES Association (ADA) has released a position statement to update the assessment and treatment of hypertension among patients with diabetes. The position statement, published in Diabetes Care, includes advances in care since the ADA last published a statement on this topic in 2003. “Treatment should be individualized to the specific patient based on their comorbidities; their anticipated benefit for reduction in ASCVD, heart failure, progressive diabetic kidney disease, and retinopathy events; and their risk of adverse events,” according to the ADA. “This conversation should be part of a shared decision-making process between the clinician and the individual patient.” The ADA’s recommendations include the following:

• Clinicians should measure blood pressure at every routine clinical care visit. Patients with elevated blood pressure ≥140/90 mmHg should have blood pressure confirmed with multiple readings to diagnose hypertension. Grade B • Hypertensive patients with diabetes should have home blood pressure monitoring to identify white-coat hypertension. Grade B • The systolic blood pressure goal should be <140 mmHg, and the diastolic blood pressure goal should be <90 mmHg for most individuals with diabetes and hypertension. Grade A • Patients with confirmed blood pressure ≥140/90 m m Hg should have timely titration of pharmacologic therapy to achieve blood pressure goals,

The ADA recommends blood pressure monitoring in patients with diabetes at every routine clinical care visit.

in addition to lifestyle therapy. Grade A • Patients with confirmed blood pressure ≥160/100 mmHg should have prompt initiation and timely titration of 2 drugs or a single-pill combination of drugs demonstrated to reduce cardiovascular events in patients with diabetes, in addition to lifestyle therapy. Grade A

THE ANTI-INFLAMMATORY drug canakinumab is associated with a significantly lower rate of recurrent cardiovascular events compared with placebo, a finding that was independent of lipid-level lowering, according to research published in the New England Journal of Medicine. The Canak inumab A ntiin f la m mator y Th rombosis Outcome Study (CANTOS) included 10,061 patients who had a previous myocardial infarction and a high-sensitivity C-reactive protein (hsCRP) level of 2 mg/L or greater. Investigators compared 3 doses of canakinumab (50 mg,

The reduced CV event risk was independent of lipid-level lowering.

150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Participants had a mean age of 61 years, 25.7% were women, and 40.0% had diabetes. At 48 months, the median reduction from baseline in the hsCRP level was 26 percentage points greater in the group who received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than


in the placebo group. Lipid levels from baseline were not reduced with use of canakinumab. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. Compared with placebo, the hazard ratios were 0.93 in the 50-mg group, 0.85 in the 150-mg group, and 0.86 in the 300-mg group.


Anti-inflammatory drug may reduce risk of CV events

AMONG POSTMENOPAUSAL women, hormone therapy with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality, according to a study in JAMA. Researchers used follow-up data from 2 Women’s Health Initiative hormone therapy trials. In the first trial, 16,608 women with a uterus were randomly assigned to receive CEE 0.625 mg/d plus MPA 2.5 mg/d or placebo. In the second trial, 10,739 women with a hysterectomy were randomly assigned to receive daily oral CEE 0.625 mg alone or placebo. After 18 years of follow-up, the all-cause mortality in the overall pooled cohort was 27.1% in women receiving hormone therapy vs 27.6% in the placebo group (hazard ratio [HR], 0.99). Additionally, all-cause mortality was 26.4% in women receiving CEE plus MPA vs 26.0% for placebo (HR, 1.02). For women receiving CEE alone, the all-cause mortality was 28.3% vs 30.0% for placebo (HR, 0.94). The cardiovascular mortality rate in the pooled cohort was 8.9% in the hormone therapy group vs 9.0% in the placebo group (HR, 1.00), and the cancer mortality rate was 8.2% in the hormone therapy group vs 9.0% in the placebo group (HR, 1.03). Mortality for other causes was 10.0% in the hormone group vs 10.7% in the placebo group (HR, 0.95).

CDC’s flu vaccine recommendations THE ADVISORY Committee on Immunization Practices (ACIP) has issued new recommendations for the prevention and control of seasonal influenza with vaccines for the 2017-2018 season. For the upcoming season, the following flu vaccines will be available: • Trivalent inf luenza vaccine (A/Michigan/45/2015 (H1N1)pdm09–like virus, an A/Hong Kong/4801/2014 [H3N2]-like virus, and a B/ Brisbane/60/2008–like virus [Victoria lineage]) • Quadrivalent inf luenza virus (includes three viruses listed for Trivalent vaccine + additional B vaccine virus [B vaccine virus, a B/ Phuket/3073/2013–like virus]) • Recombinant inf luenza vaccine (both trivalent and quadrivalent)

The CDC issues major updates for preventing and controlling seasonal influenza with vaccines for 2017–2018.

Major updates for the upcoming season include the following: • A change in the inf luenza A(H1N1)pdm09 virus component from the previous season • The availability of Af luria Quadrivalent (Seqirus), an inactivated influenza vaccine indicated for active immunization against influenza A subtype viruses and type B viruses for patients 18 years of age and older • The availability of Flublok Quadrivalent (Protein Sciences), a recombinant protein-based vaccine for active immunization against disease caused by influenza A virus subtypes and influenza B virus in patients 18 years of age and older • While still a licensed product, the ACIP does not recommend use of live attenuated influenza vaccine.

Vitamin D beneficial for depressive symptoms VITAMIN D supplement use is linked to reduced depressive symptoms and cardiac events for patients with moderate to severe depressive symptoms, according to a study in the European Journal of Cardiovascular Nursing. Participants completed a 3-day food diary to determine dietary vitamin D deficiency. Patients were split into 4 groups by dietary vitamin D adequacy vs deficiency and vitamin D supplement use vs non-use. Depressive symptoms were assessed at baseline and 6 months later. After exclusion criteria, a total of 177 patients were included in the final analysis. About 30% of patients were females and 86 patients (48.6%) were older than 65 years (range of 32 to 89 years). Sixty-six

patients (37.3%) had dietary vitamin D deficiency and 80 (45.2%) used vitamin D supplements. In patients with moderate to severe depressive symptoms, the group with dietary vitamin D deficiency and no supplements had the highest PHQ-9 score at 6 months (β=0.542) and shortest cardiac event-free survival among the 4 groups. “The most compelling finding of this study was that patients with heart failure who had dietary vitamin D deficiency and did not use vitamin D supplements had the highest risk for depressive symptoms and hospitalization or death due to cardiac problems compared to other groups, but only when patients had moderate to severe depressive symptoms,” the authors concluded. n • THE CLINICAL ADVISOR • OCTOBER 2017 11


HRT safe for menopause


Opioids and naloxone for pain management Co-prescribing naloxone and opioids in primary care may be recommended for patients who have a high risk for opioid overdose.


Opioid overdose is a risk when managing chronic pain patients in primary care.



early 308 million Americans see a clinician each year primarily because of pain. Of these, 100 million are living with chronic pain, or pain lasting longer than 3 months.1 An opioid prescription is given to 20% of patients who have nonmalignant acute or chronic pain. In 2012, clinicians wrote 259 million prescriptions for opioid analgesics, equal to the number of adults in the United States. From 2007 to 2012, the number of opioid prescriptions written increased 7.3% per capita. Rates of prescribing increased more in primary care practices than in specialty practices.2,3 More than 50% of patients who have received uninterrupted opioid therapy for 3 months are still receiving it after 4 years.3 After the implementation of strategies to reduce opioid prescribing, the number of prescriptions written decreased to 207 million in 2013.4 The increased use of opioid prescriptions to treat chronic pain has resulted in the rise of opioid use disorder, addiction, and abuse. In 2013, 1.9 million people in the United States met the criteria for opioid analgesic abuse or dependence, according to the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition.5 Patients at increased risk for opioid misuse and/or opioid use disorder include those with a history of behaviors such as seeking early refills and “doctor shopping,” a personal and family history of substance abuse, a history of sexual abuse during preadolescence, or comorbid psychiatric disorders.3 The nonmedical use of opioid analgesics and the reduction strategies instituted to eliminate the overprescribing of these agents has

led to an increase in heroin abuse. Most current heroin users were introduced to opioids as prescribed medications. Also, a major change has occurred in the demographic profile of persons with heroin addiction, who now comprise a populace that is older, more rural, and more gender equal, with fewer members of racial and social minorities.5 Paralleling the increase in the availability of opioid analgesics, opioid use disorder, and heroin use has been a rise in the number of deaths from prescription opioid overdose. Unintentional opioid analgesic overdose is a leading cause of accidental death in the United States.6 More than 16,000 deaths in the United States yearly are ascribed to prescription opioids.7 This is more than twice the number related to heroin use in 2013.8 As early as 2006, opioid drug poisoning deaths had surpassed the number of deaths related to heroin, cocaine, and psychostimulants collectively.4 Known contributing factors to opioid overdose include overprescribing by clinicians for the management of chronic pain, solicitation by patients from multiple providers or from profit-driven, high-volume pain management clinics (“pill mills”), and the nonmedical use of opioids by patients (ie, selling, sharing, and/or recreational use).9 As the dose of opioids increases, so does the death rate.5 Opioid overdose has become a major public health crisis in the United States. It has also contributed to a substantial financial burden. The annual medical costs of opioid poisoning total $72 billion.9,10 Patients at increased risk for overdose are those with medical comorbidities that have the potential to cause respiratory depression or failure (eg, sleep apnea, lung disease, heart failure); those receiving benzodiazepines or sedative-hypnotics; those with psychiatric comorbidities (eg, depression, anxiety); and those with problematic alcohol use.3 Opioid morbidity and mortality may be prevented through the early administration of an antidote.7 The administration of naloxone, an opioid antidote, by laypersons or nonmedical witnesses of an opioid emergency provides a quick, lifesaving intervention to someone who may die before emergency services arrive, especially in rural locations or in situations in which witnesses are afraid to call emergency services.9 The management of chronic pain is necessary and unavoidable in primary care, especially in rural or remote areas of the country where the number of pain specialists to whom patients can be referred is limited. Chronic pain is often managed in primary care. Thus, it is necessary for primary care providers to meet the needs of patients at high risk for opioid overdose by co-prescribing naloxone. Naloxone for opioid overdoses

Naloxone is a 40-year-old drug that the US Food and Drug Administration (FDA) approved in 2015 for the rapid reversal

of respiratory depression induced by heroin or prescription opioid overdose.11 Naloxone is a high-affinity, short-acting opioid mu-receptor antagonist. It produces a discernible pharmacologic action only if opioid agonists are present. In the United States, a prescription is required to distribute a sterile solution of naloxone for parenteral (injected or intranasal) administration.4,12 The recommended dose of naloxone is 0.4 mg, which may be repeated in 2 to 3 minutes if arousal is unsatisfactory after first administration.2,13 In July 2014, Kaleo launched Evzio®, a 1-mg/mL naloxone hydrochloride auto-injector. This drug and device combination product has an electronic audio system that voices stepby-step instructions on how to administer an intramuscular or subcutaneous tissue injection. A carton contains two 0.4-mg/0.4 mL auto-injectors and a reusable trainer device.14 Adapt Pharma has acquired the right to use the brand name for naloxone, Narcan®, for its naloxone nasal spray, which has received FDA approval for safety and efficacy.11,14 Clinicians have not widely adopted the co-prescription of naloxone with opioids or the distribution of naloxone kits and education to laypersons in the past for fear of legal ramifications. As of July 2016, there were 46 states with a naloxone access law. Prescribers have immunity from criminal action for prescribing, dispensing, or distributing naloxone to a layperson in 32 states and immunity from civil liability in 36 states. In 41 states, third-party individuals who may have the ability to respond quickly to an overdose are authorized to prescribe naloxone, and 40 states have legalized standing orders for naloxone to pharmacies and community-based naloxone dispensing programs. Laypersons are protected by Good Samaritan laws from criminal liability in 32 states and from civil liability in 40 states. In 14 states, there is no criminal liability if someone is discovered to be in possession of naloxone.15 As legal restrictions have decreased, financial restrictions have increased.14,16 A carton of Kaleo auto-injectors has been priced at four times the invoice price of a box of same-strength 2-mL naloxone syringes. Also, the cost of Amphastar Pharmaceuticals’ 10-pack container of 2-mL naloxone syringes has increased by 60%, whereas the price of Hospira’s 10-pack container of 1-mL vials (0.4 mg/mL) is half the Amphastar price. A 2-mL naloxone syringe that fits an atomizer for intranasal administration is priced at $50.14 Kits containing a single intramuscular dose of naloxone have cost the health department of Baltimore, Maryland, $40 each.16 As legislation expands, so does FDA approval of naloxone, and because research supports the use of naloxone for atrisk patients undergoing pain management with opioids, there is a push to allow over-the-counter (OTC) access to Continues on page 16 • THE CLINICAL ADVISOR • OCTOBER 2017 13


Opioid-related emergency department visits were lower in patients who received naloxone than among the patients who did not receive naloxone. naloxone with brief education or written instructions.12 To make naloxone even more accessible, Dr. Karen Mahoney in 2016 released the FDA opioid action plan initiative to identify ways to aid manufacturers in acquiring approval for an OTC version of naloxone.17 A consumer-friendly Drug Fact Label (DFL) is required. The FDA has developed a DFL model with simple icons that correspond to the label directions; these provide consumers with the information needed to use naloxone safely. As of December 2016, press releases by two popular US pharmacies, Walgreens and CVS, had announced the OTC distribution of naloxone in 24 and 30 states, respectively.18,19 The term OTC as used in the press releases is misleading, however. An individual wishing to purchase naloxone does not need a prescription in hand from a prescriber, but the participating pharmacies do, through a standing order or collaborative practice agreement.20 Naloxone use in the community

For more than 30 years, paramedics have used naloxone to reverse respiratory depression resulting from opioid overdose. It has proved to be effective and safe in the field.21 Opioid overdose and naloxone distribution (OEND) programs were first established in 1996, and their numbers have increased dramatically since then, with approximately 140 organizations known to provide naloxone kits to individuals at 644 sites in the United States in 2014.21 Evidence shows that laypersons who observe an overdose and have received appropriate education can and do use naloxone to reverse the effects of opioid overdoses.21 In one OEND program, the Baltimore Student Harm Reduction Coalition, it was found that the distribution of naloxone, together with training in intramuscular administration and the recognition of overdose risk factors and signs, successfully increased self-efficacy for overdose prevention and response. This self-efficacy persisted at 8 to 12 months after the completion of training.21 In a literature review, McDonald and Strang evaluated the association between take-home naloxone programs and overdose survival. The association was found to be strong, with a successful overdose reversal rate of 96.3% in 2336 cases in which take-home naloxone was administered. Coffin et al6 conducted a 2-year study of naloxone and opioid co-prescribing for high-risk primary care patients receiving long-term opioid pain therapy in San Francisco,

California. The numbers of opioid-related emergency department visits at 6 months and 1 year were found to be lower among the patients who received naloxone than in the patients who did not receive naloxone. At the US Army military installation at Fort Bragg, North Carolina, the number of emergency department visits for opioid overdose declined from eight to zero per month after naloxone coprescribing started.6,22 In North Carolina, Project Lazarus partnered a community-based prevention program with local clinicians in which naloxone was offered to suspected opioid abusers and to patients undergoing opioid treatment for pain who were considered to be at high risk for opioid overdose as part of their regular medical care. As a result of the co-prescribing and enhanced education for prescribers and laypersons, the number of opioid-associated deaths decreased by 50% in a single year.4,22 Therefore, researchers recommend that naloxone be co-prescribed to primary care patients being treated with opioids for pain, with emphasis placed on those who have established risk factors, including receiving higher doses of opioids and having a record of opioid-related emergency department visits in the past.6 The number of community-based organizations providing naloxone kits to individuals is increasing. Nonetheless, in 2013, there were 20 states that did not have an organization providing naloxone kits to laypersons, and nine states had fewer than one layperson per 100,000 who had received a naloxone kit. Of the 29 states with marginal or no layperson access to overdose rescue kits, 11 had overdose death rates higher than the national median, underscoring the need for naloxone and opioid co-prescribing in primary care clinics.8 In response to the idea that clinicians’ fear of offending patients creates a barrier to naloxone prescribing in primary care, Behar et al evaluated the experience of patients undergoing opioid treatment for chronic pain with naloxone and their reactions to the offer of a naloxone prescription.22 Overall, offers of naloxone prescriptions were acceptable to primary care patients receiving opioids. Most responded positively and believed that naloxone was appropriate. Furthermore, 60% of the patients had never heard of naloxone before the intervention, and more than one-third noted positive behavioral changes after receiving naloxone, with no negative behavioral changes. Behar et al propose that primary care clinicians may serve a population that community naloxone distribution does not reach, thus aiding a reduction in the morbidity and mortality of opioid poisoning.


Naloxone and opioid co-prescribing is not necessary for all patients whose chronic pain is being managed in primary care. Following the recommendations of the US Substance Abuse and Mental Health Services Administration, the American College of Emergency Physicians (ACEP) has issued guidelines for prescribing naloxone as an early antidote to at-risk patients in the following situations7: • Discharged from an emergency department after opioid overdose • Prescribed high-dose opioids or receiving chronic pain management • Prescribed a rotating opioid medication regimen • Having a history of substance abuse • Receiving extended-release/long-acting opioid preparation • Undergoing a court-ordered opioid detoxification or abstinence program • Newly released from prison and with a history of opioid abuse Proposal for co-prescribing in primary care

Primary care providers who care for patients with chronic pain must work to reduce opioid-related risks by using routine urine drug testing, assessing state prescription monitoring programs, implementing pill counts, practicing more cautious and constrained prescribing, and referring patients to substance abuse specialists after an assessment indicates deviant drug use behavior.4 The primary care provider must also protect high-risk patients whose pain is being managed with opioids against the potential for overdose. Offering naloxone kits to at-risk patients reduces overdose deaths, and the practice is safe and cost-effective. International and US


Which of the following statements do you most agree with? n=371

■ Naloxone should be available without a prescription. ■ Naloxone should be available only with a prescription. ■ I am concerned that increasing availability of naloxone will encourage the use of illicit drugs.

33.69% 46.9% 19.41%

For more polls, visit

health organizations consider that providing naloxone kits in primary care to individuals who may witness an opioid overdose, to patients in substance use treatment programs, and to persons being released from prison and jail is a component of responsible opioid prescribing.8 Naloxone and opioid co-prescribing is not necessary for all patients whose chronic pain is being managed in primary care; it is recommended only for patients at high risk for opioid overdose. Patients with any of the following factors are considered to be at high risk4: history or diagnosis of substance abuse, including alcohol abuse; need for high doses of opioids; being introduced to and/or continuing methadone; methadone has a long-half life, so the risk for toxic accrual is increased during therapy initiation; polypharmacy, especially co-administration of benzodiazepines; comorbid psychiatric disorders, especially an increased risk for suicide; and impairments of cognitive function that could result in the ingestion of excessive amounts of opioids. The Centers for Disease Control and Prevention also recommends that a history of overdose be considered a risk factor and defines a high opioid dose as one equal to or greater than 50 MME (morphine milligram equivalents) per day.2 The World Health Organization released guidelines for the community management of opioid overdose in 2014, adding to its list of high-risk opioid users those with other significant medical conditions (HIV infection, liver or lung disease) and members of the households of people taking high-dose opioids.13 Education is an essential component in training clinicians who are co-prescribing naloxone while treating high-risk patients with chronic pain. Training must be provided not only to the patient receiving the opioid and naloxone coprescription but also to laypersons who may be close to them (ie, family members, household members, friends). The training provided to potential overdose witnesses differs from the that given to the individuals who disclose opioid use. First, these persons do not use opioids themselves and may not be acquainted with substance use and signs of overdose. Thus, an opportunity to offer education regarding substance use and addiction to reduce stigma is recommended. Also, such training may encourage the third party to talk with the individual at risk for overdose about substance use and overdose. Therefore, training can be beneficial in teaching the third party to provide support beyond the administration of naloxone.21 • THE CLINICAL ADVISOR • OCTOBER 2017 17


Naloxone education should include how to identify an overdose, call emergency services, and administer naloxone.4 Evidence has shown that education can be provided briefly as well as at length.4,12 It can be provided by a clinician directly, sent to the patient’s home in written form, or recorded and delivered by a rescue device.4 Screening tools to identify at-risk patients, standardized prescribing guidelines to help providers prescribe naloxone appropriately, and patient education resources are available at PrescribeToPrevent (

9. Mitchell KD, Higgins LJ. Combating opioid overdose with public access to naloxone. J Addictions Nurs. 2016;27(3):160-179. 10. Addressing prescription drug abuse in the United States: current activities and future opportunities. US Department of Health and Human Services. abuse_report_09.2013.pdf. Accessed July 17, 11. FDA moves quickly to approve easy-to-use nasal spray to treat opioid overdose. US Food and Drug Administration. http://www.fda. gov/NewsEvents/Newsroom/PressAnnouncements/ucm473505.htm. Published November 18, 2015. Accessed July 17, 2017. 12. Behar E, Santos G, Wheeler E, Rower C, Coffin PO. Brief overdose


education is sufficient for naloxone distribution to opioid users. Drug

Overdose is a risk in the management of chronic pain with opioids in primary care. Because clinicians are on the front lines in the care of patients with chronic pain in rural and remote areas, it is essential that these clinicians institute the practice of providing prescriptions for naloxone along with opioids in their protocols for the treatment of patients at high risk for opioid poisoning. Further research on the use of naloxone co-prescribing in primary care is encouraged in the realm of nursing because few data are currently available in primary care medicine or nursing. Furthermore, it is essential that clinicians in primary care lobby for broader naloxone access. n

Alcohol Depend. 2015;148:209-212. 13. Community management of opioid overdose. World Health Organization. Published 2014. Accessed July 17, 2017. 14. Thompson CA. Naloxone access increases, as does price. Am J Health Syst Pharm. 2015;72:1426-1427. 15. Naloxone overdose prevention laws. The Policy Surveillance Program: A LawAtlas Project. Accessed July 17, 2017. 16. Johnson, SR. Price hikes hamper use of naloxone against opioids. Modern Healthcare. Published September 3, 2016. Accessed July 17, 2017.

Lesley Cooper, DNP, FNP-C, is a nurse practitioner currently residing in Bahrain.

17. Mahoney K. FDA supports greater access to naloxone to help reduce opioid overdose deaths. US Food and Drug Administration. FDA Voice. https://


access-to-naloxone-to-help-reduce-opioid-overdose-deaths/. Published

1. American Academy of Pain Medicine. AAPM facts and figures on pain. http://

August 10, 2016. Accessed July 17, 2017. Accessed July 17, 2017.

18. Walgreens enables no-Rx access to naloxone in Louisiana. Chain

2. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids

Drug Review.

for chronic pain – United States, 2016. MMWR Recomm Rep. 2016;65:1-49.

access-to-naloxone-in-louisiana. Published November 23, 2016. Accessed

3. Lembke A, Humphreys K, Newmark J. Weighing the risks and benefits

July 17, 2017.

of chronic opioid therapy. Am Fam Physician. 2016;93:982-990.

19. CVS Health makes overdose-reversal drug naloxone available without

4. Coe MA, Walsh SL. Distribution of naloxone for overdose prevention

a prescription in Idaho. CVS Health.

to chronic pain patients. Prev Med. 2015;80:41-43.


5. Compton WM, Boyle M, Wargo E. Prescription opioid abuse: problems

able-without. Published August 12, 2016. Accessed July 17, 2017.

and responses. Prev Med. 2015;80:5-9.

20. Davis C. “Over the counter” naloxone access, explained. The Network

6. Coffin PO, Behar E, Rowe C, et al. Nonrandomized intervention study

for Public Health Law.

of naloxone coprescription for primary care patients receiving long-term


opioid therapy for pain. Ann Intern Med. 2016;165:245-252.

Published March 1, 2016. Accessed July 17, 2017.

7. American College of Emergency Physicians. Naloxone prescriptions by

21. Lewis DA, Park JN, Vail L, Sine M, Welsh C, Sherman SG. Evaluation

emergency physicians. Ann Emerg Med. 2016;67:149-150.

of the overdose education and naloxone distribution program of the

8. Wheeler E, Jones S, Gilbert MK, Davidson PJ; Centers for Disease

Baltimore Student Harm Reduction Coalition. Am J Public Health.

Control and Prevention (CDC). Opioid overdose prevention programs


providing naloxone to laypersons – United States, 2014. MMWR Morb

22. Behar E, Rowe C, Santos G, Murphy S, Coffin PO. Primary care patient

Mortal Wkly Rep. 2015;64:631-635.

experience with naloxone prescription. Ann Fam Med. 2016;14:431-436.



Preventing sudden death in young athletes Hypertrophic cardiomyopathy, myocarditis, valvular heart disease, and dilated cardiomyopathy are among the most common causes.


Hypertrophy of the cardiac interventricular septum.


udden death (SD) in individuals between the ages of 12 and 25 years (particularly those participating in organized sports activities) may not be a common occurrence, but it is a particularly devastating event for families and communities.1 Even though SD can occur in any population, most discussions of SD focus on young athletes. Although a mandatory reporting system for SD in young people is lacking, SD in young athletes arouses considerable public interest. Vigorous physical activity in young persons with undetected cardiovascular risk factors increases their risk for SD.1 The harsh reality is that SD occurs in 1 of every 53,703 college athletes yearly in the United States, with the majority of these deaths occurring in male athletes of Afro-Caribbean descent.1-3 The most common cause of SD in young people is hypertrophic cardiomyopathy (HCM), although congenital coronary anomalies, myocarditis, valvular heart disease, dilated cardiomyopathy, Wolff-Parkinson-White (WPW) syndrome, and ion channelopathies are also seen in a small number of cases of SD.1,2 Table 1 lists the pathophysiology, risk factors, and presentation of some of the common causes of SD in young athletes. However, it is important to keep in mind that this number of deaths is relatively low compared with the number of deaths from other causes in the same age group.1 Preparticipation screening

It is a common practice in the United States for individuals participating in sanctioned sports in • THE CLINICAL ADVISOR • OCTOBER 2017 19


high school and college to undergo some type of preparticipation screening to detect factors associated with a high risk for injury and/or death; however, this screening process has yet to be standardized.1 In 2014, the American Heart Association (AHA) and the American College of Cardiology (ACC) published recommendations for the screening of young people to detect cardiovascular disease, along with the role of 12-lead electrocardiography (ECG) in such screening. To assist in the detection of the genetic and congenital cardiac conditions that are largely responsible for SD, the recommendations include 14 elements that should be evaluated during the preparticipation history and physical examination that are mandatory for all athletes wishing to participate in competitive sports. In the position paper, the AHA and ACC make it clear that they do not currently support universal 12-lead ECG testing in asymptomatic individuals.1 However, the importance of automated external defibrillators (AEDs) in responding to cardiac emergencies is stressed, and AEDs are considered an invaluable tool in the prevention of death.2

The 14 elements that the AHA and ACC recommend be included in the preparticipation screening of competitive athletes cover personal history, family history, and a physical examination. The personal history should include information regarding the following: exertional chest pain or discomfort; unexplained syncopal or near-syncopal episodes; exertional dyspnea, fatigue, or palpitations; prior history of a heart murmur; hypertension; prior restrictions on sports activities; and prior cardiovascular evaluation. The family history should be evaluated for the following: death of a first-degree relative before the age of 50 years that was attributed to heart disease; disability of a close relative before the age of 50 years due to heart disease; and a family history of HCM, dilated cardiomyopathy, long-QT syndrome or other ion channelopathies, Marfan syndrome, clinically significant arrhythmias, or other genetic cardiac conditions. A positive response to even one of these questions can be sufficient to require a referral for a more comprehensive cardiovascular evaluation. The examiner should take care

TABLE 1. Some common causes of sudden death in young people Cause


Risk factors

Hypertrophic cardiomyopathy

Autosomal-dominant genetic condition • Family history of hypertrophic resulting in left ventricular hypertrophy cardiomyopathy in combination with disproportionate • Abnormal blood pressure thickening of the interventricular septum response to exercise • History of nonsustained ventricular tachycardia

• Most cases asymptomatic • Dyspnea • Chest pain with exertion • Exercise intolerance • Syncope • Arrhythmias • Systolic heart murmur


Inflammation of the myocardium, most commonly caused by coxsackievirus group B infection

• Fever • Myalgias • Exertional dyspnea

Valvular heart disease

Dysfunction of the heart valves • History of rheumatic heart disease resulting from any number of disorders, • Family history of valvular disorders including congenital defects, trauma, • History of congenital heart defects and inflammation

• Murmur • Dyspnea • Palpitations • Chest pain • Weakness • Fatigue

Dilated cardiomyopathy

Ventricular enlargement with a reduction of ventricular wall thickness and impairment of systolic function, which can be inherited, idiopathic, or caused by infections or exposure to toxins

• Dyspnea • Orthopnea • Decreased exercise tolerance

• Recent viral, bacterial, or fungal infection • History of autoimmune diseases • History of acquired immunodeficiency syndrome (AIDS)

• Family history of dilated cardiomyopathy • History of exposure to environmental toxins

Adapted from Cornelius J.8



to ensure the accuracy of the responses when appropriate. Finally, the physical examination should at minimum include the following: an assessment for organic murmurs with the patient in the supine and standing positions, an assessment of the femoral pulses and blood pressure, and a search for the physical signs and symptoms of Marfan syndrome.1,4 A screening tool based on these 14 elements is shown in Figure 1 that can assist examiners in completing the preparticipation screening of young athletes for cardiovascular risks. Identifying at-risk athletes

The AHA and ACC state that covering the 14 elements can be useful in identifying at-risk athletes; however, available data show that this method tends to be insensitive in identifying athletes at risk for SD for various reasons, the most important of which is the frequent lack of physical findings in ion channelopathies, WPW syndrome, and some of the less common structural cardiac diseases that can be responsible for SD. However, the technique can be more successful

in identifying athletes with HCM. In fact, a systolic heart murmur (indicating left ventricular outflow obstruction) is identified in 25 percent of individuals with HCM while they are at rest, and in an additional 50 percent while they are a standing position or during the Valsalva maneuver. This finding is important to consider because HCM is the most common cause of SD. Additionally, most at-risk athletes have warning signs and symptoms of HCM. However, such symptoms must be reported accurately if they are to be taken into consideration. The frequent lack of disclosure of important symptoms, such as chest pain and syncopal episodes, can prevent the identification of risk factors. Finally, it can be challenging for the examiner to determine the importance of the history and physical examination findings. Differentiating between a functional and an organic heart murmur can be difficult, as can determining whether or not chest pain is a significant finding.1 Table 2 lists for examiners the characteristics of pathologic murmurs and their associated conditions.

FIGURE 1. Preparticipation screening checklist for examiners attempting to detect cardiovascular risk factors in young athletes. (Adapted from Maron et al.1) Family History



  1. Has premature (before 50 years of age) cardiac death occurred in any close family member (male or female)?   2. Has any close family member had a disability from heart disease before 50 years of age?   3. H  as hypertrophic cardiomyopathy, Marfan syndrome, an arrhythmia, or long-QT syndrome been diagnosed in a family member, or does a family member have specific knowledge of another genetic cardiac condition? Personal History   4. Have you experienced chest pain or discomfort, chest tightness, or chest pressure related to exertion?   5. Have you had any unexplained loss of consciousness?   6. Have you had any unexplained shortness of breath, fatigue, or palpitations associated with exercise?   7. Have you ever been told that you have a heart murmur?   8. Have you ever been told that you had an elevated blood pressure?   9. Do you have any prior restrictions on participation in sports? 10. Has a physician ever previously ordered any testing for your heart? Physical Examination 11. Organic heart murmur detected in the supine and/or standing position during auscultation? 12. A  ny signs of Marfan syndrome, such as pectus excavatum or carinatum, scoliosis, disproportionately long limbs, or musculoskeletal abnormalities? 13. Are the femoral pulses diminished or absent? 14. Is any difference between the brachial artery blood pressures of 15 mm Hg or greater detected when the pressures are obtained in both arms with the patient in the sitting position? • THE CLINICAL ADVISOR • OCTOBER 2017 21


Despite the readily apparent insensitivity of the history and physical examination, the AHA and ACC still do not think that mass screening with 12-lead ECG will improve the identification of at-risk athletes.1 The data regarding the efficacy of 12-lead ECG screening in reducing SD are too conflicting to support 12-lead ECG screening once the financial and logistical burden of a widespread screening program has been taken into consideration. Administering 12-lead ECG to all young athletes would cost $51 billion to $69 billion dollars a year.2 In addition, the results of 12-lead ECG may not be abnormal in the setting of dangerous cardiovascular abnormalities, and alterations on 12-lead ECG do not always indicate a pathologic process.1,2 Physiologic processes can often mimic pathologic processes on ECG, resulting in false-positive results, and false-negative results can be seen in more than 10 percent of patients who have HCM, with completely normal findings in a significant number of these individuals.1 In addition, the interpretation of ECG results varies according to the knowledge and skills of the interpreter, further increasing their lack of reliability.2 Finally, the AHA and ACC note that mass screening with 12-lead ECG does not meet the World Health Organization (WHO) criteria for screening because 12-lead ECG is not a “a precise, validated, and suitable screening test known to reliably distinguish the affected from the nonaffected.”1 For the reasons presented above, the AHA and ACC stand by their recommendation for use of the 14 elements to screen all athletes. Athletes who are thought to be at risk on the basis of the history and physical examination should then be referred for aggressive follow-up testing (including 12-lead ECG) with appropriate specialists.1,2 It is strongly felt that standardization of

the questionnaire that examiners use for preparticipation evaluations is necessary to improve consistency among examiners. The recommendation remains that universal mass screening of all individuals 12 to 25 years of age, whether by history and physical examination or 12-lead ECG, is not necessary.1 Evaluating risk factors for sudden death remains difficult

Even with the AHA and ACC recommendations regarding the 14 elements, evaluating the risk factors for SD in young athletes remains difficult. The preliminary or screening examinations, including family history, personal history, physical examination, and even 12-lead ECG, are primary tools to prevent SD in young athletes. Although primary prevention tools have been the major focus of the AHA and ACC, false-negative and false-positive results continue to be a major issue limiting their effectiveness.5 Because a measurement of true risk has not been established to date and because events are often spontaneous, secondary prevention strategies must be implemented to achieve a significant reduction in overall mortality.3,5 Having AEDs available in high-risk areas, along with individuals trained in cardiopulmonary resuscitation (CPR) and emergency management, is necessary to respond effectively to unpredictable events. According to Piper and Stainsby, secondary prevention strategies have received less attention than primary prevention strategies, especially in high school sports; however, the recent changes in the CPR guidelines support the need for an increased focus on secondary prevention and the use of AEDs.5 The AHA guidelines for CPR have shifted from airway, breathing, and chest compression (ABC) to chest

TABLE 2. Pathologic heart murmurs and associated conditions Type of murmur


Associated conditions


Begins in systole and continues into diastole; harsh, machine-like sound heard at the upper left sternal border

Patent ductus arteriosus (PDA)


Loudest at left ventricular border; radiates to base of heart or to axilla and back; best heard in left lateral decubitus position

Mitral valve regurgitation (MVR)

Early diastolic

Regurgitant flow through an incompetent valve; high-frequency sound beginning during S2 heard at 3rd and 4th left intercostal spaces and apex

Aortic regurgitation, pulmonary regurgitation


Disturbed inflow in stenotic valve or high volume in nonstenotic mitral or tricuspid valve; heard best over apex and left mid precordium with bell of stethoscope

Ventricular septal defect (VSD), atrial septal defect (ASD)

Late diastolic

Narrowing of atrioventricular valve; begins after S2 and extends to S1 in a crescendo

Mitral stenosis (MS)

Adapted from Crawley S.9


compression, airway, and breathing (CAB) techniques for emergency cardiovascular care.5 With this recommendation that chest compression begin immediately, the availability of AEDs at high school sports events is paramount. The overall goal of the AHA is to reduce mortality rates by applying CPR and defibrillation within 3 to 5 minutes.6 Practice guidelines for incorporating an emergency response, the availability of trained staff, and the distribution of AEDs have the potential to increase survival rates.7 Although the guidelines differ in their approaches to reduce the risk for SD, a holistic approach incorporating updated screening techniques as primary prevention and emergency management as secondary prevention can decrease overall mortality rates. n Angelique B. Allemand, DNP, RN, ACNP-BC, FNP-C, CNS, is an associate professor of nursing at Nicholls State University, and Bridget Miller Guidry, DNP, FNP-C, WHNP-C, RN, is an associate professor of nursing at Nicholls State University in Thibodaux, Louisiana.

“Who’s been nibbling at my kale house?”

References 1. Maron BJ, Friedman RA, Kligfield P, et al. Assessment of the 12-lead ECG as a screening test for detection of cardiovascular disease in healthy ment from the American Heart Association and the American College of Cardiology. Circulation. 2014;130:1303-1334. 2. Jacob JA. Interassociation task force punts decision on universal ECG screenings for athletes. JAMA. 2016;316:19-21. 3. Schmied C, Borjesson M. Sudden cardiac death in athletes. J Intern Med. 2014;275:93-103. 4. Hauk L. Preparticipation screening for CVD in competitive athletes: recommendations from the AHA/ACC. Am Fam Physician. 2016;94:170. 5. Piper S, Stainsby B. Addressing the risk factors and prevention of sudden cardiac death in young athletes: a case report. J Can Chiropr Assoc. 2013;57:350-355. 6. Higgins J, Ananaba I, Higgins C. Sudden cardiac death in young athletes: preparticipation screening for underlying cardiovascular abnormalities and approaches to prevention. Phys Sportsmed. 2013;41:81-93. 7. Garritano N, Willmarth-Stec M. Student athletes, sudden cardiac death, and lifesaving legislation: a review of the literature. J Pediatr Health Care. 2015;29:233-242. 8. Cornelius J. Disorders of cardiac function. In: Grossman SC, Porth CM, eds. Porth’s Pathophysiology: Concepts of Altered Health States. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014:665-667. 9. Crawley S. Diastolic murmurs. In: Walker HK, Hall WD, Hurst JW, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston, MA: Butterworths; 1990. NBK346/. Accessed July 8, 2017.

“You’re in his blind spot.” • THE CLINICAL ADVISOR • OCTOBER 2017 23

Top, bottom: © The New Yorker Collection 2017 from All Rights Reserved. Middle: © Harley Schwadron, 2017.

general populations of young people (12-25 years of age): a scientific state-


n EDUCATIONAL OBJECTIVES As a result of participating in the activity, learners should be better able to: • Select the appropriate direct-acting antiviral agent (DAA) for hepatitis C virus (HCV) infection based on viral genotypes (and subtype) and associated complications • Identify the emergence of HCV resistance-associated variants (RAVs) following treatment with selected DAA regimens • Implement strategies, including the spectrum of molecular testing protocols, to identify and monitor disease progression and treatment efficacy and potentially avert HCV treatment resistance • Facilitate better linkage of care among specialists and other providers to strengthen screening, treatment, and monitoring practices, particularly for underserved and marginalized populations n COMPLETE THE POSTTEST: Page 34

Release Date: August 29, 2017 Expiration Date: August 29, 2018 Estimated Time to Complete: 30 minutes Accredited Provider: This activity is provided by Haymarket Medical Education. Commercial Supporter: This activity is supported by an educational grant from Quest Diagnostics. Program Description: Over the last few years, a number of rapidly evolving new treatment options for chronic hepatitis C virus (HCV) infection have become available, including the emergence of new direct-acting antiviral agents (DAAs). Treatment with these DAAs—which include 3 NS3-4A protease inhibitors, 5 NS5A inhibitors, and 2 NS5B polymerase inhibitors in multiple combination regimens for the management of 6 HCV genotypes—has led to dramatic advances in terms of treatment efficacy, with sustained viral response (SVR) rates greater than 95% and minimal associated side effects. Although monitoring of clinical response and adverse events has been greatly simplified, many factors should be considered to determine the most appropriate DAA regimen, such as HCV genotype (including associated subtypes). Identifying genotype at baseline to differentiate treatment failure or re-infection has an important role. Assessment of liver fibrosis in HCV infection also is considered a relevant part of patient care and key for decision making. Intended Audience: Gastroenterologists, hepatologists, infectious disease specialists, internists, primary care clinicians, and other healthcare providers (HCPs) who treat patients with hepatitis C Conflict of Interest Disclosure Policy: In accordance with the ACCME Standards for Commercial Support, HME requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. HME resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational activities. Faculty Nancy Reau, MD Professor of Medicine Chief, Section of Hepatology Associate Director, Solid Organ Transplantation Rush University Medical Center Chicago, IL Dr. Reau is a consultant for AbbVie Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., and Merck & Co. She receives research funds from AbbVie Inc., Genfit SA, Shire, and TARGET PharmaSolutions.

Accredited Provider Disclosure: Haymarket Medical Education staff involved in the planning and content review of this activity have no relevant financial relationships to disclose. Accreditation Statement: Haymarket Medical Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Designation Statement: Haymarket Medical Education designates this enduring material for a maximum of 0.50 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Disclosure of Unlabeled Use: This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options for a specific patient’s medical condition. Disclaimer: The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Haymarket Medical Education and Quest Diagnostics. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Instructions: There are no fees for participating in and receiving CME credit for this activity. During the period August 29, 2017 through August 29, 2018, participants must: 1) read the learning objectives and faculty disclosures; 2) complete the preassessment test; 3) study the educational activity; and 4) complete the posttest and submit it online. A statement of credit will be issued only upon receipt of the above elements and a posttest score of 70% or higher. All components must be completed and submitted online at Oct17feature. If you have any questions relating to the CME certification of this activity, please contact HME at If you have any questions relating to your certificate or other issues with this activity, please contact Provided by



The spectrum of molecular testing protocols for HCV Implementation of strategies to identify and monitor hepatitis C virus progression and treatment efficacy are key to averting therapy resistance.


Hepatitis C viral protease molecule


epatitis C virus (HCV) infection leads to significant morbidity and increased mortality.1,2 The infection causes hepatic fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) and is currently the most common indication for liver transplantation in the United States.1,2 Data gathered from 1999 to 2002 yielded a US prevalence estimate of 4.1 million persons with HCV, most of them “baby boomers” born between 1945 and 1964.1,3 Today, however, HCV should no longer be viewed as the “baby-boomer virus.” The Centers for Disease Control and Prevention (CDC) has estimated 33,900 new HCV infections in 2015, with some states particularly hard hit (Figure 1).4 HCV is occurring in younger people, as evidenced by a spike in infections among pregnant women in Appalachia.5,6 Injection drug use is the primary risk factor for new infections.4,7 New cases of HCV infection are occurring at a time of unprecedented treatment options. We have curative antiviral therapies, and we know how to target these therapies to HCV genotype. However, several issues compromise our ability to cure HCV infection, including patient identification, access to therapy, and the specter of antiviral drug resistance. On the road to a cure, the clinician must forge ahead with treatment while remaining vigilant for the roadblocks of resistance and nonadherence. Laboratory testing is crucial to that effort, as the following case study shows. • THE CLINICAL ADVISOR • OCTOBER 2017 25



FIGURE 1. Acute hepatitis C virus infection incidence rate ratiosa — United States,b 20154

5A (NS5A) resistance-associated substitutions (RASs), conducted to determine appropriate treatment and duration, is negative. Brett was not co-infected with HIV or hepatitis B virus (HBV) infection (HBsAg-negative, HBcAb-negative, and HBsAb-positive). POLLING QUESTION

Which of the following would you recommend as an initial approach to Brett’s therapy? (Select all that apply.)

>1.9 0.6-1.9 <0.6 Not available a

The national rate (0.8 per 100,000 population) is the denominator. Seven states have rates at least twice the national average: Indiana, Kentucky, Maine, Massachusetts, New Mexico, Tennessee, and West Virginia. Ten states have rates above the national average (but not twice the national average): Alabama, Montana, New Jersey, North Carolina, Ohio, Oklahoma, Pennsylvania, Utah, Washington, and Wisconsin.



Patient identification Brett is a 39-year-old male in recovery from injectable opioid abuse. At last month’s county fair, Brett visited an HCV screening booth. His screening test was positive, and he was instructed to see a physician. Diagnostic workup Brett visits a primary care physician (PCP) at a local healthsystem clinic. Physical examination is unremarkable. History includes 3-year abstinence from injectable drugs and no report of chronic medical illness. Complete blood count values are all within normal ranges, including hemoglobin at 15.3 g and hematocrit at 49.0. Serum chemistries showed mild elevation of alanine transaminase (ALT) and aspartate transaminase (AST) at 2 times the normal range. HCV infection is confirmed by replication of a screening test, and Brett is referred to a physician at a health system in a nearby city. Workup after referral included quantitative RNA HCV levels and genotype testing. Viral load is 7 million IU/mL, and the genotype is 1a. A FibroTest (known as FibroSure in the United States) assessment of fibrosis and inflammation yields a score of 0.52 (METAVIR F2), indicative of moderate hepatic fibrosis.8 Baseline testing for nonstructural protein

a. Sofosbuvir (400 mg) once daily and weight-based ribavirin for 24 weeks b. Ledipasvir (90 mg)/sofosbuvir (400 mg) once daily for 12 weeks c. Ledipasvir (90 mg)/sofosbuvir (400 mg) once daily for 8 weeks d. Elbasvir (50 mg)/grazoprevir (100 mg) once daily for 12 weeks

Initial treatment Brett’s physician prescribes ledipasvir (90 mg)/sofosbuvir (400 mg) once daily, which is indicated for genotype 1a HCV. Given that Brett has a viral load greater than 6 million IU, therapy is recommended for 12 weeks. 4-week follow-up Repeat quantitative HCV RNA testing shows a reduction in viral load to 15 IU. Brett reports 2 adverse events (AEs), fatigue and insomnia, but he is not sure whether these AEs are the result of treatment or due to the stress imposed by a busy schedule at work and a gravely ill relative. Brett is asked to continue with therapy. POLLING QUESTION

Which of the following risks could you anticipate and try to mitigate, based on Brett’s 4-week visit? (Select all that apply.) a. b. c. d.

Risk of poor adherence to therapy due to psychosocial stresses Risk of poor adherence to therapy as the result of AEs Risk of antiviral drug resistance Risk of HBV reactivation

12-week follow-up End-of treatment HCV RNA testing reveals a viral load somewhat higher than the 4-week levels. Brett admits to taking his medication only intermittently after week 6, due to extra shifts at work and a death in the family. Testing for antiviral drug resistance is performed again, and this time comes back as “probable” for genotype 1a NS5A drug resistance. Brett and his physician decide to defer another round of treatment, but schedule an appointment for later in the year


to discuss an appropriate second-line ribavirin-containing regimen. Brett expresses concern about the costs of retreatment and the need to miss more workdays to come to the city for care. SUMMARY OF GUIDELINES FOR TESTING

Brett’s case illustrates the need for laboratory testing at every juncture in the clinical course. Testing shown is in accordance with joint guidelines issued by the AASLD/IDSA (Table 1).9 The CDC also has recommendations for testing in persons born between 1945 and 1965, and a testing update was issued in 2013.13,14 TESTING-GUIDED MANAGEMENT OF HCV INFECTION

Screening The CDC, AASLD/IDSA, and the US Preventive Services Task Force (USPSTF) all recommend one-time HCV screening in the baby-boomer population (individuals born from 1945 to 1965).9,13,15 Risk-benefit analysis conducted by the USPSTF determined moderate net benefit from screening in this birth cohort.15 The primary benefit is that antiviral drug regimens produce an SVR, with improved clinical outcomes.14 This benefit outweighs potential harms such as antiviral drug AEs or complications of liver biopsy; use of liver biopsy is decreasing, as clinicians opt for minimally invasive laboratory tests and elastography to assess hepatic fibrosis and cirrhosis.15 Birth-cohort screening (birth years 1946 to 1970) has been projected to result in 84,000 fewer cases of cirrhosis, 46,000 fewer cases of HCC, and 10,000 fewer liver transplants.16 Compared with risk-based screening, this birthcohort screening reduces estimated overall costs due to an aggregate reduction in advanced liver disease with treatment.16 The rise in injection drug use in the United States has produced a rise in young adult HCV infections.4,17 Screening for HCV infection is recommended in this risk group,9 and it is also recommended in intranasal illicit drug users, persons who have been incarcerated, those tattooed in unregulated settings, and persons with HCV-infected blood or tissue exposure through medical care or work.9 To screen, a sample should be tested for HCV antibody (antiHCV) with US Food and Drug Administration (FDA)-approved laboratory-based and point-of-care assays.9,14 A test that reflexes to HCV polymerase chain reaction (PCR) is advocated to improve diagnostic accuracy and evidence of current infection.9 Workup Patient assessment also includes an examination, laboratory testing, and imaging studies that verify current HCV

TABLE 1. Summary of AASLD/IDSA testing guidelines9 Recommendation

Evidence rating

One-time HCV screening in: All persons born from 1945 to 1964 with no ascertainment of risk

Class I, Level B

Other persons with HCV risk factors (eg, injection drug use)

Class I, Level B

Testing to follow up initial positive screen: Confirm current infection with sensitive HCV RNA test

Class I, Level A

Test for HCV genotype

Class I, Level A

Testing prior to initial treatment: Test for staging of hepatic fibrosis

Class I, Level C

Tests for CBC, hepatic function panel, calculated GFR and, if interferon use is planned, TSH

Class I, Level C

If DAA use is planned, HBV co-infection test

Class IIa, Level B

Baseline test for NS5A RAS in genotype-1– infected patients

Class IIb, Level B

Testing in the event of NS5A treatment failure: Test for resistance-associated variants conferring decreased susceptibility to NS3 protease inhibitors and to NS5A inhibitors in patients with HCV genotype

Class IIb, Level C

AASLD, American Association for the Study of Liver Diseases; CBC, complete blood count; DAA, direct-acting antiviral agent; GFR, glomerular filtration rate; IDSA, Infectious Diseases Society of America; HBV, hepatitis B virus; HCV, hepatitis C virus; NS3, nonstructural protein 3; NS5A, nonstructural protein 5A; RAS, resistance-associated substitution; RNA, ribonucleic acid; TSH, thyroid-stimulating hormone.

infection; establish genotype; assess overall health, hepatic function, and other end-organ function; and ascertain the presence of antiviral drug resistance.9 HCV RNA. Once a patient has a positive antibody test, the clinician must use HCV RNA testing to confirm a current, active infection that requires treatment (Figure 2).9,14 The recommended testing modality is an FDA-approved nucleic-acid test.9 Genotype. The patient should also have genotype testing, because determining which HCV genotype is associated with a patient’s infection provides data crucial to treatment selection.9 HCV is characterized by genomic heterogeneity, and the • THE CLINICAL ADVISOR • OCTOBER 2017 27



FIGURE 2. CDC-recommended testing sequence for identifying current HCV infection9,14

HCV antibody




Not detected


No HCV antibody detected

Current HCV infection

No current HCV infection


Link to care

Additional testing as appropriateb

CDC, Centers for Disease Control and Prevention; HCV, hepatitis C virus. a For persons who might have been exposed to HCV within the past 6 months, testing for HCV RNA or follow-up testing for HCV antibody is recommended. For persons who are immunocompromised, testing for HCV RNA can be considered. b To differentiate past resolved HCV infection from biologic false positivity for HCV antibody, testing with another HCV antibody assay can be considered. Repeat HCV RNA testing if the person tested is suspected to have had HCV exposure within the past 6 months or has clinical evidence of HCV disease, or if there is concern regarding the handling or storage of the test specimen.

genomic sequence of different HCV isolates can vary by up to 35%.18,19 This heterogeneity explains both viral persistence and the difficulties in developing an HCV vaccine.17 Hepatic fibrosis and inflammation. Elevated hepatic transaminases, when identified in an asymptomatic patient, are a signal of hepatic inflammation.20 ALT elevation can be indicative of hepatocellular damage in HCV infection, but data suggest that ALT alone may not be a useful surrogate marker for hepatic fibrosis and inflammation.21 Thus, evaluation of fibrosis and inflammation requires specific diagnostic modalities, such as laboratory testing or elastography. Biopsy, while certainly an accurate method, is generally avoided if possible in the clinical setting due to risk of complications.9

Serum fibrosis marker panels provide evidence of the degree of liver injury.7 Results can be reported relative to a scale—eg, the METAVIR scale score—used to interpret liver biopsies. Panel composition may include tests for α-2-macroglobulin (α-2-M), apolipoprotein A1 (Apo A1), haptoglobin, collagen markers, and matrix metalloproteinases (MMPs), along with conventional studies of liver transaminases and bilirubin.22 Liver elastography can reliably assess the likelihood of cirrhosis9; liver stiffness observed via elastography correlates strongly with histologic fibrosis stage in HCV infection.23 A recent consensus statement from the Society of Radiologists in Ultrasound (SRU) considers the various elastography techniques—transient elastography (TE) and acoustic radiation force impulse (ARFI)—to be equivalent, with a few investigators suggesting greater accuracy with ARFI.23 In many patients, it may not be necessary to obtain both serum fibrosis marker panels and elastography, and cost and convenience factors can be considered.21 Research has shown that combining the FibroTest panel with TE (FibroScan) or ARFI produces high diagnostic accuracy, with the caveat that FibroTest and ARFI have demonstrated a comparable ability to detect cirrhosis.24-28 Baseline resistance prior to initial treatment. Testing for polymorphism that can trigger antiviral drug resistance should also be part of the initial workup in genotypes 1a and 3.9 RAS testing is crucial in treatment-naïve patients and in retreatment to identify therapy that would confer optimal efficacy.9 (Testing for resistance in treatment-experienced patients is described below.) About 10% to 15% of genotype 1–infected patients (13% and 18%, respectively, for genotypes 1a and 1b) without prior exposure to NS5A-inhibiting antivirals have detectable NS5A RASs.8,29 This can cause a reduction in the activity of NS5A inhibitors sufficient in some cases to diminish efficacy of treatment.9 For example, baseline NS5A RASs are a predictor of poorer treatment outcomes with the NS5A-containing dual regimen elbasvir/grazoprevir in genotype 1a.9,30 Therefore, testing for NS5A RASs is recommended prior to initiation of elbasvir/grazoprevir for patients with HCV genotype 1a.9 Moreover, in patients considered for therapy with elbasvir/ grazoprevir, the AASLD/IDSA recommends treatment extension to 16 weeks instead of the usual 12 weeks with the addition of weight-based ribavirin, based on clinical evidence.9,31 In addition, NS5A testing prior to initiation of daclatasvir plus sofosbuvir should be considered for patients with genotype 1a and cirrhosis.32 Rare RASs (2.5% incidence) to sofosbuvir, an NS5B polymerase inhibitor, have also been reported in a study of resistance to ledipasvir/sofosbuvir.33


The AASLD/IDSA guidelines also recommend HCV genotype 3 NS5A drug resistance testing prior to prescribing daclatasvir- or velpatasvir-containing regimens for patients with cirrhosis.9 (Also see Treatment selection: presence or absence of cirrhosis.) Other RASs to second-generation protease inhibitors have seldom been detected in genotype 1.33 Within the NS5A gene, RASs were identified in 7.1% and 17.6% of genotype 1a and 1b, respectively.34 RASs to non-nucleoside NS5B inhibitors were reported in 3.5% and 44.4% of genotype 1a and 1b patients, respectively.32 Moreover, NS3 genotype testing is strongly recommended for patients with HCV genotype 1a infection before prescribing simeprevir and should be considered for those with Q80K polymorphism.35 In the NS3 gene, Q80K polymorphism has been reported in 34.7% and 2.1% of genotype 1a and 1b patients, respectively.34 A finding of baseline resistance always raises the question of prognostic impact. Q80K polymorphism does not have a clinical impact in all-oral therapy.9,36,37 Reverse transcription PCR and DNA sequencing assays are effective in identifying resistance to NS5A-inhibitor therapy directed to genotype 138 and genotype 339,40; to NS5B-inhibitor therapy (ie, sofosbuvir) for genotype 1a or 1b infection38; and to NS3 protease inhibitors targeting HCV genotype 1 patients.41,42 HBV/HIV co-infection testing. The presence of HBV and HIV co-infection has been associated with a poorer prognosis in patients with HCV infection.9 Moreover, directacting antivirals (DAAs) may reactivate HBV; this risk has elicited a warning from the FDA.43 Treatment selection Several categories of DAAs are available to treat HCV infection.9 Most all-oral therapy is a combination of one of the following classes: NS5A inhibitors; NS3/4A protease inhibitors; and NS5B inhibitors. There are also additional agents, including interferons—the traditional treatment prior to the availability of DAAs—and ribavirin. Guidelines recommend that initial treatment be offered to all patients with chronic HCV infection except those with short life expectancies who cannot be remediated by treating HCV, transplantation, or other directed therapy.9 Numerous medical and psychosocial factors influence treatment selection in the treatment-naïve patient with HCV infection. Three key factors, however, stand out. These are genotype and subtype, the presence or absence of cirrhosis (METAVIR F4 or higher fibrosis23), and the presence or absence of antiviral resistance.9 Attention to these factors is crucial to attaining the

goals of therapy9: reducing all-cause mortality and hepatic adverse outcomes (eg, end-stage liver disease and HCC) by achieving a virologic cure measured by SVR. Genotype and subtype. Table 2 summarizes current oral antiviral treatment options by genotype.44,45 Genotypes 1 and 4 can be managed with more choices of regimen than can other genotypes. Treatment recommendations also vary distinctly by genotype and subtype. For genotype 1a, which is associated with our presentation of Brett’s case, AASLD/ IDSA recommends a number of antiviral combination therapies and therapeutic alternatives, as shown in Table 3.9 Presence or absence of cirrhosis. A robust body of evidence supports achieving SVR at all stages of liver injury.46 Patients at earlier stages of fibrosis (METAVIR F2 or lower) benefit significantly from antiviral treatment.46,47 For example, long-term follow up in 820 patients with stage F0 or F1 fibrosis showed a significantly better 15-year survival rate in treated patients (93%) vs those who failed treatment (82%) or were untreated (88%; P = .003).9,46,47 The patient with higher stages of fibrosis also benefits from antiviral treatment, which must be tailored to the presence of cirrhosis. Data consistently show that attaining SVR in the patient with advanced fibrosis is associated with better outcomes, including a lower mortality rate, than failure to attain SVR.48 Pooled data in treatment-naïve HCV-infected patients who received interferon-based therapies showed that, in a subgroup of 153 patients with cirrhosis, almost 50% experienced a reversal of cirrhosis.49 Table 3 summarizes recommendations for treatment of genotype 1a in the absence of cirrhosis and in the presence of compensated cirrhosis.9 It should be noted that there are separate AASLD/IDSA recommendations for decompensated cirrhosis that override any genotype 1a recommendations for compensated cirrhosis.9 Clinicians need to be mindful that patients who are already very ill may be best managed in a liver transplant center and may not benefit sufficiently from DAA therapies.9,50 Treatment failure With DAA therapy, rates of treatment failure—defined as failure to achieve HCV viral elimination—have been estimated at about 1% to 15% of patients.51 Data presented in 2015 indicated a 5% rate of failure to attain SVR with current therapy.52 Causes. Poor adherence is a significant cause of treatment failure and can result from multiple factors. These include lack of knowledge of HCV and medication options, social and economic pressures, fears of treatment, inability to manage adverse drug effects, lack of a sense of urgency when • THE CLINICAL ADVISOR • OCTOBER 2017 29



TABLE 2. Currently approved all-oral regimens for HCV infection44,45 Regimen

Component classes

Approved genotypes


Protease inhibitor + NS5A inhibitor

1, 4


Protease inhibitor + NS5A inhibitor


Ombitasvir/paritaprevir/ritonavir + dasabuvir

Protease inhibitor + NS5A inhibitor + polymerase inhibitor


Sofosbuvir + daclatasvir

Nucleotide polymerase inhibitor + NS5A inhibitor

1, 3


Nucleotide polymerase inhibitor + NS5A inhibitor

1, 4, 5, 6

Simeprevir + sofosbuvir

Nucleotide polymerase inhibitor + protease inhibitor


Nucleotide polymerase inhibitor + NS5A inhibitor

1, 2, 3, 4, 5, 6


Nucleotide polymerase inhibitor + NS5A inhibitor + NS3/NS4A protease inhibitor

1, 2, 3, 4, 5, 6


HCV, hepatitis C virus; NS5A, nonstructural protein 5A.

HCV infection is asymptomatic, and psychiatric illness.10 Antiviral drug resistance might also contribute to treatment failure, as can stage of fibrosis; response to prior, non-DAA therapy; viral load; and genotype.53 It is notable that many patients who fail therapy do not demonstrate the emergence of NS3/NS5A/NS5B RASs.54 The degree to which resistance undermines treatment efficacy remains to be fully determined.55 Current guidelines recommend RAS testing in some patients with genotype 1 or 3 HCV and in patients who have failed DAA-based therapy and are considering retreatment.9 The AASLD/IDSA guidelines also recommend that for patients with cirrhosis or other patients who require urgent retreatment, testing is recommended for RASs that confer decreased susceptibility to NS3 protease inhibitors and to NS5A inhibitors.9 Management options. When treatment failure occurs, recommended strategies are genotype-specific.9 Retreatment with different regimens is an option, and the selection can be influenced by the findings of resistance testing conducted at the time of treatment failure.9 In July 2017, the FDA approved a fixed-dose combination of sofosbuvir, velpatasvir, and voxilaprevir, the first treatment approved for adult patients with genotypes 1 through 6 without cirrhosis or with mild cirrhosis who had been previously treated with an NS5A inhibitor.45,56 For example, in our patient Brett’s case, a failure of ledipasvir (NS5A) plus sofosbuvir (NS5B) most likely results from poor adherence, with the potential influence of emergent NS5A resistance. In a genotype-1 patient who fails any

NS5A-containing regimen, it is recommended that retreatment be deferred if there is no cirrhosis and no urgent need to treat.9 When treatment is re-initiated, it should be designed to overcome NS5A resistance; the AASLD/IDSA guidelines currently recommend that clinicians consider longer-duration (eg, 24 weeks), nucleotide-based (eg, sofosbuvir) dual, triple, or quadruple DAA regimens and the addition of ribavirin.9 However, the approval of the sofosbuvir/velpatasvir/voxilaprevir combination may obviate that requirement.45 Of course, a longer, more complex retreatment regimen, with the potential for more AEs and more costs than the initial regimen, raises the risk of nonadherence.10 Re-treating a patient like Brett requires a concerted patient support and monitoring plan. Continuing care. At the time of treatment failure, the clinician must also identify and attend to any unrecognized psychosocial needs that impair adherence.10,55 It is also a time to assess any comorbidities and potential drug-drug interactions that began during the period of treatment, which may hinder effective therapy going forward.9 Something as simple as the patient starting to take St. John’s wort during therapy could reduce the efficacy of some components of DAA regimens.9 Clearly, the patient who has failed treatment has a complex condition and is best managed in specialty care. There is, however, an unmet need for better access to specialty care in the HCV-infected population. Only a minority (32% to 38%) of individuals in the United States who have been diagnosed with HCV had been linked to specialty care.57-59 This is attributed in part to the overall lower likelihood of patients


TABLE 3. Summary of AASLD/IDSA-recommended therapy for treatment-naïve patients with genotype-1a HCV infection9 Recommendation

Evidence rating

PATIENTS WITHOUT CIRRHOSIS Recommended regimens Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks (no baseline high-fold change in NS5A RAVsa for elbasvir is detected)

Class I, Level A

Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

Class I, Level A

Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dasabuvir (250 mg) with weight-based ribavirin for 12 weeks

Class I, Level A

Daily simeprevir (150 mg) plus sofosbuvir (400 mg) for 12 weeks

Class I, Level A

Daily daclatasvir (60 mg ) plus sofosbuvir (400 mg) for 12 weeks

Class I, Level B


Alternative regimen Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight-based ribavirin for 16 weeks (presence of baseline high-fold change in NS5A RAVsa for elbasvir)

Class IIa, Level B

PATIENTS WITH COMPENSATED CIRRHOSISC Recommended regimens Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeksa (no baseline high-fold change in NS5A RAVsa for elbasvir is detected)

Class I, Level A

Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

Class I, Level A

Alternative regimens Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dasabuvir (250 mg) with weight-based ribavirin for 24 weeks

Class I, Level A

Daily simeprevir (150 mg) plus sofosbuvir (400 mg) with or without weight-based ribavirin for 24 weeks (no Q80K polymorphism detected)

Class I, Level A

Daily daclatasvir (60 mgb) plus sofosbuvir (400 mg) with or without weight-based ribavirin for 24 weeks

Class IIa, Level B

Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight-based ribavirin for 16 weeks (presence of baseline high-fold change in NS5A RAVsa for elbasvir

Class IIa, Level B

AASLD, American Association for the Study of Liver Diseases; HCV, hepatitis C virus; IDSA, Infectious Diseases Society of America; NS5A, nonstructural protein 5A; RAVs, resistance-associated variants. a  Includes G1a polymorphisms at amino acid positions 28, 30, 31, or 93. b  Dose of daclatasvir may need to increase or decrease when used concomitantly with cytochrome P450 3A/4 inducers and inhibitors, respectively. c  There are separate recommendations for decompensated cirrhosis.

with chronic HCV infection to have health insurance or an established PCP and medical home.60 Solving this problem requires close collaboration between primary care and gastroenterology/hepatology—which is necessary to enhance specialty care.61,62 Another way to improve access may be shared decision-making—a model of patient-centered care that enables and encourages patients with HCV to play an active role in the management of their own health.61,63 Shared decision-making may help a patient make a commitment to specialty care and may drive a collaborative effort to find ways to finance that care for patients who need economic assistance.


In this case presentation, laboratory assessment guides decision making at every juncture in the clinical course. Brett is screened for the virus and begins therapy with a regimen selected on the basis of testing for fibrosis, virologic load, and antiviral resistance. Although Brett’s treatment fails due to nonadherence, both the failure and the planning for next steps are informed by the assessment of virologic response and emergent NS5A resistance. As Brett’s case shows, regular and strategic use of laboratory testing enables the clinician to choose the proper next steps on the road to a cure. n • THE CLINICAL ADVISOR • OCTOBER 2017 31




a birth cohort screening program for hepatitis C virus. Hepatology.

1. Chak E, Talal AH, Sherman KE, et al. Hepatitis C virus infection in USA:


an estimate of true prevalence. Liver Int. 2011;31(8):1090-1101.

17. Page K, Morris MD, Hahn JA, et al. Injection drug use and hepatitis C

2. Seeff LB. Natural history of chronic hepatitis C. Hepatology.

virus infection in young adult injectors: using evidence to inform compre-


hensive prevention. Clin Infect Dis. 2013;57(suppl 2):S32-S38.

3. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis

18. Zein NN. Clinical significance of hepatitis C virus genotypes. Clin

C virus infection in the United States, 1999 through 2002. Ann Intern Med.

Microbiol Rev. 2000;13(2):223-235.


19. Okamoto HK, Kurai S, Okada K, et al. Full-length sequence of a hepati-

4. Campbell CA, Canary L, Smith N, et al. State HCV incidence and poli-

tis C virus genome having poor homology to reported isolates: compara-

cies related to HCV preventive and treatment services for persons who

tive study of four distinct genotypes. Virology. 1992;188:331-341.

inject drugs—United States, 2015-2016. MMWR Morb Mortal Wkly Rep.

20. Giboney PT. Mildly elevated liver transaminase levels in the asymptom-


atic patient. Am Fam Physician. 2005;71:1105-1110.

5. Patrick SW, Bauer AM, Warren MD, Jones TF, Wester C. Hepatitis C

21. Sanai FM, Benmousa A, Al-Hussaini H, et al. Is serum alanine transami-

virus infection among women giving birth—Tennessee and United States,

nase level a reliable marker of histologic chronic hepatitis C infection? Liver

2009-2014. MMWR Morb Mortal Wkly Rep. 2017;66(18):470-473.

Int. 2008;28(7):1011-1018.

6. Ly KN, Jiles RB, Teshale EH, et al. Hepatitis C virus infection among

22. Rossi E, Adams LA, Bulsara M, Jeffrey GP. Assessing liver fibrosis with

reproductive-aged women and children in the United States, 2006 to

serum marker models. Clin Biochem Rev. 2007;28:3-10.

2014. Ann Intern Med. 2017;166(11):775-782.

23. Barr RG, Ferraioli G, Palmieri ML, et al. Elastography assessment of

7. Zibbell JE, Iqbal K, Patel RC, et al. Increases in hepatitis C virus infection

liver fibrosis: Society of Radiologists in Ultrasound consensus conference

related to injection drug use among persons aged ≤30 years—Kentucky,

statement. Radiology. 2015;276(3):845-861.

Tennessee, Virginia, and West Virginia, 2006–2012. MMWR Morb Mortal

24. Papasterglou V, Tsochatzis E, Burroughs AK. Non-invasive assessment

Wkly Rep. 2015;64:453-458.

of liver fibrosis. Ann Gastroenterol. 2012;25(2):218-231.

8. Patel K, Friedrich-Rust M, Lurie Y, et al. FibroSURE and FibroScan in

25. Castera L, Vergniol J, Foucher J, et al. Prospective comparison of tran-

relation to treatment response in chronic hepatitis C. World J Gastroenterol.

sient elastography, Fibrotest, APRI, and liver biopsy for the assessment of


fibrosis in chronic hepatitis C. Gastroenterology. 2005;128:343-350.

9. American Association for the Study of Liver Diseases (AASLD)/

26. Sebastiani G, Halfon P, Castera L, et al. SAFE biopsy: a validated meth-

Infectious Diseases Society of America (IDSA). HCV Guidance:

od for large-scale staging of liver fibrosis in chronic hepatitis C. Hepatology.

Recommendations for testing, managing, and treating hepatitis C. http://


27. Castera L, Sebastiani G, Le Bail B, et al. Prospective comparison of two

April_12_2017_b.pdf. Accessed May 28, 2017.

algorithms combining non-invasive methods for staging liver fibrosis in

10. McGowan CE, Fried MW. Barriers to hepatitis C treatment. Liver Int.

chronic hepatitis C. J Hepatol. 2010;52:191-198.


28. Boursier J, de Ledinghen V, Zarski JP, et al. A new combination of blood

11. Wyles DL. Antiviral resistance and the future landscape of hepatitis C

test and Fibroscan for accurate non-invasive diagnosis of liver fibrosis

virus infection therapy. J Infect Dis. 2013;207(suppl 1):S33-S39.

stages in chronic hepatitis C. Am J Gastroenterol. 2011;106:1255-1263.

12. Fridell RA, Wang C, Sun JH, et al. Genotypic and phenotypic analysis of

29. Zeuzem S, Mizokami M, Pianko S, et al. NS5A resistance-associated

variants resistant to hepatitis C virus nonstructural protein 5A replication

substitutions in patients with genotype 1 hepatitis C virus: prevalence and

complex inhibitor BMS-790052 in humans: in vitro and in vivo correlations.

effect on treatment outcomes. J Hepatol. 2017;66(5):910-918.

Hepatology. 2011;54(6):1924-1935.

30. Zeuzem S, Rockstroh JK, Kwo PY, et al. Predictors of response to

13. Smith BC, Morgan RI, Beckett GA, et al. Recommendations for the

grazoprevir/elbasvir among HCV genotype 1 (GT1)–infected patients:

identification of chronic hepatitis C virus infection among persons born

integrated analysis of phase 2-3 trials. Hepatology. 2015;62(suppl 1):abstr

during 1945-1965. MMWR Morb Mortal Wkly Rep. 2012;61(4):1-32.


14. Centers for Disease Control and Prevention (CDC). Testing for HCV

31. Jacobson IM, Asante-Appiah E, Wong P, et al. Prevalence and impact

infection: an update of guidance for clinicians and laboratorians. MMWR

of baseline NSA resistance associated variants (RAVs) on the efficacy of

Morb Mortal Wkly Rep. 2013;62(18):362-365.

elbasvir/grazoprevir (EBR/GZR) against GT1a infection – 16 weeks vs 12

15. Moyer VA; U.S. Preventive Services Task Force. Screening for hepatitis

weeks. Presented at: 66th Annual Meeting of the American Association

C virus infection in adults: U.S. Preventive Services Task Force recommen-

for the Study of Liver Diseases (AASLD); November 13-17, 2015; San

dation statement. Ann Intern Med. 2013;159:349-357.

Francisco, CA. Abstract LB-22.

16. McGarry LJ, Pawar VS, Panchmatia HR, et al. Economic model of

documents/2015/TLM_Abstracts/LB22.pdf. Accessed July 29, 2017.


32. Daklinza [package insert]. Princeton, NJ: Bristol-Myers Squibb Company;

48. Singal AG, Volk ML, Jensen D, et al. A sustained viral response is associ-

2016. Accessed June 26, 2017.

ated with reduced liver-related morbidity and mortality in patients with

33. Sarrazin C, Dvory-Sobol H, Svarovskaia ES, et al. Prevalence of resistance-

hepatitis C virus. Clin Gastroenterol Hepatol. 2010;8:280-288.

associated substitutions in HCV NS5A, NS5B, or NS3 and outcomes of treat-

49. Poynard T, McHutchison J, Manns M, et al. Impact of pegylated inter-

ment with ledipasvir and sofosbuvir. Gastroenterology. 2016;151(3):501-512.

feron alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis

34. Dietz J, Susser S, Berkowski C, et al. Consideration of viral resistance

C. Gastroenterology. 2002;122:1303-1313.

for optimization of direct antiviral therapy of hepatitis C virus genotype

50. Fernandez-Carrillo C, Lens S, Llop E, et al. Treatment of hepatitis C

1-infected patients. PLoS One. 2015;10(8):e0134395.

virus in patients with advanced cirrhosis: always justified? Analysis of the

35. Simeprevir [package insert]. Titusville, NJ: Janssen Therapeutics; 2013.

HEPA-C registry. Presented at: EASL International Liver Congress 2016;

April 13-17, 2016; Barcelona, Spain. Abstract GS01.

pdf. Updated December 2013. Accessed June 26, 2017.

51. Buti M, Esteban R. Management of direct antiviral agent failures. Clin

36. Jacobson IM, Dore GJ, Foster GR, et al. Simeprevir with pegylated

Molec Hepatol. 2016;22:432-438.

interferon alfa 2a plus ribavirin in treatment-naive patients with chronic

52. Rockstroh JK. Summary from AASLD 2015 for hepatitis C. Beyond

hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised,

95% SVR cure rates: still room for improvement? Presented at: 66th

double-blind, placebo-controlled trial. Lancet. 2014;384:403-413.

Annual Meeting of the American Association for the Study of Liver

37. Lin MV, Chung R. Recent FDA approval of sofosbuvir and simeprevir:

Diseases (AASLD); November 13-17, 2015; San Francisco, CA. http://

implications for current HCV treatment. Clin Liver Dis. 2014;3(3):65-68. Accessed June 13, 2017.

38. Lontoc E, Harrington P, Howe A, et al. Hepatitis C virus drug resis-

53. Hassanein T, Shiffman ML, Zein NN. The practical management of

tance-associated substitutions. Hepatology.2015;62:1623-1632.

treatment failure in chronic hepatitis C. Gastroenterol Hepatol. 2007;3(6

39. Hernandez D, Zhou N, Ueland J, et al. Natural prevalence of NS5A poly-

suppl 20):4-32.

morphisms in subjects infected with hepatitis C virus genotype 3 and their

54. Ahmed A, Felmlee DJ. Mechanisms of hepatitis C resistance to direct

effects on the antiviral activity of NS5A inhibitors. J Clin Virol. 2013;57(1):13-18.

acting antivirals. Viruses. 2015;7(12):6716-6729.

40. McCormick AL, Wang L, Garcia-Diaz A, et al. Prevalence of baseline poly-

55. Jiménez-Pérez M, González-Grande R, Contreras PE, et al. Treatment

morphisms for potential resistance to NS5A inhibitors in drug-naive individu-

of chronic hepatitis C with direct-acting antivirals: the role of resistance.

als infected with hepatitis C genotypes 1-4. Antivir Ther. 2015;20(1):81-85.

World J Gastroenterol. 2016;22(29):6573-6581.

41. Pawlotsky JM. Treatment failure and resistance with direct-acting anti-

56. Bourlière, M, Gordon SC, Flamm SL, et al; POLARIS-1 and POLARIS-4

viral drugs against hepatitis C virus. Hepatology. 2011;53:1742-1751.

Investigators. Sofosbuvir, velpatasvir, and voxilaprevir for previously treat-

42. Vermehren J, Sarrazin C. The role of resistance in HCV treatment.

ed HCV infection. N Engl J Med. 2017; 376(22):2134-2146.

Best Pract Res Clin Gastroenterol. 2012;26:487-503.

57. McWilliam R, Dundas P, Fraser A. Follow-up of HCV patients referred

43. US Food and Drug Administration (FDA). FDA Drug Safety

to specialist services—where do they all go? Gut. 2010;59(suppl 2):A46-

Communication: FDA warns about the risk of hepatitis B reactivating in

A47. Abstract P88.

some patients treated with direct-acting antivirals for hepatitis C [news

58. Moorman AC, Gordon SC, Rupp LB, et al. Baseline characteristics

release]. Silver Spring, MD: FDA; Updated October 12, 2016. https://www.

and mortality among people in care for chronic viral hepatitis: the chronic Accessed June 13, 2017.

hepatitis cohort study. Clin Infect Dis. 2013;56:40-50.

44. Falade-Nwulia D, Suarez-Cuervo C, Nelson DR, et al. Oral direct-

59. Brown KA, Nerenz DR, Atkinson R, et al. Barriers to cure for hepa-

acting agent therapy for hepatitis C virus infection: a systematic review.

titis C: data from a large integrated health system. Hepatology. 2013;58(4

Ann Intern Med. 2017;166:637-648.

suppl):1291A. Abstract 2240.

45. US Food and Drug Administration (FDA). FDA approves Vosevi for

60. Stepanova M, Kanwal F, El-Serag HB, et al. Insurance status and treat-

Hepatitis C [news release]. Silver Spring, MD: FDA; July 18, 2017. https://

ment candidacy of hepatitis C patients: analysis of population-based data

from the United States. Hepatology. 2011;53:737-745.

htm. Updated July 20, 2017. Accessed August 4, 2017.

61. Rossaro L, Torruellas C, Dhaliwal S, et al. Clinical outcomes of hepatitis

46. Solinís RN, Ugarte FA, Rojo A, Gonzalez YS. Value of treating all stages

C treated with pegylated interferon and ribavirin via telemedicine consul-

of chronic hepatitis C: a comprehensive review of clinical and economic

tation in northern California. Dig Dis Sci. 2013;58(12):3620-3625.

evidence. Infect Dis Ther. 2016;5:491-508.

62. Miller L, Fluker SA, Osborn M, et al. Improving access to hepatitis C

47. Jezequel C, Bardou-Jacquet E, Desille Y, et al. Survival of patients

care for urban, underserved patients using a primary care-based hepatitis

infected by chronic hepatitis C and F0F1 fibrosis at baseline after a 15

C clinic. J Natl Med Assoc. 2012;104(5-6):244-250.

years follow-up. J Hepatol. 2015;62(suppl 2):S589. http://www.journal-of-

63. Elwyn G, Frosch D, Thomson R, et al. Shared decision making: a model

for clinical practice. J Gen Intern Med. 2012;27(10):1361-1367. • THE CLINICAL ADVISOR • OCTOBER 2017 33




POSTTEST Expiration date: August 29, 2018

A statement of credit will be issued only upon receipt of a completed preassessment test, activity evaluation form, and posttest with a score of 70% or higher. All components must be completed and submitted online at CREDITS: 0.50 | The spectrum of molecular testing protocols for HCV

1. Which persons should have a one-time hepatitis C virus (HCV) screening? a. All persons born between 1945 and 1964, with no ascertainment of other risk b. All persons born after 1964 living in geographic regions of highest HCV risk c. Persons of any age with HCV risk factors (eg, illicit injection drug use) d. Both a and c 2. Which of the following is not an appropriate test for level of hepatic fibrosis/inflammation in a patient with HCV infection? a. Serum fibrosis marker panel (eg, FibroTest) b. Hepatic transaminase testing c. Transient elastography (TE; eg, FibroScan) d. Acoustic radiation force impulse (ARFI) 3. In a treatment-naïve patient with genotype 1a HCV infection and without cirrhosis, which of the following regimens is recommended by the American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA) for initial therapy? a. Monotherapy with pegylated interferon, ribavirin, or a direct-acting antiviral agent (DAA) b. Daily simeprevir (150 mg) plus sofosbuvir (400 mg) for 12 weeks

c. Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) with or without weight-based ribavirin for 24 weeks d. Daily fixed-dose combination of paritaprevir (150 mg)/ ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin for 12 weeks 4. What is the frequency of NS5A resistance-associated substitutions (RASs) among patients with genotypes 1a and 1b who have not been exposed to NS5A-inhibiting antivirals? a. In less than 1% of patients b. In about 1% to 5% of patients c. In about 13% to 18% of patients d. In about 25% to 31% of patients 5. Which of the following summarizes the best approach to retreatment in a patient with genotype 1a HCV infection without cirrhosis who has failed therapy that included an NS5A inhibitor? a. Re-treat immediately with another course of DAAs. b. Re-treat with a 4-drug regimen after antiviral resistance testing is complete and patient access to specialty care is assured. c. Defer retreatment and re-initiate treatment with a plan to address resistance and adherence. d. Defer retreatment and re-initiate with an alternative regimen to DAAs (eg, pegylated interferon or ribavirin).

TO TAKE THE POSTTEST please go to:


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Advisor Forum These are letters from practitioners around the country who want to share their clinical problems and successes, observations, and pearls with their colleagues. Responding consultants are identified below. We invite you to participate.

YOUR COMMENTS IMMUNIZATION IN HEALTHCARE PROVIDERS: COMMENTS FROM OUR READERS As an RN formerly working in an emergency room of a small community hospital, the attending physician and I contracted pertussis from a patient. I then gave it to my husband. Luckily, I did not pass this on to my son or to any infant I was caring for at the time. This was several years ago, and Tdap was relatively new. I had thought that when I was next due for a Td, I would request the Tdap. Who knows how many others the physician and I exposed due to this unfortunate situation. My husband and I coughed nonstop for 3 months. We were both fully immunized as children, as was my son who was 11 at the time and the only one who did not get whooping cough. This case [“Legal Advisor,” July, p. 49] was settled exactly how it should have been, as I am not convinced that this woman would have been at any Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 275 7th Avenue, 10th Floor, New York, NY 10001.You may contact us by e-mail at If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter. No anonymous contributions will be accepted.

risk receiving the vaccine. But she would have put countless others at risk by not having it.—KATHLEEN CHARETTE, RN, MEd, MSN, North Grosvenordale, Conn. (228-1) This is an excellent rule. Doctors have to be held accountable for their “excuse notes” medically, legally, and morally. That doctor knew that there were no actual contraindications when he wrote the note. He knew that having an unvaccinated healthcare worker puts everyone in the hospital at risk. If this nurse had an issue with the new vaccination requirements of her employer, she could go find a new one. The doctor who wrote that ridiculous excuse should be ashamed, and the hospital is correct and appropriate to adhere to their guidelines. Great case! Keep up the good work of ridding the healthcare field with these problematic employees.—SARAH RECUPERO, PA-C, RRT, MCMSc, San Francisco (228-2)

MY MOST MEMORABLE PATIENT TRANSCENDING THE EMOTIONAL BARRIERS BETWEEN PROVIDER AND PATIENT When Katya’s Russian doctors exhausted all treatment options, she boarded a plane in Moscow and arrived 36 hours later in our small American city where her sister lived. In the airport, hugs were exchanged, a few tears were shed, and then they


Philip R. Cohen, MD,

is clinical associate professor of dermatology, University of Texas Medical Center, Houston.

Deborah L. Cross, MPH, CRNP, ANP-BC, is associate program

director, Gerontology NP Program, University of Pennsylvania School of Nursing, Philadelphia.

Abimbola Farinde, PhD, PharmD,

is a professor at Columbia Southern University in Orange Beach, Ala.


Laura A. Foster, CRNP, FNP,

Abby A. Jacobson, MS, PA-C,

practices family medicine with Palmetto Primary Care Physicians in Charleston, S.C.

is an assistant professor at Thomas Jefferson University and a dermatology PA at Family Dermatology of Reading, Pa.

drove straight to our emergency room doors. Soon after, exhausted and painful, Katya arrived on our oncology unit. She cradled her left arm at an odd angle. When I introduced myself as her nurse, she looked at me without responding. Her sister interpreted, explaining that Katya spoke no English. Gently, I helped Katya undress and noted a rotting smell exuding from her body. As the clothing came away, I saw the source of her misery. Protruding from her left upper chest was a grotesquely large, draining, cancerous growth. For months Katya came and went from our oncology unit. The language barrier between us was significant, but over time we created our own language of signing, smiling, and occasionally laughing. When in doubt, Katya would talk to me in Russian. I, in turn, would respond in English. Neither understood the words, only the intent. To say that Katya spoke no English was not exactly true. She knew two English expressions: “Thank you” and “I love you.” Soon after her arrival, she began sprinkling these expressions liberally between the gaps in our communication. At first I was surprised to hear her say, “Thank you, Reeger. I lufve you.” I wondered, did she really mean that she loved me? Was it appropriate for me to respond with, “I love you, too”? In medicine there are emotional lines separating providers from patients, lines meant to keep us objective, thereby protecting us from grief when life’s hardships unfold before us. However, given the fact that Katya and I only had five words in common, my concerns for objectivity versus love seemed existentially misguided. I could not struggle to communicate with Katya, then deny the use of the few words we shared in common, even if in so doing, I ran the risk of becoming emotionally vulnerable. Initially, with radiation therapy, her tumor shrank, but then it grew again. A CT scan was completed. Katya understood

Debra August King, PhD, PA,

is senior physician assistant at New York-Presbyterian Hospital, New York City.

Mary Newberry, CNM, MSN,

provides well-woman gynecologic care as a midwife with Prima Medical Group, Greenbrae, Calif.

that the doctors were worried that the cancer had spread, but because of the language barrier she couldn’t ask them. So she asked me. While pointing to her liver, she spoke rapidly in Russian, ending with what I assumed was the Russian equivalent of, “Well?” Even when speaking the same language, it is difficult to tell someone she has metastatic cancer. The irony was that our hard work of learning how to communicate had paid off, and now I was the one she turned to for the truth. I hesitated in responding, not wanting or even knowing, how to tell her. She saw my reluctance but would have none of my sentimentality. She looked me hard in the eyes and then firmly pointed to her cancer, then her liver, and then crossed her arms over her chest, closed her eyes, and for added effect, stuck her tongue out the side of her mouth. When she opened her eyes, she saw my eyes had filled with tears. Quietly, we looked at each other. Finally, she simply said, “Okay.” Katya died peacefully at her sister’s home not long after. Fifteen years have passed, and now I am a family nurse practitioner. Over the years, I have learned many lessons about the art and science of medicine, but no education has affected my practice more profoundly than my experience of caring for Katya. Keeping an objective distance from the hardships before us does not protect us from grief. But neither does crossing the line of objectivity into emotional caring make the grief any worse. Given these facts, why not transcend the emotional barriers between provider and patient? What waits on the other side is not a lesser or weaker version of our professional selves, but rather a stronger, more balanced one, a professional who understands that even though the science of medicine is amazing, ultimately, what we all need is the art of medicine. Therein lies connection, and therein lies our universal need to give and receive human compassion.— REEGER CORTELL, FNP-C, Medford, Ore. (228-3) n

Claire O’Connell, MPH, PA-C,

an associate professor at the Rutgers University Physician Assistant Program, Piscataway, N.J.


Katherine Pereira, DNP, FNP,

is assistant professor, Duke University School of Nursing, Durham, N.C.

Sherril Sego, FNP-C, DNP,

is an independent consultant in Kansas City, Mo. • THE CLINICAL ADVISOR • OCTOBER 2017 37

COMMENTARY Abimbola Farinde, PhD, PharmD, is a professor at Columbia Southern University in Orange Beach, Ala.

Opioid use in middle-aged adults The use of opioids is a major health crisis that has infiltrated mainstream America and has led to abuse, addiction, overdose, and death. The number of deaths that have been attributed to illicit opioid use increased sharply in 2015, according to the Centers for Disease Control and Prevention. State and government officials, as well as hospitals and clinics, face a growing challenge with prescription pain medications, which are considered to be the major driving force behind the opioid epidemic. In 2012, the National Institute on Drug Abuse (NIDA) reported that between 26.4 million and 36 million people abuse opioids around the world, and in the United States an

Clinicians are in the unique position to educate and counsel middle-aged adults about their opioid use and influence strategies needed to provide effective pain control.

estimated 2.1 million patients have a substance use disorder that is associated with an opioid pain reliever. The number of unintentional overdoses related to prescription pain relievers has affected and devastated communities and families across the nation, so it is with great urgency that the issue be placed at the forefront of conversations. A population that has been particularly affected is middle-aged adults, who have chronic, and at times unrelenting, pain. If their pain is not adequately managed, they are likely to misuse opioids, similar to other populations. Healthcare professionals have the responsibility of providing safe and cost-effective pain management to middle-aged adults without further contributing to the increasing opioid epidemic. We are in the unique position to educate and counsel this population and influence strategies that are needed to provide effective pain control. It will take a concerted effort and commitment to reverse the current state of affairs. Americans have become the world leader in the use of prescription pain medications. The United States spends about $635 billion on chronic pain, which can affect more people than cancer, heart disease, and diabetes combined. The existence of severe and persistent pain has the potential to significantly impair mental, physical, and social functioning, and quality of life, but the abuse of opioids can also contribute to fatal overdoses. The ability to effectively

38 THE CLINICAL ADVISOR â&#x20AC;˘ OCTOBER 2017 â&#x20AC;˘

manage the pain can be challenging for middleaged to older adults due to comorbid conditions, disease states, and other potential vulnerabilities. But this epidemic must be addressed to prevent the loss of more lives. With the increasing rate of opioid abuse, there has been a concerted effort to minimize or prevent inappropriate prescribing of this class of agents by regulators, payers, and other agencies. In the process, however, attention has not been paid to the consequences that can come from untreated pain. The goal is to achieve pain management without abusing opioids. Education should start with primary prescribers, who prescribe about 50% of opiates. Also, education needs to be provided to patients who use these medications. The dose of opioids can be increased by clinicians who may not necessarily possess the formal training or practical background to do so. A multidisciplinary approach that may not require opiates should be applied. There is still hope to understand this complex issue and how to better manage pain in middleage adults. The advent of evidence-based recommendations can help guide providers to develop effective strategies for addressing chronic and persistent pain in this population. Middle-aged Americans should not have to suffer the consequences of a system that is currently focused on eradicating this epidemic and not receive appropriate pain management as a result. n

Dermatology Clinic CASE #1

A pruritic rash and rippled plaques on a woman’s shin BEN VARUGHESE, CHRISTOPHER RIZK, MD

A 52-year-old Hispanic woman presents with a 3-year history of a very pruritic rash over her shins bilaterally. On examination, both shins are covered in hyperpigmented papules that have coalesced to form thin, rippled plaques. The patient is very concerned about the appearance of her legs and the intense pruritus in the areas of the rash. The patient has no other medical problems and has no systemic symptoms. She has no relevant social or family history and does not take any medications. What is your diagnosis? Turn to page 40


Red bumps on a young boy’s fingers ESTHER STERN, NP

A 13-year-old boy presents to the dermatology clinic concerned about the development of red, itchy, and sometimes painful bumps on his fingers. He first noted seeing the lesions 2 months prior, in early December. Although the initial lesions have since resolved, new lesions appeared after a skiing trip the previous weekend. The patient is otherwise healthy, with no significant past medical history, and he does not take any medications. Physical examination reveals erythematous, tender papules on the lateral and dorsal aspects of the distal fingers. What is your diagnosis? Turn to page 41 • THE CLINICAL ADVISOR • OCTOBER 2017 39

Dermatology Clinic CASE #1

Lichen amyloidosis

Lichen amyloidosis (LA) is a dermatologic condition caused by abnormal amyloid deposition. LA most commonly manifests as highly pruritic lichenoid papules on the anterior tibia bilaterally. It is the most prevalent form of primary localized cutaneous amyloidosis; the other subtypes are macular, nodular, and familial. It is a disorder that primarily affects individuals of Asian, Middle Eastern, or Hispanic descent, and is particularly common in Chinese individuals. Typically, it occurs in older individuals in their fifth or sixth decade of life, and affects men twice as often as women. There is also an association between LA and individuals with Fitzpatrick skin types III and IV.1-3 Clinically, LA is characterized by multiple discrete, hyperkeratotic, hyperpigmented papules that can merge, giving the appearance of a rippled pattern on the patient’s skin. These individual papules can also coalesce to form infiltrated plaques over time that are difficult to treat. Although the extensor surfaces of the lower extremities are usually the primary location involved in LA, these lesions may occur less frequently on the upper extremities, back, thighs, and face. Intense pruritus is often the chief complaint; however, in a minority of cases the patient is asymptomatic.

Most patients with lichen amyloidosis desire treatment for cosmetic reasons and for relief of the pruritus associated with it. The precise etiology of LA is still under debate; however, the largest known risk factor for its development remains frictional rubbing and chronic irritation of the skin. Factors such as race, sex, seasonal changes, autoimmunity, and genetic predisposition are also thought to play a role in the pathogenesis of the disease. Some believe that LA may be a consequence of the intense pruritus because the pruritus often precedes skin findings by years.4-6 Another competing theory suggests a relationship between Epstein-Barr virus and the development of LA, but newer studies are finding the true association between these two harder to delineate. LA has

also been associated with other systemic conditions, such as Sjögren syndrome, systemic lupus erythematosus, primary biliary cirrhosis, and multiple endocrine neoplasia type 2A.3 LA is a keratinocyte-derived cutaneous amyloidosis. The amyloid deposits, which contain primarily keratin, are thought to be necrotic basal keratinocytes that have undergone conversion to amyloids after being exposed to frictional damage.5 Histologic examination reveals eosinophilic globules in the upper dermis.5 Epidermal findings may include hyperkeratosis and acanthosis. The amyloid deposits stained with Congo red exhibit characteristic apple-green birefringence under polarized light.4 Diagnosis of LA is usually based on clinical findings of the characteristic pretibial hyperkeratotic, hyperpigmented papules. The differential diagnosis for LA includes prurigo nodularis, lichen simplex chronicus, pretibial myxedema, and hypertrophic lichen planus.2 In difficult cases, a routine skin biopsy sent for histologic examination reveals the characteristic amyloid deposits discussed above. Few treatment options provide adequately curative or effective results. If the patient is not bothered by the LA, there is no need for treatment, because LA has no malignant potential. However, most patients desire treatment for cosmetic reasons and for relief of the intense pruritus that is usually associated with LA. The first step in treating LA often involves disrupting the itch-scratch cycle through patient education about how chronic friction precipitates development and exacerbates LA. Patients should be told to stop scratching the lesion and to reduce friction. This can be achieved by the use of potent topical or intralesional corticosteroids that reduce pruritus and improve cosmesis. Other options include topical keratolytic agents such as salicylic acid or topical calcineurin inhibitors.3 Patients may apply topical medications under occlusion for maximized results; occlusion serves to improve the efficacy of the topical medications and reduces frictional irritation. In severe cases of LA, other treatment options such as dermabrasion, light therapy, and oral medications can be used. Dermabrasion has found some utility, as it allows for re-epithelialization in the damaged areas of tissue. Use of psoralen plus ultraviolet A or ultraviolet B phototherapy was shown to have moderate effects in improving pruritus and roughness in 1 study.3 Systemic medications such as acitretin and cyclosporine have shown benefits in a small group of patients.1 The patient in this clinical vignette was diagnosed with LA and educated about the need to stop the itch-scratch cycle and reduce friction to the area. She was prescribed clobetasol ointment (a potent topical steroid) to apply twice daily under


occlusion. With the use of steroids under occlusion, the pruritus subsided and her rash started to improve clinically. Ben Varughese is a medical student at the Baylor College of Medicine, and Christopher Rizk, MD, is a dermatology resident at the Baylor College of Medicine in Houston. References

with symptoms often lasting until the month of April. Although patients of any age may be affected, perniosis is most common in young to middle-aged women.2 Most patients presenting with perniosis will report a history of recurrent pruritic and painful bumps on the fingers and/or toes. In addition, many report that their fingertips often look blue or purple in cooler temperatures; some describe numbness and tingling in affected digits.

1. Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012. 2. Chen JF, Chen YF. Answer: can you identify this condition? Can Fam Physician. 2012;58(11):1234-1235. 3. James WD, Berger TG, Elston DM, Neuhaus IM, eds. Andrews’ Diseases of the Skin: Clinical Dermatology. 12th ed. Philadelphia, PA: Elsevier; 2016.

Clinically, perniosis presents with single or multiple erythematous, dusky papules or nodules that are often tender on palpation.

4. Rapini RP. Deposition and metabolic diseases. In: Rapini RP ed. Practical Dermatopathology. 2nd ed. Philadelphia, PA: Elsevier Mosby; 2012:119-137. 5. Salim T, Shenoi SD, Balachandran C, Mehta VR. Lichen amyloidosis: a study of clinical, histopathologic and immunofluorescence findings in 30 cases. Indian J Dermatol Venereol Leprol. 2005;71(3):166. 6. Weyers W, Weyers I, Bonczkowitz M, Diaz-Cascajo C, Schill WB. Lichen amyloidosis: a consequence of scratching. J Am Acad Dermatol. 1997;37.6:923-928.



Perniosis, also known as pernio or chilblains, is an inflammatory skin condition characterized by cold-induced painful erythematous papules on the distal aspect of the fingers or toes. Perniosis may be idiopathic; less commonly, it can be secondary to a systemic disease, such as systemic lupus erythematosus. This is condition is different than, and should not be confused with, lupus pernio, which is a form of cutaneous sarcoidosis. Perniosis presents as an exaggerated response to cold and wetness in predisposed individuals. It is seen most commonly in Northern Europe and the northern United States,1 particularly in areas with nonfreezing cool temperatures and increased humidity. Symptoms commonly begin in early winter and resolve by spring as cold exposure decreases. However, patients may develop recurrences during subsequent winters or may progress to chronic persistent disease

Clinically, perniosis presents with single or multiple erythematous, dusky papules or nodules that are often edematous and tender on palpation. In more severe cases, ulcerations or necrosis may be present. The disease typically affects the distal and dorsal aspect of phalanges of the fingers and toes. However, the lesions may also appear on heels, lower legs, thighs, nose, and ears. Chronic untreated disease can lead to scarring, depigmentation, and superinfection.3 The lesions typically appear 12 to 24 hours after a cold exposure and often spontaneously resolve within 2 to 3 weeks. The direct cause of perniosis is cold exposure, including prolonged contact with the wet lining in boots. Factors contributing to disease expression include abnormal vasoconstriction, vasospasm, hyperviscosity, or autoimmunity. Chronic cases may be secondary to underlying disease. For this reason, it is important to rule out other conditions, such as cryoglobulinemia, antiphospholipid antibody syndrome, Raynaud disease, hemolytic anemia, chronic myelomonocytic leukemia, celiac disease, and systemic lupus erythematosus. Patients with anorexia nervosa are more likely to develop perniosis due to low body mass index and impaired thermoregulation. Additionally, 40% of patients with the genetic disease Aicardi-Goutières syndrome will develop perniosis, with disease often appearing in infancy.4 Results of a skin biopsy of lesional skin help confirm diagnosis. Results of hematoxylin and eosin staining will reveal a T-cell papillary and deep infiltrate with perieccrine reinforcement, associated with dermal edema and necrotic keratinocytes; these are the hallmarks of chilblains of the hands.5 Persistent or atypical cases should undergo laboratory workup to rule out underlying cause. Appropriate tests include complete blood count, erythrocyte sedimentation rate, antinuclear • THE CLINICAL ADVISOR • OCTOBER 2017 41

Dermatology Clinic

“No, this isn’t hell! This is ‘heck’ where non-cursers are sent.”

Esther Stern, NP, is a family nurse practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J. References 1. Paller AS, Mancini AJ. Collagen vascular disorders. In: Paller AS, Mancini AJ, eds. Hurwitz Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence. 4th ed. Philadelphia, PA: Elsevier Saunders; 2011:497-527. 2. Yang X, Perez OA, English JC 3rd. Adult perniosis and cryoglobulinemia: a retrospective study and review of the literature. J Am Acad Dermatol. 2010;62(6):e21-e22. 3. Almahameed A, Pinto DS. Pernio (chilblains). Curr Treat Options Cardiovasc Med. 2008;10(2):128-135. 4. Abdel-Salam GM, El-Kamah GY, Rice GI, et al. Chilblains as a diagnostic sign of Aicardi-Goutières syndrome. Neuropediatrics. 2010;41(1):18-23. 5. Cribier B, Djeridi N, Peltre B, Grosshans E. A histologic and immunohistochemical study of chilblains. J Am Acad Dermatol. 2001; 45(6):924-929. 6. James WD, Berger TG, Elston DM. Dermatoses resulting from physical factors. In: James WD, Berger TG, Elston DM, eds. Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, PA: Saunders-Elsevier; 2011:18-44. 7. Al-Sudany NK. Treatment of primary perniosis with oral pentoxifylline (a double-blind placebo-controlled randomized therapeutic trial). Dermatol Ther. 2016;29:263-268.

“I don’t know if it’s love, but I can’t get her ringtone out of my mind.”


Top, bottom: © Harley Schwadron, 2017. Middle: © The New Yorker Collection 2017 from All Rights Reserved.

antibody measurement, antiphospholipid antibody panel, and testing for levels of cold-insoluble proteins, including the cryoglobulins, cryofibrinogens, and cold agglutinins. It is important to note that for cold-insoluble protein testing, the blood sample must be kept at 37° C until centrifugation. The best treatment approach is prevention. Patients should be educated to keep acral areas warm and dry with appropriate protective clothing, including wool socks and protective gloves. In addition, avoidance of nicotine is strongly encouraged.6 Lesions are usually self-limiting and last 2 to 3 weeks. Anecdotal reports suggest the benefit of topical corticosteroids to relieve symptoms. Severe cases may require the use of nifedipine, a calcium channel blocker, and peripheral artery vasodilator. Results of a recent small study showed a clear benefit for the use of pentoxyfilline,7 a xanthine derivative that reduces blood viscosity. For the patient above, a 3-mm punch skin biopsy taken from lesion skin revealed histologic changes consistent with perniosis. Results of further blood testing to rule out underlying systemic conditions were negative. The patient and his parents were educated regarding the condition and the importance of avoiding exposure to cool and humid temperatures. A prescription for triamcinolone cream was given, to be applied up to 3 times as needed for symptomatic flares. ■

Dermatologic Look-Alikes A brown macule on the arm and face POOJA REDDY; CHRISTOPHER RIZK, MD



A 52-year-old man presents with a lesion on his left arm. He came into the office because his wife asked him to “have the spot checked out.” On examination, the lesion is a 1.2 × 0.8-cm irregularly pigmented, asymmetric brown macule, with color variegation and irregular borders. The patient says the lesion itches a little bit but does not bother him otherwise. He says that the lesion has been growing quickly. Aside from the lesion, the patient does not have any other medical problems or family history.

A 60-year-old woman presents with a lesion on her face. She says that the lesion arose around 1 year ago and that it “hasn’t changed much” since. On examination, the lesion is a 0.7 × 0.7-cm well-circumscribed, brown, round-shaped macule. The lesion does not bother her; she only wants to make sure that it is not malignant. Aside from the lesion, the patient does not have any other medical problems. In addition, the patient does not have any relevant social or family history. • THE CLINICAL ADVISOR • OCTOBER 2017 43

Dermatologic Look-Alikes CASE #1


Melanoma is a complex, heterogeneous cancer that is commonly cutaneous in origin.1,2 In 2014, there were an estimated 1.1 million people living with cutaneous melanoma in the United States, with a higher prevalence in men compared with women.3 Signified by the transformation of melanocytes (specialized pigmented cells predominantly found in the basal layer of the epidermis) to tumor cells, primary melanoma has a complex pathogenesis.1 Genetic and environmental factors, specifically ultraviolet radiation, characterize the etiology of the disease, as well as highlights risk factors for disease development.1,4 Notably, the strongest independent risk factors—increased number of common melanocytic nevi, presence of atypical melanocytic nevi, and presence of solar lentigines (SLs)—reflect both genetic susceptibility and environmental exposure.2 Because early recognition is critical to improving survival, several initiatives have been utilized to improve public awareness on the evaluation of pigmented lesions. The ABCDE acronym (Asymmetry, Border irregularity, Color variegation, Diameter, and Evolving lesions) highlights typical features, though not all melanomas present with all 5 characteristics.1,2 Clinical diagnosis can be augmented by the use of dermoscopy or skin surface microscopy, which increases clinical diagnostic sensitivity.2 Skin biopsy, however, remains the standard practice for diagnosing cutaneous melanoma. It is thought that melanomas progress through 2 phases. The radial growth phase, characterized by horizontal and infiltrative spread of melanocytes, is not considered to have metastatic potential, whereas the vertical growth phase—the presence of dermal nests of large, atypical melanocytes— does have metastatic capacity.1,2 The 4 major subtypes of cutaneous melanoma, based on the histologic patterns of the early, radial growth phase, include (1) superficial spreading melanoma (SSM), (2) nodular melanoma, (3) lentigo maligna melanoma (LMM), and (4) acral lentiginous melanoma (ALM).2 SSM is the most common subtype of cutaneous melanoma, and is responsible for the highest proportion of fatal melanomas.2,5 Usually, SSM begins as an asymptomatic macule distinguished by color variations, irregular borders, and a

predominant radial growth phase. It is most frequently found on the trunks of men and the legs of women.2,5 Pagetoid and nested epithelioid cells in the intraepidermal portion typify the histological characteristics of SSM.1 Nodular melanoma is the second most common subtype of cutaneous melanoma. Lesions tend to be more varied in color, ranging from pink-red to blue-black, and present clinically as firm papules or nodules, commonly associated with ulceration.6 Though nodular melanomas can occur at any body site, they tend to have a predilection to sunexposed areas such as the head and neck. Histologically, nodular melanoma lacks significant intraepidermal tumor cells beyond the edges of the dermal component.2,6 LMM occurs in chronically sun-damaged skin, commonly on the face, particularly the nose and cheek. LMM presents as a gradually enlarging tumor that is flat and multipigmented.1 It tends to occur much later in life (most commonly the seventh decade) due to its requisite for cumulative sun exposure.2,7 Histologically, tumor cells show a lentiginous spread. The presence of a sun-damaged background, demonstrated by epidermal atrophy, solar elastosis, and dermal thinning, distinguishes LMM from the other subtypes.1,2 ALM is one of the least common subtypes of cutaneous melanoma. Clinically, it presents as an asymmetric, brown to black macule with color variation and irregular borders.1 ALM typically occurs on hairless areas such as the palms and soles, distinguishing it from the other subtypes. Diffuse lentiginous proliferation of tumor cells along the basal layer characterize early histologic findings.2

Genetic and environmental factors, specifically ultraviolet radiation, characterize the etiology of melanoma. A few differential diagnoses (divided into melanocytic and nonmelanocytic) to consider when considering melanoma include SL, atypical nevus, seborrheic keratosis (SK), and pigmented basal cell carcinoma (BCC). Because these cutaneous lesions share many of the same clinical features as melanoma, dermoscopy or skin biopsy are usually needed to aid in diagnosis.1,2 Dermoscopy is particularly useful in distinguishing melanocytic lesions—characterized by the presence of a pigmented network, streaks, aggregated globules, homogenous blue pigment, or parallel pattern—from nonmelanocytic ones.2


An SL, a melanocytic lesion, presents as a tan or brown macule on sun-exposed areas of the skin. Under the dermoscope, an SL can display diffuse brown pigmentation, fingerprint-like structures, and a fine regular network.2 Biopsy results of an SL demonstrate basilar hyperpigmentation of keratinocytes with a possibly mild increase in the number of melanocytes.8 An atypical nevus, distinguished by asymmetrical borders, large size, or varied coloration, is a benign melanocytic lesion. Clinically, an atypical nevus may fulfill many of the features highlighted by the ABCDE acronym. Atypical nevi also manifest the histologic atypia seen in melanoma. Though there is significant overlap between the 2, atypical nevi are distinguished by their general stability in size and color.9,10 SK is characterized by a waxy, “stuck-on,” verrucousappearing papule or plaque. It is a nonmelanocytic lesion, and thus dermoscopic analysis assists in distinguishing an SK from a melanoma. However, any dark or atypical appearing SK should be biopsied to confirm the diagnosis.2 BCC is a neoplasm of basal keratinocytes with several subtypes, one of which is pigmented BCC. Described as blue, brown, or black papules or nodules with border irregularities and possible color variegation, pigmented BCCs clinically resemble melanomas. Dermoscopy can aid in differentiating the two since pigmented BCCs lack melanocytic features, such as the pigmented network. Biopsy results formally confirm diagnosis.11 If a patient comes into the clinic with a lesion suspected of being melanoma, the patient should be referred to a dermatologist for a skin biopsy. Biopsy results can confirm the diagnosis of melanoma, and can aid in the prognosis and management of the patient. Due to the possible role of ultraviolet (UV) light, the United States Preventative Services Task Force recommends that primary care physicians counsel patients on sun-protective strategies, including the regular use of sunscreen.1,2,4 Secondary prevention involves early detection because late stages, characterized by increased thickness and evidence of ulceration, are associated with poorer prognosis.1 Treatment of melanoma largely revolves around surgical excision with increasing margins for increasing tumor thickness.2 Depending on the stage of the melanoma and if metastases, patients may also be treated with chemotherapy and other biologic therapies. Further understanding of the genetic factors underlying disease pathogenesis, including the mitogen-activated protein kinase (MAPK), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and programmed death 1 (PD-1) pathways, has allowed for the development of targeted biologic therapies.12 Close

clinical surveillance of patients after diagnosis of melanoma is imperative, as patients are at risk for local or systemic recurrences and second primary melanomas. 2 Patients diagnosed with melanoma should have a skin check every 3 months after their diagnosis for 1 to 2 years. If no other concerning lesions arise within the first 2 years of melanoma diagnosis, skin checks can be performed every 6 months. A biopsy of the lesion on the patient in this vignette was performed, and a diagnosis of SSM was confirmed. Due to the depth of invasion into the dermis, the patient was referred to a surgical oncologist for sentinel node biopsy and treatment. He is now in remission.


Solar lentigo

Approximately 90% of the white population older than 60 years have SLs. Though mainly observed in the white population, SLs can also occur in people of other ethnicities.13,14 Lentigines usually appear later in life on chronic sun-exposed skin. The association with age and sun damage is well reflected in the different names used for SLs, including age spots, lentigo senilis, sun-induced freckles, and sunburn freckles.14 However, it is important to note that SL can also be seen in younger individuals with extensive UV radiation (UVR) exposure, as well as in young children with certain genetic conditions (specifically xeroderma pigmentosum).13 Ranging in color from tan to dark brown to black, SLs are well-circumscribed, round, oval, or irregularly shaped macules that vary from 3 mm to 2 cm in diameter.13 As stated above, SLs have a predilection for sun-exposed areas, and are commonly found on the dorsal aspects of hands and forearms, the face, the upper chest, and the back.15 The pathogenesis of SLs is in line with a history of chronic UVR exposure; in response to UV stress, a cytokine cascade results in fibroblast proliferation, causing epidermal hyperplasia, and an increased production of melanosomes by melanocytes, which are subsequently transferred to neighboring keratinocytes. It is this complex interplay among cytokines, melanocytes, keratinocytes, and fibroblasts that ultimately manifests as an SL.16,17 Further studies • THE CLINICAL ADVISOR • OCTOBER 2017 45

Dermatologic Look-Alikes TABLE 1. Clinical characteristics of melanoma and solar lentigo Melanoma

Solar lentigo

Dermatologic presentation

• ABCDE acronym (asymmetry, border irregularity, color variegation, • diameter, and evolving lesions) highlights typical features • Not all melanomas present with all 5 characteristics

• Well-circumscribed, round, oval, or irregularly shaped macules that vary from 3 mm to 2 cm in diameter


• Increased number of common melanocytic nevi, presence of atypical melanocytic nevi, and presence of solar lentigines increases risk

• Chronic sun exposure • Genetic conditions such as xeroderma pigmentosum


• Complex interplay between genetic and environmental factors, specifically ultraviolet light

• Complex interplay among cytokines, melanocytes, keratinocytes, and fibroblasts • Genetic component (variants in the melanocortin-1 receptor gene and mutations in FGFR3 and PIK3CA)

Characteristic location

• Lesions can be located anywhere on the body • SSM: commonly on the trunk of men and the legs of women • Nodular melanoma and LMM: sun-exposed areas • ALM: hairless areas such as the palms or soles

• Commonly found on the dorsal aspects of hands and forearms, the face, the upper chest, and the back


• SSM: pagetoid and nested epithelioid cells in the intraepidermal portion • Nodular melanoma: lacks significant intraepidermal tumor cells beyond • the edges of the dermal component • LMM: sun-damaged background, (epidermal atrophy, solar elastosis, and dermal thinning) • ALM: diffuse lentiginous proliferation of tumor cells along the basal layer

• Hyperpigmented basal layer and elongated epidermal ridges, forming a reticulated pattern • In some cases, there may be an increase in melanocyte number


• Dermoscopy useful in distinguishing nonmelanocytic from melanocytic lesions • Skin biopsy for definitive diagnosis

• Largely clinical • Dermoscopy and skin biopsy can also be employed


• Surgical excision with wide margins • Depending on tumor depth: chemotherapy, targeted biologic therapies, etc.

• None required • Laser therapy • Cryotherapy

Abbreviations: ALM, acral lentiginous melanoma; LMM, lentigo maligna melanoma; SSM, superficial spreading melanoma.

have also highlighted a genetic component (variants in the melanocortin-1 receptor gene and mutations in FGFR3 and PIK3CA) in the pathogenesis of SL.15,17 Due to their evolving nature and association with sun exposure, further evidence is sometimes needed to confirm the diagnosis, and, more importantly, to rule out cutaneous malignancy. Dermoscopy, or skin surface microscopy, is commonly employed. Dermoscopic evaluation of SL reveals features of a benign, melanocytic lesion: diffuse opaque-brown pigmentation, sharply demarcated borders, fingerprinting, and a reticular network of thin lines.13,18 A more invasive approach, skin biopsy, is used if uncertainty remains in the diagnosis. Histologic features of SLs show a hyperpigmented basal layer and elongated epidermal ridges, forming a reticulated pattern.13 In some cases, there may be an increase in melanocyte number. Other findings include presence of melanophages and mild lymphocytic infiltrate in the superficial dermis.13 Several conditions may mimic solar lentigines. Some differential diagnoses to consider include lentigo simplex, macular SK, melanocytic nevus, ephelides, and melanoma.

Lentigo simplex appears clinically similar; lesions are described as being homogenous pigmented macules, ranging from light brown to black, that are well circumscribed with regular borders.13 Lentigo simplex lesions, however, tend to be much smaller (usually <5 mm) and can be found anywhere on the skin, including mucous membranes and palmoplantar surfaces. Clinically, it may be difficult to distinguish macular SK from SL, and many believe these lesions to be on the same continuum. Dermoscopy is particularly helpful because SKs lack melanocytic features, such as a pigmented network, which is found in SLs. In addition, SKs have distinguishing features, such as comedo-like openings and fissures, which are linear, keratin-filled depressions.18,19 A skin biopsy demonstrating a keratotic surface with horn cysts is consistent with SK.13 Melanocytic nevi are well-demarcated, symmetric, round to oval lesions that are not limited to sun-exposed skin. There are three forms of melanocytic nevi: junctional, dermal, and compound. These distinctions are based on the location of melanocytic nests in the epidermis, dermis,


or both, respectfully.13,20 Clinically, junctional nevi are flat, whereas dermal and compound nevi are papular. Dermoscopic evaluation reveals melanocytic findings, such as a globular architecture.13,20 Ephelides, also commonly known as freckles, are welldemarcated, round, oval, or irregularly shaped lesions found only on sun-exposed areas. In contrast to Sls, ephelides appear in early childhood and usually fade with reduced UVR exposure. Dermoscopic features include uniform pigmentation and moth-eaten edges.17 Melanoma is a malignant cancer signified by the transformation of melanocytes—specialized pigmented cells predominantly found in the basal layer of the epidermis— to tumor cells. The SSM and LMM subtypes clinically

3. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Melanoma of the Skin. National Cancer Institute website. Updated 2014. Accessed September 6, 2017. 4. Berwick M, Erdei E, Hay J. Melanoma epidemiology and public health. Dermatol Clin. 2009;27(2):2015-2214. 5. Egger ME, Stepp LO, Callender GG, et al. Outcomes and prognostic factors in superficial spreading melanoma. Am J Surg. 2013;206(6):861-868. 6. Menzies SW, Moloney FJ, Byth K, et al. Dermoscopic evaluation of nodular melanoma. JAMA Dermatol. 2013;149(6):699-709. 7. Pralong P, Bathelier E, Dalle S, Poulalhon N, Debarbieux S, Thomas L. Dermoscopy of lentigo maligna melanoma: report of 125 cases. Br J Dermatol. 2012:167(2):280-287. 8. Byrom L, Barksdale S, Weedon D, Muir J. Unstable solar lentigo: a

Solar lentigos are benign, though their presence indicates chronic UV exposure, a risk factor for cutaneous malignancies.

defined separate entity. Australas J Dermatol. 2016;57(3):229-234. 9. Crutcher WA, Cohen PJ. Dysplastic nevi and malignant melanoma. Am Fam Physician. 1990;42(2):372-385. 10. Bolognia JL, Lin A, Shapiro PE. The significant of eccentric foci of hyperpigmentation (‘small dark dots’) within melanocytic nevi. Analysis of 59 cases. Arch Dermatol. 1994:130(8):1013-1017. 11. Habif TP. Premaligant and malignant nonmelanoma skin tumors. In

resemble SLs. Melanomas tend to be larger and asymmetrical with irregular pigmentation and color variegation. Biopsy is usually needed and reveals a lentiginous spread of tumor cells with a sun-damaged background, demonstrated by epidermal atrophy, solar elastosis, and dermal thinning.1,2 SLs are benign lesions, though their presence does indicate chronic UV exposure, a risk factor for the development of cutaneous malignancies. As such, preventative measures to limit sun exposure, such as the regular use of sunscreen and protective clothing, should be encouraged. If patients do want to pursue treatment, laser therapy and cryotherapy are first-line management strategies.21 The patient in this vignette was advised that her lesion was benign. Due to her concern, the lesion was biopsied and the diagnosis of SL was confirmed. She was advised that no further treatment was necessary. ■

Habif TP, ed. Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:809-854. 12. Marzuka A, Huang L, Theodosakis N, Bosenberg M. Melanoma treatments: advances and mechanisms. J Cell Physiol. 2015;230(11):2626-2633. 13. Rabinovitz HS, Barnhill RL. Benign melanocytic neoplasms. In: Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012:1851-1885. 14. Ezzedine K, Mauger E, Latreille J, et al. Freckles and solar lentigines have different risk factors in Caucasian women. J Eur Acad Dermatol Venereol. 2012;27(3):345-356. 15. Hafner C, Stoehr R, van Oers JM, et al. FGFR3 and PIK3CA mutations are involved in the molecular pathogenesis of solar lentigo. Br J Dermatol. 2008;160(3):546-551. 16. Goorochurn R, Viennet C, Granger C, et al. Biological processes in solar lentigo: insights brought by experimental models. Exp Dermatol. 2016;25(3):174-177. 17. Praetorius C, Sturm RA, Steingrimsson E. Sun-induced freckling: epheli-

Pooja Reddy, is a medical student at the Baylor College of Medicine, and Christopher Rizk, MD, is a dermatology resident at the Baylor College of Medicine in Houston.

des and solar lentigines. Pigment Cell Melanoma Res. 2014;27(3):339-350. 18. Tanaka M, Sawada M, Koboyashi K. Key points in dermoscopic differentiation between lentigo maligna and solar lentigo. J Dermatol. 2011;38(1):53-58. 19. Braun RP, Rabinovitz H, Oliviero M, Kopf AW, Saurat JH. Dermoscopic


diagnosis of seborrheic keratosis. Clin Dermatol. 2002;20(3):270-272.

1. Tuong W, Cheng LS, Armstrong AW. Melanoma: epidemiology, diagno-

20. Hauschild A, Egberts F, Garbe C, et al; expert group “Melanocytic

sis, treatment, and outcomes. Dermatol Clin. 2012;30(1):113-124.

nevi”. Melanocytic nevi. J Dtsch Dermatol Ges. 2011;9(9):723-734.

2. Garbe C, Bauer J. Melanoma. In: Bolognia JL, Jorizzo JL, Schaffer JV, eds.

21. Ortonne JP, Pandya AG, Lui H, Hexsel D. Treatment of solar lentigines.

Dermatology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012:1885-1915.

J Am Acad Dermatol. 2006;54(5):262-271. • THE CLINICAL ADVISOR • OCTOBER 2017 47



Fired after violating a patient’s privacy A nurse notifies other clinicians that a patient is positive for hepatitis C. ANN W. LATNER, JD

Ms D always tried to do the right thing. The 30-year old nurse was committed to doing the best for her patients as well as for her co-workers. That is why she was so particularly upset at how and why she was fired from her job. The incident leading up to the loss of her job was, according to Ms D, completely unremarkable. She had worked in a midsized hospital, had been there for more than 2 years, and was well-liked by the other staff members. After encouragement by her co-workers, Ms D was considering returning to school to get an advanced practice degree. On the day in question, Ms D was working in the postanesthesia care unit, assisting an electrocardiogram technician and physician by prepping a patient for a transesophageal echocardiogram. The patient, who was positive for hepatitis C, was in an examination area behind a curtain. Other patients and medical personnel were nearby and in other curtained-off areas. Prior to the echocardiogram, Ms D made sure that the patient understood what was going to happen and that all the diagnostic tools were available. After doing so, and because

A nurse in a postanesthesia care unit tells a physician and EKG technician that a patient is positive for hepatitis C and that they should wear gloves.


she thought it was right to make sure that the physician and technician were protected, she informed them that the patient had hepatitis C and that they should wear gloves. Sometime thereafter, the patient filed a complaint with the hospital, alleging that his confidential health information was improperly disclosed because Ms D’s voice was loud enough to be heard by other patients and medical personnel in the area. Ms D was notified that she was being placed on administrative leave while the hospital completed an investigation. After the investigation, Ms D was informed that she was being terminated from her job based on her violation of the Health Insurance Portability and Accountability Act of 1996 (HIPAA) for unnecessarily disclosing confidential health information. Ms D was shocked at losing her job and believed strongly that the decision was unfair. Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

She consulted with an attorney about whether she could sue the hospital. “You were an at-will employee,” the attorney told her. “That basically means that they can fire you for any reason … you understand this?” “Yes,” said Ms D. “But I never violated HIPAA. And employees of the hospital are saying I did, and it’s ruining my reputation.” After some discussion, the attorney filed a lawsuit against the hospital, alleging that Ms D was wrongfully terminated from her job, and that she had been defamed by a hospital employee who said that she had been fired for a HIPAA violation. The lower court dismissed both counts, and Ms D appealed. On appeal, the Court of Appeals first looked at the alleged wrongful termination. As mentioned by the attorney, Ms D was an at-will employee, meaning that an employee could be fired for almost any justification, unless the employee was fired for refusing to violate the law, or because the employee exercised a statutory right. After looking at the facts in the case, the Court of Appeals agreed with the lower court that Ms D was fired because she had violated patient confidentiality provisions of HIPAA, not because she refused to violate a law or any other exception. The court dismissed the wrongful termination claim.

A medical provider must use the minimum amount of protected health information to accomplish the necessary purpose. Next, the Court of Appeals looked at Ms D’s defamation complaint. She claimed that an employee of the hospital had written in her work record and verbally told a third party that the reason she had been fired was due to a HIPAA violation. While Ms D admitted that she had, at most, engaged in “incidental disclosure” of patient information, which is not actionable under HIPAA, the Court of Appeals disagreed, and sided with the trial court, which had held that Ms D’s disclosure was unnecessary, because, as a matter of law, “a physician should not require being told that a patient has an infectious disease as a reminder to wear personal protective equipment such as gloves.” In reaching this conclusion, the court reasoned that, under HIPAA regulations, “a medical provider must use the minimum amount of protected health information to accomplish

the necessary purpose.” According to the court, because Ms D’s statement was not the minimum amount necessary to accomplish the warning to “wear gloves,” she violated HIPAA. Thus, the Court of Appeals also dismissed the count of defamation because truth is an absolute defense to defamation, and it was true that Ms D was terminated for a HIPAA violation. Legal background

At-will employment generally means that an employee may be fired for good cause, bad cause, or no cause at all. There are, however, a number of exceptions. Employees are protected from being fired in retaliation for refusing to commit an illegal act. Employers cannot fire employees if it would violate that state’s public policy doctrine or a state or federal statute. Thirtysix states have an implied contract exception, preventing an employer from firing an employee “when an implied contract is formed between an employer and employee, even though no express, written instrument regarding the employment relationship exists.” (Proving the terms of an implied contract is difficult, however, and the burden of proof is on the employee.) Also, there are statutory exceptions to at-will employment. For example, an employee cannot be fired for taking leave for a reason outlined in the Family and Medical Leave Act of 1993 (FMLA). Nor can an employee be fired for federally prohibited discriminatory reasons such as race, color, religion, sex, national origin, handicap status, or age (older than age 40). Protecting yourself

Know your own employment status—are you an at-will employee? A contract employee? Part of a union? A civil servant? These all have different rules in relation to job termination. Regarding HIPAA, Ms D was doing what she thought was the right thing to do—ensuring that her colleagues were proceeding in a safe manner. However, she clearly went too far by announcing the patient’s hepatitis C status verbally and broadcasting this information to anyone within earshot. Protect yourself by being aware of your surroundings and of who else might be within hearing distance when you are speaking to, or about, your patient. Use the least amount of personal information possible when conveying information. Ms D could simply have reminded the physician to use gloves (if a reminder was even necessary) without stating the exact nature of the patient’s condition. ■ Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y. • THE CLINICAL ADVISOR • OCTOBER 2017 49


What you should know about the herbs and supplements patients use By Sherril Sego, FNP-C, DNP Ms. Sego is an independent consultant in Kansas City, Mo.



Kefir, sometimes called milk kefir, is a fermented beverage made from milk inoculated with kefir grains, otherwise considered a traditional yeastlike starter.1 This beverage can be found in cultures around the world, but it is believed to have originated in Russia.2 Properly fermented kefir yields a thick, slightly sour liquid with a mild sparkle from the small amount of alcohol. Kefir was first documented as a health supplement in the 1880s, but in the last decade it has gained worldwide attention. Kefir is generally included in the category of natural probiotics, with the added benefits of vitamins, minerals, and some proteins.

Background Kefir can be made from most any kind of milk product, including cow’s milk, soy, or coconut milk. The difference in the final product is seen in the variation of types of bacteria contained in the starter, or grains. In traditional cultures, these starters were handed around the community as needed, much like some popular bread recipes. For those wishing to grow their own kefir, usually a starter culture can be purchased from a health food store. From there, follow the simple directions. Because gut flora play a key role in immunity, proponents of alternative therapies believe that products such as kefir have tremendous potential for promoting health and preventing disease.

Scientific data One common malady that kefir is useful in managing is lactose intolerance. Because of the fermentation process, lactose in the milk is broken down, leaving a product that is basically lactose

free. In a randomized study, 15 healthy adults with diagnosed lactose intolerance were given premeasured milk, yogurt, or kefir following a 12-hour fast.3 Outcome measurements were breath hydrogen excretion and subjective symptoms. Compared with the milk group, those who drank kefir showed a 250% reduction in both exhaled hydrogen level and subjective symptoms, which was similar to results in the plain yogurt group. Another disease that causes significant health impact is rotavirus. In an in vitro study, kefir was introduced into an isolated strain of rotavirus to determine the degree to which it could inhibit the rotavirus activity.4 After the incubation period, the reduction in human rotavirus averaged 72% compared with no treatment. Researchers also examined the effect of adding kefir to standard triple therapy used to treat Helicobacter pylori.5 They randomly assigned 82 patients with symptomatic H. pylori infection confirmed by urea breath testing. The treatment group was given the usual triple therapy along with 1 cup of kefir daily, while the control group received triple therapy


and a milk placebo. Because H. pylori tends to either recur or resist therapy, all participants were retested for infection after 45 days. The kefir group achieved a 50% higher eradication rate than those in the placebo group.

Home preparation of kefir opens the door to many questions of safety, because individual kitchens and products cannot be controlled. Milk products and kefir starters can contain any number of harmful agents. Interactions to the kefir itself would more likely be to the base milk product than to the probiotic component. Many medications, especially antibiotics, are not appropriately absorbed when taken in conjunction with milk products. Otherwise, no interactions have been noted.

Cost, dose, and how supplied

Safety, interactions

Kefir has been shown to inhibit rotavirus activity in humans.

Commercially prepared kefir is considered to be safe, mainly as a result of the pasteurization process that is required for dairy products.

Summary Kefir is yet another natural product that has become popular in recent years but has been a staple in many cultures for centuries. Most likely born out of necessity because of the lack of any method of refrigeration, kefir is now in the spotlight of the world of alternative medicine. Not unlike many alternative therapies, the actual scientific data from controlled human trials are nearly nonexistent. However, because the safety data are relatively benign, and some laboratory studies seem to indicate the superiority of probiotics in a base such as kefir compared with capsule supplements, kefir is an acceptable choice and one that can be reliably approved in primary care practices. n References 1. Otles S, Cagindi O. Kefir: a probiotic dairy-composition, nutritional and therapeutic aspects. Pakistan J Nutrition. 2003;2:54-59. 2. Editors of Webster’s New World Dictionaries. Webster’s New World Dictionary. 4th ed. Kefir. Boston, MA: Houghton Mifflin Harcourt; 2012. 3. Hertzler SR, Clancy SM. Kefir improves lactose digestion and tolerance in adults with lactose maldigestion. J Am Diet Assoc. 2003;103:582-587. 4. Song J-O, Kim T-J, Kim Y-H. Inhibitory effect on rotavirus by exopolysaccharides extracted from kefir [in Korean]. Korean J Food Sci Ani Resour. 2007;27:538-542.

Commercially prepared kefir is considered safe, mainly as a result of the pasteurization process that is required for dairy products. The downside of this is that many feel the best probiotics are also killed during this process, even if supplements are added after the heating of the product.

5. Bekar O, Yilmaz Y, Gulten M. Kefir improves the efficacy and tolerability of triple therapy in eradicating Helicobacter pylori. J Med Food. 2011;14:344-347. 6. Aghajani A, Pourahmad R. Effect of lactulose and inulin on physicochemical and microbial properties of synbiotic yogurt. Ann Biol Res. 2012;3:5692-5696. • THE CLINICAL ADVISOR • OCTOBER 2017 51


Commercially prepared kefir is usually purchased in containers very similar to a quart of milk. Kefir is not inexpensive, averaging $5 to $20 per quart in retail outlets. As one would imagine, home-cultured kefir costs about onehalf that amount, depending on the type of milk used and the kefir grains purchased. As far as dosing, there are no actual dose recommendations. Kefir may by consumed in whatever quantity preferred. The literature has a wide range of examples from 1 tablespoon to ½ cup per day, but to date, there has been no attempt to standardize the dose because the mixture itself is not consistent. In a laboratory study using mice, researchers compared fermented milk products with different added concentrations of the prebiotic inulin.6 Subsequently, they evaluated the level of active probiotics in the gut correlated with the concentration of inulin. It was found that the higher the level of inulin, the more robust the probiotic activity. Although this obviously would need to be verified in human trials, it would seem that probiotics in actual functional foods such as kefir are more viable and active than those in capsule or another supplement form. Anecdotal information on several websites estimates that probiotics consumed in actual foods are “hundreds of times” more effective than supplements, but there are no studies to validate this claim.

October 2017 Clinical Advisor