June 2016 Clinical Advisor by The Clinical Advisor

THE CLINICAL ADVISOR • JUNE 2016

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■ Medical errors and death ■ Hepatitis C mortality ■ COPD and renal failure FEATURE Sex Trafficking of Minors

Missed clinical opportunities

JUNE 2 016

| www.ClinicalAdvisor.com

A STEPWISE APPROACH TO

ASTHMA CARE Progressive bronchial tube narrowing during an asthma attack.

LEGAL ADVISOR

Prescription refill goes wrong STAT CONSULT

Lyme disease

■ Dermatology Clinic

HYPOTRICHOSIS IN AN INFANT PAGE 51

VOLUME 19, NUMBER 6

■ Dermatologic Look-Alikes

DARKENED SKIN ON A WOMAN’S HIP PAGE 63

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Editor Colby Stong, editor@ClinicalAdvisor.com Senior editor Sandhya George Associate digital content editor Hannah Dellabella Assistant editor Lauren Biscaldi 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 director Ada Figueroa Circulation manager Paul Silver National accounts manager Alison McCauley, 973.224.6414 alison.mccauley @ haymarketmedical.com Publisher Kathleen Hiltz, 201.774.1078 kathleen.hiltz@haymarketmedia.com Editorial director Kathleen Walsh Tulley Senior vice president, digital products and medical magazines Jim Burke, RPh Senior vice president, medical communications John Pal CEO, Haymarket Media, Inc. Lee Maniscalco All correspondence to: The Clinical Advisor 114 West 26th Street, 4th 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 19, Number 6, 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., 114 West 26th Street, 4th Floor, New York, NY 10001. Single copy: $20 U.S.; $30 foreign. www.ClinicalAdvisor.com. 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 © 2016

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EXPERTS If a patient has you stumped, write us and we’ll forward your query to one of our consultants and publish the response in Advisor Forum.You can also use this space to contribute a clinical pearl of your own or comment on another letter.

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.

CLINICAL PEARLS

It cannot be beat.—TERRI JORDAN, ARNP, Daytona Beach, Fla. (202-2)

NEUTROPHILS AND LYMPHOCYTES In interpreting a complete blood count with differential, anytime the neutrophils and lymphocytes are numerically close, it is a viral cause; when the neutrophils and lymphocytes are numerically distant, it is a bacterial cause. This is very helpful in determining treatment.—DONNA CARTER, FNP-C, Scottsburg, Ind. (202-1) GENERIC “CAINE” IS EFFECTIVE FOR WOUND CARE For pain relief, most pharmacies offer a “caine” at 2-510%, and basically nothing higher, for between $5 and $30 per tube. I work in wound care and use Walmart’s

INTRA-ARTICULAR INJECTIONS FOR SEVERE OSTEOARTHRITIS Patients with severe osteoarthritis in the knees seem to do better with intra-articular injections if you have them sit up and dangle their legs off the examination table and distract the knee slightly when administering the injection.—ROSEMARY LEDBETTER, PhD, PA, Troy, Ill. (202-3)

YOUR COMMENTS SLIPPED CAPITAL FEMORAL EPIPHYSIS IN OBESE ADOLESCENTS I just read the CME/CE article by Marilou Shreve, DNP, APRN, entitled, “Assessing and treating pediatric obesity” [ June 2015]. I was concerned regarding the oversight of a critical issue in obese adolescents: the increased risk of slipped capital femoral epiphysis (SCFE). This was not addressed in the article. The case study (p. 55) gave incomplete advice regarding the evaluation of an obese adolescent male with knee pain. The most common etiology of the insidious onset of knee pain in children is the hip, due to referred pain from the

Equate brand—vagicaine 20% benzocaine. When using this before debriding a wound, give it three minutes to sedate the nerves, then perform the procedure. I get good results, as patients say. It relieves pain and burning for $1.88.

Advisor F

Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001. You may contact us by e-mail at editor@ clinicaladvisor.com. 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.

orum

These are lette and successe rs from practitioners s, observat around the below. We ions, and country who OUR CONSULTANTS pearls with invite you want to shar to participa their colle e their clinic agues. Resp te. al problems onding cons ultants are identified CON SULTAT IONS

TREATM ENT FOR INFECT URINAR ION SGLT2 REC MALE CHI S IN THE UNC Y TRACT IRCUMCI LD FOR DIA EPTOR BLOCKE If a male SED child conti Deborah L. Cross, MPH, CRNP, Laura A.BET Foster,ES CRNP, FNP, Abby A. Jacobson, PA-C, RS Abimbola Farinde, PhD, PharmD, With the nues toassociate ANP-BC, is practices family medicine is a physician assistant is a professor redevprogram adven t ofPrimary circu SGLT2 recep at Delaware Valley urinaryattract director, Gerontology NP elop Program, mcisi Columbia Southern moda litywith Palmetto on be perfo for type tor infecPhysicians Dermatology University of Pennsylvania School blockersGroup University 2 diabe rmed? regarding inCare as a treatm in Wilmington, Del. in Orange Beach, Ala. useCharleston, S.C. tes, is there ent urology is of Nursing, Philadelphia. any evide NATHAN in patients with to protect the is well advise nce or data type 1 diabe GARDNE d tes mellitus?— R, PA-C, continues to to recommend a circum upper tracts, the kidne CPAAPA, ys. develo cision It p recurr•ent 44 THE ADVISOR AUGUST 2015 •on www.ClinicalAdvisor.com Castleton, severaCLINICAL l consideration urinary tract the male child who As it currently stands N.Y. , SGLT2 s that infections. for glycemic impede the receptor blocke There are control in ability to cleansenter into this decisio rs are FDA adults with n. Poor hygien should the e and quell -approved child have e may appro diet and exercise, but with type 2 diabetes phimosis, simpl infection potential. appropriate the in ved conjun FDA for use in patien Moreover, AdvisorForum_CA0815.indd urine 44 9/29/15ction 2:38 PM e cathet culture can ts with type has stated that they ketoacidosi steroid cream be a challenge. erization to obtain s, or those are not may tempo an FAR with severe 1 diabetes, patients with Having a short tion of the rarily solve renal functi diabetic steroid the trial of informINDE, PhD, Pharm these issues tenden , though after for infection D (See bottom on.—ABIMBOL ation about once again.—C cy redevelops, placin cessaA Dr. Farinde.) of this page Milwaukee g (203-2) for more , Wis. (203- OLEEN ROSEN, the child at risk 1) DNP, FNP -C, CLI Philip R. Cohen, MD,

is clinicaltions associate professor , shou ld of dermatology, University a of Texas Medical Center, The focus of Houston.

NICAL

Send us your letter Advisor Forum, The s with questions New York, and comm Clinical Advisor ents to: , 114 clinicaladvisoNY 10001. You may contacWest 26th Street , please indicatr.com. If you are writing in t us by e-mail at 4th Floor, each item. e so by including response editor@ to a the Letters are policy is edited for number in parent published letter, to heses at length and contribution print the author ’s name with clarity. The Clinicathe end of s will be accepted. l Advisor the letter. No anonym ’s ous

Write us today.

OUR CO

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PEARLS

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VAGINA L RESULT DISCHARGE AND ING FRO If a female M TAMPON ODOR patient has USE a ask if she uses tamp history of vaginal disch ons. If she the pelvic arge with says “yes,” exam when cond odor, that you woul , do not enter ucting the rotating of d to take a pap smea vagina in the same the specu way r. Instead, the cervix. lum Most retain from side to side start shallow until reach ed tampons ing are lodge d in the fold

Philip R.

Cohen, MD, is clinical associa te profess of dermat or ology, of Texas MedicaUniversity l Center, Houston.

62 THE CLINI

Deborah L. Cross, MPH, ANP-B

CRNP, C, is associa te program director, Geronto logy NP Program University of Pennsyl vania School , of Nursing , Philadelphia.

CAL ADVI

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SEND TO The Clinical Advisor 114 West 26th Street, 4th floor New York, NY 10001 AdvisorForum_

CA0915

MBER 2015

Abimbo la Farinde

, PhD,

is a profess PharmD, or at Columb ia Souther n Univers in Orange ity Beach, Ala.

• www.Clinic

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Laura A.

Foster,

practices familyCRNP, FNP, with Palmett medicine o Primary Care Physicia ns in Charles ton, S.C.

Abby A.

Jacobso

is a physicia n, PA-C, n at Delawa assistant re Dermatology Valley in Wilmington,Group Del.

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9/29/15

2:44 PM

E-MAIL editor@ClinicalAdvisor.com

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2016 3

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CONTENTS JUNE 2016

NEWS AND COMMENT 14 Newsline ■■Medical errors are now the third leading cause of death in the United States. ■■Hepatitis C–associated mortality is increasing and is the leading cause of death among all infectious diseases in the United States. ■■Swaddling sleeping infants increases the risk of SIDS. ■■One-third of outpatient oral antibiotic prescriptions may be inappropriate. ■■Comprehensive Primary Care Initiative: a mid-term report ■■COPD may increase risk for renal failure. ■■Metformin versus sulfonylureas regarding cardiovascular mortality in patients with diabetes. ■■Influenza vaccinations are more effective when administered in the morning. 81 Commentary The bravery of people with dementia

36 CME/CE Tailoring asthma treatment using a stepwise approach As highlighted in this case, optimal asthma care is a step-by-step process that involves recognizing disease variants and considering individualized options. 44 CME/CE Feature posttest Swaddling infants linked to SIDS risk 16

Domestic minor sex trafficking 26

63 Dermatologic Look-Alikes Darkened skin in a 45-year-old Hispanic woman and an 18-yearold Hispanic woman Continues on page 6

26 Identifying domestic minor sex trafficking An awareness of the risks and red flags among adolescent patients who are being trafficked for sex is the key to intervention in this vulnerable population.

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

51 Dermatology Clinic n Deformity of the breast in a premenopausal woman n Hypotrichosis in a woman and infant

FEATURES

MAKING CONTACT

DEPARTMENTS

Another clinician’s prescription 70

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CONTENTS DEPARTMENTS, cont’d 70

Legal Advisor Another clinician’s prescription.

Stat Consult Lyme disease

Alternative Meds Update Bromelain

“What’s this they say, Billy, about a new, more virulent strain of teenager?”

Your Comments ■ Identifying cervical lesions

Clinical Pearls ■ Applying ointment to a child ■ An alarm clock can help patients remember to take their medication

Case Files ■ Hemorrhoid medication

Consultations ■ Kenalog injection for allergies

ADVISOR FORUM

“Hey, I’ll get to the meeting on time. It’s those creative types you ought to be checking on.”

HOW TO CONTACT US R • JUNE 2016

FEATUR E

Sex Traffi cking of Mino

Missed clinic

al opportu

nities

LEGAL ADV

ISOR

Prescription refill goes STAT CO NSU

Lyme disease

• Send it by e-mail to editor@ClinicalAdvisor.com

wrong

NER S

JUNE 2 016

| www.Clin icalA

dvisor.com

A STEPW

ISE APPR OACH TO

ASTHMA

C ARE Progressi ve bronchial tube narr owing durin g an asthma attack.

■ Dermatolo gy Clinic

HYPOTRIC AN INFAN HOSIS IN T PAGE 51

19, NUMB ER 6

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IEWE D FORU M FOR NUR SE PRAC TITIO

TO SUBMIT A CLINICAL QUESTION FOR PUBLICATION: • www.ClinicalAdvisor.com/AdvisorForum

• Mail it to The Clinical Advisor, 114 W. 26th St., 4th Floor, New York, NY 10001

A PEER -REV

NEWSLIN

■ Medical errors and death ■ Hepatitis C mor tality ■ COPD and renal failure

VOLUM E

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■ Dermatolo gic

DARKENEDLook-Alikes A WOMAN’SSKIN ON HIP PAGE

5/24/16 4:49 PM

EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com Web Exclusives

The Waiting Room

ClinicalAdvisor.com/News

Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom

Hepatitis C mortality increasing, now leading cause of death among all infectious diseases The number of deaths associated with hepatitis C is higher than the total number of deaths resulting from 60 other infectious diseases.

Sean P. L’Huillier, MS, APRN, FNP-C, CEN A bumpy transition into the role of an FNP Sometimes, stepping into a new professional role takes longer than expected. Sharon M. O’Brien, MPAS, PA-C Increased risk of Parkinson disease in female patients with sleep apnea The sleep concerns of female patients are often diagnosed as depression rather than obstructive sleep apnea, leading to increased risks for certain diseases.

Swaddling sleeping infants increases risk of SIDS Infants who are swaddled while they sleep have an increased risk of SIDS, and the risk increases with age.

One-third of antibiotic prescriptions may be inappropriate, per study by JAMA and CDC Research findings support the need to establish a goal of increased antibiotic stewardship among physicians.

Jillian Knowles, MMS, PA-C What in the world is Vasalgel? A form of male birth control called Vasalgel, which works by injecting a polymer gel into the vas deferens, is being developed in the United States.

Cartoon Archive

Multimedia

The Clinical Advisor’s monthly cartoons are also available online.

ClinicalAdvisor.com/Multimedia

ClinicalAdvisor.com/cartoons

“Giddydown.”

MAKING CONTACT

Fatal medical errors are a leading cause of death Medical errors are the third leading cause of death in the United States. Martin Makary, MD, discusses why medical errors are usually ignored. Watch it here: ClinicalAdvisor.com/FatalErrorsVid Rotating night shifts associated with coronary heart disease Women who work rotating night shifts have an increased risk of coronary heart disease. The longer a woman worked on this schedule, the higher her risk of developing coronary heart disease. Watch it here: ClinicalAdvisor.com/NightShiftsCHDVid

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8 THE CLINICAL ADVISOR • JUNE 2016 • www.ClinicalAdvisor.com

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Advisor Dx

EXCLUSIVE TO THE WEB

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 ClinicalAdvisor.com/AdvisorDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

Ortho Dx

In partnership with

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Journal of Orthopedics for Physician Assistants

Valgus deformity of the knee A 57-year-old man presents with knee pain and valgus deformity of his right knee. He has failed conservative treatment for osteoarthritis and has decided to proceed with a right total knee arthroplasty. An anteroposterior radiograph is taken. WHICH COMPLICATION COULD ARISE?

• • • •

Foot drop Arthrofibrosis Flexion contracture Varus instability

● See the full case at ClinicalAdvisor.com/OrthoDx_June16

Derm Dx Comedones on the cheeks A 79-year-old man presents for treatment of a forehead cyst that has been excised surgically. An incidental finding on examination is multiple open comedones aﬀecting both cheeks. The patient’s facial skin is sallow, thickened, and leathery. He worked outdoors for decades and has smoked cigarettes since he was a teenager. CAN YOU DIAGNOSE THE CONDITION?

• • • •

Chloracne Nevus comedonicus Favre-Racouchot syndrome Colloid milia

● See the full case at ClinicalAdvisor.com/DermDx_June16

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2016 9

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Newsline J U N E 2 016

Swaddling may increase the risk of SIDS page 16

Brief resolved unexplained events in infants page 18

COPD linked to higher risk of renal failure page 25

MEDICAL ERRORS are now the third leading cause of death in the United States, trailing only heart disease and cancer, according to a study in BMJ. Martin Makary, MD, and Michael Daniel from the Johns Hopkins University School of Medicine in Baltimore, found that medical errors accounted for more than 251,000 deaths in the US in 2013, compared with 611,000 deaths from heart disease and 585,000 deaths from cancer. The CDC has compiled an annual list of the most common causes of death in the United States. However, the list is based

on death certificates, which rely on International Classification of Disease (ICD) codes to identify the cause of death, and ICD codes do not take into account human and system factors. Medical error was defined in the report as an “unintended act (either of omission or commission) or one that does not achieve its intended outcome, the failure of a planned action to be completed as intended (an error of execution), the use of a wrong plan to achieve an aim (an error of planning), or a deviation from the process of care that may or may not cause harm to the patient.”

Medical errors are third leading cause of death in United States Medical errors accounted for more than 251,000 deaths in the US in 2013, according to a study in BMJ.

Using research reported since a 1999 study from the Institute of Medicine found an incidence of 44,000 to 98,000 deaths occurring annually due to medical errors, and extrapolating to the total number of US hospital admissions in 2013, Makary and Daniel found a mean rate of death from medical errors of 251,454 per year. “Comparing our estimate to CDC rankings suggests that medical error is the third most common cause of death in the US,” the researchers stated.

Hepatitis C is leading cause of death among all infectious diseases HEPATITIS C VIRUS (HCV)–associated mortality is increasing and is now the leading cause of death among all infectious diseases, with a record-high 19,659 deaths occurring in 2014, according to the CDC. As reported in Clinical Infectious Diseases, Kathleen N. Ly, MPH, an epidemiologist with the CDC’s Division of Viral Hepatitis in Atlanta, and colleagues also found that the number of deaths associated with hepatitis C in 2013 was greater than the combined number of deaths resulting from 60 other infectious diseases, including HIV, pneumococcal disease, and tuberculosis. The researchers noted that because the two studies used data from death certificates, which often underreport hepatitis C, the actual number of hepatitis C-related deaths may be even greater. The CDC’s findings may also suggest a new wave of hepatitis C infections among people who inject drugs. Since 2010, acute

cases of hepatitis C infection have more than doubled, with 2,194 reported cases in 2014. The new cases most commonly occurred in young, white persons who have a history of injection drug use and live in rural and suburban areas of the Midwest and Eastern United States. “Once hepatitis C testing and treatment are as routine as they are for high cholesterol and colon cancer, we will see people living the long, healthy lives they deserve,” stated Jonathan Mermin, MD, director of the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention. “Because hepatitis C often has few noticeable symptoms, the number of new cases is likely much higher than what is reported,” stated John W. Ward, MD, director of the CDC’s Division of Viral Hepatitis. “Due to limited screening and underreporting, we estimate the number of new infections is closer to 30,000 per year.”

14 THE CLINICAL ADVISOR • JUNE 2016 • www.ClinicalAdvisor.com

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Newsline Swaddling sleeping infants increases risk of SIDS

SWADDLING INFANTS, especially when they are sleeping in a prone position or on their side, may increase the risk for sudden infant death syndrome (SIDS), according to a study published in Pediatrics. The overall, age-adjusted odds ratio (OR) for swaddling was 1.58, though the risk varied by position placed for sleep. The risk of SIDS

For infants placed in the prone and side positions to sleep, swaddling doubled the risk for SIDS.

associated with swaddling seemed to increase in older infants. The meta-analysis included 4 studies that used SIDS as an outcome and also included data on swaddling for the last or reference sleep. The studies span 2 decades and parts of England, Tasmania, and the US (Chicago). From all 4 studies, there were 760 SIDS cases compared with 1,759 control participants. The risk of SIDS with swaddling increased with age, with infants aged 6 months and older having the greatest risk (OR, 2.53). For infants placed in the prone and side positions to sleep, swaddling doubled the risk for SIDS (OR, 12.99 for prone infants; OR, 3.16 for infants on their side) compared with non-swaddled infants. There was a small but significant risk of SIDS for swaddled infants

placed on their back to sleep (OR, 1.93) compared with nonswaddled infants. Although being swaddled and then found sleeping prone was a rare occurrence (<1% among control subjects and 8% among infants with SIDS), it increased the risk of SIDS 19-fold. Two studies included data on both the sleeping position the infants were placed in and the position they were found in. Of the 124 control infants who were swaddled, none was placed prone, 49 were placed on their side (24 remained on their side; 25 rolled onto their back) and 1 was placed supine (and was found prone). Of the 16 swaddled infants with SIDS who were found prone, 3 were placed and found prone, 8 were placed on their side and found prone, and 5 were placed supine and found prone.

NEARLY 30% of outpatient oral antibiotics prescribed between 2010 and 2011 may have been inappropriate, according to research published in JAMA. Katherine E. Fleming-Dutra, MD, of the CDC, and colleagues used data gathered from the 2010-2011 National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey to estimate rates of prescription for outpatient oral antibiotics; data were analyzed by age and diagnosis. “Half of antibiotic prescriptions for acute respiratory conditions may have been unnecessary,

representing 34 million antibiotic prescriptions annually,” Dr Fleming-Dutra noted. Across nearly 185,000 sampled visits, the researchers found that 12.6% of the visits resulted in an antibiotic prescription. Sinusitis was associated with the most prescriptions, with 56 prescriptions per 1000 population, followed by suppurative otitis media (47 prescriptions) and pharyngitis (43 prescriptions). In total, 221 antibiotic prescriptions per 1000 population were written annually for acute respiratory conditions; only 111 of these prescriptions were deemed

About 30% of oral antibiotic use may not be appropriate.

appropriate. Among all ages and conditions, researchers estimated that 506 antibiotic prescriptions had been written per 1000 population, of which only 353 were appropriate. “Despite the likely conservative estimate of inappropriate outpatient antibiotic use … these findings offer an important and useful starting point to understand prescribing practices in the ambulatory care setting,” wrote Prantina D. Tamma, MD, MHS, and Sara E. Cosgrove, MD, MS, of the Johns Hopkins University School of Medicine, in an accompanying JAMA editorial.

One-third of antibiotic prescriptions may be inappropriate

16 THE CLINICAL ADVISOR • JUNE 2016 • www.ClinicalAdvisor.com

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Newsline Brief resolved unexplained events: a practice guideline THE AMERICAN Academy of Pediatrics (AAP) has released a clinical practice guideline for the evaluation and management of brief resolved unexplained events (formerly known as apparent life-threatening events) in lower-risk infants. The guideline is published in the May issue of Pediatrics. The clinical practice guideline has 3 main objectives: 1. Recommending the replacement of the term apparent lifethreatening event (ALTE) with the new term, brief resolved unexplained event (BRUE) 2. Providing an approach to evaluating patients based on the risk of

The BRUE clinical guideline applies to lower-risk infants.

the infant having a repeat event or serious underlying disorder 3. Providing management recommendations for lower-risk infants The AAP def ines the term BRUE as “an event occurring in an infant younger than 1 year when the observer reports a sudden, brief, and now resolved episode of ≥1 of the following: (1) cyanosis or pallor; (2) absent, decreased, or irregular breathing; (3) marked change in tone (hyperor hypotonia); and (4) altered level of responsiveness. A BRUE is diagnosed only when there is no explanation for a qualifying event after conducting an appropriate history and physical examination.”

Infants who present with a BRUE can either be classified as lower- or higher-risk, based on history and physical examination. The AAP’s guidelines only apply to lower-risk patients who have the following characteristics: • Older than 60 days • Gestational age of ≥32 weeks and postconceptional age of ≥45 weeks • Occurrence of only 1 BRUE • Duration of the BRUE is less than 1 minute • No CPR required by trained medical provider • No concerning history features • No concerning physical examination findings

MIDWAY THROUGH the Comprehensive Primary Care Initiative, practices reported significant improvements in the delivery of primary care, but Medicare expenditures and patient experience have seen little change, according to a study in the New England Journal of Medicine. Participating primary care practices were required to make changes in care delivery to improve 5 functional areas: 1. Access to and continuity of care 2. Planned care for preventive and chronic needs 3. Risk-stratified care management 4. Engagement of patients and their caregivers 5. Coordination of care with patients’ other care providers At the 2-year midpoint of the initiative, the researchers compared

changes in Medicare expenditures, healthcare use, claims-based measures of quality, and patient experience for Medicare fee-for-service beneficiaries in initiative practices and a group of matched comparison practices. The researchers assessed practice transformation with a 37-item survey that each participating practice self-scored on a scale of 1 to 12

Significant improvements were seen in the delivery of primary care.

points, with higher scores reflecting better delivery of primary care. The initiative practices’ survey scores suggested significant improvement, with average scores increasing from 6.5 at baseline to 8.8 after 2 years. Risk-stratified care management and access to care saw particularly significant increases in average scores from baseline to 2 years, increasing from 4.6 to 9.7 and from 7.0 to 9.6, respectively. No significant differences were observed between initiative and comparison practices in changes in average monthly Medicare expenditures per beneficiary, both when care-management fees were taken into account and when they were not. The initiative practices had a 3% reduction in primary care visits, compared with control practices.

Comprehensive Primary Care Initiative: a mid-term report

18 THE CLINICAL ADVISOR • JUNE 2016 • www.ClinicalAdvisor.com

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Newsline COPD may Metformin vs. sulfonylureas for CV increase risk for mortality in diabetes patients renal failure compared the efficacy and safety of FOR PATIENTS with type 2 CV PATIENTS WITH chronic obstructive pulmonary disease (COPD) have an increased risk of renal impairment and renal failure, according to a study published in Respiratory Care. In patients w ith COPD, decreases in estimated glomerular filtration rates were more indicative of chronic renal failure than serum creatinine levels. The study included 136 participants with COPD (who were divided into 2 groups according to a combined assessment) and 104 controls. The researchers compared the clinical factors, renal function, estimated glomerular filtration rate, and spirometry data of the groups. The COPD groups had significantly worse renal function and significantly decreased glomerular filtration rates compared with the placebo group. The COPD groups also had a greater percentage of participants with concealed chronic renal failure compared with the placebo group. The 2nd COPD group had a significantly higher percentage of concealed chronic renal failure compared with the 1st COPD group and the control group. In all 3 groups, the percentages of participants with concealed chronic renal failure were greater than those with overt chronic renal failure. Estimated glomerular filtration rate was significantly correlated with all clinical and spirometry data.

diabetes, metformin reduces the relative risk of cardiovascularrelated mortality by 30% to 40% more than sulfonylureas, according to a meta-analysis that was published in the Annals of Internal Medicine. “Metformin looks like a clear winner,” said Nisa Maruthur, MD, MHS, assistant professor of medicine at the Johns Hopkins University School of Medicine. “This is likely the biggest bit of evidence to guide treatment of type 2 diabetes for the next 2 to 3 years.” This review provides an update to 2 previous analyses, the most recent of which was published in 2011. Since then, more than 100 new studies have compared the efficacy of blood sugar-reducing drugs, and several new drugs have been introduced. The study

mortality is lower in patients with diabetes who used metformin.

monotherapy (thiazolidinediones, metformin, sulfonylureas, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium-glucose cotransporter 2 [SGLT-2] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists) and several metformin-based combinations in adults with type 2 diabetes. The researchers found that cardiovascular mortality was lower in patients who used metformin compared with those who used sulfonylureas, but the evidence on all-cause mortality, cardiovascular morbidity, and microvascular complications was insufficient or low strength. All monotherapies and metformin-based combinations resulted in similar reductions in HbA1c values except for DPP-4 inhibitors, which resulted in smaller reductions.

Morning flu vaccinations yield higher efficacy INFLUENZA VACCINATIONS are more effective when administered to patients in the morning, according to research published in Vaccine. Researchers analyzed data from 276 adults aged 65 years and older who were administered the influenza vaccine between 2011 and 2013. The vaccine protected against 3 strains of the flu and was administered either between 9 and 11AM, or 3 and 5 PM. For 2 of the 3 strains, patients vaccinated between 9 and 11 AM showed a significantly larger increase in antibody concentration during the month following vaccination.

“We know there are fluctuations in immune responses throughout the day and wanted to examine whether this would extend to the antibody response to vaccination,” said Anna Phillips, PhD, MSc, BSc, principal investigator, of the School of Sport, Exercise, and Rehabilitation Sciences at the University of Birmingham. “Being able to see that morning vaccinations yield a more efficient response will not only help in strategies for flu vaccination, but might provide clues to improve vaccination strategies more generally,” Dr Phillips concluded. n

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FEATURE: MICHELLE PARDEE, DNP, FNP-BC, MICHELLE MUNRO-KRAMER, PHD, FNP-BC, CNM, APRIL BIGELOW, PHD, AGNP-BC, AND GINA DAHLEM, PHD, FNP-BC

Identifying domestic minor sex trafficking An awareness of the risks and red flags among adolescent patients who are being trafficked for sex is key to intervention in this vulnerable population.

Victims of sex trafficking are often reluctant to disclose their situation.

uman trafficking, or modern day slavery, is a heinous violation of human rights, and it is a hidden crime that has infiltrated communities around the world.1,2 According to the Victims of Trafficking and Violence Protection Act of 2000 and its 2003, 2005, 2008, and 2013 reauthorizations, human trafficking occurs if a person is induced through the use of force, fraud, or coercion to perform labor or a commercial sex act.3 Human trafficking does not require that a person or persons be transported across geographical borders and can include cases in which victims are exploited within their own community.1 Victims may be forced or coerced by physical or psychological means; in fact, the profound impact of psychological coercion and control is often overlooked.4 Sex trafficking may encompass such activities as prostitution, escort services, working in brothels, stripping, and pornography.5 The legal definition specifically refers to the “recruitment, harboring, transportation, provision, or obtaining of a person for the purpose of a commercial sex act,” or a sex act in which something of value was given or received by any person.3 Domestic minor sex trafficking (DMST), or child sex trafficking, explicitly refers to a situation in which the individual engaging in a commercial sex act is younger than 18 years of age.3 The purpose of this article is to provide information for primary care providers that they can use to assess, identify, and intervene with adolescent patients who are being trafficked for sex, so that missed clinical opportunities can be prevented.

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Domestic minor sex trafficking

Because of the sensitive nature of the crime and underreporting, current statistics on DMST within the United States are limited. However, the US Department of Health & Human Services estimates that between 100,000 and 325,000 American youth are at risk for sexual exploitation.1 DMST transcends racial, ethnic, gender, and educational barriers and can potentially affect any youth.6 Age is one of the primary factors related to being trafficked, and young people are considered the most vulnerable group in the United States for exploitation as victims of sex trafficking.5 Youth are often more susceptible to the psychological tactics used by traffickers, including manipulation, deception, and romantic advances.7 The average age of girls at entry as female juvenile prostitutes is 12 to 14 years.7,8 Additionally, a number of secondary factors have been linked to a higher risk for DMST. For instance, environmental factors such as family situation (ie, domestic violence, abuse, neglect, parental substance abuse, single-parent homes), frequent encounters with child welfare services, poverty, and homelessness appear to be significant risk factors for DMST.6,7 Childhood sexual abuse has also been demonstrated to be a significant risk factor.6 Runaway or throwaway children are also at high risk for becoming victims of child sex trafficking. Current estimates are that 1 in 6 runaways are likely to be victims of child sex trafficking.9 These youth are often recruited into sex trafficking within days of running away and frequently become involved as a means to procure basic necessities such as food, water, and shelter, a situation termed survival sex.7 It is important to recognize that despite the lack of clarity on prevalence rates, the sexual exploitation of American youth would not be so widespread or lucrative were it not for the demand.5 In American society, the demand for sex and sexuality is high, and the media have made terms such as prostitution, pimps, and johns part of everyday vocabulary. With an estimated $150 billion in yearly profits,10 human trafficking has been cited as the third largest source of revenue (behind narcotics and arms sales) and the fastest-growing criminal industry in the world.11 Missed clinical opportunities

Identifying victims of human trafficking within the clinical setting is an onerous task. Victims are often reluctant to disclose their situation, and they generally do not present with glaring risk factors to indicate their predicament. However, failure to identify victims of sex trafficking within the clinical setting can lead to missed opportunities and potentially devastating outcomes.

A missed opportunity is often described in everyday conversation as a missed chance, lost opportunity, or failure to do something. Within the clinical setting, a missed opportunity may encompass failure to provide patient education, health promotion, preventative care, or referrals to resources. As the health care system continues to evolve with technological advances, new methods of patient–provider interaction (telephone, urgent care, e-mail), and increased access to over-the-counter treatment options, the potential for losing opportunities to provide comprehensive care increases. These lost opportunities to provide care can be reflected in decreased patient satisfaction, patient safety, and comprehensive care and in increased cost. The increased cost related to DMST can be represented in terms of the actual financial expense and of the loss of care that should be offered to a disempowered group such as adolescent victims of sex trafficking. Furthermore, from the perspective of a clinician, missed opportunities in health care are just as important as successful patient encounters. As mentioned earlier, this article offers information that can be used in the primary care setting to assess, identify, and intervene with adolescent patients who are being trafficked for sex. The following is a description of a clinical scenario that represents a missed clinical opportunity. Case study: Anna

While staying in a short-term shelter for runaway and homeless youth, Anna (name has been changed), age 17, presented to the medical clinic for mandatory history and physical examination. She completed a comprehensive history form, which was reviewed by the nurse practitioner, and underwent a physical examination.

POLL POSITION

Which of the following best describes your experience as a clinician regarding domestic minor sex trafficking? n=377

■ I have never knowingly encountered a case. ■ I have encountered a case(s) and was able to intervene. ■ I have not encountered a case, but I routinely educate my patients about the risks of trafficking.

9.28% 5.84%

84.88%

For more polls, visit ClinicalAdvisor.com/Polls.

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DOMESTIC MINOR SEX TRAFFICKING

Specific geographical regions, such as areas near border crossings, may see more victims of trafficking than others. Anna lived with her family in a suburb of a large metropolitan city. She was the oldest of three children, with two siblings younger than 10 years of age. Anna said she had come to the shelter because of a stressful relationship and disagreements with her parents. Anna’s medical history was negative for any chronic disease or acute illnesses, daily medication, or current complaints. Her social history revealed no cigarette smoking and no alcohol or drug use. However, a review of her sexual history indicated that Anna had had multiple sexual partners (more than 50 in the prior 3 months). Further questioning revealed that she was having sex for money. She said she had a “friend” who would connect her with men across a large metropolitan city for sexual services. She proudly reported that she had a different name, depending on where in the city she was working. She stated that her “friend” provided her with clothes and phones so that she would be ready when he called her with an appointment. At that visit, she was not questioned further to determine if she was being forced, coerced, or threatened to participate in these activities. Her head-to-toe physical examination (excluding a pelvic examination) was completed and did not identify any physical abnormalities. The visit was concluded, and Anna left to attend a counseling session within the shelter. Anna remained at the shelter for about 10 days, and although she did not present again to the medical clinic, further details were disclosed to the social workers about the conflicts at home. It was discovered that Anna’s “friend” was threatening the family with physical harm if they did not stop interfering with her sexual activities. Throughout her entire stay at the shelter, Anna never indicated that she was being forced or coerced into participating in these sexual activities, and she did not want to pursue legal action. She did not indicate any desire to quit or that she was worried about her safety. Unfortunately, when she left the shelter, all follow-up was lost. Although Anna was seen only once in the clinic, she did willingly provide comprehensive medical and social information at her visit. In-depth questions were asked regarding her sexual activity; however, at that time, the clinician did not make the connection to potential trafficking. Unfortunately, Anna’s case is not unusual in that her age is a primary risk factor for DMST.5 However, she did not present with many of the other risk factors that are often used to help identify sex trafficking victims. Anna came from an intact family, and she did not disclose any history of physical, sexual, or

emotional abuse. She denied drug or alcohol use/abuse and presented as an emotionally stable and happy young woman.6,7 Ultimately, the first step to decrease DMST is early identification of a potential trafficking victim. Currently, there is no concise clinical screening tool to identify trafficking victims that can be used quickly during a patient encounter. Polaris (www.polarisproject.org) is an organization aimed at uncovering areas of trafficking, identifying victims, connecting victims to services, and initiating long-term social change.12 A wealth of resources and knowledge, the organization has identified some red flags and health indicators (Table 1) for clinicians to consider when they determine a patient’s trafficking risk. Limiting missed clinical opportunities

Specific geographical regions, such as areas near border crossings, may see more victims of trafficking than others. Continues on page 30

TABLE 1. Red flags and health indicators for clinicians determining a patient’s risk for trafficking Subjective findings

Objective findings

Missing legal documentation or using false identification; lacking insurance

Avoiding eye contact

Inconsistencies in history

Exhibiting paranoia, anxiety, fear, or submission during visit

Not speaking for self

Malnourishment or poor health

Loss of sense of time/space

Signs of physical abuse

Large number of sexual partners, history of sexually transmitted infections, frequent pregnancies

Signs of sexual abuse or trauma

Adolescent reporting relationships with older adults/men

Evidence of addiction to drugs or alcohol

Evidence of controlling or dominating relationships

Inappropriate dress

History of abuse or familial dysfunction

Presence of unexplained or unusual scar tissue, tattoos, or branding

Use of language consistent with involvement in prostitution

Evidence of residual fibers or other unusual findings during vaginal examination

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DOMESTIC MINOR SEX TRAFFICKING

BOX 1. Sample follow-up questions to ask a patient with red flags of domestic minor sex trafficking • Can you leave your job if you want to? • Can you come and go as you please? • Have you been hurt or threatened if you tried to leave? • Has your family been threatened? • Do you live with your employer? • Where do you sleep and eat? • Are you in debt to your employer?

Nonetheless, all clinicians need to be aware of risk factors and red flags, know how to assess patients, and know what resources to use for potentially trafficked patients. Education. Clinicians need to be sure that they are educating their patients early and often about the risks of human trafficking. Clinics who care for persons without insurance, refugees, or adolescents should consider education at every visit. Clinicians should educate patients on the definition of trafficking, how to seek help, and what resources are available. Identification. Early identification of a patient who is a potential victim of DMST is key in limiting long-term sequelae and poor health outcomes. Clinicians should assess for red flags, identify any safety issues or concerns, and document their findings thoroughly and appropriately. Documentation and open communication with colleagues may help identify a trafficking victim who reports a portion of his or her story to one clinician and another portion to a different clinician or

member of the health care team, or to office personnel. Specific attention should be paid to the discussion of consensual versus nonconsensual activities. The U.S. Department of State13 has identified follow-up questions to be used during a visit (Box 1). Intervention. To provide proper intervention, clinicians need to be aware of the local laws, resources, and support systems available to patients potentially being subjected to trafficking (Table 2). Ensuring the safety of the patient and family, limiting the short-term effects, and decreasing the risk for long-term consequences are top priorities. It is essential that clinicians assess for immediate danger to the patient and notify local law enforcement if immediate danger is suspected. Likewise, clinicians must take care to ensure their own safety. Providing simple outreach cards, hotline numbers, or other resources directly to the patient in a discreet way (eg, written on toiletries or soaps) offers support while maintaining patient and clinician safety. Finally, clinicians should call the National Human Trafficking Resource Center (NHTRC, (888) 373-7888) to report suspected or confirmed cases. The NHTRC can connect patients and clinicians with local law enforcement and social services. For instance, the University of Michigan Law School maintains a Human Trafficking Clinic (https://www.law.umich.edu/clinical/humantraffickingclinicalprogram/Pages/humantraffickingclinic.aspx), which receives a number of its referrals from the NHTRC. Follow-up. Clinicians can use scheduled follow-up as a way to communicate their concern and care to the patient, ensure ongoing safety, and monitor for long-term physical and mental health outcomes, such as post-traumatic stress

TABLE 2. Human trafficking resources for primary care clinicians Name

Description

Contact information

National Human Trafficking Resource Center (NHTRC) Hotline

To report an incident or locate local services for victims; available to answer calls anywhere 24 hours a day, 7 days a week, every day of the year in more than 200 languages.

(888) 373-7888

NHTRC Web site

Helps victims and survivors with access to support and services to stay safe and provides community with anti-trafficking training.

http://www.traffickingresourcecenter.org

Polaris

Global leader in fighting to end human trafficking and restore survivors. Offers comprehensive social services to victims.

http://www.polarisproject.org

Recognizing and responding to human trafficking in a healthcare context

Online human trafficking training for health care clinicians.

http://www.traffickingresourcecenter.org/ resources/recognizing-and-responding-humantrafficking-healthcare-context

Text BeFree

Short code texting to help victims find safety; call specialists will assist victims in planning their escape and/or connect them to services.

Text HELP or INFO to BeFree (233733)

Human trafficking assessment for medical professionals

Four-page document for quick assessment in identifying victims during clinic visits.

https://traffickingresourcecenter.org/resources/ human-trafficking-assessment-medical-professionals

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disorder, severe depression, and sexual dysfunction. As the case study of Anna underscores, each patient presents differently. It is important for clinicians to be alert to the signs, symptoms, and red flags associated with DMST and to approach each patient in a sensitive manner. They should be familiar with local resources and provide patients with this information after ensuring their safety. Ultimately, it is of the utmost importance to investigate any risks or red flags so as to diminish the potential for DMST. n Michelle Pardee, DNP, FNP-BC, is a clinical assistant professor; Michelle Munro-Kramer, PhD, FNP-BC, CNM, is an assistant professor; April Bigelow, PhD, AGNP-BC, is a clinical associate professor; and Gina Dahlem, PhD, FNP-BC, is a clinical assistant professor, all at the University of Michigan School of Nursing in Ann Arbor.

“Lots of new faces this year.”

References 1. Clawson HJ, Dutch N, Solomon A, Grace GL. Human trafficking into and within the United States: a review of the literature. U.S. Department of Health & Human Services. https://aspe.hhs.gov/basic-report/human-trafficking-and-within-united-states-review-literature. Published August 30, 2009. 2. McClain NM, Garrity SE. Sex trafficking and the exploitation of adolescents. J Obstet Gynecol Neonatal Nurs. 2011;40(2):243-252. 3. Victims of Trafficking and Violence Protection Act of 2000. Pub L No. 106386, HR 3244, §103. http://www.state.gov/documents/organization/10492.pdf. 4. Logan TK, Walker R, Hunt G. Understanding human trafficking in the United States. Trauma Violence Abuse. 2009;10(1):3-30. 5. Kotrla K. Domestic minor sex trafficking in the United States. Soc Work. 2010;55(2):181-187. 6. Choi KR. Risk factors for domestic minor sex trafficking in the United States: a literature review. J Forensic Nurs. 2015;11(2):66-76. © The New Yorker Collection 2016 from cartoonbank.com. All Rights Reserved.

7. Smith LA, Vardaman SH, Snow MA. The National Report on Domestic Minor Sex Trafficking: America’s Prostituted Children. Arlington, VA: Shared Hope International; 2009. 8. Boxill NA, Richardson DJ. Ending sex trafficking of children in Atlanta. Affilia. 2007;22(2):138-149. 9. National Center for Missing & Exploited Children. Child sex trafficking. http://www.missingkids.com/1in6. 2016. 10. United Nations Children’s Fund (UNICEF). End trafficking. https:// www.unicefusa.org/mission/protect/trafficking/end. 11. Deshpande NA, Nour NM. Sex trafficking of women and girls. Rev Obstet Gynecol. 2013;6(1):e22-e27. 12. Polaris. Recognize the signs. https://polarisproject.org/recognize-signs. 13. U.S. Department of State. Identify and assist a trafficking victim. http:// www.state.gov/j/tip/id. All electronic documents accessed April 29, 2016.

“What this book lacks in content it more than makes up for in the reflective quality of its pages.”

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CME FEATURED COURSE

n EDUCATIONAL OBJECTIVES At the conclusion of this activity, participants should be better able to: • Discuss the impact of asthma pathophysiology and phenotype on therapeutic choices and decisions for the management of asthma • Apply the National Asthma Education and Prevention Program (NAEPP) guidelines stepwise approach to care when individualizing treatment for asthmatic patients at different stages of disease severity, including uncontrolled asthma • Select an appropriate device based on patient needs and educate patients on the importance of adherence and proper inhaler technique to improve their overall outcomes n COMPLETE THE POST-TEST: Page 44

Release Date: October 20, 2015 Expiration Date: December 31, 2016 Estimated Time to Complete: 30 minutes Accredited Provider: This educational activity is provided by Albert Einstein College of Medicine. Commercial Supporter: This activity is supported by an educational grant from Boehringer Ingelheim. Program Description: Asthma is increasingly understood as a heterogeneous disease, with variants that respond differently to treatment. Optimal patient care depends on recognizing these differences and designing treatment plans accordingly. Inhaled treatment is the mainstay of asthma management, so in addition to considering such clinical aspects as symptoms, exacerbations, response to prior treatment, and rate of disease progression, clinicians must also consider the range of available inhalation devices available on the market. Because suboptimal inhalation technique by the patient can undermine asthma control, initial patient education on and ongoing monitoring of inhaler use are important factors in effective asthma management. Intended Audience: Pulmonologists, internists, hospitalists, family practice and general practice physicians, nurse practitioners, physician assistants, and other healthcare professionals who treat and manage asthma Conflict of Interest Disclosure Policy: It is the policy of Albert Einstein College of Medicine to ensure balance, independence, objectivity, and scientific rigor in all its educational activities. All faculty participating in our programs are expected to disclose any relationships they may have with commercial companies whose products or services may be mentioned, so that participants may evaluate the objectivity of the presentations. In addition, any discussion of off-label, experimental, or investigational uses of drugs or devices will be disclosed by the faculty. Faculty Nicola A. Hanania, MBBS, MD Associate Professor of Medicine Pulmonary and Critical Care Medicine Director, Asthma Clinical Research Center Baylor College of Medicine Houston, TX Course Director David L. Rosenstreich, MD Professor, Departments of Medicine, Microbiology & Immunology, and Otorhinolaryngology Albert Einstein College of Medicine Chief, Division of Allergy & Immunology Department of Medicine Montefiore Medical Center Bronx, NY Faculty Dislosures: Dr. Hanania receives grants/research support from Boehringer Ingelheim, Genentech, GlaxoSmithKline, Mylan Pharmaceuticals, and Sunovion Pharmaceuticals. He is a consultant for Genentech, Novartis, and Sunovion Pharmaceuticals. Dr. Hanania serves on the speakers' bureau for Genentech.

Dr. Rosenstreich has received grant/research support from Genentech and Merck & Co. He is a consultant for GlaxoSmithKline. Accredited Provider Disclosure: The staff of the Center for Continuing Medical Education of Albert Einstein College of Medicine has nothing to disclose with regard to commercial support. Publishing Staff Disclosure: Jill Rovitzky Black, Eileen McCaffrey, and Rachel Moss of Haymarket Medical Education have nothing to disclose with regard to commercial support. Accreditation Statement: Albert Einstein College of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Designation Statement: Albert Einstein College of Medicine designates this enduring activity for a maximum of 0.50 AMA PRA Category 1 Credit(s)TM. Physicians should claim only credit commensurate with the extent of their participation in the activity. Disclosure of Unlabeled Use: This educational activity may contain discussion of approved and/or investigational uses of agents that are not indicated by the FDA. Boehringer Ingelheim, Albert Einstein College of Medicine, and Haymarket Medical Education do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Boehringer Ingelheim, Albert Einstein College of Medicine, or Haymarket Medical Education. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. If you have any questions relating to the accreditation of this activity, please call Einstein CME at 718-920-6674. Instructions: There are no fees for participating in and receiving CME credit for this activity. During the period October 20, 2015 through December 31, 2016, participants must: 1) read the learning objectives and faculty disclosures; 2) complete the pre-assessment test; 3) study the educational activity; 4) complete all polling questions; 5) complete the posttest and submit it online. A statement of credit will be issued only upon receipt of the above elements and a post-test score of 70% or higher. All components must be completed and submitted online at myCME.com/June16CAfeature. Provided by

In collaboration with

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CME

FEATURED COURSE: NICOLA A. HANANIA, MBBS, MD

Tailoring asthma treatment using a stepwise approach As highlighted in this case, optimal asthma care is a step-by-step process that involves recognizing disease variants and considering individualized options.

Progressive bronchoconstriction resulting from muscle spasms during an asthma attack

laine R., 48 years old, presents to a pulmonologist for worsening asthma. She was diagnosed with allergic asthma in childhood. Her condition was adequately controlled with montelukast for many years. However, the past 2 years have included multiple asthma-related emergency department (ED) visits and 1 hospitalization per year for asthma. She has missed so much time at work that she is concerned about losing her job. Elaine has never smoked but is exposed to secondhand smoke through her work as a waitress in a bar. She reports a history of nasal stuffiness and postnasal drip along with cough and chest pain. The latter symptoms tend to worsen at night as well as during and after her work shifts. She reports having started the job in a smoking facility about 2.5 to 3 years ago. Current medications include an albuterol inhaler as needed and a combination inhaled corticosteroid and long-acting β2-agonist (ICS/LABA) medication (fluticasone/salmeterol 500/50 inhalation powder, 1 puff twice daily). She reports using albuterol for symptom control every day and twice weekly at night. Physical examination is significant for overweight (body mass index 28 kg/m2) and bilateral wheezing. Fractional exhaled nitric oxide (FENO) measures 85 parts per billion (ppb). Spirometry results were as follows: • Forced vital capacity (FVC): 5.15 L (95%) • Forced expiratory volume in 1 second (FEV1): 2.7 L (61%)

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CME

FEATURED COURSE

• FEV1/FVC: 52% • Postbronchodilator FEV1: 2.85 L (65%); change .15 L (5%) The pulmonologist ordered allergy skin testing, which was positive for dust mites. Blood test results were: • Total immunoglobulin E (IgE): 246 IU/L • Hemoglobin: 15.8 g/dL • White blood cell count: 10.8 K/μL • Absolute eosinophil count: 1.59 K/μL First steps: Confirm the diagnosis and address potentially exacerbating factors

The Sidebar below displays the European Respiratory Society (ERS) and the American Thoracic Society (ATS) definitions of severe and uncontrolled asthma.1 Elaine meets the ERS/ ATS criteria for uncontrolled asthma based on her annual asthma-related hospitalizations and her spirometry results. Prior to classifying a patient’s asthma as severe, however, the clinician should confirm the diagnosis of asthma and identify and address any potentially exacerbating comorbidities.1 The patient’s history of symptoms, triggers, and possible environmental or occupational contributors to symptoms should be evaluated (Table 1), and other conditions that may explain the patient’s symptoms should be considered. Conditions that may be mistaken for severe

asthma in adults include chronic obstructive pulmonary disease (COPD), congestive heart failure, hyperventilation with panic attacks, and adverse drug reactions (eg, cough associated with angiotensin-converting enzyme inhibitor therapy).1 Misdiagnosis of asthma is common. In 1 study, 38% of patients with frequent exacerbations of physiciandiagnosed asthma (n=171) or COPD (n=162) were found to be misdiagnosed after undergoing spirometry and evaluation by a pulmonologist.2 Spirometry, before and after bronchodilation, must be performed to confirm the presence of reversible airflow limitation that is required to diagnose asthma.1 Significant postbronchodilator reversibility is defined as an increase in FEV1 of more than 200 mL and at least a 12% increase in FEV1 from baseline. The patient’s relative lack of response to bronchodilators (5% increase)3 may result from her use of LABA therapy on the morning of the test day. The pulmonologist may consider withdrawing her from the LABA component of her medication and repeating spirometry to uncover additional reversibility. Elaine’s self-reported childhood history of allergic asthma, her bilateral wheezing upon examination, and her pattern of symptoms (cough and chest pain worsening at night as well as during and for a few hours after her work shifts), her high total IgE level (>2 standard deviations from normal, strongly suggesting the presence of allergic

Distinguishing asthma severity from asthma control Severity: The intrinsic intensity of the disease process. Severity is measured most easily and directly in a patient not receiving long-term-control therapy.1 Control: The degree to which the manifestations of asthma (symptoms, functional impairments, and risks of untoward events) are minimized and the goals of therapy are met.2 Severe asthma: When a diagnosis of asthma is confirmed and comorbidities have been addressed, severe asthma is defined as “asthma that requires treatment with high-dose ICS plus a second controller and/or systemic corticosteroids to prevent it from becoming ‘uncontrolled’ or that remains ‘uncontrolled’ despite this therapy.” 2 Uncontrolled asthma is defined as at least 1 of the following2: 1. Poor symptom control: ACQ consistently >1.5, ACT <20 (or ‘‘not well controlled’’ by NAEPP/GINA guidelines)

2. F requent severe exacerbations: 2 or more bursts of systemic corticosteroids (>3 days each) in the previous year 3. Serious exacerbations: at least 1 hospitalization, ICU stay, or mechanical ventilation in the previous year 4. A irflow limitation: after appropriate bronchodilator withholding, FEV1 <80% predicted (in the face of reduced FEV1/FVC defined as less than the lower limit of normal) 5. Controlled asthma that worsens on tapering of high-dose ICS, systemic corticosteroids, or additional biologics ICS, inhaled corticosteroids; ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; NAEPP, National Asthma Education and Prevention Program; GINA, Global Initiative for Asthma; ICU, intensive care unit; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity. References 1. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Clinical Practice Guidelines. Bethesda, MD: National Heart, Lung, and Blood Institute; 2007. Report No. 07-4051. http://www.ncbi. nlm.nih.gov/books/NBK7232/?report=reader. Accessed September 28, 2015. 2. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343-373.

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disease),4 and her positive test for dust mite allergy are consistent with a diagnosis of asthma triggered by exposure to smoke at work and dust mites in her bedroom. Her nasal congestion and postnasal drip could stem from her allergy to dust mites. The patient’s asthma control appears to have deteriorated within 6 months to a year of her starting work in a facility that permits smoking. It is possible that occupational exposure to secondhand smoke exacerbated her disease. For people with asthma, environmental tobacco smoke exposure has been associated with lower lung function, increased rescue inhaler use, worse quality of life, greater bronchodilator responsiveness, and higher risk for ED visits, hospitalization, and intensive care unit admission.5 The pulmonologist urges Elaine to try to find a job in a nonsmoking setting. He recommends that she reduce dust mite exposure by removing carpets from her bedroom, enclosing her mattress and pillows in dust mite protectors, laundering sheets and blankets weekly in hot water (≥130oF), and reducing indoor humidity to ≤60%.3 He also instructs her to return within a week or so for repeat spirometry after withholding the LABA for 12 hours.6 Before Elaine leaves the clinic, the pulmonologist’s respiratory therapist observes the patient’s inhaler technique using the ICS/LABA disk and the albuterol inhaler. She counsels Elaine about how to improve her use of the albuterol inhaler but notes that she is using the ICS/LABA disk correctly. She asks Elaine to bring all her inhalers to the office at her next visit. Adherence and inhaler technique

Instructing patients in proper inhaler technique and reinforcing that technique are important to support adherence and control. Upon observing inhaler technique in more than 2400 patients, 1 study reported that 58% of patients demonstrated incorrect technique on the first try and 52% on the second attempt. Incorrect use of a pressured metered-dose inhaler was significantly associated with poor asthma control and systemic steroid use within the prior year, according to this study.7 Finding that inhalers are expired or empty when needed is also common, with roughly half of patients or caregivers reporting these experiences (n=366 adults with asthma, 224 parents of children with asthma). Of those who reported finding that their rescue inhaler was empty when needed, 10.4% visited the ED for treatment and 6.7% missed work or school for an unscheduled clinician visit. Another 20% went without treatment.8 Asking patients to bring their

inhalers to the visit may prompt detection of these issues before an emergency occurs. Follow-up visit

At her next visit 2 weeks later, the patient reports removing the area rug from her bedroom and laundering her bedding as directed. She is looking for another job. She reports using albuterol for symptom control more frequently over the last week. The respiratory therapist observes the patient’s inhaler technique with all 3 inhalers. She again counsels Elaine about how to improve her use of the albuterol inhaler but notes that she is using the ICS/LABA disk correctly. She also notes that Elaine’s albuterol inhaler is empty, which Elaine had not noticed. The therapist points out the counter on the inhaler and suggests refilling when she has 5 actuations remaining. Spirometry reveals reversible airway obstruction (>15% change postbronchodilator). Other results were: • FVC: 4.95 L (91%) • FEV1: 2.4 L (54%) • FEV1/FVC: 48% • Postbronchodilator FEV1: 3.1 L (70%); change, 0.7 L (29%) The ERS/ATS task force on lung-function testing suggests that in patients maintained on a LABA-containing agent, the clinician may consider repeating spirometry after withdrawing the LABA in order to “uncover additional reversibility.”8 Withholding the LABA in this case revealed TABLE 1. Comorbidities and other factors that may exacerbate asthma GERD (if symptomatic) Hormonal influences (eg, premenstrual, menopause) Hyperventilation syndrome Medications: aspirin, NSAIDs, β-adrenergic blockers, ACEIs Obesity Obstructive sleep apnea Psychological factors (eg, symptom perception, anxiety, depression) Rhinosinusitis, nasal polyps Smoking/smoking-related disease Thyroid disorders Vocal cord dysfunction GERD, gastroesophageal reflux disease; NSAIDs, nonsteroidal anti-inflammatory drugs; ACEIs, angiotensin-converting enzyme inhibitors. Source: Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343-373.

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Investigational therapies for eosinophilic asthma Several therapies targeted to cytokines mediating eosinophilic asthma have demonstrated efficacy in clinical trials. Dupilumab, a human monoclonal antibody (mAb), blocks interleukin (IL)-13 as well as IL-4 signaling.1,2 IL-4 and IL-13 have long been viewed as important components of allergic airway inflammation.3 An interim (12-week) analysis of a 24-week phase 2 study presented at the 2015 American Thoracic Society meeting indicated that the agent significantly improved forced expiratory volume in 1 second (FEV1) and reduced the annualized severe exacerbation rate when added to background therapy.2 These benefits occurred among participants with either high or low eosinophil count at baseline (<300 or ≥300/μL). Study participants (N=776) were adults with uncontrolled asthma despite medium-/high-dose inhaled corticosteroid (ICS) and longacting β2-agonist (LABA) therapy. Adverse event rate was 70% and 74% with dupilumab, depending upon dose, and 67% with placebo. The agent is administered subcutaneously1; injection site reactions were the most common side effect.2 An earlier phase 2a, proof of concept study reported that adding dupilumab was associated with fewer exacerbations when LABAs and medium- or high-dose ICS were withdrawn according to a predetermined schedule in patients (N=104) with persistent, moderate to severe asthma and eosinophilic asthma (blood eosinophil count ≥300 cells/ μL or sputum eosinophils ≥3%). Dupilumab was associated with reduced fractional exhaled nitric oxide (FENO) and

the patient’s underlying reversibility. The pulmonologist determines that the findings confirm a diagnosis of severe, uncontrolled asthma. It is noteworthy that a component of fixed airway obstruction does not rule out an asthma diagnosis. Some patients with asthma display only partial reversibility due to airway remodeling.3 Risk factors for irreversible airway obstruction in asthma include frequent exacerbations, occupational exposure to a symptom trigger, and ongoing eosinophilic airway inflammation as well as smoking, airway hyperresponsiveness, and adult onset of asthma.9 Elaine has the first 3 risk factors: her recent history of ED visits and hospitalizations, occupational exposure to secondhand smoke, and eosinophilia. Severe asthma phenotypes

Severe asthma is a heterogeneous disease, with differing clinical presentations, physiologic characteristics, and

immunoglobulin E (IgE) compared with placebo, though not with decreases in eosinophils.1 Lebrikizumab, a humanized mAb to IL-13,3,4 has improved FEV1 significantly after 12 weeks compared with placebo when added to ICS therapy (200-1000 μg of inhaled fluticasone propionate dry powder daily, or the equivalent).4 About 81% of the 219 participants also used LABAs; mean baseline FEV1 was 65%. A baseline level of the biomarker periostin at or above the cohort median was associated with greater response; FEV1 did not improve significantly in those with lower levels of periostin. A subsequent study documented a significantly reduced rate of asthma exacerbations (by 60% vs placebo) in patients with high levels of periostin after a median of 24 weeks’ therapy. Effect in patients with low levels of periostin was nonsignificant (5% reduction in exacerbation rate vs placebo). 5 Lebrikizumab was administered subcutaneously once a month in these studies. The agent was associated with musculoskeletal side effects (13.2% vs 5.4% with placebo, P=.045) in the 12-week study.4 Rates of arthralgia were similar across treatment groups in the 24-week study. 5 Mepolizumab, an anti-IL-5 humanized mAb, has significantly reduced the rate of exacerbations in patients with at least 2 asthma exacerbations within the prior year requiring systemic corticosteroids, despite high-dose ICS.6 The safety profile was similar to that of the placebo control arm. Patients in this 32-week phase 3 study were also required to have an eosinophil count of at least 150 cells/μL in the

outcomes. The concept of phenotyping developed to categorize the different presentations of severe asthma. No accepted asthma phenotypes have emerged yet, but evidence points to likely classifications based on age of asthma onset, disease duration, frequency of exacerbations, presence/absence of sinusitis, personal and family atopic history, and inflammatory characteristics (eg, eosinophils in sputum).1 Two phenotypes for which evidence appears most consistent are an early-onset, atopic type and a lateonset, eosinophilic type. Assessment of phenotype may contribute to improved asthma management.1 The pulmonologist measured Elaine’s blood eosinophils. Eosinophilic asthma is associated with eosinophilia (>0.4 K/μL=consistent with eosinophilia)10 and basement membrane thickening.11 Elaine’s eosinophil count of 1.59 K/μL suggests a high level of eosinophilic inflammation. The pulmonologist also measured Elaine’s FENO.

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peripheral blood or at least 300 cells/μL at some point during the previous year. An earlier 50-week study also demonstrated that adding mepolizumab significantly reduced exacerbations in patients with refractory asthma, a history of at least 2 exacerbations requiring prednisolone therapy within the prior year, and sputum eosinophil percentage of at least 3% within the prior 2 years despite high-dose corticosteroid treatment. Mepolizumab also significantly reduced eosinophil counts in blood and sputum.7 A US Food and Drug Administration (FDA) advisory committee has recommended the drug for approval as add-on maintenance therapy in adults with severe eosinophilic asthma, using the eosinophil count entry criteria of the phase 3 trial.8 IL-5 has been called “the most potent eosinophilic cytokine known.” Its receptor is found on both eosinophils and basophils.3 Mepolizumab was given intravenously or subcutaneously in the phase 3 study.6 Only the subcutaneous formulation was proposed for marketing.8 Reslizumab, another anti-IL-5 humanized mAb, has reduced the frequency of asthma exacerbations in patients with at least 1 exacerbation in the prior year and whose disease was inadequately controlled by medium- to highdose ICS-based therapy. This finding comes from 2 phase 3 studies in which patients were randomly assigned to receive reslizumab (3.0 mg/kg) or placebo every 4 weeks for 1 year. Participants were also required to have a blood eosinophil count of at least 400 cells/μL.9 Common adverse events

Elevated levels are considered a marker of Th2-type inflammation atopy, eosinophilic inflammation (if >50 ppb) and, in symptomatic patients, corticosteroid responsiveness.1 High FENO levels are also associated with persistent and/or high allergen exposure12 as well as with a more exacerbationprone phenotype of severe asthma.1 Elaine has persistent allergen exposure and a history of frequent exacerbations. Elaine displays a high level of FENO (85 ppb), consistent with eosinophilic asthma. Although this level of FENO suggests corticosteroid responsiveness, her asthma remains uncontrolled despite a high level of ICS. She claims to be adherent to her controller therapy. Partial adherence or poor inhaler technique are possible explanations for the findings in this case. Although patients with eosinophilic asthma and mild or moderate disease generally respond to ICS, some patients with severe disease continue to display eosinophilia despite high-dose ICS.1

observed with reslizumab were similar to those seen with placebo. Reslizumab is administered intravenously. A biologics license application for the product has been filed with the FDA, seeking an indication for treatment of inadequately controlled asthma in adult and adolescent patients with elevated blood eosinophils despite an ICS-based regimen.10 References 1. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368(26):2455-2466. 2. Wenzel SE, Wang L, Pirozzi G, et al. Dupilumab improves lung function and reduces severe exacerbations in uncontrolled asthmatics with baseline eosinophil levels above and below 300 cells/μL. Am J Respir Crit Care Med.2015;191:A6362. 3. Fajt ML, Wenzel SE. Asthma phenotypes and the use of biologic medications in asthma and allergic disease: the next steps toward personalized care. J Allergy Clin Immunol. 2015;135(2):299-310. 4. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365(12):1088-1098. 5. Hanania NA, Noonan M, Corren J, et al. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax. 2015;70(8):748-756. 6. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371(13):1198-1207. 7. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360(10):973-984. 8. Food and Drug Administration Center for Drug Evaluation and Research. Summary minutes of the Pulmonary-Allergy Drugs Advisory Committee Meeting: June 11, 2015. FDA website. http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/ UCM462804.pdf. Accessed September 28, 2015. 9. Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3(5):355-366. 10. Teva announces FDA acceptance of the biologics license application for reslizumab [press release]. Jerusalem: Business Wire; June 15, 2015. http://www.tevapharm.com/ news/?itemid={EC293769-FC43-4AEA-A0AF-5C4898748653}. Accessed September 11, 2015.

Choice of immunotherapy

Systemic steroids Evidence suggests that patients with severe asthma may require higher doses of steroids or systemic steroids administered orally or through intramuscular injection to achieve control. However, the adverse event profile of high-dose systemic steroids limits their usefulness.1 The pulmonologist in this case views systemic steroids as a last choice. Immunotherapy Current National Asthma Education and Prevention Program (NAEPP) guidelines recommend considering allergen immunotherapy “when there is clear evidence of a relationship between symptoms and exposure to an allergen to which the patient is sensitive.”3 Elaine has a positive allergen test for house dust mites. The timing of her asthma control deterioration, however, suggests that secondhand

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smoke exposure also may contribute to her symptoms, so it is unclear whether dust mites are the primary culprits. Long-acting anticholinergic therapy No long-acting anticholinergic therapy is currently approved by the US Food and Drug Administration (FDA) for use in asthma; these agents are approved for the treatment of COPD. Tiotropium, an inhaled, long-acting anticholinergic agent, has been recently studied as add-on asthma therapy in patients symptomatic on ICS treatment, and an application has been filed with the FDA seeking approval for an asthma indication.13 Tiotropium has been approved in the European Union as add-on therapy for asthma in patients already receiving ICS (≥800 µg budesonide/day or equivalent) and LABA therapy and who experienced 1 or more severe exacerbations in the previous year.14 Adding a long-acting inhaled tiotropium soft mist inhaler (5 or 10 μg) to high-dose ICS and LABA therapy has improved FEV1 significantly after 8 weeks in patients with severe, uncontrolled asthma.15 When administered to patients with poorly controlled asthma despite high-dose ICS and LABA therapy, tiotropium bromide (5 μg) significantly improved FEV1 and reduced the risk of a severe exacerbation (21%; P=.003) compared with placebo over 24 weeks.16 Adverse events in these studies were similar in the placebo and tiotropium groups, excepting a higher incidence of dry mouth on the higher dose (10 μg) of tiotropium.15,16 Like Elaine, the populations in the above-referenced studies had long histories of asthma (mean 29.7 years; median, 28 years), mean postbronchodilator FEV1 in the low to mid 60% range at baseline, and poor control on ICS and LABA therapy. Participants in 1 study also had at least 1 severe exacerbation within the past year.16 Adding a long-acting inhaled tiotropium bromide dry powder inhaler (18 μg) to ICS therapy in patients with poorly controlled asthma significantly improved FEV1 and symptom scores compared with doubling the ICS dose.17 Tiotropium in this study was noninferior to adding a LABA (salmeterol) for symptom improvement and was superior to the LABA in improving prebronchodilator FEV1. Patients received each therapy for 14 weeks in a 3-way, double-blind, triple-dummy, crossover trial. Participants had a long history of asthma (26.1±14.1 years), but somewhat better lung function than Elaine and subjects in the aforementioned studies (mean baseline FEV1, 71.5% prebronchodilation).17 Factors predicting improved FEV1 response to tiotropium in this trial were acute response to a short-acting bronchodilator, decreased FEV1/FVC ratio, and higher cholinergic tone.18

Omalizumab A recombinant humanized monoclonal antibody (mAb) that binds to free IgE, omalizumab was the first biologic medication to receive FDA approval for asthma therapy. It is indicated for adults and adolescents (≥12 years old) with moderate to severe persistent asthma inadequately controlled with ICS and a positive skin test or in vitro reactivity to a perennial aeroallergen.19 The ERS/ATS guidelines on severe asthma suggest a therapeutic trial of omalizumab in patients with severe allergic asthma who have confirmed IgE-dependent allergic asthma (total serum IgE 30-700 IU/mL) and whose disease remains uncontrolled despite optimized management and allergen avoidance. A trial of 4 months is sufficient to assess response.1 The medication requires subcutaneous injection every 2 to 4 weeks in a healthcare setting capable of managing anaphylaxis, a rare side effect (0.2% in postmarketing spontaneous reports).19 In a large (N=850), 48-week-long, multicenter trial including patients with severe, inadequately controlled asthma despite ICS and LABA therapy, adding omalizumab significantly reduced the rate of protocol-defined asthma exacerbations by 25% (relative reduction) compared with adding placebo (P=.0006). Protocol-defined exacerbations involved at least 3 days of systemic corticosteroids or, for those maintained on oral steroids, a 20-mg increase in the average daily dose of oral prednisone.20 Omalizumab also has improved symptoms and reduced use of rescue albuterol compared with placebo.20,21 Another trial also reported reduced rates of exacerbations and ED visits when adding omalizumab to background therapy in patients with inadequately controlled severe asthma despite high-dose ICS and LABA therapy (n=419; 28 weeks).22 Adding omalizumab to ICS therapy has allowed for greater median reductions in ICS dose compared with adding placebo (N=246). A higher proportion of patients randomized to omalizumab achieved at least a 50% ICS dose reduction over 16 weeks.21 Treatment with omalizumab has also reduced airway and blood eosinophils.11 Given the cost and possible risk of anaphylaxis, it is important to identify those individuals most likely to respond to this agent. Factors associated with response among patients with severe, inadequately controlled asthma despite ICS and LABA therapy are elevated levels of FENO, peripheral blood eosinophils, or the investigational biomarker serum periostin.23 Elaine appears to be a good candidate for omalizumab therapy. She has high levels of FENO and blood eosinophils. Her total serum IgE level falls within the range suggested by the ERS/ATS guidelines, based on the population

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studied in clinical trials. She also has a positive skin test for an aeroallergen.

Accessed September 20, 2015. 5. Comhair SA, Gaston BM, Ricci KS, et al. Detrimental effects of environmental tobacco smoke in relation to asthma severity. PLoS One.

Patient-clinician discussion

2011;6(5):e18574.

Elaine realizes that she needs to do more to control her asthma. She is reluctant to add another medication but is more willing to try another inhaler rather than an injectable treatment. The patient and the pulmonologist agree to try the tiotropium soft mist inhaler 5 μg/day in 2 puffs once daily. The respiratory therapist demonstrates proper use of the new inhaler, highlighting the differences in technique from the rescue inhaler. She stresses the importance of adherence to all medications and urges the patient to call the office with questions or any change in her asthma.

6. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-338. 7. Levy ML, Hardwell A, McKnight E, Holmes J. Asthma patients' inability to use a pressurised metered-dose inhaler (pMDI) correctly correlates with poor asthma control as defined by the global initiative for asthma (GINA) strategy: a retrospective analysis. Prim Care Respir J. 2013;22(4):406-411. 8. Storms WW, Tringale M, Ferro TJ. The impact of expired and empty quick-relief asthma inhalers: The Asthma and Allergy Foundation of America's Asthma Inhaler Design Survey. Allergy Asthma Proc. 2015;36(4):300-305. 9. ten Brinke A. Risk factors associated with irreversible airflow limitation

Summary

in asthma. Curr Opin Allergy Clin Immunol. 2008;8(1):63-69.

Before concluding that a patient has severe, uncontrolled asthma, it is important to confirm the diagnosis of asthma and identify and address any potentially exacerbating factors. If the diagnosis of asthma is confirmed and addressing contributing factors does not lead to control of symptoms and impairment, then biomarkers such as eosinophil levels and FENO may help inform treatment choice. Reinforcing appropriate inhaler technique and the importance of adherence are key elements in therapy. Decisions about changes in treatment require communication and collaboration with the patient who must adhere to the therapy and use the inhalers or other devices. Emerging information about asthma phenotypes and investigational therapies targeted to specific mediators [See Sidebar, Investigational therapies for eosinophilic asthma] may facilitate increased personalization of treatment choice in the future. ■

10. George BJ, Reif DM, Gallagher JE, et al. Data-driven asthma endotypes defined from blood biomarker and gene expression data. PLoS One. 2015;10(2):e0117445. 11. Walford HH, Doherty TA. Diagnosis and management of eosinophilic asthma: a US perspective. J Asthma Allergy. 2014;7:53-65. 12. Dweik RA, Boggs PB, Erzurum SC, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011;184(5):602-615. 13. Asthma: Boehringer Ingelheim announces U.S. FDA filing acceptance of NDA for Spiriva® Respimat ® in asthma [press release]. Ingelheim, Germany: Boehringer Ingelheim; November 4, 2014. https://www. boehringer-ingelheim.com/news/news_releases/press_releases/2014/04_ november_2014_asthma.html. 14. Asthma: new indication for Spiriva® (tiotropium) Respimat ®* in the EU may offer millions of adults a significant advance in asthma care [press release]. Ingelheim, Germany: Boehringer Ingelheim; September 8, 2014. https://www.boehringer-ingelheim.com/news/news_releases/press_

References

releases/2014/08_september_2014_asthma.html.

1. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines

15. Kerstjens HA, Disse B, Schroder-Babo W, et al. Tiotropium improves

on definition, evaluation and treatment of severe asthma. Eur Respir J.

lung function in patients with severe uncontrolled asthma: a randomized

2014;43(2):343-373.

controlled trial. J Allergy Clin Immunol. 2011;128(2):308-314.

2. Jain VV, Allison DR, Andrews S, et al. Misdiagnosis among frequent

16. Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma

exacerbators of clinically diagnosed asthma and COPD in absence of con-

poorly controlled with standard combination therapy. N Engl J Med.

firmation of airflow obstruction. Lung. 2015;193(4):505-512.

2012;367(13):1198-1207.

3. National Asthma Education and Prevention Program. Expert Panel

17. Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide

Report 3: Guidelines for the Diagnosis and Management of Asthma. Clinical

step-up therapy for adults with uncontrolled asthma. N Engl J Med.

Practice Guidelines. Bethesda, MD: National Heart, Lung, and Blood

2010;363(18):1715-1726.

Institute; 2007. Report No. 07-4051. http://www.ncbi.nlm.nih.gov/books/

18. Peters SP, Bleecker ER, Kunselman SJ, et al. Predictors of response to

NBK7232/?report=reader. Accessed September 28, 2015.

tiotropium versus salmeterol in asthmatic adults. J Allergy Clin Immunol.

4. Mayo Medical Laboratories. Test: IGE. Immunoglobulin E (IgE), Serum.

2013;132(5):1068-1074.e1.

Clinical and Interpretative. Mayo Clinic website. http://www.mayo-

19. Xolair [package insert]. South San Francisco, CA: Genentech, Inc.; 2014.

medicallaboratories.com/test-catalog/Clinical+and+Interpretive/8159.

20. Hanania NA, Alpan O, Hamilos DL, et al. Omalizumab in severe

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allergic asthma inadequately controlled with standard therapy: a random-

add-on therapy in patients with severe persistent asthma who are inad-

ized trial. Ann Intern Med. 2011;154(9):573-582.

equately controlled despite best available therapy (GINA 2002 step 4

21. Holgate ST, Chuchalin AG, Hebert J, et al. Efficacy and safety of a

treatment): INNOVATE. Allergy. 2005;60(3):309-316.

recombinant anti-immunoglobulin E antibody (omalizumab) in severe aller-

23. Hanania NA, Wenzel S, Rosen K, et al. Exploring the effects of omali-

gic asthma. Clin Exp Allergy. 2004;34(4):632-638.

zumab in allergic asthma: an analysis of biomarkers in the EXTRA study.

22. Humbert M, Beasley R, Ayres J, et al. Benefits of omalizumab as

Am J Respir Crit Care Med. 2013;187(8):804-811.

CME

POST-TEST

Expiration date: December 31, 2016 Credit Designation: Albert Einstein College of Medicine designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. A statement of credit will be issued only upon receipt of a completed pre-assessment test, polling questions, activity evaluation form, and post-test with a score of 70% or better. All components must be completed and submitted online at myCME.com/June16CAfeature. CREDITS: 0.50

| Tailoring asthma treatment using a stepwise approach

1. Which of these findings is associated with the eosinophilic phenotype of asthma? a. Low elevated fractional exhaled nitric oxide (FENO) levels (<50 parts per billion [ppb]) b. Corticosteroid responsiveness (in symptomatic patients) c. Non–allergy-related asthma d. High levels of eosinophils in sputum but not in blood 2. According to the European Respiratory Society and the American Thoracic Society (ERS/ATS) guidelines definition, severe asthma requires which of these therapies to prevent it from being uncontrolled, or it remains uncontrolled despite this therapy: a. High-dose inhaled corticosteroids (ICS) or systemic corticosteroids b. Systemic corticosteroids c. High-dose ICS plus another controller and/or systemic corticosteroids d. Long-acting β2-agonist (LABA) 3. Classifying a patient’s asthma as severe requires: a. Confirming the diagnosis of asthma b. Measuring FENO and blood eosinophil levels c. Identifying no evidence of fixed airway obstruction on spirometry d. Measuring immunoglobulin E (IgE) levels and performing allergy skin testing

4. Evaluating patient use of inhalers should include: a. Observing patients’ inhaler technique and instructing them in the correct technique b. Having patients bring their inhalers to a visit c. Asking patients how often they use their inhaler(s) d. All of the above 5. Which of the following statements is most accurate? a. The ERS/ATS guidelines on severe asthma suggest a trial of omalizumab only in patients with a positive skin test for an aeroallergen b. Long-acting inhaled tiotropium has demonstrated efficacy in patients with long histories of asthma, mean postbronchodilator forced expiratory volume in 1 second (FEV1) in the low to mid 60% range at baseline, and poor control on ICS and LABA therapy c. Patients whose asthma has a component of fixed airway obstruction are more likely to respond to long-acting inhaled tiotropium d. The ERS/ATS guidelines on severe asthma suggest a trial of omalizumab in any patients with total serum IgE of 30 IU/mL to 700 IU/mL and a positive skin test for an aeroallergen

TO TAKE THE POST-TEST please go to: myCME.com/June16CAfeature

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Conference Roundup

45 THE CLINICAL ADVISOR • MONTH 2016 • www.ClinicalAdvisor.com

American Academy of Neurology 2016 Annual Meeting Vancouver

BOTULINUM TOXIN GUIDELINES UPDATED FOR SPASTICITY, HEADACHE After reviewing recent research, the American Academy of Neurology (AAN) has updated its 2008 guidelines on the use of botulinum toxin for the treatment of spasticity, cervical dystonia, blepharospasm, and now chronic migraine. The guidelines, which were also published in Neurology, cover the use of all 4 drug formulations: abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA, and rimabotulinumtoxinB. Botulinum toxin as a whole helps to reduce muscle contraction and transmission of pain signals, and has been deemed generally safe and effective for the treatment of spasticity in adults, cervical dystonia, blepharospasm, and chronic migraine. The different formulations are not interchangeable, however. In this review, efficacy of botulinum toxin was based on symptomatic control, as there is no evidence indicating disease modification. In total, the AAN guidelines development subcommittee reviewed 23 research articles on blepharospasm, 23 on cervical dystonia, 86 on spasticity, and 28 on headache. Based on the available literature, the following formulations have been recommended. Blepharospasm

• OnabotulinumtoxinA (onaBoNT-A) and incobotulinumtoxinA (incoBoNT-A) are probably effective (Level B evidence). • AbobotulinumtoxinA (aboBoNT-A) is possibly effective (Level C). Cervical dystonia

• AboBoNT-A and rimabotulinumtoxinB (rimaBoNT-B) are effective (Level A).

• OnaBoNT-A and incoBoNT-A are probably effective (Level B). Spasticity in adults

• AboBoNT-A, incoBoNT-A, and onaBoNT-A are effective (Level A). • RimaBoNT-B is probably effective for upper limb spasticity (Level B). • AboBoNT-A and onaBoNT-A are effective for lower limb spasticity (Level A). Headache

The guidelines are updated for botulinum toxin treatment of spasticity, cervical dystonia, blepharospasm, and chronic migraine.

• OnaBoNT-A is effective for increase in headache-free days (Level A) and probably effective for improvement of quality of life (Level B) in chronic migraine. • OnaBoNT-A is ineffective for episodic migraine (Level A) and probably ineffective for chronic tension-type headache (Level B). Although the 2008 guidelines also covered disorders including essential tremor and hemifacial spasm, no new evidence for these disorders was available for review and therefore was not included in the guidelines update. The guidelines were supported by the American Academy of Neurology and have been endorsed by the American Association of Neuromuscular & Electrodiagnostic Medicine and the American Society of Plastic Surgeons.

ASPIRIN USE BEFORE STROKE MAY LOWER STROKE SEVERITY Antecedent aspirin use may be neuroprotective in acute ischemic stroke, according to researchers. Although aspirin has been recognized as a preventive measure for stroke, its role in mitigating stroke severity is not well known. Previous studies measuring the benefit of antecedent aspirin www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2016 45

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Conference Roundup use on National Institutes of Health Stroke Scale (NIHSS) score did not account for acute infarct volume. To investigate the effect of antecedent aspirin use on stroke severity independent of infarct size, Sarah Nelson, MD, of Massachusetts General Hospital, and colleagues conducted a retrospective database analysis of consecutive patients presenting with acute ischemic stroke. Patients were included in the study if magnetic resonance imaging (MRI) of the brain obtained at admission was available for volumetric analysis of acute infarct size. In total, 610 patients were included in the analysis. Among them, 241 (39.5%) used aspirin prior to stroke onset. In univariate analysis, antecedent aspirin use, history of atrial fibrillation, acute infarct volume, initial systolic blood pressure, admission glucose level, and stroke subtype were associated with stroke severity. In multivariate analysis, antecedent aspirin use, history of atrial fibrillation, acute infarct volume, systolic blood pressure, and glucose level remained independent predictors of stroke severity. While the mechanism behind the apparent protective association between antecedent aspirin and stroke severity is not clear, the authors suggest that patients at a high risk for stroke may benefit from an aspirin regimen.

MENTALLY STIMULATING ACTIVITIES MAY REDUCE RISK OF MCI Mentally stimulating activities, such as reading and computer use, may help decrease the risk of incident mild cognitive impairment (MCI), researchers reported. Researchers led by Janina Krell-Roesch, PhD, of the Mayo Clinic in Scottsdale, Arizona, conducted a prospective cohort

Reading, engaging in crafts, computer use, and social activity were associated with a decreased risk of mild cognitive impairment.

study of 1929 cognitively normal adults aged ≥70 years from the Mayo Clinic Study of Aging. Using a questionnaire, participants provided information about engaging in mentally stimulating activities 1 year prior to baseline evaluation. Participants were followed until they were diagnosed with incident MCI by an expert consensus panel. Over a median follow-up of 4 years, researchers observed that playing games (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.65–0.95), reading magazines (HR, 0.66; 95% CI, 0.54–0.82), engaging in craft activities (HR, 0.72; 95% CI, 0.57–0.90), computer use (HR, 0.70; 95% CI, 0.57–0.85), and social activities (HR, 0.77; 95% CI, 0.63–0.94) were associated with a decreased risk of incident MCI. After accounting for APOE-ε4 status, the findings for noncarriers remained the same, while only computer use (HR, 0.65; 95% CI, 0.46–0.92) and social activities (HR, 0.62; 95% CI, 0.43–0.89) appeared to decrease the risk of MCI in carriers of the genetic mutation. While the data do not indicate a causal effect, they do suggest that continued engagement in mentally stimulating activities in late life may promote overall brain health.

DEPRESSION, ANXIETY PLUS BETA AMYLOID MAY INCREASE MCI RISK Patients with beta amyloid and depression or anxiety have an increased risk for mild cognitive impairment (MCI), researchers reported. The presence of beta amyloid deposits, together with depression or anxiety, appears to elevate the risk MCI in cognitively normal adults. While previously recognized as independent risk factors for cognitive impairment, the effects of the interaction between the characteristic plaques and neuropsychiatric symptoms had not been explored. To examine the potential interaction and its effect on patient outcomes, researchers led by Yonas Geda, MD, of the Mayo Clinic, in Rochester, Minnesota, conducted a prospective cohort study from the Mayo Clinic Study of Aging. In total, the researchers analyzed outcomes from 950 cognitively normal participants aged 50 years and older for a median of 28 months or to diagnosis of incident MCI. Patients underwent positron emission tomography with Pittsburgh compound B (PiB-PET) imaging and were evaluated based on the Beck Depression Inventory II (BDI-II) and Beck Anxiety Inventory (BAI). Participants were classified as PiB-positive (≥1.4) or PiB-negative (<1.4) based on global cortical-to-cerebellar ratio cut-point. Depression was indicated as a BDI-II score ≥13, and anxiety was indicated with a BAI score ≥10. Cognitive diagnosis was determined by an expert consensus panel.

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The researchers found that patients receiving onabotulinumtoxinA had significant improvements compared with those receiving placebo in MAS (−0.81 vs −0.61), CGI (0.86 vs 0.65), and passive GAS scores (week 12, −0.6 vs −0.9). When stratified by the time of treatment initiation after stroke (≤24 months, n=153; >24 months, n=315, post hoc), patients who were treated within 24 months following stroke experienced greater improvements in MAS and passive GAS scores. Among participants treated within 24 following stroke, a greater proportion achieved at least 1-point improvement in active (week 12) and passive (week 8) GAS scores vs placebo. The researchers also found that onabotulinumtoxinA 300 to 400 U was well tolerated with no new safety findings. Patients with depression or anxiety along with the presence of beta amyloid have an increased risk for mild cognitive impairment.

Participants who were PiB-positive and depressed had a more than 3-fold increased risk of MCI (hazard ratio [HR] 3.56; 95% confidence interval [CI], 1.46–8.63) compared with controls. Those who were PiB-positive and anxious had a more than 5-fold increased risk for MCI (HR, 5.38; 95% CI, 2.35–12.3]) compared with controls. Positive interaction between both beta amyloid and depression and beta amyloid and anxiety was statistically significant.

BOTOX MAY BE EFFECTIVE FOR LOWER LIMB SPASTICITY AFTER STROKE Early intervention with onabotulinumtoxinA (Botox) may be effective for adults who experience lower limb spasticity after a stroke, according to researchers. Atul T. Patel, MD, from the Kansas City Bone & Joint Clinic in Overland Park, Kansas, and colleagues conducted a multicenter, phase 3, placebo-controlled study. They enrolled 468 participants with poststroke lower limb spasticity (Modified Ashworth Scale [MAS] score ≥3) of the ankle. During the 12-week double-blind phase, the participants were randomly assigned either onabotulinumtoxinA (n=233; 300 U to mandatory muscles [gastrocnemius, soleus, tibialis posterior]; and ≤100 U to optional lower limb muscles [flexor digitorum longus, flexor hallucis longus, flexor digitorum brevis, extensor hallucis, rectus femoris]) or placebo (n=235). The primary end point was the average of the MAS change from baseline scores at weeks 4 and 6; secondary end points were the average score of weeks 4 and 6 of the physicianassessed Clinical Global Impression of Change (CGI) and the physician-assessed Goal Attainment Scale (GAS; active and passive at weeks 8 and 12).

CONCEPTION, PREGNANCY OUTCOMES IN WOMEN WITH EPILEPSY COMPARABLE TO HEALTHY PEERS Women with epilepsy are as likely to become pregnant and have similar pregnancy outcomes as their healthy peers, according to study results. Jacqueline A. French, MD, director of epilepsy research and clinical trials at NYU Langone Medical Center, and colleagues enrolled 88 women with epilepsy and 109 healthy controls aged 18 to 41 with similar demographics in the Women With Epilepsy: Pregnancy Outcomes and Deliveries (WEPOD) study. Study participants used an electronic diary to track medication use, seizures, sexual activity, and menstrual bleeding. Pregnancy tests were performed if no menses occurred by cycle day 35. During the course of the study, 61.4% of women with epilepsy achieved pregnancy within a median time of 6 months (95% confidence interval [CI]: 3.8–10.5) compared with 60.6% of healthy controls who achieved pregnancy within a median of 9 months (95% CI: 6.9–12.9). No difference in time to pregnancy was observed between the groups after controlling for age, body mass index, parity, and race. Notably, both parity and race were significantly associated with time to pregnancy. Among those who achieved pregnancy, a similar proportion of miscarriage (12.9% vs 19.7%), live birth (80% vs 80.3%), or other outcomes (5% vs 0%) occurred in women with epilepsy and healthy controls, respectively. n These articles originally appeared on NeurologyAdvisor.com

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YOUR COMMENTS IDENTIFYING CERVICAL LESIONS I am an experienced colposcopist and teach in the areas of human papillomavirus (HPV), cervical cancer prevention, and colposcopy. I am always happy to see articles that update clinicians on the subject of cervical cancer screening, as guidelines have changed significantly in recent years and there is significant confusion among clinicians. I found the article in the January 2016 issue of The Clinical Advisor [“Cervical cancer screening: why less is best,” p. 24] to be informative and evidence-based for readers, but I had a concern regarding the accompanying photograph of a cervix. The photo appears to be a normal cervix with a large immature transformation zone. Most cervical lesions are visible and defined, after the application of acetic acid. They have borders and degrees of acetowhitening, vessel patterns, and margins. Precancerous areas are not “dark red and puffy” as the caption suggests. While biopsy and Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001. You may contact us by e-mail at editor@ clinicaladvisor.com. 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.

histology is the final arbiter, this photo does not appear to represent the presence of a cervical lesion. In addition, the photo shows the cervix after the application of iodine, which obscures the presence of acetowhite lesions but does reveal immature epithelium lacking glycogen or abnormal areas lacking glycogen, and there does not appear to be a defined lesion, in this example. I just felt a need to address this. I have been involved in reviewing colposcopy photos for educational purposes. Sometimes it is difficult to see a representation of clinical abnormalities on photos, and we try to avoid photos that are difficult to assess.—NANCY R. BERMAN, MSN, ANPBC, NCMP, FAANP, Southfield, MI (212-1)

CLINICAL PEARLS APPLYING OINTMENT TO A CHILD If you have to apply a nonsterile ointment to a child or any person you may be caring for, and it only needs to be applied to a small area, instead of donning a pair of gloves you can use a square of plastic wrap over one finger and massage it onto the area. This will make sure that it gets to the area intended, keeps it off of your hands, and allows you to use a smaller amount. And the ointment will not stick to the plastic wrap like it would to a cotton tip or gauze pad.—TERI KNIGHT, RN, Cuyahoga Falls, Ohio. (212-2)

OUR CONSULTANTS

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.

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AN ALARM CLOCK CAN HELP PATIENTS REMEMBER TO TAKE THEIR MEDICATION To help people to remember to take their medication, especially in the morning rush, set a reliable alarm clock that has a snooze button next to or near the medicine bottle. (This alarm clock is only for medication purposes and should not be used to awaken with.) When the alarm rings, you can hit the snooze button if you cannot take the medication right then and there, and then it will ring again in a few minutes (hopefully, when the client is less distracted). Instruct the client to not shut off the alarm until after the medication is taken. This can work better than setting alarms on iPhones and smart phones in the morning, because it is way too easy to shut off the alarm on the phone, while the snooze button will keep reminding the patient to take the medication.— MARY ANDERSEN, APRN, CNS, MSN, Apple Valley, MN (212-3)

CASE FILES A MISCOMMUNICATION ON HOW TO TAKE HEMORRHOID MEDICATION This is a case of miscommunication regarding taking medication. I had a patient who just had hemorrhoid surgery, and the surgeon ordered pain medication for him. During the patient’s first return visit to my office, I was discussing the outcome with him. He said, “Terri, I still have much anal pain. I am taking my pain medication, but it doesn’t work.” I asked if he was taking the medication 3 times per day as ordered. He said, “Yes, I put them in with the cream on my finger. But they don’t work.” Of course, he was taking the medication incorrectly, but I did not want

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.

to add anything to his embarrassment, so I told him to try taking the medication orally and I would see him in 1 week. Next visit, he shyly said to me, “I was taking them wrong, wasn’t I?” I said, “Well, yes, but you didn’t know and your surgery was anal, so anyone could have made that mistake.” He felt much better. All patients do not know HOW to take medications. We assume they know, but here is one patient who did not know. —TERRI JORDAN, ARNP, Daytona Beach, Fla. (212-4)

CONSULTATIONS HOW EFFECTIVE IS A KENALOG INJECTION FOR SEASONAL ALLERGIES? My daughter (age 9) and I (age 44) suffer from seasonal allergies in the spring. We would like to receive a Kenalog injection. Can you confirm if this is safe as a one-time injection for both of us?—KYLIE YANNUZXI, RN, Danville, Calif. Although a short course of systemic corticosteroids is effective at relieving symptoms of allergic rhinitis, the corticosteroids should be used with great caution. Side effects of systemic steroids are widely known, including osteoporosis, aseptic necrosis, Cushing syndrome, hyperglycemia, and many more. Intranasal corticosteroids are by far a better choice and should be used daily during the allergy season; in fact, for patients with moderate to severe predictable allergic rhinitis, treatment should begin immediately preceding the season. Combination with a nonsedating antihistamine, if needed, is the recommendation for best control of symptoms.—CLAIRE O’CONNELL, MPH, PA-C (212-5) (See photo at the bottom of page 49 for more information about Ms. O’Connell.) n

Claire O’Connell, MPH, PA-C,

Katherine Pereira, DNP, FNP,

teaches in the PA Program at the New Jersey Medical School and Rutgers University, Piscataway, N.J.

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

Sherril Sego, FNP-C, DNP,

is an independent consultant in Kansas City, Mo.

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Dermatology Clinic CASE #1

Deformity of the breast in a premenopausal woman ASHLEY TURKELTAUB, BS, AND MAURA HOLCOMB, MD

A 48-year-old premenopausal woman, who has had one pregnancy and has delivered once, presents with a 15-month history of left breast deformity. She began having pain in the region 2 months ago. A review of systems is negative for weight loss, fever, or nipple discharge. Physical examination is notable for extensive left nipple inversion and retraction, a large underlying mass in the central breast, edema and ulceration of the overlying skin of the breast, and matted ipsilateral axillary nodes. The right breast is unremarkable. What is your diagnosis? Turn to page 52.

CASE #2

Hypotrichosis in a woman and infant YASMIN QASEEM, MD, AND MAURA HOLCOMB, MD

A 30-year-old Hispanic woman presents with her 1-yearold son, concerned he has only some thin, wispy hair on his head and none elsewhere. He has no teeth yet, he has a large forehead and ears, and he has been irritable and crying for the past day. The mother says she experiences very high body temperatures and usually remains indoors with air conditioning, especially in summer. On examination, she has sparse hair on her scalp and eyebrows and eczematous patches on her bilateral lower extremities. What is your diagnosis? Turn to page 53. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2016 51

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Dermatology Clinic CASE #1

Nipple inversion secondary to neglected malignancy

Nipple retraction or inversion occurs when the nipple is pulled inward. Although the terms retraction and inversion are often used interchangeably, the term retraction should be used when only a slit-like area of the nipple is drawn in, whereas the term inversion should be used when the entire nipple is pulled inward. Inversion of the nipple can be acquired or congenital, unilateral or bilateral, and umbilicated or invaginated. Umbilicated nipples can be pulled out from beneath the surface of the areola whereas invaginated nipples cannot.1 Approximately 3% of women have congenitally inverted nipples, of which approximately 87% are bilateral.1 Differentiating between congenital and acquired nipple inversion is important, as congenital nipple inversion typically has no pathologic implications. Benign retractions tend to be symmetrical, slow developing, and bilateral.2 A unilateral, asymmetric, and rapidly progressing inversion should therefore raise concern for more serious underlying pathology such as malignancy. Other acquired causes include trauma, surgery, infection, and inflammation, such as duct ectasia and periductal mastitis.3 Unlike nipple inversion secondary to malignancy, cases associated with duct ectasia typically do not involve the areola and can be easily everted. Patients tend to be older women with a long history of bilateral, symmetrical inversion and a creamy or greenish nipple discharge. Periductal mastitis tends to occur in younger women who smoke. Normally, a thin layer of contractile muscle in surrounding tissue allows the nipple to protrude centrally through the areola. Congenital nipple inversion can result when the underlying mesenchymal tissue fails to proliferate and project the nipple papilla outward.1 With malignancy, the balance between forces that pull and protrude the nipple and skin of the breast become skewed. Retraction or inversion is present in approximately 4% of breast cancer patients and occurs most often with a malignancy in the retroareolar region.4 Retraction of the skin results from shortening of Cooper ligaments due to tumor invasion. This connective tissue, which extends from the clavicle and branches out to the dermis overlying the breast, normally functions to suspend the breast.

Invasive ductal carcinoma can cause periductal fibrosis resulting in subsequent contraction and nipple inversion.5 Due to greater infiltrative behavior, invasive ductal and invasive lobular carcinoma are more frequently associated with nipple inversion. Thorough physical examination, imaging, and biopsy are necessary for evaluation of new-onset nipple inversion or retraction. Unilateral nipple inversion and asymmetry are more often associated with underlying malignancy.

Unilateral nipple inversion and asymmetry are more often associated with underlying malignancy. Subtle nipple or skin retraction can be accentuated by certain physical maneuvers, such as having the patient raise her arms above her head. Extensive skin retraction may indicate a neglected tumor or a multicentric or multifocal invasive carcinoma. This is most often seen with lobular carcinomas, as they tend to be multifocal.4 If malignancy is suspected, clinicians should look for other signs, including edema, ulceration, nipple discharge, and lymphadenopathy. Although nipple inversion secondary to malignancy can be due to tumor deep within the breast, it is most often caused by tumors in the retroareolar region. Because the retroareolar tissue is more radiographically dense than the rest of the breast, carcinomas in the region are more difficult to identify on mammography than elsewhere in the breast. In such cases, ultrasound is a useful adjunct to evaluate for a possible subareolar mass not visible on mammography.6 Although contrast-enhanced magnetic resonance imaging is not usually part of the workup, it may be valuable if results of both ultrasound and mammography are inconclusive.7 Biopsy should be performed if malignancy is suspected. Patients with nipple inversion or retraction secondary to suspected malignancy should undergo complete evaluation to exclude or confirm breast cancer. If a biopsy confirms malignancy, then determination of hormone receptor status, staging, and any indicated additional imaging studies should be done. Staging is based on the American Joint Committee on Cancer and the International Union for Cancer Control TNM classification. Most patients newly diagnosed with breast cancer have disease confined to the breast with limited or no lymph node involvement. Extensive imaging

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studies are not routinely performed unless there are signs or symptoms suspicious for locally advanced disease or distant metastasis. Treatment approach depends on such factors as staging, hormone receptor status, and the medical fitness of the patient. Treatment may include surgery, radiation, chemotherapy, endocrine therapy, or ERBB2-directed agents. Patients who have nipple inversion and centrally located tumors may still be eligible for breast-conserving therapy.8 The patient in our case was referred to the oncology department and underwent a diagnostic mammogram and ultrasound, followed by a biopsy confirming stage III invasive ductal carcinoma. A whole body positron emission tomography/computed tomography scan did not reveal evidence of distant metastasis. The patient was initially treated with neoadjuvant chemotherapy, followed by total mastectomy and axillary dissection, radiation, and hormonal therapy. She is doing well, with no evidence of recurrence of the disease 2 years after her diagnosis. Ashley Turkeltaub, BS, is a medical student and Maura Holcomb, MD, is a dermatology resident at Baylor College of Medicine in Houston. References 1. Park HS, Yoon CH, Kim HJ. The prevalence of congenital inverted nipple. Aesthetic Plast Surg. 1999;23(2):144-146. 2. Whitaker-Worth DL, Carlone V, Susser WS, et al. Dermatologic diseases of the breast and nipple. J Am Acad Dermatol. 2000;43(5 Pt 1): 733-751.

CASE #2

Hypohidrotic ectodermal dysplasia

Hypohidrotic ectodermal dysplasia is a genetic disorder commonly inherited in an X-linked pattern due to mutations of the EDA gene, which codes the protein ectodysplasin A.1 Patients t ypically present during childhood with the triad of hypohidrosis, hypodontia, and hypotrichosis, along with other prominent features of the disease.1 The patient’s reduced ability to sweat can lead to abnormalities of body temperature regulation.2 Scant amounts of hair may be present on the patient’s body, and there is typically delayed and abnormal dental development.1 Diagnosis is made clinically based on multiple physical manifestations of the condition.1 This genetic disease can generally be detected during early childhood. Scant, lightcolored hair is usually present on the scalp and body.1 High body temperatures generally cause babies to cry and become irritable and suggest a lack of appropriate cooling mechanisms.1 If this is suspected, the function of sweat glands can be evaluated in the office. Covering skin with iodine and raising the body temperature may reveal reduction in function of sweat glands; a patient with normally functioning sweat glands will sweat, which changes the color of the iodine from yellow to blue.1 Absence of this color change indicates dysfunction of the sweat glands. Facial abnormalities may also be present, including frontal bossing, saddle nose, thick

3. Da Costa D, Taddese A, Cure ML, et al. Common and unusual diseases of the nipple-areolar complex. Radiographics. 2007;27(suppl 1): S65-S77. 4. Lanyi M. Mammography: Diagnosis and Morphological Analysis. Berlin, Germany: Springer-Verlag; 2003. 5. Powell R. Breast examination. In: Walker H, Hall W, Hurst J, eds. Clinical

Patients typically present during childhood with the triad of hypohidrosis, hypodontia, and hypotrichosis.

Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston, MA: Butterworths; 1990. 6. Giess CS, Keating DM, Osborne MP, et al. Retroareolar breast carcinoma: clinical, imaging, and histopathologic features. Radiology. 1998;207(3):669-673. 7. An H, Kim K, Yu I, et al. Image presentation. The nipple-areolar complex: a pictorial review of common and uncommon conditions. J Ultrasound Med. 2010;29(6):949-962. 8. Haffty BG, Wilson LD, Smith R, et al. Subareolar breast cancer: longterm results with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys. 1995;33(1):53-57.

lips, and large ears. These abnormal facies may be mistaken for the manifestations of congenital syphilis.2,3 Wrinkled or hyperpigmented skin may be present in the periorbital area.1 Dental examination reveals few small, conical teeth.1 Patients may also have patches of eczema and dry, peeling skin.3 Some patients may have respiratory difficulties, including frequent upper respiratory infections or asthma due to thick nasal secretions.2,3 Postpregnancy attempts at breast-feeding may reveal mammary gland hypoplasia.1

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Dermatology Clinic Hypohidrotic ectodermal dysplasia is just one of several ectodermal dysplasias, an array of syndromes that involve abnormal development of ectodermal tissues, including hair, teeth, and others. However, this specific disorder can often be distinguished based on careful physical examination. Differential diagnosis includes Schöpf-Schulz-Passarge syndrome, odonto-onychodermal dysplasia syndrome, Witkop tooth and nail syndrome, Trichodento-osseous syndrome, and Clouston syndrome.1,2 Unlike several of these syndromes, hypohidrotic ectodermal dysplasia lacks significant nail abnormalities.1 Clouston syndrome, or hidrotic ectodermal dysplasia, presents similarly to hypohidrotic ectodermal dysplasia but lacks sweat gland involvement.2 The most common form of hypohidrotic ectodermal dysplasia is Christ-Siemens-Touraine syndrome,2 which demonstrates X-linked inheritance. Autosomal dominant and autosomal recessive variants also exist.1 Therefore, genetic testing may be beneficial in family members for appropriate management. When evaluating patients for hypohidrotic ectodermal dysplasia, it is important to bear in mind that patients may exhibit mosaicism.1 Additionally, if evaluating a patient with X-linked hypohidrotic ectodermal dysplasia, it is important to note that women may not have full involvement.4 In this case report, the child had much more severe involvement when compared with his mother. As mentioned earlier, mutations leading to hypohidrotic ectodermal dysplasia usually affect ectodysplasin A (EDA), which functions in the tumor necrosis factor signaling pathway and is important in organ development.5 The EDA, EDA receptor (EDAR), and EDAR-associated death domain (EDARADD) genes that correspond to a ligand, a receptor, and an adapter, respectively, have all been implicated in association with this disease.1,2,5 There are many more mutations of the EDA gene that cause hypohidrotic ectodermal dysplasia than mutations of the EDAR or EDARADD genes.5 Interestingly, there are also many different mutations in EDA that can lead to a similar phenotype; however, certain mutations of EDA can instead lead to dental dysgenesis without the accompanying syndrome.5 Most mutations leading to hypohidrotic ectodermal dysplasia are null mutations, although missense mutations may occur also.5 Treatment involves managing each component of this condition. Currently, no cure is available, although ongoing clinical trials are evaluating the viability of the EDI200 protein in patients with hypohidrotic ectodermal dysplasia. In order to manage hypohidrosis, patients should inhabit a cool environment to minimize risk of hyperthermia.1 Cosmetic appearance of hypotrichosis can be improved with the use of

wigs or topical minoxidil.1,2 From a dental perspective, patients may require dental implants or dentures, with regular dental examinations and dental radiographs.1 Oral lubrication may be necessary in certain patients to reduce risk of dental caries.1 Complications of hypohidrotic ectodermal dysplasia should be managed simultaneously. For example, eczematous dermatitis should be managed with topical corticosteroids.3 Humidifiers can be used to loosen nasal secretions, and removal of mucus can be performed with suction.1

Patients should undergo evaluation by a medical geneticist to determine the implications of disease for future progeny. Patients should also undergo evaluation by a medical geneticist in order to determine implications of disease for future progeny. Family members may also decide to undergo genetic evaluation to determine carrier status. Future directions for treatment of this disease include gene therapy targeting downstream genes, as well as research to elucidate upstream pathways in the EDA sequence.5 In our case, genetic testing revealed that the mother was heterozygous for an X-linked mutation of the EDA gene, whereas the child was homozygous for this mutation, which is consistent with their clinical presentation. They were both treated with topical corticosteroids for the eczematous dermatitis associated with the disease. n Yasmin Qaseem, MD, is now a dermatology resident at HarborUCLA Medical Center in Torrance, Calif., and Maura Holcomb, MD, is a dermatology resident at Baylor College of Medicine in Houston. References 1. Wright JT, Grange DK, Richter MK. Hypohidrotic ectodermal dysplasia. GeneReviews website. http://www.ncbi.nlm.nih.gov/books/NBK1112. Updated May 15, 2014. Accessed April 25, 2016. 2. Anoop TM, Simi S, Mini PN, et al. Hypohydrotic ectodermal dysplasia. J Assoc Physicians India. 2008;56:268-270. 3. Lu PD, Schaffer JV. Hypohidrotic ectodermal dysplasia. Dermatol Online J. 2008 15;14(10):22. 4. Bansal M, Manchanda K, Pandey SS. Hypohidrotic ectodermal dysplasia. Int J Trichology. 2012;4(3):167-168. 5. Mikkola ML. Molecular aspects of hypohidrotic ectodermal dysplasia. Am J Med Genet A. 2009;149A(9):2031-2036.

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Dermatologic Look-Alikes Darkened skin KATE TRAVIS, BA, AND RANA MAYS, MD

CASE #1

CASE #2

A 45-year-old Hispanic woman presents with a 2-year history of darkened skin on her face and neck, which started out as small patches on her cheeks and extended to her forehead and neck. Some family members have a similar rash. She has occasional mild pruritus. The patient is frequently in the sun and rarely wears sun protection. She has a history of hypertension and hyperlipidemia. Her medications include fenofibrate and metoprolol.

An 18-year-old Hispanic woman presents with a 5-year history of darkened skin on her hip. She denies any pruritus or pain in the area. However, the patient says that the lesions have been consistently growing. She also says the area had had increased hair growth in the past few years. The patient has not tried to treat the lesion. She is otherwise healthy and takes no medications. Her mother says she does not recall seeing a “birthmark” at birth.

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Dermatologic Look-Alikes CASE #1

Lichen planus pigmentosus

First described in 1974, lichen planus pigmentosus (LPP) is an uncommon macular variant of cutaneous lichen planus.1 LPP is characterized by the insidious onset of small, ill-def ined, oval-to-round macules that merge to form large areas of hyperpigmentation over time.2 Pigmentation among individuals varies from slate grey to brownish-black, but in a single patient, LPP is relatively uniform in color.2 Diffuse hyperpigmentation is the most common clinical pattern of LPP, but reticular, zosteriform, blaschkoid, perifollicular, generalized, and linear patterns have also been reported.3-6 LPP lesions tend to be bilaterally symmetrical and affect flexural areas and sun-exposed regions, with the head and neck being the most frequent sites of involvement, followed by the trunk and upper and lower limbs.2 The forehead and preauricular region (including the temples) tend to be the first sites of presentation and are affected in the majority of patients. Widespread involvement can occur, with approximately 30% of patients exhibiting over 10% body surface area involvement, though the palms, soles, nails, and usually, oral mucosa are spared.2 LPP with predominant localization of the disease in intertriginous areas, mainly the axillae, is referred to as LPP inversus.7 LPP tends to appear in the third or fourth decade of life; men have an earlier onset than women by a decade. The disease displays a slight predilection in women and is more commonly encountered in darker-skinned individuals.5 LPP has a chronic course with relapses and remissions. With time, new lesions may appear and existing lesions may enlarge slowly at the periphery and deepen in color. The duration of LPP ranges from months to years; approximately 50% of patients have the disease for 6 months to 3 years.2 In approximately 25% of patients, LPP lesions are accompanied by lesions of classical lichen planus, which are described by the “Six Ps”: planar, purple, polygonal, pruritic, papules, and plaques. The characteristic histopathologic features of LPP include atrophy of the epidermis with loss of rete ridges, vacuolar degeneration of the basal cell layer, perivascular or lichenoid infiltrate, and dermal melanophages.2,4 Based on these histopathologic alterations, it is suspected that LPP represents

Lichen planus pigmentosus vs. Becker nevus Lichen planus pigmentosus

Becker nevus

Characteristic clinical presentation

Insidious onset of small, ill-defined, oval to round macules that merge to form large areas of slate grey to brownish-black hyperpigmentation; within a single patient, pigmentation is uniform and tends to be diffuse and bilaterally symmetric

Isolated, unilateral, flat, hyperpigmented patch that ranges in color from light tan to dark brown; the lesion has an irregular, sharply demarcated border, measuring from a few centimeters in diameter to palm-size or larger with small peripheral islets of skin; intralesional hypertrichosis and acne may develop

Typical age of presentation

Third or fourth decade of life, with men having an earlier onset by approximately 1 decade

Second decade of life

Sex predilection

Slight predilection in women

Predilection in men

Clinical course

Chronic course with relapses and remissions; with time, new lesions may appear and existing lesions may enlarge slowly and deepen in color

Slowly enlarges for 1-2 y, then reaches a stable course

Commonly involved sites

Flexural and sun-exposed regions; the head and neck are the most common sites of presentation

Shoulder, arm, upper chest, and back; nearly all patients have upper trunk involvement

Histology

Atrophy of the epidermis with loss of rete ridges, vacuolar degeneration of the basal cell layer, perivascular or lichenoid infiltrate, and dermal melanophages

Melanotic hyperpigmentation of the basal cell layer and variable presence of dermal smooth muscle hamartoma; acanthosis, papillomatosis, keratotic plugging, and rete ridge elongation, flattening, and fusion are common

Treatment

Not required; for cosmetic purposes, hydroquinone, local and systemic corticosteroids, retinoids, dimethyl sulfoxide, keratolytics, chloroquine, immunomodulators, and tacrolimus have been used with inconsistent results

Screening for systemic abnormalities of Becker nevus syndrome; treatment is otherwise not required, but for cosmetic purposes, hyperpigmentation can be reduced with a pigment laser, and hypertrichosis can be reduced with laser therapy, shaving, or trimming

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a type of lichenoid tissue reaction to an unknown antigen or stimulus. LPP may have a similar pathogenesis to lichen planus, for which there is evidence of a cytotoxic immune reaction against basal-layer keratinocytes. Although the etiology of LPP remains elusive, various factors, including topical mustard oil and amla oil, henna, hair dyes, hepatitis C virus infection, and sunlight exposure, have been proposed as triggering agents.2,3 LPP has also

The main entity in the differential diagnosis of lichen planus pigmentosus is erythema dyschromicum perstans. been reported in association with head and neck cancer and with concurrent acrokeratosis paraneoplastica.8 Treatment of LPP is often unsatisfactory, as there is no reliable, effective treatment currently available. Hydroquinone, local and systemic corticosteroids, retinoids, dimethyl sulfoxide, keratolytics, chloroquine, and immunomodulators have been used with inconsistent results. When applied twice daily for an average of 12 weeks, topical tacrolimus, a calcineurin inhibitor, lightened LPP lesions in seven of 13 patients in one prospective study and is therefore used in the treatment of some patients.4 Recently, low-fluence Q-switched neodymium-doped yttrium aluminum garnet (QS-Nd:YAG) laser therapy successfully cleared one case of LPP on the cheeks that was recalcitrant to several topical treatments and cleared one case of LPP on the forehead in combination with topical tacrolimus.9,10 Intense pulsed light (IPL) was also used to successfully treat a case of LPP that was associated with classical lichen planus and resisted treatment with hydroquinone, glycolic acid, corticosteroids, and sunscreen.11 However, due to the scarcity of research on IPL and laser therapy for LPP, topical agents remain the mainstay of therapy for LPP. LPP lesions tend to be asymptomatic, but approximately one-third of patients report mild pruritus and/or a burning sensation.2 Some patients also report photosensitivity. The primary concern regarding LPP, however, stems from the disease’s cosmetic burden, long clinical course, and poor response to treatment, leading to psychologic trauma and frustration. The differential diagnosis of LPP includes erythema dyschromicum perstans (also known as ashy dermatosis), melasma, Riehl melanosis, Addison disease, fixed drug eruption, Becker nevus, and postinflammatory pigmentation.

The main entity in the differential diagnosis of LPP is erythema dyschromicum perstans, as the two diseases share numerous clinical and histopathologic features. However, early lesions of erythema dyschromicum perstans often have an inflammatory phase, in which a thin erythematous border surrounds the hyperpigmented macules and patches, whereas LPP lesions are not associated with an inflammatory phase.12 Furthermore, melanin deposition is located in the superficial dermis in LPP lesions, but it is located in the deeper dermis in lesions of erythema dyschromicum perstans.12 Both Becker nevus and LPP can manifest with hyperpigmented patches, but Becker nevus lesions can be distinguished by their earlier age of presentation (second decade rather than third or fourth decade of life) and frequently associated hypertrichosis. Furthermore, LPP presents with numerous lesions that often have a grey tint, whereas a Becker nevus patch is usually solitary and tan or brown in color. In our case, a 4-mm punch biopsy was performed, confirming LPP. The patient was prescribed a mild topical steroid cream twice daily and sun protection. After 3 months of this regimen, her hyperpigmentation was unchanged, but her pruritus had improved.

CASE #2

Becker nevus

Becker nevus, also known as Becker melanosis, Becker pigmentary hamartoma, and pigmented hairy epidermal nevus, is a relatively common cutaneous hamartoma that presents more frequently in men, with a male-to-female ratio ranging from 2:1 to 6:1.13,14 Few studies have reported the prevalence of Becker nevus, but in a survey of 19,302 adolescent boys and men age 17 to 26 years in France, the prevalence was 0.52%,13 and in a study of 5,837 young Italian men, the prevalence was 2.1%.15 Occurrence of Becker nevus is usually sporadic but occasionally shows familial aggregation, suggesting a paradominant mode of inheritance in which Becker nevus is only manifested clinically by a regional loss of heterozygosity.16 Becker nevus tends to present during the second decade of life as an isolated, unilateral, flat, hyperpigmented patch that enlarges gradually and may become slightly raised.

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Dermatologic Look-Alikes The most common sites of presentation are the shoulder, arm, upper chest, and back; nearly all patients have upper trunk involvement.17 Hypertrichosis may develop after hyperpigmentation, especially in older men, and, over time, the hairs become coarser and darker.17 The lesion has a sharply demarcated and irregular border and is surrounded by small peripheral islets of affected skin that can fuse with the primary lesion. Becker nevus lesions range in color from light tan to dark brown and can measure from a few centimeters in diameter to palm-size or larger. Adolescents may develop acne within the Becker nevus, which is likely attributable to heightened local androgen sensitivity.18 Histopathologically, Becker nevus is characterized by epidermal changes with melanotic hyperpigmentation of the basal cell layer and variable presence of dermal smooth muscle hamartoma. Acanthosis, papillomatosis, keratotic plugging, and rete ridge elongation, flattening, and fusion are common histopathologic findings.19 Increased expression of androgen receptors has been reported in lesional skin, bolstering support for the theory that androgens play a pathogenic role in Becker nevus.20 An androgenic basis for the development of Becker nevus also explains the diseaseâ&#x20AC;&#x2122;s more frequent diagnosis in men, increased prominence after puberty, and histologic findings of acanthosis, dermal thickening, acne, hirsutism, and smooth muscle bundles.20 In women, diagnosis of Becker nevus may be overlooked, as the lesion often presents with less intense pigmentation and mild or absent hypertrichosis. Because Becker nevus is less conspicuous in women, the true sex ratio may be closer to 1:1.21 Most Becker nevus lesions occur as isolated cutaneous defects, but there is systemic involvement in approximately 5% of patients.22 In 1997, the term Becker nevus syndrome was coined to describe the simultaneous occurrence of Becker nevus and ipsilateral mammary hypoplasia or other cutaneous, muscular, or skeletal defects, including scoliosis, spina bifida, and limb asymmetry.21 As a result, all patients with Becker nevus should be screened for bone, muscle, breast, and other associated abnormalities of Becker nevus syndrome. Because most Becker nevus lesions are benign and asymptomatic, treatment is not necessary for the majority of patients. However, therapeutic intervention is often desired by patients as the disease can be a distressing cosmetic handicap. Therapy requested by patients, therefore, has two major goals: (1) to reduce the hyperpigmentation, and (2) to reduce hypertrichosis.

Reduction of hyperpigmentation can be accomplished with a variety of laser treatments, including the erbiumdoped yttrium aluminum garnet (Er:YAG) laser, Q-switched (QS-) ruby laser, Q-switched neodymium-doped yttrium aluminum garnet (QS-Nd:YAG) laser, frequency-doubled QS-Nd:YAG laser, QS long-pulse alexandrite laser, and fractional resurfacing with 1550-nm Er fiber laser. In a comparative study between Er:YAG and QS-Nd:YAG, a single pass with an Er:YAG laser decreased pigmentation of Becker nevus lesions better than three treatment sessions with the QS-Nd:YAG laser.23 In a study to test the efficacy of the long-pulse alexandrite laser, two of 11 patients had greater than 75% pigment clearance, five had 50% to 75% clearance, and four had 25% to 50% clearance.24

Because most Becker nevus lesions are benign and asymptomatic, treatment is not necessary for the majority of patients. A case report of two patients treated by fractional resurfacing, a newer treatment modality, showed that five to six treatment sessions at 4-week intervals reduced pigment by more than 75% in 1 month.25 Unfortunately, despite the existence of many treatment modalities, recurrence rates of Becker nevus are high and postinflammatory hyperpigmentation can occur. Shaving or trimming of excess hair can offer temporary relief from hypertrichosis. However, treatment of Becker nevus with ruby laser in the normal or long-pulsed mode can provide a longer-lasting solution. Use of high-repetition-rate diode lasers is another therapeutic modality that was proposed in a recent study to treat hypertrichosis of Becker nevus lesions. In this study, 15 patients with Becker nevus underwent eight sessions of hair removal with low-fluence, high repetition-rate diode laser therapy (808-810 nm); when hair clearance was quantified at 6 and 12 months, all patients had significant hair reduction with no adverse events.26 Electrolysis is another well-established method of epilation, but its use in the removal of hair from Becker nevus has not been reported. Without treatment, Becker nevus can persist indefinitely. Standard acne treatments should be used for patients presenting with intralesional acne. Patients with Becker Continues on page 69

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Dermatologic Look-Alikes nevus should be advised to avoid direct sunlight, since sun exposure has the potential to deepen the pigmentation of lesional skin. The principal entities that mimic Becker nevus are congenital melanocytic nevus, postinflammatory hyperpigmentation, lichen planus, café-au-lait macule, and nevus spilus. The diagnosis of Becker nevus can usually be made based on clinical appearance. Clinical findings most suggestive of Becker nevus include the presence of a single, brown, irregular patch of skin with relatively uniform color on the upper trunk, peripheral islets of hyperpigmented skin, intralesional hair and acne, and onset during childhood or adolescence with increased prominence after puberty. Clinical findings that disfavor the diagnosis of Becker nevus include pruritus or pain, scaliness, smooth borders, multiple lesions, onset in late life, variation in color, and rapid growth. In diagnostically uncertain cases, Becker nevus can be distinguished histologically by basal hyperpigmentation, papillomatosis, elongated rete ridges, acanthosis, keratotic plugging, and hamartomatous features. In our case, biopsy of the patient’s lesion was consistent with Becker nevus. The patient was reassured of the harmless nature of Becker nevus, and education was provided. ■

8. Sassolas B, Zagnoli A, Leroy JP, Guillet G. Lichen planus pigmentosus associated with acrokeratosis of Bazex. Clin Exp Dermatol. 1994;19(1):70-73. 9. Kim JE, Won CH, Chang S, et al. Linear lichen planus pigmentosus of the forehead treated by neodymium:yttrium–aluminum–garnet laser and topical tacrolimus. J Dermatol. 2012;39(2):189-191. 10. Han XD, Goh CL. A case of lichen planus pigmentosus that was recalcitrant to topical treatment responding to pigment laser treatment. Dermatol Ther. 2014;27(5):264-267. 11. Parada MB, Yarak S, Michalany NS. Treatment of lichen planus pigmentosus with intense pulsed light. Surg Cosmet Dermatol. 2009;1(4):192-194. 12. Rieder E, Kaplan J, Kamino H, et al. Lichen planus pigmentosus. Dermatol Online J. 2013;19(12):20713. 13. Tymen R, Forestier JF, Boudtet B, Colomb D. Late Becker’s nevus. One hundred cases [in French]. Ann Dermatol Venereol. 1981;108(1):41-46. 14. Danatri R, König A, Salhi A, et al. Becker’s nevus syndrome revisited. J Am Acad Dermatol. 2004;51(6):965-969. 15. Ballone E, Fazii P, Lappa G, et al. Prevalence of Becker’s nevi in a population of young men in central Italy. J Am Acad Dermatol. 2003;48(5):795. 16. Happle R. Loss of heterozygosity in human skin. J Am Acad Dermatol. 1999;41(2 Pt 1):143-164. 17. Rasi A, Ardestani HB, Tabaie SM. Hypertrichosis is not so prevalent in Becker’s nevus: analysis of 47 cases. ISRN Dermatol. 2014;2014:953747. 18. Burgreen BL, Ackerman AB. Acneform lesions in Becker’s nevus. Cutis. 1978;21(5):617-619.

Kate Travis, BA, is a medical student and Rana Mays, MD, is a dermatology resident at Baylor College of Medicine in Houston.

19. Kim YJ, Han JH, Kang HY, et al. Androgen receptor overexpression in Becker nevus: histopathologic and immunohistochemical analysis. J Cutan Pathol. 2008;35(12):1121-1126.

References

20. Grande Sarpa H, Harris R, Hansen CD, et al. Androgen receptor

1. Bhutani LK, Bedi TR, Pandhi RK, Nayak NC. Lichen planus pigmentosus.

expression patterns in Becker’s nevi: an immunohistochemical study.

Dermatologica. 1974;149(1):43-50.

Am Acad Dermatol. 2008;59(5):834-838.

2. Kanwar AJ, Dogra S, Handa S, et al. A study of 124 Indian patients with

21. Happle R, Koopman RJ. Becker nevus syndrome. Am J Med Genet.

lichen planus pigmentosus. Clin Exp Dermatol. 2003;28(5):481-485.

1997;68(3):357-361.

3. Vachiramon V, Suchonwanit P, Thadanipon K. Bilateral linear lichen

22. Patrizi A, Medri M, Raone B, et al. Clinical characteristics of Becker’s

planus pigmentosus associated with hepatitis C virus infection. Case Rep

nevus in children: report of 118 cases from Italy. Pediatr Dermatol.

Dermatol. 2010;2(3):169-172.

2012;29(5):571-574.

4. Al-Mutairi N, El-Khalawany M. Clinicopathological characteristics of

23. Trelles MA, Allones I, Moreno-Arias GA, Vélez M. Becker’s nae-

lichen planus pigmentosus and its response to tacrolimus ointment: an

vus: a comparative study between erbium:YAG and Q-switched

open label, non-randomized, prospective study. J Eur Acad Dermatol

neodymium:YAG; clinical and histopathological findings. Br J Dermatol.

Venereol. 2010;24(5):535-540.

2005;152(2):308-313.

5. Vasudevan B, Verma R, Venugopal R. Pigmented variants of skin dis-

24. Choi JE, Kim JW, Seo SH, et al. Treatment of Becker’s nevi with long-

orders. In: Lahiri K, Chatterjee M, Sarkar R, eds. Pigmentary Disorders: A

pulse alexandrite laser. Dermatol Surg. 2009;35(7):1105-1108.

Comprehensive Compendium. New Delhi, India: Jaypee Brothers Medical

25. Glaich AS, Goldberg LH, Dai T, et al. Fractional resurfac-

Publishers; 2014:121-128.

ing: a new therapeutic modality for Becker’s nevus. Arch Dermatol.

6. Kumar YH, Babu AR. Segmental lichen planus pigmentosus: an unusual

2007;143(12):1488-1490.

presentation. Indian Dermatol Online J. 2014;5(2):157-159.

26. Lapidoth M, Adatto M, Cohen S, et al. Hypertrichosis in Becker’s

7. Pock L, Jelínková L, Drlík L, et al. Lichen planus pigmentosus inversus.

nevus: effective low-fluence laser hair removal. Lasers Med Sci.

J Eur Acad Dermatol Venereol. 2001;15(5):452-454.

2014;29(1):191-193.

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LEGAL ADVISOR CASE

Another clinician’s prescription

BY ANN W. LATNER, JD

Ms. N, age 51, was a nurse practitioner w orking independently in a rural family practice. The community in which Ms. N practiced was extremely small and close-knit, and the clinician had known most of her patients for years. Mrs. V, age 70, who Ms. N had been treating for the past 11 years, had a medical history of a myocardial infarction, cardiac arrhythmia, hyperlipidemia, and hypothyroidism. Mrs. V had also been diagnosed with metastatic colon cancer and was undergoing chemotherapy and radiation treatments at the nearest medical center, which was an hour’s drive away. The travel was very difficult for the patient. Because she was unable to tolerate the long drive for additional doctors’ appointments, the patient often called Ms. N for medication refills, rather than make appointments with her oncologist and/or cardiologist. One day, Mrs. V’s husband showed up at Ms. N’s office, requesting a refill of amiodarone for his wife. The drug had initially been prescribed four months prior, due to a cardiac event during Mrs. V’s colectomy and resection procedure.

A communication failure when one clinician refills a prescription written by another has a dire result.

Mrs.V’s husband showed up at Ms. N’s office, requesting a refill of amiodarone for his wife.

“She’s really feeling poorly,” Mr. V said of his wife. “The chemo has made her so sick. She is nauseous and throwing up. She really can’t handle the 60-minute drive to the cardiologist. Can you please refill this?” Ms. N, who understood the difficult situation the patient was in, felt sympathetic toward both Mr. and Mrs. V. The patient’s illnesses had been difficult for the couple, who were just about to celebrate 50 years of marriage. The medical center was a long drive away, and it was winter—the roads were not in good shape. “Okay,” Ms. N said to Mr. V. “I’ll give her a 30-day refill as a courtesy. I know what that drive is like, especially if she’s feeling queasy, but please make an appointment with her cardiologist for future refills.” Mr. V said he would, thanked her, and left with the prescription. Continues on page 72

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.

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LEGAL ADVISOR Thirty days later, however, he returned by himself again asking for another refill of amiodarone. “I’m so sorry,” Mr. V told the clinician. “She missed her appointment with the cardiologist because of the big snowstorm we had, and her medication will be finished before the next appointment.” Again, Ms. N refilled the prescription without speaking to the cardiologist, evaluating the patient, or looking up the medication, with which she was not terribly familiar. Three weeks later, Mrs. V experienced shortness of breath and was admitted to the hospital for acute respiratory failure. While at the hospital, Mrs. V was diagnosed with pulmonary fibrosis and amiodarone lung toxicity, and she died shortly after admission. Mrs. V’s grown children encouraged their father to seek the advice of a plaintiff’s attorney as to whether there might be a case for medical malpractice in the death of their mother. Mr. V met with an attorney and explained what had happened. The attorney agreed to take the case, and sued Ms. N, the cardiologist, and the medical center for medical malpractice.

Three weeks later, Mrs.V experienced shortness of breath and was admitted to the hospital for acute respiratory failure. Ms. N contacted her medical malpractice insurance company and met with the defense attorney who was provided for her. The attorney asked whether she was familiar with the risks or side effects of amiodarone. Ms. N confessed that she was not. “I’ll retain some defense medical experts to look at the patient’s files and review the claim,” the attorney said. “Then we’ll have a better idea of what we’re up against.” In the meantime, during investigation of the case it was discovered that the patient’s cardiologist was not the one who originally prescribed the amiodarone. It was actually prescribed by the surgeon who performed the patient’s colectomy and resection. The medical center and the cardiologist were thus dismissed from the lawsuit, leaving Ms. N as the sole defendant. The medical experts retained by Ms. N’s attorney to review the records were critical of Ms. N’s lack of knowledge about the side effects of amiodarone and of her failure to contact the cardiologist to discuss the patient’s medication. Given the expert opinions and because Ms. N was now the only defendant left in the case, the case was settled out of court for the policy limits on Ms. N’s malpractice insurance.

Legal background

Medical experts are almost always used in medical malpractice cases. Both sides (plaintiff and defendant) typically have their own medical experts who will review the medical records and advise the attorneys whether they believe the defendant acted properly or not, based on the evidence. Experts are also used at trial to testify as to the standard of care owed by a clinician to her patient. Often, the decision of whether to attempt to settle a case is based on the input of medical experts who weigh in on whether the defendant breached the applicable standard of care. Protecting yourself

When nurse practitioners are sued for medical malpractice, claims typically involve diagnostic errors (misdiagnosis, delayed diagnosis, failure to diagnose), treatment errors (failure to treat, improper treatment), or prescribing errors (failure to recognize contraindications, improper prescribing, improper medication management), and these errors are often the result of communication failures or documentation errors. This month’s case examines how a nurse practitioner’s attempt to be helpful to a patient in a difficult situation ended up causing harm to both the patient and the clinician. While Ms. N was trying to be kind to a long-time patient with serious problems, her kindness backfired for both the patient and herself. A simple call to the cardiologist to confirm whether Mrs. V should still be on the medication, and at what dose, would have been an easy way to avoid the problem. It would also have been professional courtesy to let the cardiologist know that the patient was asking for a refill from the nurse practitioner. Aside from not contacting the cardiologist (or prescribing physician), Ms. N made several other mistakes. She admittedly was unaware of the numerous side effects of the medication she was prescribing. She never evaluated, or even spoke to, the patient during the two refill incidents. She never spoke to any of the patient’s other physicians about the medication or refilling the amiodarone herself. Protect yourself by having timely and proactive discussions with physicians and other members of the patient’s care team to ensure that everyone understands the patient’s treatment plan. Speak with a pharmacist about questions regarding unfamiliar medication side effects or interactions. And finally, do not refill a prescription from another clinician without first checking with the clinician. n Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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Writers’ Guidelines The Clinical Advisor welcomes submissions from its readers. Writing for us is an opportunity to share your knowledge and experience with your colleagues — and to collect a fee in the bargain! We pay an honorarium for every submission we accept. We’ll be glad to work with you to develop your ideas into compelling articles. As for length, that depends on which kind of article you submit. CLINICAL FEATURES update our readers on the latest information about conditions seen in everyday practice. Running approximately 2,500 to 5,000 words, including the references, features can be written either as regular narratives or as a series of questions and answers. Topics should be selected with the busy primary-care clinician in mind; specialists should review specialty topics from the primary-care point of view. If at all possible, articles should be accompanied by clinical photos. Charts, tables, and algorithms are also encouraged. Please include your title and affiliation. CLINICAL CHALLENGE is our popular department comprising histories of difficult cases. Each case is presented as a step-by-step, chronological account, revealing the author’s thought processes along the way. It is divided into sections in this order: the patient presentation; the patient history; the twists and turns eventually leading to a diagnosis; the treatment and outcome; and a discussion of the lessons learned or of the condition in general. The length should be about 1,500 words, and accompanying images are encouraged. Please include your title and affiliation. DERMATOLOGY CLINIC is a department that presents photos of actual cases and asks readers to identify the condition. Each case opens with one or two color photos and a 75-to-100-word description of the patient presentation, without giving away the diagnosis. This is followed by a 750-to-1,000-word summary that includes a fuller description of the ailment, an explanation of how the correct diagnosis was reached, a general review of the condition along with a differential diagnosis, and a description of the patient’s treatment and outcome. Topics must be approved by the editor prior to submission. Please include your title and affiliation. COMMENTARY is our guest editorial page. It gives you the opportunity to sound off on an issue of importance to your colleagues nationwide. A typical Commentary runs about 600 words in length. Please include your title and affiliation. To discuss your editorial ideas, contact us by phone at 646.638.6078; by e-mail to editor@ClinicalAdvisor.com; or by mail to The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2016 75

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Stat Consult

A quick review of common conditions, using the best global evidence

Description

Lyme Disease

• most common tickborne infection in North America and Europe Also called

• Lyme borreliosis Types

BY ALAN DRABKIN, MD

Dr. Drabkin is a senior clinical writer for DynaMed (www.ebscohost. com/dynamed), a database of comprehensive updated summaries covering more than 3,200 clinical topics, and assistant clinical professor of population medicine at Harvard Medical School.

The Lyme disease spirochete, Borrelia burgdorferi, is an obligate parasite.

• early Lyme disease ——early localized Lyme disease—single erythema migrans (EM) lesion at site of tick bite ■■ round, flat or raised, erythema expanding in diameter over days to weeks ■■ may have area of central clearing (“target lesion”) ■■ appears about 7 -14 days after tick detaches ■■ often in axilla, back, abdomen, groin, and popliteal fossa ■■ may also have »»systemic symptoms (fever, chills, fatigue, arthralgias, or myalgias) »»regional lymphadenopathy ——early disseminated Lyme disease ■■ multiple EM lesions ■■ early neurologic Lyme disease »»cranial nerve palsy »»meningitis »»acute radiculopathy »»mononeuropathy multiplex ■■ Lyme carditis - atrioventricular block and/or myopericarditis ——borrelial lymphocytoma (rare) ■■ cutaneous solitary bluish-red swelling < few centimeters in size ■■ often due to Borrelia afzelii in Europe • late Lyme disease ——Lyme arthritis ■■ monoarticular or oligoarticular ■■ affects knee, other large joints or TMJ ——late neurologic Lyme disease ■■ encephalomyelitis ■■ encephalopathy ■■ peripheral neuropathy ——acrodermatitis chronica atrophicans

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Estimated incidence

■■

Associated conditions

IgM positive when both

»»≥ 2 of 3 specific bands present »»duration of infection < 4 weeks

• about 329,000 cases annually in US and 85,000 in Europe

IgG positive when both »»≥ 5 of 10 specific bands present »»duration of infection > 4 weeks ——if negative in early Lyme disease, consider repeat testing • other testing may include ——CSF ——synovial fluid ——skin biopsy (rare) ■■

• co-infection with anaplasmosis or babesiosis • flaviviruses Pathogens

• Borrelia burgdorferi sensu lato spirochete species complex • common species ——B. burgdorferi (USA) ——B. afzelii (Europe) ——B. garinii (Europe) ——B. spielmanii and B. bavariensis Transmission

• Ixodes ticks ——I. scapularis (previously I. dammini) in northeast and upper midwestern US (primarily transmits B. burgdorferi) ——I. pacificus in western US (B. burgdorferi ) ——I. ricinus in Europe (B. garinii and B. afzelii ) ——I. persulcatus in Asia (B. garinii and B. afzelii ) • reservoir hosts ——I. scapularis ■■ white-tailed deer ■■ small mammals, especially white-footed mouse ——I. ricinus ■■ large mammals (cattle, deer) ■■ small rodents (wood mice, voles) • injection of nymphal tick saliva during feeding ——I. scapularis and I. pacificus need 36-72 hours feeding to transmit enough spirochetes to cause infection ——B. afzelii transmission may be more rapid • nymphal tick activity most active late May-September • average incubation period 7-10 days Testing

• with EM, empiric diagnosis (compatible history, potential exposure, and exam findings) without testing • routine blood tests ——WBC, hemoglobin, and platelets usually normal unless co-infection with Anaplasma phagocytophilum, Babesia microti, or tick-borne encephalitis virus ——LFTs slightly elevated in early disease ——ESR elevations common, rarely > 80 mm/hour • for non-EM presentations, 2-tiered serologic testing recommended ——screening immunoassay—if negative, no further testing ——if positive, supplementary Western blot

Differential diagnosis

• co-infection ——babesiosis ——human granulocytic anaplasmosis (“ehrlichiosis”) • other Borrelial infection ——southern tick-associated rash illness (STARI) (Borrelia lonestari ) ——Borrelia miyamotoi Treatment

• hospitalization advised for symptomatic Lyme carditis • usual antibiotic treatment for adults (IDSA guidelines) ——early Lyme disease ■■ for EM without complications, any of »»doxycycline 100 mg orally twice daily for nonpregnant patients ≥ 8 years old for 14 days »»amoxicillin 500 mg orally 3 times daily for 14 days »»cefuroxime axetil 500 mg orally twice daily for 14 days ■■ for early neurologic Lyme disease »»ceftriaxone 2 g IV once daily for 14 days »»alternatives if normal renal function ˚˚ cefotaxime 2 g IV every 8 hours ˚˚ penicillin G 18-24 million units/day in 6 divided doses ˚˚ doxycycline 200-400 mg/day orally in 2 divided doses if unable to tolerate beta-lactam antibiotics »»for seventh cranial nerve palsy ˚˚ if both clinical and laboratory evidence of CNS involvement, use same for early neurologic Lyme disease ˚˚ if CSF exam normal/unnecessary, use 14-day regimen for EM ■■ for Lyme carditis, treat for 14-21 days with »»ceftriaxone 2 g IV once daily (inpatients) »»oral regimen as for EM (outpatients or to complete therapy after hospitalization)

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Stat Consult ——late Lyme disease ■■ for Lyme arthritis without neurologic involvement, treat for 28 days using EM dosing with doxycycline or amoxicillin or cefuroxime ■■ for late neurologic Lyme disease, treat for 2 to 4 weeks with antibiotics used for early neurologic Lyme disease ■■ for Lyme arthritis with neurologic involvement, treat with antibiotics and duration as for late neurologic Lyme disease ■■ for acrodermatitis chronic atrophicans, treat for 21 days with antibiotics used for EM ——avoid doxycycline if pregnant or lactating • other treatments ——temporary pacemaker (if advanced heart block) ——arthroscopic synovectomy (if persistent synovitis) • alternative therapies ——Bismacine (Chromacine) NOT recommended ——no evidence to support alternative therapies Follow-up

——decreased time in tick-infested habitats ——light-colored clothing with long pants tucked into socks and long-sleeve shirts ——tick repellents and use of permethrin-treated clothing • bite care ——preferred method of tick removal is using forceps or tweezers grasping tick as close to skin surface as possible and pulling upward with steady pressure ——disinfect bite site and save tick for identification ——avoid use of physical substances (such as petroleum jelly) or heat (ineffective for tick removal) • antibiotic prophylaxis following tick-bite (IDSA guidelines) ——routine prophylaxis not recommended ——consider single-dose doxycycline (200 mg for adults, 4 mg/kg (maximum 200 mg) for children ≥ 8 years old) if ■■ tick adherent for ≥ 36 hours ■■ area endemic for B. burgdorferi ■■ < 72 hours after bite ——single-dose doxycycline 200 mg within 72 hours of Ixodes scapularis tick bite may be effective n

• test of cure should not be performed (seroreactivity can persist for years) Complications

Prognosis

• untreated EM typically resolves in 3-4 weeks • excellent long-term prognosis with early antibiotic treatment • repeat episodes of EM more likely to be re-infection than relapse • post-Lyme disease syndromes ——no evidence for existence of symptomatic chronic B. burgdorferi infection after recommended treatment regimen ——antibiotic therapy not proven to be useful and not recommended for patients with chronic (≥ 6 months) subjective symptoms after recommended treatment Prevention

• arthritis • carditis • neurologic ——facial nerve paly ——meningitis ——encephalomyelitis ——radiculoneuropathies

• tick avoidance measures include 78 THE CLINICAL ADVISOR • JUNE 2016 • www.ClinicalAdvisor.com

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ALTERNATIVE MEDS UPDATE

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.

Bromelain

If you have ever cut up a fresh pineapple and noticed how smooth your hands felt afterward, you have experienced the basic action of bromelain. Pineapple (Ananas comosus) is a well-known tropical plant that has been used for centuries for both its medicinal purposes and its food value. Bromelain is a complex chemical found in the aqueous extract of the pineapple and is composed largely of proteolytic enzymes.1 As an individual product, bromelain has been available commercially since 1957. Other components of this substance include glycoproteins, complex carbohydrates, protease inhibitors, and peroxidases.1

Background Bromelain’s first commercially recognized use was as a meat tenderizer because of its ability to degrade animal proteins. Since then, it has been studied for its potential as an anti-inflammatory, an immune modulator, and even as an anticancer therapy. Bromelain-containing pharmaceutical products are available in other countries both by prescription and over the counter, depending on the intended use. Multiple clinical trials are ongoing in the United States.

Science The most studied and proven action of bromelain is as a proteolytic enzyme. Clinical trials of bromelain-containing products for the nonsurgical debridement of burn eschar have been very favorable. This procedure, long known for being horribly painful, is nonetheless essential for proper healing of severe burns. Because deep and full-thickness burns routinely require performing this

painful procedure multiple times during the healing process, skin grafting is also commonly needed for adequate wound coverage. Skin grafting then not only compounds the cosmetic damage but also adds more pain and discomfort. Products containing bromelain are being studied for their potential role in this process, with some very promising results. One leading bromelain compound has been found to reduce healthy skin tissue by up to 50%, while also reducing the number of surgical procedures required by more than 75%.2 Overall recovery rates average 85%, with 70% of these patients able to avoid skin grafting completely.2 In one prospective noncomparative trial using a bromelain-derived debriding agent in 130 patients with 332 second- and thirddegree burns, wound debridement was accomplished in more than 75% of cases with 1 to 3 applications.2 There is also interest in bromelain for the treatment of osteoarthritis. The proposed mechanism of action is similar to that of other nonsteroidal anti-inflammatory drugs. Taken orally, bromelain acts to block prostaglandin synthesis, thereby

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ALTERNATIVE MEDS UPDATE reducing the nociceptive perception of pain.3 Another immune-modulatory effect of bromelain is its ability to alter the cellular adhesion of lymphocytes.4,5 In a double-blind randomized study, 103 participants with confirmed osteoarthritis of the knee were treated for 6 weeks with either oral diclofenac or a combination containing bromelain.3 Patient performance was graded by the Lequesne Algofunctional Index and by subjective complaint index.3,6 At the end of the trial, researchers found that the enzymatic compound was as effective as standard diclofenac. Bromelain is also considered for its possible antitumoral effects, which are thought to be related to the same pathways as its anti-inflammatory and immune-modulating effects. In vitro studies of bromelain’s action on cultures of cancerous human cell lines have been conducted.7

Safety, interactions There have been no phase 2 clinical trials in the United States of bromelain, but adverse events reported in human trials to date were usually mild and were resolved by lowering the dose or discontinuing treatment.8 Anyone allergic to pineapple should not receive bromelain therapy. Because of its anti-inflammatory action, bromelain can interact with blood clotting by interfering with the action of fibrin.8

better-controlled human clinical trials. Similar to many botanicals, the appeal of “natural” may seem alluring to some. However, the potential for side effects is the same as for a patented medication, and botanicals are not as well-studied. As a treatment for serious burns, the use of bromelain-containing products should be considered when used as an aid in the process of debridement. Otherwise, perhaps the pineapple should remain in the Hawaiian drinks with the umbrella. n Bromelain-containing products may aid in the process of debridement.

Adverse events with bromelain were usually mild and were resolved by lowering the dose or discontinuing treatment.

How supplied, dose, cost

References 1. National Institutes of Health National Center for Complementary and Integrative Health. Bromelain. https://nccih.nih.gov/health/bromelain. August 2014. 2. Rosenberg L, Lapid O, Bogdanov-Berezovsky A, et al. Safety and efficacy of a proteolytic enzyme for enzymatic burn debridement: a preliminary report. Burns. 2004;30(8):843-850. 3. Akhtar NM, Naseer R, Farooqi AZ, et al. Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee—a doubleblind prospective randomized study. Clin Rheumatol. 2004;23(5):410-415. 4. Kleef R, Delohery TM, Bovbjerg DH. Selective modulation of cell adhesion molecules on lymphocytes by bromelain protease 5. Pathobiology. 1996;64(6):339-346. 5. Müller S, März R, Schmolz M, et al. Placebo-controlled randomized clinical trial on the immunomodulating activities of low- and high-dose bromelain after oral administration—new evidence on the anti-inflammatory mode of

Summary

action of bromelain. Phytotherapy Res. 2013;27(2):199-204. 6. Dawson J, Linsell L, Doll H. Assessment of the Lequesne index of severity for osteoarthritis of the hip in an elderly population. Osteoarthritis Cartilage. 2005;13(10):854-860. 7. Báez R, Lopes MT, Salas CE, Hernández M. In vivo antitumoral activity of stem pineapple (Ananas comosus) bromelain. Planta Med. 2007;73(13):1377-1383. 8. Pavan R, Jain S, Singh S, Kumar A. Properties and therapeutic application of bromelain: a review. Biotech Res Int. 2012;2012:976203. 9. Brien S, Lewith G, Walker A, et al. Bromelain as a treatment for osteoarthritis: a review of clinical studies. Evid Based Complement Alternat Med. 2004;1(3):251-257.

The role of bromelain in alternative medicine is certainly intriguing, but it requires larger,

All electronic documents accessed May 5, 2016.

Human clinical trials to ascertain the optimal dose of bromelain, especially in inflammatory arthritis, have shown efficacy beginning at as little as 160 mg/day.9 Although higher doses are used frequently, the incidence of side effects appears to be dose-dependent, with more frequent reports of adverse effects at higher dose ranges. Bromelain is available in tablets or capsules, and the cost is as little as $5 per month for the low- to mid-dose ranges.

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COMMENTARY Jim Anderson, MPAS, PA-C, ATC, DFAAPA, is a physician assistant in Seattle.

The bravery of people with dementia People with dementia are some of the bravest people I have ever known. My mom and dad succumbed to Alzheimer’s disease, and lately I’ve been thinking about their courage as they moved through the disease process. My father’s birthday was on March 23rd — he would have been 91 years old. In his prime, he was a skilled woodworker, sometimes spending hours each day in his shop making tables, chairs, frames, and decorative novelty items. He loved to give away his work, and I think he also loved the time alone to create and reflect. As he got sicker, his work changed dramatically, moving toward a more

I hope I have the same courage as I move through the inevitable end—the courage to urgently create and comfort others in the face of loss.

crude style. He knew he was changing — that his brain was wearing out — but he showed a gritty determination to continue to build and create to the end. Although some of his family was saddened by this, I found it inspiring and uplifting, almost celebratory. My wife Pat and I try to keep reminders around the house of the heroic way my dad worked throughout the disease. There are 2 examples that Pat and I look at every day that capture this spirit. One is a birdhouse that he put together from a kit. To think of him making this through the fog of his dementia is so moving. The other reminder we have is a fort he put together. He created a wild structure, complete with stairs leading to nowhere, asymmetrical little rooms, and a welcome sign on the front. The result makes me smile every single day I see it in my bedroom. My mom’s courage took a different form. Her decline was pretty fast, although similar to many families, we looked away during the early stages, denying what we probably knew at some level. When she first moved to a nursing home, she was upset. But in a matter of days, she had a renewed spark — the same spark that had led her through life. I went to visit her soon afterward and was invited to join her for a meal. When I approached her at the table, she leapt to her feet in the same way that someone would introduce the Queen of England to guests.

“Everybody, I would like to introduce you to my son Jim Anderson!” she said — the same Jim Anderson who, much to her chagrin, had brought her here just a few days earlier. To have such grace and forgiveness in such circumstances reflected an immense amount of bravery. Later, she would spend some time in a geriatric psychiatry unit. This was late in her dementia; at this point, she was having great difficulty communicating, although there were occasional, brief interludes of alertness. One of the nights my wife and I visited, Mom was lying in bed, not looking very human — just flat and detached. I sat on the bed next to her and stroked her hair. “Mom, I’m really, really sorry about all of this,” I said. There was a pause and then she rallied some amazing energy, from out of nowhere. She looked right at me, smiled softly, shrugged, and said with smiling resignation, “Well, what can ya do?” Then she drifted back away to wherever people with dementia go. Who knows what they were seeing and thinking? Maybe nothing, maybe something, but I like to think they see colors, hear music, and see a pastiche of all the things, people, and pets that they have loved. I hope I have the same courage as I move through the inevitable end—the courage to urgently create in the face of loss and the courage to comfort others even when they are struggling. n

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