January 2018 Clinical Advisor by The Clinical Advisor

THE CLINICAL ADVISOR • J ANUARY 2018

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■■Hormone therapy ■■Urinary tract infections ■■Atrial fibrillation and stroke FEATURE

Noninvasive screening for colorectal cancer LEGAL ADVISOR

Dosage change and a lawsuit

n Dermatologic Look-Alikes

A BILATERAL, ITCHY RASH PAGE 53

✶ FREE CME COURSE!

VOLUME 21, NUMBER 1

n Feature

INJECTED DRUG USE AND HCV PAGE 34

JANUARY 2018

| www.ClinicalAdvisor.com

PREVENTING THE SPREAD OF

HPV INFECTION The risk of male-to-female transmission of HPV is significant.

Editor Colby Stong editor@clinicaladvisor.com Associate editor Madeline Morr Assistant editor Rita Aghjayan

Unsure about a diagnosis or treatment?

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

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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

NSULTA

PEARLS

NTS

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.

SEND TO The Clinical Advisor 275 7th Avenue, 10th floor New York, NY 10001

62 THE CLINI

AdvisorForum_

CA0915

E-MAIL editor@clinicaladvisor.com

4 THE CLINICAL ADVISOR • JANUARY 2018 • www.ClinicalAdvisor.com

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

SOR • SEPTE

MBER 2015

Abimbo la Farinde

, PhD,

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

• www.Clinic

alAdvisor.c

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.

.indd 62

9/29/15

2:44 PM

CONTENTS JANUARY 2018

NEWS AND COMMENT 16

Newsline ■■The USPSTF has released its final recommendation statement on the use of menopausal hormone therapy for the primary prevention of chronic conditions, as published in JAMA. ■■The USPSTF has issued a series of draft recommendations on osteoporosis screening in US adults aged 50 years or older. ■■Symptomatically treating uncomplicated lower urinary tract infections with NSAIDs decreases antibiotic usage but not symptom relief time, according to a study in the BMJ. ■■Coffee consumption appears to be generally safe and is more likely to be beneficial than harmful, with peak benefits associated with drinking 3 to 4 cups per day. ■■Direct acting oral anticoagulants, especially apixaban, prevent strokes better than warfarin in patients with atrial fibrillation, researchers reported.

Noninvasive colorectal cancer screening 24

CME Feature posttest

DEPARTMENTS

A painless, non-itchy rash on the leg 51

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

Dermatology Clinic n Papules on the soles of the feet of an infant n A painless and non-itchy rash on a woman’s lower leg

Continues on page 6

Preventing human papillomavirus in males The importance of male vaccination cannot be overemphasized, because the risk of male-to-female HPV transmission is significant.

MAKING CONTACT

34 CME A 29-year-old man with a history of injected drug use The opiate epidemic has dramatically increased cases of hepatitis C virus. This case reviews the challenges in determining optimal treatment. 44

FEATURES 9 1

Noninvasive colorectal cancer screening The FIT and the MT-sDNA are evidence-based tests that should be considered for CRC screening when a colonoscopy cannot be performed.

Legal Advisor: a dosage change and lawsuit 60

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CONTENTS 53

Dermatologic Look-Alikes A bilateral, itchy rash

Legal Advisor A dosage change over the phone

ADVISOR FORUM 46

Your Comments ■ Referral to a psychiatric provider

My Most Memorable Patient ■ Signs of physical abuse in a patient

Case Files ■ Pulsatile tinnitus: a pounding sound inside the ear

Consultations ■ Treatment for a patient with an epididymal cyst

“I’m getting your dear, departed husband—he can’t believe you paid forty-five dollars for this.”

“No, Barry, I want you to help bury the evidence.”

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■ Hormone therapy ■ Urinary trac ■ Atrial fibr t infections illation and stroke FEATURE

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Dosage cha nge

and a lawsuit

■ Dermatolo gic Look-Alik

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

es A BILATERA RASH PAGE L, ITCHY 53

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21, NUM BER 1

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Noninvasiv e screening for colorect al cancer

■ Feature

INJECTED AND HCV DRUG USE PAGE 34

ION ERS

JAN UARY

2018

| www.Clinic alA

dvisor.com

PREVEN TING TH E SPREAD OF

HPV INFEC

TION The risk male-to-fem of transmissio ale n of HPV is sign ificant.

DEPARTMENTS cont’d

EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com Web Exclusives

Multimedia

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ClinicalAdvisor.com/Multimedia

Low-fat diets may reduce all-cause mortality risk in obese patients Researchers from the University of Aberdeen in Scotland found evidence that weight-reducing diets for adults with obesity were associated with an 18% reduction in premature mortality. Reduced effectiveness of last season’s flu vaccine traced to mutation in chicken eggs The limited effectiveness of the 2016-2017 influenza vaccine may be due to a glycoprotein mutation in fertilized chicken eggs, resulting in 43% effectiveness. Oral insulin does not prevent type 1 diabetes in relatives of patients A series of trials were conducted to determine if oral insulin could help family members of patients with type 1 diabetes prevent or delay the development of the disease.

Type 2 diabetes may be reversed with weight loss, physician care New research from Newcastle University suggests type 2 diabetes can be reversed in less than a year with the help of a significant weight loss program as well as physician care. Watch the video here: ClinicalAdvisor.com/DiabetesWeightLossVideo Clinical Quiz: Diagnosing and managing ADHD Take our latest quiz and test your knowledge about attention-deficit/ hyperactivity disorder (ADHD). Take the quiz here: ClinicalAdvisor.com/ADHDClinicalQuiz

The Waiting Room Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Sharon M. O’Brien, MPAS, PA-C Dermographism: Writing on the skin The cause of dermatographic urticaria is unknown but appears to be related to a mast cell abnormality and is probably autoimmune in nature.

Cartoon Archive The Clinical Advisor’s monthly cartoons are also available online. ClinicalAdvisor.com/cartoons

Sean P. L’Huillier, MS, APRN, FNP-C, CEN Managing pain in primary care Clinicians should have an open avenue of discussion with their patients about the expectations of pain management in primary care. Sean P. L’Huillier, MS, APRN, FNP-C, CEN It’s going to be a bad day How do we encourage non-compliant patients to follow our perfectly crafted plans that optimize multimodal therapy?

MAKING CONTACT

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14 THE CLINICAL ADVISOR • JANUARY 2018 • www.ClinicalAdvisor.com

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Advisor Dx

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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

TheJopa.org

Journal of Orthopedics for Physician Assistants

Severe pelvic pain after childbirth A 19-year-old woman complains of severe pain in her pelvis after a vaginal delivery of her first child. One day after her delivery, she is unable to get out of bed due to the pain. On examination, she has no loss of sensation or motor weakness in the lower extremities. WHAT IS THE NEXT STEP IN TREATMENT?

• Non-weight bearing • Partial weight bearing • Weight bearing as tolerated • Open reduction and internal fixation ● See the full case at ClinicalAdvisor.com/OrthoDx_Jan18

Derm Dx Pink plaques and crusting ulcerations A 53-year-old Caucasian woman with a history of hypertension, post-traumatic stress disorder, substanceinduced mood disorder, borderline personality disorder, alcohol abuse, and amphetamine dependence presents with painful wounds on the bilateral antecubital fossa. CAN YOU DIAGNOSE THIS CONDITION?

• Hidradenitis suppurativa • Cutaneous anthrax • Neurotic excoriation • Skin popping ● See the full case at ClinicalAdvisor.com/DermDx_Jan18

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2018 15

Newsline J A N U A RY 2 018

Treating urinary tract infections in women page 18

Drinking coffee provides perks for health page 18

Preventing stroke in patients with atrial fibrillation page 18

THE US Preventive Services Task Force (USPSTF) has released its final recommendation statement on the use of menopausal hormone therapy for the primary prevention of chronic conditions, as published in JAMA. For the use of combined estrogen and progestin hormone therapy, the USPSTF found convincing evidence that combination therapy is associated with moderate harms, including increased risk of invasive breast cancer and venous thromboembolism, and a small to moderate harm of increased risk of coronary heart disease. The USPSTF also found adequate evidence of other moderate harms, such as

increased risk of stroke, dementia, gallbladder disease, and urinary incontinence. Therefore, the USPSTF recommends against the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal women. The USPSTF found adequate evidence that use of estrogen alone is associated with moderate harms, including an increased risk of stroke, dementia, gallbladder disease, urinary incontinence, and venous thromboembolism. The task force recommends against the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal women who have had a hysterectomy.

Hormone therapy in postmenopausal women

The USPSTF found convincing evidence that combination therapy is associated with moderate harms.

This recommendation statement applies to asymptomatic, postmenopausal women who are considering hormone therapy for the primary prevention of chronic medical conditions. It does not apply to women who are considering hormone therapy for the management of menopausal symptoms, such as hot flashes or vaginal dryness. It also does not apply to women who have had premature menopause (primary ovarian insufficiency) or surgical menopause.

USPSTF recommends osteoporosis screening in women 65 and older THE US PREVENTIVE Services Task Force (USPSTF) has released a series of draft recommendations on osteoporosis screening in US adults aged 50 years or older. The USPSTF found convincing evidence that screening with bone mineral testing can detect osteoporosis and that treatment of women with osteoporosis can provide at least a moderate benefit in preventing fractures in women aged 65 years and older as well as postmenopausal women younger than 65 years at increased risk for osteoporosis. The USPSTF found inadequate evidence on the benefits and harms of treating screen-detected osteoporosis to reduce the risk of osteoporotic fractures in men. The task force also found convincing evidence that bone measurement tests are accurate for predicting osteoporotic fractures in both women and men. The most commonly used test is

central dual-energy X-ray absorptiometry (DXA) of the hip and lumbar spine. Although several bone measurement tests similarly predict the risk of fracture, DXA directly measures bone mineral density, and most treatment guidelines use central DXA to define osteoporosis and the treatment threshold to prevent osteoporotic fractures. The USPSTF found adequate evidence that clinical risk assessment tools are moderately accurate in identifying the risk of osteoporosis and osteoporotic fractures. The task force found no studies that described harms of screening for osteoporosis in men or women. Based on the nature of screening with bone measurement tests and the low likelihood of serious harms, the USPSTF found adequate evidence to identify these harms as low risk. Harms associated with screening may include radiation exposure from DXA and opportunity costs, such as time and effort required by the patient.

16 THE CLINICAL ADVISOR • JANUARY 2018 • www.ClinicalAdvisor.com

SYMPTOMATICALLY treating uncomplicated lower urinary tract infections (UTIs) with nonsteroidal anti-inflammatory drugs (NSAIDs) decreases antibiotic usage but not symptom relief time, according to a study in the BMJ. Computer-generated randomization was used to distribute either diclofenac (133 women) or an antibiotic treatment containing norfloxacin (120 women). In the primary outcome, 72 women on diclofenac (54%) reported that their symptoms were resolved on day 3, and 96 women on norfloxacin (80%) had symptom resolution in the same time (risk difference, 27%). The median symptom resolution time for

Women who took an NSAID were 27% less likely to have symptom relief by day 3 and 12% less likely after day 7 compared with those on antibiotic therapy.

patients taking diclofenac vs norfloxacin was 4 days and 2 days, respectively (hazard ratio, 1.64). At day 30, 82 women (62%) in the diclofenac group and 118 (98%) in the norfloxacin group had taken an antibiotic for their UTI. Of the 82 women taking diclofenac, 71% took an antibiotic during the first 3 days. Fosfomycin was optionally administered as a rescue antibiotic, taken by 95% of the women who took an antibiotic from the diclofenac group. Women who took an NSAID were 27% less likely to have symptom relief by day 3 and 12% less likely after day 7 compared with the women taking the antibiotic treatment.

Stroke prevention in atrial fibrillation DIRECT ACTING ORAL anticoagulants (DOACs), especially cost-effective apixaban, prevent strokes better than warfarin in patients with atrial fibrillation, according to a study in the BMJ. Researchers included 23 randomized trials (94,656 patients; median age, 70) that focused on 3 direct factor Xa inhibitors and 1 direct factor II inhibitor. Treatment ranged from 3 to 30 months. Apixaban (5 mg twice daily), dabigatran (150 mg twice daily), edoxaban (60 mg once daily), and rivaroxaban (20 mg once daily) were compared with warfarin. Apixaban (odds ratio [OR], 0.79), dabigatran (OR, 0.65), edoxaban (OR, 0.86), and rivaroxaban (OR, 0.88) all reduced stroke or systemic embolism risks,

Using DOACs compared with warfarin reduced allcause mortality risk and major intracranial bleeding risk but increased gastrointestinal bleeding.

compared with warfarin. Stroke or systemic embolism risks were greater in patients taking edoxaban (OR, 1.33) and rivaroxaban (OR, 1.35) compared with dabigatran. When compared with warfarin, all 4 non-vitamin K antagonists reduced bleeding risks, although bleeding risks were higher in patients taking dabigatran 150 mg twice daily or rivaroxaban 20 mg once daily than in patients taking apixaban 5 mg once daily. Using DOACs compared with warfarin reduced all-cause mortality risk and major intracranial bleeding risks but increased gastrointestinal bleeding in patients with atrial fibrillation. The cost effectiveness analysis resulted in all DOACs rating higher than warfarin.

18 THE CLINICAL ADVISOR • JANUARY 2018 • www.ClinicalAdvisor.com

Coffee linked to potential health benefits COFFEE consumption appears to be generally safe and is more likely to be beneficial than harmful, with peak benefits associated with drinking 3 to 4 cups per day, according to a study published in the BMJ. Researchers found that coffee consumption was beneficial for multiple health outcomes, including: type 2 diabetes, oral cancer, cirrhosis, renal stones, Parkinson disease, leukemia, mortality after myocardial infarction, gout, liver cancer, and chronic liver disease. The highest exposure of coffee consumption (7 cups a day) was linked to a 10% lower risk for all-cause mortality (relative risk, 0.90). However, the largest relative risk reduction was linked to consuming 3 cups a day (0.83). Coffee was not significantly associated with harmful health outcomes. However, the highest relative risk estimates were in acute childhood leukemia, lung cancer, pregnancy loss, rheumatoid arthritis, low birth weight, lymphoma, laryngeal cancer, first trimester preterm birth, third trimester preterm birth, and oral cleft malformation. The investigators observed inconsistencies regarding harmful associations of coffee consumption with health outcomes related to pregnancy. Compared with low coffee consumption, high consumption was linked with a higher risk for pregnancy loss (odds ratio, 1.46) and low birth weight (odds ratio, 1.31). n

Urinary tract infections in women

FEATURE: PATRICIA A. OBULANEY, DNP, RN, ANP-C; LYDIA T. MADSEN, PHD, RN, CNS;

KRISTIN OWNBY, PHD, RN, ACHPN, AOCN, CNS-BC

Preventing human papillomavirus in males The importance of male vaccination cannot be overemphasized, because the risk of male-to-female HPV transmission is significant.

he efforts of the healthcare community to promote female human papillomavirus (HPV) vaccination and reduce the incidence of cervical cancer have overshadowed the importance of male HPV immunization. A need for greater emphasis on promoting male vaccination for HPV was magnified through the recent results of the 2013-2014 National Health and Nutrition Examination Survey (NHANES), which brought to light the importance of protecting males against HPV.1 In a subset of 1,868 men, the overall genital HPV infection prevalence was 45.2%, and the highrisk oncogenic HPV prevalence was 29.5%.1 Per NHANES, the oral HPV infection rate among males is 11.5%, which translates to 11 million men and is three times the prevalence rate of female oral HPV infection.2 The Centers for Disease Control (CDC) estimates that 74% of the 19.7 million new sexually transmitted infections in the United States each year are HPV infections.3

HPV and associated cancers

HPV can affect the hands, feet, mucous membranes, and genitals.

Eight HPV genotypes—HPV 16, 18, 31, 33, 35, 45, 52, and 58—have been identified as oncogenic; that is, these genotypes have an increased risk of mutating into cancer.4 HPV 16 and 18 are the genotypes most commonly associated with the development of anal, oropharyngeal, penile, cervical, vaginal, and vulvar cancers.5 Although all cases of HPV exposure and infection do not result in cancer development, the HPV vaccine series provides hope for significant long-term

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2018 19

PREVENTING HUMAN PAPILLOMAVIRUS IN MALES

For optimal effectiveness, HPV immunization should be offered to all adolescents at age 11 or 12 years or before the onset of sexual intimacy. reduction of HPV-related cancer incidence among males and females. For optimal vaccine effectiveness, HPV immunization should be offered to all adolescents at age 11 or 12 years or before the onset of sexual intimacy.6 The most recent estimates show that 42% of adolescent boys have received one or more doses of the HPV vaccine, an increase of 8% from the 2013 National Immunization Survey–Teen estimates for boys.7 These statistics reflect a very gradual increase in HPV vaccine uptake. However, it is notable that with currently fewer than 50% of males being vaccinated, a segment of the male population annually ages out of the recommended age vaccine cohort but remains at risk for exposure and uptake of all HPV genotypes. Current data suggest that HPV infection rates in young males may range from 45% to 93% when both low- and high-risk populations are considered.8 The importance of recommending male vaccination cannot be overemphasized, because the risk of male-to-female HPV transmission is significant. A recent meta-analysis examining HPV concordance among heterosexual couples indicated that HPV is more readily transmissible from infected males to females than the reverse.9 HPV vaccine recommendations

In October 2011, the CDC began recommending that adolescent males receive the HPV vaccine. In February 2015, the CDC incorporated the recently approved HPV9 vaccine in the recommendations for HPV prevention, thus rendering HPV9 or HPV4 vaccines accessible and approved for males.10 For a vaccine schedule initiated at age 11, the second dose is recommended 6 to 12 months after the initial dose (see Table 1). In instances in which the providers do not

know which HPV vaccine was previously administered, the HPV vaccine available to the provider may be administered to continue or complete the series for males; if the vaccine schedule is interrupted, the series does not need to be restarted.10 In May 2017, HPV9 became the only HPV vaccine available in the United States.11 Most recent updates from the CDC11 now recommend that when administered to adolescents between the ages of 11 and 14 years, two doses of the vaccine, at least 6 months apart, provide effective protection; however, teens who begin the series at age 15 must complete the 3-dose series.11 Heterosexual males must complete the series by age 21. Special populations

Men who have sex with men (MSM), transgender persons, and certain immunocompromised males are a subgroup of males with an even higher risk for contracting HPV; oncogenic subtypes of HPV are transmitted via anal intercourse, penetrating the anogenital mucosa and leading to infection and possibly anal cancer. The incidence of HPV is higher in individuals who engage in anal intercourse, especially the receptive partner.12 The average age of disclosure of sexual orientation among MSM is the early 20s, and most MSM have had an average of 8 sexual partners by the time they disclose their sexual orientation.12 Moreover, the prevalence of HPV in MSM may be as high as 30%, compared with approximately 8% in heterosexual men.13 Because of the strong relationship among HPV, anal intercourse, and anal cancer, current CDC guidelines for HPV vaccination differ for MSM and their heterosexual counterparts because MSM have an increased risk for contracting HPV and not clearing the virus. For MSM who Continues on page 22

TABLE 1. Current HPV vaccine recommendations from the CDC Ages

Gender

Modifiers

Dosing

9 to 14

Males and females

None

2 doses with second shot given within 6 to 12 months

9 to 26

Males and females

Immunocompromised

3 doses within 6 months

15 to 26

Males

Transgender, bisexual, MSM

3 doses within 6 months

15 to 21

Males

Heterosexual

3 doses within 6 moths

20 THE CLINICAL ADVISOR • JANUARY 2018 • www.ClinicalAdvisor.com

PREVENTING HUMAN PAPILLOMAVIRUS IN MALES

were not vaccinated as adolescents or did not complete the 3-dose series, the CDC recommends HPV vaccination up to age 26 years.14 The guidelines are different for MSM who are infected with the human immunodeficiency virus (HIV). According to current CDC guidelines, persons with an immunocompromising disease such as HIV need to receive the 3-vaccine series.15 As their immune function declines, patients with HIV have an even greater risk for developing an HPVrelated cancer. One concern about administering the HPV vaccine to HIV-positive young adult men is the potential diminished immune response to the vaccine. Although data are limited, one study of 109 HIV-positive men aged 18 years or older found the quadrivalent HPV vaccine safe, without appreciable effect on the subjects’ CD4 cell counts or viral loads, and highly immunogenic, with seroconversion rates of 95%.16 Vaccine promotion in the clinical setting

Missed opportunity is a significant impediment to HPV vaccination in the male adolescent population. Bernstein and Bocchini17 noted that 65% of parents never received a recommendation for their child to receive the HPV vaccine, although provider recommendation has been shown to have a very positive influence on vaccination uptake.18 In a national survey, 600 men aged 18 to 59 years were asked about their willingness to be vaccinated against HPV. The results revealed that 60% wanted to receive the vaccine when told it could prevent cancer, compared with 42% who were willing to receive the vaccine when told it

would protect only against genital warts. The study results emphasized the importance of healthcare providers educating parents and young male adults that HPV vaccination is a cancer prevention measure.19 Another study recently reported that a 3-dose regimen of the 4-valent HPV vaccine was immunogenic, clinically effective, and generally well tolerated in preadolescents and adolescents throughout 10 years of follow-up.20 Although routine vaccinations and follow-ups continue to occur during childhood and adolescence, the opportunity may be missed for providers to emphasize the value of HPV vaccine as cancer prevention of males and females during these visits. Recent studies indicate that HPV vaccines can be safely administered when giving routine adolescent immunizations such as tetanus, diphtheria, pertussis, and meningococcal.21 When advising young males and their parents to consider HPV vaccination, providers should remind them that men continue to be susceptible to HPV infection with increasing age.19 ■ Patricia A. Obulaney, DNP, RN, ANP-C, is an assistant professor, clinical; Lydia T. Madsen, PhD, RN, CNS, is an assistant professor, clinical; and Kristin Ownby, PhD, RN, ACHPN, AOCN, CNS-BC, is an associate professor, clinical, Department of Acute and Continuing Care, Cizik School of Nursing, University of Texas Health Science Center at Houston. References 1. Han JJ, Beltran TH, Song JW, Klaric J, Choi S. Prevalence of genital human papillomavirus infection and human papillomavirus vaccination rates among US adult men: National Health and Nutrition Examination Survey (NHANES) 2013-2014. JAMA Oncol. 2017;3:810-816.

POLL POSITION

2. Sonawane K, Suk R, Chiao EY, Chhatwal J, Qiu P, Wilkin T, et al. Oral

Which of the following statements do you most agree with?

human papillomavirus infection: differences in prevalence between sexes and concordance with genital human papillomavirus infection, NHANES 2011 to 2014. Ann Internal Med. 2017;167:714-724. 3. CDC. Sexually transmitted infections in the United States. Available at:

■ I frequently have difficulty with parents agreeing to have their sons receive the HPV vaccine. ■ I frequently have difficulty with parents agreeing to have their daughters and sons receive the HPV vaccine.

13.36%

https://www.cdc.gov/nchhstp/newsroom/2013/sti-graphics.html 4. Guo M, Lin CY, Gong Y, Cogdell DE, Zhang W, Lin E, et al. Human papillomavirus genotyping for the eight oncogenic types can improve

53.07%

specificity of HPV testing in women with mildly abnormal Pap results. 33.57%

■ I have seen an increase in HPV vaccine rates during the past 5 years.

For more polls, visit ClinicalAdvisor.com/Polls.

Mod Pathology. 2008;21:1037-1043. 5. Marklund L, Hammarstadt L. Impact of HPV in oropharyngeal cancer. J Oncol. Available at: http://citeseerx.ist.psu.edu/viewdoc/download;jsessio nid=FEA8D1D0581A9F5C3B47F3E2A3D33327?doi=10.1.1.292.6471&rep =rep1&type=pdf 6. CDC. HPV (Human papillomavirus) VIS. Available at: https://www.cdc. gov/vaccines/hcp/vis/vis-statements/hpv.html

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7. CDC. Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the Advisory Committee on Immunization Practices. Available at: https://www.cdc.gov/mmwr/preview/ mmwrhtml/mm6411a3.htm 8. Smith JS, Gilbert PA, Melendy A, Rana RK, Pimenta JM. Age-specific prevalence of human papillomavirus infection in males: a global review. J Adolesc Health. 2011;48:540–552. 9. Schuler CL, DeSousa NS, Coyne-Beasley T. Parents’ decisions about HPV vaccine for sons: the importance of protecting sons’ future female partners. J Community Health. 2014;39:842–848. 10. CDC. VFC-ACIP vaccine resolutions. Available at: http://www.cdc.gov/ vaccines/programs/vfc/providers/resolutions.html 11. CDC. HPV vaccine for preteens and teens. Available at: https://www.cdc.gov/vaccines/parents/diseases/teen/hpv.html 12. Chin-Hong PV, Vittinghoff E, Cranston RD, Browne L, Buchbinder S, Colfax G, et al. Age-related prevalence of anal cancer precursors in homosexual men: the EXPLORE study. J Natl Cancer Inst. 2005;97:896-905.

“If you don’t get on that plane … there’s also the 5:43, then the 9:27, but that’s got a layover in Atlanta, then …”

13. Goldstone S, Palesfsky JM, Giuliano AR, Moreira ED, Aranda C, Jessen H, et al. Prevalence of and risk factors for human papillomavirus (HPV) infection among HIV-seronegative men who have sex with men. J Infect Diseases. 2011;203;66-74. 14. Petrosky E, Bocchini JA Jr, Hariri S, Chesson H, Curtis CR, Saraiya M, et al. Use of 9-valent human papillomavirus (HPV) vaccine: updated Immunization Practices. MMWR Morb Mortal Wkly Rep. 2015;64:300-304. 15. CDC. HPV vaccines: vaccinating your preteen or teen. Available at: https://www.cdc.gov/hpv/parents/vaccine.html 16. Wilkin T, Lee JY, Lensing SY, Stier EA, Goldstone SE, Berry JM, et al. Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in HIV-1 infected men. J Infect Dis. 2010;202:1246-1253. 17. Bernstein HH, Bocchini JA Jr, Committee on Infectious Diseases. The need to optimize adolescent immunization. Pediatrics. 2017;139(3). doi: 10.1542/peds.2016-4168 18. Ylitalo KR, Lee H, Mehta NK. Health care provider recommendation, human papillomavirus vaccination, and race/ethnicity in the US National Immunization Survey. Am J Public Health. 2013;103:164-169. 19. McRee AL, Reiter PL, Chantala K, Brewer NT. Does framing human papillomavirus vaccine as preventing cancer in men increase vaccine acceptability? Cancer Epidemiol Biomarkers Prev. 2010;19:1937-1944. 20. Ferris DG, Samakoses R, Block SL, Lazcano-Ponce E, Restrepo JA, Mehlsen J, et al. 4-Valent human papillomavirus (4vHPV) vaccine in preadolescents and adolescents after 10 years. Pediatrics. 2017;140(6). pii: e20163947. doi: 10.1542/peds.2016-3947. 21. Walker TY, Elam-Evans LD, Singleton JA, Yankey D, Markowitz LE, Fredua B, et al. National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 years—United States, 2016. MMWR Morb Mortal Wkly Rep. 2017;66:874-882. Available at: https:// www.cdc.gov/mmwr/volumes/66/wr/mm6633a2.htm

“Hold on. I’ve got a call on my other wrist.”

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2018 23

HPV vaccination recommendations of the Advisory Committee on

FEATURE: AMANDA N. STRAIN, MSN, CCRN, FNP-C; CHARLOTTE C. WALING, MSN, FNP-C; FELICIA D. STEWART, DNP, NP-C, RN-BC

Noninvasive colorectal cancer screening The FIT and the MT-sDNA are evidence-based tests that should be considered for CRC screening when a colonoscopy cannot be performed.

Colored SEM of rectal adenocarcinoma cells (blue).

he second leading cause of cancerrelated deaths in the United States is colorectal cancer (CRC).1 The US Preventive Services Task Force2 anticipated that 134,000 people would be diagnosed with, and 49,000 people would die from, CRC in 2016 alone. CRC has a 90% 5-year survival rate when it is diagnosed early.1 Unfortunately, only 40% of people have CRC identified at an early, treatable stage.1 There is compelling evidence that CRC screening in asymptomatic adults from 50 to 75 years of age significantly reduces the mortality associated with CRC. A colonoscopy remains the “gold standard” in colorectal screening tests, but as many as 1 in 3 Americans, or more than 20 million people, do not adhere to their healthcare provider’s recommendation to have a screening colonoscopy.3 For example, if someone of average risk between the ages of 50 and 75 years is resistant to having a colonoscopy, are there other viable options providers can offer patients? Two stool tests to consider for colorectal screening include the fecal immunochemical test (FIT) and the multitarget stool deoxyribonucleic acid (MT-sDNA) test. The American Cancer Society4 reports that patients find these tests more attractive than a colonoscopy because of the limited preparation required and the convenience of completing the test at home. The FIT requires a small sample of stool in a test tube or card and uses antibodies to detect hemoglobin (Hgb) in the stool.4 The MT-sDNA test Continues on page 26

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NONINVASIVE COLORECTAL CANCER SCREENING

The fecal immunochemical test (FIT) requires a small sample of stool in a test tube or card and uses antibodies to detect hemoglobin in the stool. requires a full stool sample and analyzes the stool specimen for DNA markers that signal neoplastic changes.4 Both test samples must be sent to a laboratory for testing. Purpose

The purpose of this literature review is to explore the published evidence regarding the efficacy of 2 CRC screening stool tests: the FIT and the MT-sDNA test. This information will assist clinicians in determining whether these tests can be considered in lieu of a screening colonoscopy when patients decline the gold standard recommendation. This topic deserves attention because of the discrepancy between the number of people who are given the recommendation for CRC screening and the number who actually follow through with it. If the newer, noninvasive tests are effective in screening for CRC, then this may offer more choices and result in increased numbers of patients obtaining CRC screening. Search strategy

The Cochrane Library was the initial database that was searched because of the clinical nature of the topic. We searched the database for “colon cancer screening” in the title, abstract, and keyword fields, with no limitation for publishing year. Six items resulted, but they were not pertinent to the focus of this review. Similar searches were conducted for the following keywords both alone and in combination: “colorectal cancer screening,” “colon cancer,” “fecal immunochemical,” “multitarget stool,” and “stool sample test.” Four reviews resulted for “fecal immunochemical.” One systematic review focused on the FIT alone and was saved for this literature review, but the 3 other results compared the FIT with guaiac-based fecal occult blood tests and were eliminated. Fecal occult blood tests are outside the focus of this literature review. Three clinical trial reports resulted for “multitarget stool,” but no systematic reviews. Ultimately, no systematic review was found in the Cochrane Library for the MT-sDNA test or for comparison between the FIT and the MT-sDNA test. Literature searches were then conducted for studies on the topic of CRC detection using either the FIT or the MT-sDNA test. The EBSCOhost database was used to search Academic Search Complete, CINAHL, and MEDLINE for articles published from 2012 to 2017. Searches used the following key terms and combinations of terms: “colorectal cancer screening,” “DNA stool,” “stool DNA test,” “multitarget stool,” “fecal immunochemical test,” “average risk,”

“systematic review,” and “cancer.” Initial searches were conducted without limiters. In cases in which there were thousands of results, records were filtered to include reviews and/or clinical studies. Once the search yielded fewer than 150 articles, titles and abstracts were reviewed to further narrow down the results. Studies that met all inclusion criteria were set aside for further review. The inclusion criteria applied to the searches were that the studies examined CRC detection rates of either the FIT or the MT-sDNA test, the articles were published in 2012 or after, and the studies used quantitative measures to describe their findings. Studies were not excluded because they incorporated additional qualitative data on study variables such as “ease of use.” Studies of single-biomarker stool DNA tests (brand names ColoVantage and ColoSure) were excluded because this review pertains to the MT-sDNA test, which is a multiple-biomarker test (brand name Cologuard). Although this review focuses on persons at average risk for CRC, studies were not excluded for providing data for persons at higher risk resulting from familial risk or past history of CRC. This review also focuses on persons between the ages of 50 and 75 years, but studies were not excluded for having narrower age ranges or being outside this range. The youngest individuals included in the studies were aged 40 years. Abstracts of the remaining articles were checked to ensure they matched the topic and were study reports, not opinion articles. A total of 13 published articles remained at the end of the literature search process for inclusion in this literature review. Summary of findings

The studies reviewed included a variety of designs such as blinded control studies, cross-sectional studies, and cohort studies. The study settings included hospitals and outpatient centers, as well as private homes for participants who were asked to mail in stool collection cards. Typically, either a FIT or a MT-sDNA test was collected from a participant before his or her colonoscopy to compare results between the 2 screening methods. Eleven studies (totaling 44,470 participants) evaluated FITs and/or MT-sDNA, testing for detection of CRC. Accuracy (correct screening result), sensitivity (true positives), and specificity (true negatives) were reported by all studies. Eleven studies provided probability values (P values). In addition, many of the studies addressed stool collection methods, patient

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The MT-sDNA test requires a full stool sample and analyzes the stool specimen for DNA markers that signal neoplastic changes. participation, test comfort/usability, and cost-effectiveness. This literature review also includes 2 systematic reviews. Studies took place in the United States, Canada, Italy, the Netherlands, and Spain, and participants were selected using similar criteria for age (40-85 years, with a median age range of 60-65 years) and degree of risk. An average risk level was defined as being asymptomatic and without familial risk (having a first-degree relative with CRC) and applied to 10 studies (24,259 of the participants). Four studies included participants at higher risk for CRC (defined as having a first-degree relative with CRC or the participant having had a previous neoplasm). Some studies accepted patients who had colonoscopies before participation in the study. Colonoscopy results varied and included both negative and positive results for neoplastic changes, depending on the focus of the particular study (ie, testing center proficiency or diagnostic sensitivity/specificity of a specific test). All studies included quantitative design, but some mixedmethod studies provided additional qualitative data regarding the participant’s experience and the screening product’s ease of use. Measures used in data analysis included Chi square (χ2) with a confidence interval (CI) of 95%, multivariate analysis, positive predictive value, and linear regression models. Evidence related to FITs

Seven studies investigated the sensitivity and specificity of the FIT for detecting advanced neoplasia (AN) and CRC.612 Variations existed in the collection method of samples (eg, single fecal samples vs multiple samples). A prospective

cohort study with 2959 participants at average risk for CRC was conducted for a period of 7 years, during which the FIT was completed 4 times.5 The authors found a high detection rate of AN in every round. Another study included 2 cohorts with different risk levels (average vs high risk) and found no significant difference in FIT results between the 2 groups.6 Considering both cohorts, overall FIT accuracy was high (88.4%-91.7%; P =.051), and the difference between the groups was not statistically significant. Similar findings occurred in 3 additional studies reviewed.7-9 The FIT was found to be moderately successful at screening for adenomas and sessile-serrated adenomas/polyps (SSA/Ps) but even better at detecting CRC.7 FIT was best at detecting CRC vs adenomas and SSA/Ps. The proximal vs distal and left-side vs right-side location of lesions also were found to affect FIT sensitivity.7,10 This finding was supported in a later study, which also noted that FIT sensitivity and specificity were affected by the morphology of the lesion detected: flat and nonhemorrhagic lesions (SSA/Ps) were less likely to be detected than adenomas.11 The systematic review and meta-analysis found FITs to have high levels of accuracy in detecting CRC.12 They also determined the FITs had high levels of specificity (94%) and moderately high levels of sensitivity (79%) in detecting CRC (depending on cutoff values for Hgb used by the particular FIT manufacturer). Several studies included qualitative data in addition to a quantitative approach. These areas focused on practical issues of patient comfort and usability, patient participation in screening, and sample analyzation methods (eg, manual vs automated).6,8,10,12

Evidence related to MT-sDNA tests

Specimen tubes in an automatic machine for FIT.

The MT-sDNA test was used to assess colorectal neoplasms and was found to have a CRC detection rate of 85%.13 The detection rate of advanced adenomas (AAs) was not as high as those found in a later study,14 but detection rates were found to be improved with an increase in adenoma size. The location of the nonmetastatic neoplasm did not affect detection rate. The clinical performance of the MT-sDNA test was the focus of a study including 1003 individuals with average CRC risk.14 This case-controlled study occurred in multiple test centers where specimens were analyzed to measure for 5 different DNA markers. Specific cutoff levels were used to determine either positive or negative scores for www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2018 27

NONINVASIVE COLORECTAL CANCER SCREENING

to detect CRC, but this may be absent in nonhemorrhagic SSA/Ps. The authors concluded that the 2 screening tools, FIT and MT-sDNA, were comparably effective in detecting CRC and other precancerous conditions of the colon. Discussion

Identifying mutations in the RAS gene, found in a high percentage of colorectal cancers, helps determine the best treatment.

detecting CRC, AAs, and SSA/Ps. Sensitivity for CRC was high (98%) regardless of cancer stage level; specificity was 90%. Detection of AA with high-grade dysplasia had 83% sensitivity. The authors’ conclusions identified MT-sDNA as an effective tool in early detection of CRC.14 Evidence related to comparison of FIT and MT-sDNA tests

The MT-sDNA test and FIT were compared in a study including 9989 average-risk participants.15 This study found that MT-sDNA tests were more sensitive than FITs in detecting CRC, AA, SSA/P, nonadvanced findings, or negative findings for cancer. However, MT-sDNA testing results required more follow-up colonoscopies because of their lower specificity than the FIT. Of the 9989 participants, 455 had positive MT-sDNA test results but negative results on follow-up colonoscopy compared with 162 participants with positive FIT results and negative results on colonoscopy. This indicates that MT-sDNA tests produced a higher number of false-positives than FITs. Specificity in FITs was found to be higher than in the MT-sDNA test results. Both screening tests were determined to be noninvasive and more cost-effective overall than colonoscopy. Another study reviewed (with 661 participants) identified MT-sDNA testing as being superior to FITs in detection of CRC.16 This study’s findings were similar with those from other studies: MT-sDNA tests had lower specificity rates than FITs. The MT-sDNA test was used along with the FIT to detect SSA/Ps (flat lesions that are difficult to detect with FIT alone) and was found to be effective in testing for the SSA/P biomarker, mBMP3.17 All FITs assess for Hgb concentration

Colorectal cancer screening continues to be an important field of research. For this literature review, several research studies were included on the use of the FIT and the MT-sDNA test as noninvasive options for colorectal cancer screening. Each of these tests has different levels of evidence to support their use and ability to detect cancerous and precursor lesions. This literature review was completed to provide more knowledge on the FIT and MT-sDNA test so providers can make evidence-based decisions on what screening option best suits their patients. Strengths

There were several strengths in the studies included in this literature review regarding the MT-sDNA. Both of the studies focused solely on average-risk participants, which represented diverse populations.13.14 One study intentionally collected stool samples from multiple test sites.13 The other study demonstrated uniform collection and analyses by obtaining samples before screening colonoscopies.14 Many strengths were also identified concerning the FIT. Several studies focused solely on average-risk participants.5,10,12 Other studies included average-risk participants, although not exclusively.6,7,9,11 One study assessed the average-risk population with 4 rounds of FIT testing.5 Grobbee et al included previously screened individuals and newly screened individuals in their study.9 Chang et al included asymptomatic individuals who completed a colonoscopy as part of a general health check-up not specific for CRC screening purposes.11 Two of the studies included high return rates of the tests and high compliance rates among participants.9,10 Grobbee et al reported an adherence rate for a colonoscopy after a positive FIT of 90%, so they were able to adequately compare their results.9 Levy et al achieved their original goal of 700 participants with returned FITs.10 Statistical significance was reached in the study completed by Cubiella et al.6 In addition, experienced gastrointestinal pathologists were used to avoid interobserver bias.7,11 Three articles included in this literature review are headto-head comparisons of the FIT and MT-sDNA test,15-17 and it is also important to note their strengths. One included a very large sample size of 9989 participants.15 Two included only average-risk participants.15,17 One study found that the

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Continues on page 30

NONINVASIVE COLORECTAL CANCER SCREENING

The FIT and MT-sDNA are approved by the FDA, US Preventive Services Task Force, and several other organizations for use as screening tests. FIT detected a majority of sessile serrated polyps despite a relatively narrow and small size range.17 Limitations

Limitations of the MT-sDNA studies included in this literature review are also important to mention. First, only 2 articles focused on the use of the MT-sDNA test alone.13,14 This is likely related to the MT-sDNA test being a relatively new technology. Another limitation is that certain important factors were not well-controlled in both of these studies. For instance, 1 study collected stool samples both before and after a colonoscopy.14 The other study collected archived stool samples in a buffer from different storage facilities, and storage procedures were inconsistent.13 One study featured a case-control design but did not include a validation set, which can result in an overestimation of the test performance.14 Other limitations to the studies reviewed pertain to pathology measurements not always being available, the quality of the colonoscopy not being controlled, and the use of the HemoQuant, which can detect both upper and lower gastrointestinal bleeding (possibly skewing results).13 Limitations regarding the FIT studies were also noted. First, a lack of diverse populations proved to be a limit for some studies. Chang et al included only participants of Chinese descent,11 and de Wijkerslooth et al noticed the majority of their participants were Caucasian.7 An inability to obtain information from 3 testing programs to assess FITs limited the generalizability of 1 study’s results.8 The inclusion of younger participants in the systematic review could lead to a bias.12 Not all study samples were limited to persons of average CRC risk, and inclusion of participants with high risk may limit the applicability of findings to the general population.6,7,9,11 One study demonstrated a high rate of compliance for the FIT screening test (60%-62%), but a low compliance rate with colonoscopy (22%), which made it difficult to compare and verify results.7 Another limitation exists when including voluntary participants who were not screening-naive. Chang et al included participants who volunteered for health check-ups and were concerned this may have led to selection bias with highersocioeconomic-status participants.11 Although Grobbee et al included 4 rounds of FIT testing, a different method was used in the final round, so participants were less familiar with it.9 Concerns regarding the accuracy of the specificity and sensitivity results represent another limitation: Having

a limited number of positive results (8 with CRC, 24 with isolated proximal AN, and 83 with isolated distal AN from 1256 total participants) may have affected the precision of estimates regarding FIT sensitivity in CRC screening and AN detection.7 Two studies included only 1 round of FIT screening to assess accuracy.7,10 This may underestimate the sensitivity of the FIT compared with studies including data from several screenings. The systematic review noted 7 studies with at least a 2-year longitudinal follow-up, which could have led to an overestimation of sensitivity and an underestimation of specificity.12 The same review also noted the inability to determine sensitivity and specificity of the FIT for proximal vs distal sites because most of the studies in their review did not include this information. Two of the 3 head-to-head studies with the FIT and MT-sDNA tests had limitations worth noting. These studies had small sample sizes (456 and 661, respectively) which interfered with being able to analyze their results.16,17 One sample only included the Native Alaskan population.16 Considerations and implications for practice

The goal of this literature review is to provide information on both the FIT and MT-sDNA test to assist providers in advising patients on other options for colorectal cancer screening in situations when patients refuse colonoscopy. To further understand the implications for the MT-sDNA test and FIT, it is important to evaluate the performance, cost, and ease of use by patients for each of the tests. Both tests are approved by the US FDA, US Preventive Services Task Force, and several other organizations for use as screening tests. With the MT-sDNA test, there is a high degree of detection for CRC as well as precancerous lesions. Lidgard et al reported the MT-sDNA’s high sensitivity and specificity in identifying CRC (98% and 90%, respectively).14 In addition, the MT-sDNA detected lesions at both proximal and distal sites, which supports its reliability. Some authors even suggest that the use of a MT-sDNA test before a colonoscopy may aid in the detection of proximal lesions that are often missed by conventional colonoscopy.14,17 SSAs and AAs can be detected by sDNA methylation markers. Neither colonoscopy nor FIT alone is sensitive enough to detect SSAs, which makes the sDNA methylation markers useful in CRC screening. Furthermore, the FIT was unable to detect sessile serrated polyps, whereas the sDNA test detected sessile serrated polyps ≥ 1 cm.17

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There is a valid concern with the MT-sDNA test regarding its lower specificity that may lead to a higher number of false-positive results. However, there are still questions that need answered to truly validate the MT-sDNA test. Storage and collection should be optimized and consistent. Further studies need to explore how inconsistent collection procedures affect the results of the test. Additional research efforts are also needed regarding testing intervals, costs, and patient acceptance and adherence. The manufacturer for the MT-sDNA test suggests its use every 1 to 3 years for CRC screening.2 A 3-year interval seems to provide reasonable performance at acceptable costs with lower patient, clinician, and administrative burdens compared with annual screening.18 The MT-sDNA test (Cologuard) had a negative predictive value of a single test event of 99.94% for CRC and 95% for advanced adenoma when using a multiyear testing interval.15 With these data, the presence of missed significant lesions before the next screening interval would be rare. There is a valid concern with the MT-sDNA test regarding its lower specificity that may lead to a higher number of false-positive results. Patients need to understand that a positive result warrants a follow-up colonoscopy. This could lead to additional cost and risk for the patient, as well as concern about screening compliance. Another consideration that is important to note is the lack of evidence regarding appropriate longitudinal follow-up of abnormal results after a negative diagnostic colonoscopy.2 With a positive MT-sDNA test and negative follow-up colonoscopy, unnecessary close surveillance could occur because of both patient and provider concerns over the genetic component of the test. The cost of the MT-sDNA test has been a concern voiced by many organizations and researchers. An analysis of the cost-effectiveness of Cologuard at intervals of 1, 3, or

5 years compared with no screening at all was performed.18 The cost-effectiveness ratio of the MT-sDNA test with these screening intervals concluded that all intervals were cost-effective relative to a conservative willingness-to-pay threshold of $25,000 per quality-adjusted life-year. The Cologuard cost-effectiveness ratio was found to be comparable to other common cancer screening tests such as an annual Papanicolaou smear and annual mammogram. Another analysis determined the FIT and colonoscopy to be more effective and less costly than the MT-sDNA test when participation rates were equal for all strategies.19 It was determined that the participation rate of using the MT-sDNA test would need to be substantially higher to be considered a cost-effective choice. Similar to the MT-sDNA test, the FIT is an evidence-based, noninvasive CRC screening test. However, it has been on the market for a longer period of time than the MT-sDNA test. The FIT has a high level of accuracy, high specificity, and moderately high sensitivity for detection of CRC.5,7,11,12 The sensitivity of the FIT in detecting proximal and distal adenomas was similar.7 In general, these studies support the use of FIT in detecting noninvasive, nonadvanced CRC, but there are concerns with the FIT’s ability to detect premalignant lesions.11 To increase the FIT’s detection of premalignant lesions (SSA/Ps), a strategy of multiple-round testing has been suggested.11 It also has been proposed that repeating FITs would likewise increase the diagnostic yield of CRC, and that completing 3 FITs over time instead of 1 would be beneficial.7,11 However, many researchers are concerned with the idea of multiple-round testing, noting that this strategy

TABLE 1. Mt-sDNA and FIT noninvasive screening tests for colorectal cancer Multi-target stool deoxyribonucleic acid (Mt-sDNA)

Fecal immunochemical test (FIT)

Samples

Requires a full stool sample and analyzes the stool specimen for DNA markers that signal change4

Requires a small sample of stool in a test tube or card and uses antibodies to detect hemoglobin (Hgb) in the stool4

Where to analyze specimen?

Must be sent to a laboratory for testing

Age of technology

Newer

On market longer

Concerns

Few studies comparing this to colonoscopy gold standard

Variety of brands (8) with different cutoff values for Hgb and differing sensitivity and specificity12

Cost

Most costly per test

FIT + colonoscopy found more effective and less costly than MT-sDNA when participation rates are equal.19 But if doing multiple rounds, can drive up cost and reduce compliance

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TABLE 2. Clinical trial results for Mt-sDNA and FIT Multi-target stool deoxyribonucleic acid (Mt-sDNA)

Fecal immunochemical test (FIT)

• Location of nonmetastatic neoplasm did not affect detection rate. • Sensitivity in detecting proximal and distal adenomas is similar to FIT.7

• Proximal vs distal and left side vs right side of lesions affected FIT sensitivity.7,10

• CRC detection rate of 85%13

• Moderately successful at screening for adenomas and sessile-serrated adenomas/polyps (SSA/Ps) but better at detecting CRC7

• Detection rates were variable based on size of adenoma.14

• Flat and nonhemorrhagic lesions (SSA/Ps) were less likely to be detected than adenomas.11

• Sensitivity was high (98%) regardless of cancer stage.14 • Specificity was 90%. • Detection of advanced adenocarcinomas (AA) with high-grade dysplasia was 83% sensitive.

• High accuracy in detecting CRC12; 79% sensitivity, 94% specificity

• Required more follow-up colonoscopies due to their lower specificity than the FIT15

• Detected a majority of SSPs despite a relatively narrow and small size range17

• Testing was superior to FIT in detection of CRC.16

• Concern about ability to detect premalignant lesions11 • Suggestion in response to this is to perform multiple-round testing (ie, 3 tests over time instead of 1)7,11

• Effective in detecting biomarker mBMP317 • Negative predictive value of single test event (99.94% for CRC, 95% for AA) when using multiyear testing interval15

may detract from the test’s credibility, lead to increased cost, and challenge patient compliance because of the need for repeat collection. A challenge exists for providers desiring to recommend the use of FIT in practice because a variety of brands is available. Studies comparing FIT and colonoscopy are complicated by this because of the different brands all having varying Hgb thresholds for what constitutes a positive test. The different cutoff values for Hgb can lead to disparate results for both sensitivity and specificity.12 This was demonstrated in a study in which 4 different brands of the FIT were used.10 Another study compared 8 different brands of the FIT for sensitivity and specificity and found that only two-thirds of the tests performed acceptably.8 To further complicate this matter, information on proficiency testing programs is not available to the public, so it is difficult to determine whether the FIT being used is actually performing as the manufacturer claims it will in the hands of the consumer. There have been no head-to-head comparisons between the different commercial FITs, which may be useful to determine which 1 performs best. Another significant area of concern is the use of qualitative vs quantitative FITs, which vary significantly in design and testing. Qualitative FIT products often use a dipstick technology, whereas quantitative FITs are measured by technically precise, automated instruments. Advantages of

the qualitative FIT include convenience, low cost, and rapid turnaround.12 However, the quality control of the qualitative FIT is a concern. The quantitative FIT allows for the selection of a test with a specific Hgb threshold that will maximize the detection of CRC and minimize false-positive results.20 Future studies are needed to determine what the Hgb threshold should be and how to standardize these tests. Conclusion

Can providers feel confident in recommending the FIT or the MT-sDNA test for CRC screening in patients of average risk between the ages of 50 and 75 years who do not want to have a colonoscopy? The MT-sDNA test has a high sensitivity but low specificity, whereas the FIT has a low sensitivity and high specificity. The MT-sDNA test’s low specificity raises concerns of false-positives and unnecessary testing; the FIT’s low sensitivity raises concerns about what it can detect. Ultimately, more studies are needed on the MT-sDNA test and FIT. Even though they are both approved tests for CRC screening, they each have pros and cons that need to be considered. This literature review was limited because of the few published studies comparing the MT-sDNA test with the gold-standard colonoscopy. Two articles reviewed refer to a large, average-risk screening study currently underway to validate findings of the MT-sDNA test.14,17 Hopefully,

32 THE CLINICAL ADVISOR • JANUARY 2018 • www.ClinicalAdvisor.com

this study can show the current specificity of the test and how to increase it. It is possible with more research that the MT-sDNA test may earn improved coverage by insurance companies and become a more cost-effective test for CRC screening. One of the articles reviewed reports that large, randomized trials are also under way to compare the FIT with colonoscopy as a CRC screening program, but results will not be available for some time.20 Additional research for both tests is needed to optimize completion of the initial test and follow-up colonoscopy when a positive result is received. These studies could help find ways to increase the number of patients following through with CRC screening recommendation. One-third of average-risk individuals in the United States have never had colorectal cancer screening completed after a recommendation from a healthcare provider.3 Offering sound choices in CRC screening strategies should be the goal of every provider. Healthcare providers should focus on maximizing the total number of patients that participate in CRC screening because it will have the largest effect on preventing deaths related to colorectal cancer. Despite the need for additional research, the FIT and the MT-sDNA test are both evidence-based tests that should be considered for patients when presenting options for CRC screening when a colonoscopy is unable to be performed. n

4. American Cancer Society. Colorectal cancer screening tests. https:// www.cancer.org/content/cancer/en/cancer/colon-rectal-cancer/detectiondiagnosis-staging/screening-tests-used.html. Updated August 22, 2017. Accessed December 1, 2017. 5. Crotta S, Segnan N, Paganin S, Dagnes B, Rosset R, Senore C. High rate of advanced adenoma detection in 4 rounds of colorectal cancer screening with the fecal immunochemical test. Clin Gastroenterol Hepatol. 2012;10(6):633-638. 6. Cubiella J, De-Castro I, Rivera C, et al. Diagnostic accuracy of fecal immunochemical test in average- and familial-risk colorectal cancer screening. United European Gastroenterol J. 2014;2(6):522-529. 7. de Wijkerslooth TR, Stoop EM, Bossuyt PM, et al. Immunochemical fecal occult blood testing is equally sensitive for proximal and distal advanced neoplasia. Am J Gastroenterol. 2012;107(10):1570-1578. 8. Daly JM, Bay CP, Levy BT. Evaluation of fecal immunochemical tests for colorectal cancer screening. J Prim Care Community Health. 2013;4(4):245-250. 9. Grobbee EJ, van der Vlugt,M., van Vuuren AJ, et al. A randomised comparison of two faecal immunochemical tests in population-based colorectal cancer screening. Gut. 2017;66(11):1975-1982 10. Levy BT, Bay C, Xu Y, et al. Test characteristics of faecal immunochemical tests (FIT) compared with optical colonoscopy. J Med Screen. 2014;21(3):133-143. 11. Chang LC, Shun CT, Hsu WF, et al. Fecal immunochemical test detects sessile serrated adenomas and polyps with a low level of sensitivity. Clin Gastroenterol Hepatol. 2017;15(6):872-879. 12. Lee JK, Liles EG, Bent S, Levin, TR, Corley, DA. Accuracy of fecal immunochemical tests for colorectal cancer: Systematic review and metaanalysis. Ann Intern Med. 2014;160(3):171-181.

Amanda N. Strain, MSN, CCRN, FNP-C, is a family nurse practitioner at Kendrick Family Medicine in Mooresville, Ind.; Charlotte C. Waling, MSN, FNP-C, is a nurse practitioner at St. Vincent Ambulatory Care Crawfordsville, Primary Care Department, Crawfordsville, Ind.; and Felicia D. Stewart, DNP, NP-C, RN-BC, is an assistant professor, Department of Advanced Practice Nursing, Indiana State University, and family nurse practitioner at Wellness for Life in Terre Haute, Ind.

13. Ahlquist DA, Zou H, Domanico M, et al. Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology. 2012;142:248-256. 14. Lidgard GP, Domanico MJ, Bruinsma JJ, et al. Clinical performance of an automated stool DNA assay for detection of colorectal neoplasia. Clin Gastroenterol Hepatol, 2013;11(10):1313-1318. doi:10.1016/j.cgh.2013.04.023 15. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-1297. 16. Redwood DG, Asay, ED, Blake ID, et al. Stool DNA testing for screen-

References

ing detection of colorectal neoplasia in Alaska Native people. Mayo Clin

1. American Cancer Society. Can colorectal polyps and cancer be found

Proc. 2016;91(1):61-70.

early? https://www.cancer.org/cancer/colon-rectal-cancer/early-detection/

17. Heigh RI, Yab TC, Taylor WR, et al. Detection of colorectal serrated

importance-of-crc-screening.html. Updated March 2, 2017. Accessed

polyps by stool DNA testing: Comparison with fecal immunochemical

December 1, 2017.

testing for occult blood (FIT). PLoS One. 2014;9(1):e85659.

2. US Preventive Services Task Force. Final recommendation statement:

18. Berger BM, Schroy PC, Dinh TA. Screening for colorectal cancer using

Colorectal cancer screening. https://www.uspreventiveservicestaskforce.

a multitarget stool DNA test: Modeling the effect of the intertest interval

org/Page/Document/RecommendationStatementFinal/colorectal-cancer-

on clinical effectiveness. Clin Colorectal Cancer. 2016;15(3):65-74.

screening2. June 2017. Accessed December 1, 2017.

19. Ladabaum U, Manalithara A. Comparative effectiveness and cost effec-

3. Centers for Disease Control and Prevention. Colorectal cancer

tiveness of a multitarget stool DNA test to screen for a colorectal neopla-

screening rates remain low [press release]. https://www.cdc.gov/media/

sia. Gastroenterology. 2016;151(3):427-439.

releases/2013/p1105-colorectal-cancer-screening.html. November 5, 2013.

20. Robertson DJ, Imperiale TF. Stool testing for colorectal cancer screen-

Accessed December 1, 2017.

ing. Gastroenterology. 2015;149:1286-1293.

www.ClinicalAdvisor.com â&#x20AC;˘ THE CLINICAL ADVISOR â&#x20AC;˘ JANUARY 2018 33

CME FEATURED COURSE

■ EDUCATIONAL OBJECTIVES At the conclusion of this activity, participants should be better able to: • Select the appropriate direct-acting antiviral (DAA) agent for hepatitis C virus (HCV) infection based on viral genotypes (and subtype) and associated complications • Identify the emergence of HCV resistance-associated substitutions (RASs; also known as resistance-associated variants [RAVs]) following treatment with selected DAA regimens • Implement strategies, including the spectrum of molecular testing protocols, to identify and monitor disease progression and treatment efficacy and potentially avert HCV treatment resistance ■ COMPLETE THE POSTTEST: Page 44

Release Date: November 30, 2017 Expiration Date: November 30, 2018 Estimated Time to Complete: 30 minutes Accredited Provider: This educational activity is provided by the American Gastroenterological Association. Commercial Supporter: This activity is supported by an educational grant from Merck & Co., Inc. Producer: This activity was produced by Haymarket Medical Education. Program Description: The opiate epidemic has led to a dramatic increase in the incidence of new, acute hepatitis C virus (HCV) infection in the United States since 2006—a trend that is closely associated with increases in injection drug use (IDU). Furthermore, co-infection with hepatitis B and human immunodeficiency virus is not uncommon. Clinicians are challenged to determine the optimal approach to treatment in these patients, which demands selecting the appropriate treatment regimen based on viral genotypes and subtypes as well as employing protocols that promote treatment efficacy and minimize the risk of HCV treatment resistance. Intended Audience: Gastroenterologists, hepatologists, primary care clinicians, and other providers who treat patients with hepatitis C. Conflict of Interest Disclosure Policy: In accordance with the ACCME’s Standards for Commercial Support of Continuing Medical Education, all faculty and planning partners must disclose any financial relationship(s) or other relationship(s) held within the past 12 months. The AGA Institute implements a mechanism to identify and resolve all conflicts of interest prior to delivering the educational activity to learners. Faculty Mark Sulkowski, MD Professor of Medicine Johns Hopkins University Medical Director Viral Hepatitis Center Division of Infectious Diseases Johns Hopkins Hospital Baltimore, MD Dr. Sulkowski receives consulting fees from AbbVie Inc., Gilead Sciences, Inc., Janssen Pharmaceuticals, and Merck & Co., Inc. Accredited Provider Disclosure: No other individuals involved with planning and delivering the content disclosed any relevant financial relationships.

Accreditation Statement: The AGA Institute is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Designation Statement: The AGA Institute designates this enduring activity for a maximum of 0.50 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Disclosure of Unlabeled Use: This educational activity may contain discussion of approved and/or investigational uses of agents that are not indicated by the FDA. AGA Institute, Haymarket Medical Education, and Merck & Co., Inc., 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 AGA Institute, Haymarket Medical Education, and Merck & Co., Inc. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Disclaimer: AGA Institute does not provide any warranty as to the accuracy or reliability of information presented either verbally or in writing by presenters. No responsibility is assumed by AGA Institute for any injury and/or damage to persons or property resulting from any use of such information. Instructions: There are no fees for participating in and receiving CME credit for this activity. During the period November 30, 2017, through November 30, 2018, participants must: 1) read the learning objectives and faculty disclosures; 2) complete the pre-assessment test; 3) study the educational activity; and 4) complete the posttest and evaluation form and submit it online. A statement of credit will be issued only upon receipt of the above elements and a posttest score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/ Jan18feature. If you have any questions relating to the accreditation of this activity, please contact the AGA education department at education@ gastro.org or 301-654-2055. If you have any questions relating to your certificate or other issues with the activity, please contact myCME.Support@ haymarketmedical.com.

Provided by

Produced by

CME

FEATURED COURSE: MARK SULKOWSKI, MD

A 29-year-old man with a history of injected drug use The opiate epidemic has dramatically increased cases of hepatitis C virus. This case reviews the challenges in determining optimal treatment.

The opiate epidemic has led to an increased rate of HCV infection.

ay C, age 29 years, presented to a rural health clinic in West Virginia for a pre-employment physical exam. A pale, thin Caucasian male, 5 ft 8 in tall, 125 lb (body mass index [BMI], 21.3 kg/m 2), Jay reported no health issues and said he takes no medication. He stated that he exercises “occasionally,” and drinks “a few beers” at the end of every day. He is a high school graduate and has a conditional offer to work in a warehouse. Routine laboratory work was noteworthy for an alanine aminotransferase (ALT) level of 72 U/L (upper limit of the reference range is 35 U/L). A urine drug test was negative. The primary care provider (PCP) ordered an HCV antibody test with reflex to an HCV RNA test if antibody results were positive. The HCV antibody was positive and confirmatory HCV RNA level was 2.2 million IU/mL, indicating active HCV infection.1,2 Genotype testing identified genotype 3. When discussing the HCV results, Jay reported that he had used marijuana and prescription narcotics in high school and injected heroin “a few times” after high school. About 3 years ago, he completed a court-ordered addiction treatment program with buprenorphine/naloxone and counseling. He stated that he has not used drugs since that time. The young injection drug user and HCV

As a consequence of the opiate epidemic in the United States (US), the incidence of new, acute HCV infection has increased dramatically since 2006. This trend is associated with increases in www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2018 35

CME

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FIGURE 1. Acute HCV infection rate among young adults in nonurban and urban areas5

No. of cases per 100,000 population

4.5 4.0

Nonurban

3.5

Urban

3.0 2.5 2.0 1.5

1.0 0.5 0.0

2006

2007

2008

2009

2010

2011

2012

HCV, hepatitis C virus. *95% confidence interval

injection drug use (IDU) and appears to particularly affect young, white men and women in nonurban areas in the Appalachian, Midwest, and New England states.3,4 Persons aged 20 to 29 years had the highest rate of acute infection in 2015, and the greatest increase in infection rate (2010-2105).4 An examination of acute HCV cases reported to 4 states that collect data on this infection (Kentucky, Tennessee, Virginia, and West Virginia) and of drug treatment admissions data in persons 30 years old or younger in these states found significant increases in the acute HCV infection rate, in admissions for treatment of opioid dependence (up by 21%), and in the percentage of persons who identified injection as their main route of using drugs (up by 12.6%). Many individuals begin injecting after a period of oral use of prescription narcotics. Figure 1 displays the difference in infection rate in urban and nonurban areas, among individuals 30 years and younger in these 4 states, including the one in which the case patient, Jay, presented (ie, West Virginia). IDU was the most common reported risk factor for HCV, cited in 73% of cases with risk information.5 Of note, this epidemic of HCV infection among young people who inject drugs (PWIDs) includes a high proportion of women. The prevalence of HCV infection in pregnant women has increased significantly,6 suggesting that the incidence of hepatitis C in children is also increasing as a result of mother-to-child transmission. West Virginia, where this patient lives, is 1 of 7 states with acute HCV infection rates at least twice the national average. The

others are Indiana, Kentucky, Maine, Massachusetts, New Mexico, and Tennessee.7 Although many young PWIDs are infected with HCV genotype 1, there is evidence that HCV genotype 3 is being transmitted in this population.8,9 Workup

The clinician ordered further testing as recommended for evaluation of individuals newly diagnosed with HCV1: • Calculated glomerular filtration rate (GFR) • Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) • Human immunodeficiency virus (HIV) antibody • Fibrosis staging Jay was found to be negative for prior infection with hepatitis A (antibody total negative) and hepatitis B (HBsAg, HBcAb total, and HBsAb negative) and HIV. Vaccination against hepatitis A and B was recommended. He had normal complete blood count (CBC) with a platelet count of 225,000 mm3 and chemistry panel with a normal estimated GFR. His serum ALT and aspartate transaminase (AST) levels were 48 and 36 U/L, respectively, at this time. Fibrosis staging was performed using the AST-to-platelet ratio index (APRI) and office-based vibration-controlled transient elastography (VCTE). His APRI score was 0.593, consistent with minimal fibrosis. His liver stiffness score derived from VCTE was 6.5 kPa, which also is consistent with minimal fibrosis. The VCTE provided an assessment of hepatic steatosis by controlled attenuation parameter

36 THE CLINICAL ADVISOR • JANUARY 2018 • www.ClinicalAdvisor.com

FIGURE 2. Proportion of HCV patients free of cirrhosis, by HCV genotype15

Incident Cirrhosis

1.00

Proportion free of cirrhosis

0.95 0.90 0.85 0.80

Genotype 1 Genotype 2 Genotype 3 Genotype 4

0.75 0.70 0.65 0.60 0.55 0.50

Number at risk 101,862

88,511

76,216

64,709

52,900

(CAP); the patient’s CAP score was 334 dB/m, indicating pronounced steatosis. Based on the CAP score, liver ultrasound was performed and revealed a diffuse increase in hepatic echogenicity over a normal liver and a more echogenic appearance of the liver parenchyma compared with the adjacent right kidney. Both findings suggest hepatic steatosis.10,11 The PCP counseled Jay to abstain from alcohol consumption due to the risk of further liver damage.1 He also advised Jay about how to minimize the risk of transmitting HCV to others. Steatosis, fibrosis, and HCC risk in genotype 3 Compared with other HCV genotypes, genotype 3 infection displays a different pathogenic mechanism. In a study of patients with chronic HCV (n=3068), genotype 3 infection was independently associated with hepatic steatosis. Other associations with steatosis were patient and environmental factors such as diabetes, higher BMI, and ongoing alcohol use.12 Rather than acting through these known factors, evidence suggests that genotype 3 affects hepatic lipid metabolism directly.13 Supporting this hypothesis, hepatic steatosis has been demonstrated to resolve after HCV cure in most patients with genotype 3 (91%) but not in those with other genotypes (43%).14 Genotype 3 also is associated with higher rates of, and faster progression to, cirrhosis (Figure 2), as well as higher rates of hepatocellular carcinoma (HCC). In an analysis of data from US veterans (n=110,484), those with genotype 3

Year

40,099

27,596

15,900

6,822

780

were 31% more likely to develop cirrhosis and 80% more likely to develop HCC compared with individuals infected with genotype 1.15 Other studies have confirmed the association of genotype 3 with advanced liver disease (compared to others with chronic hepatitis C)16 and death (compared with those who have genotype 1).17 Ultrasound has demonstrated reliability in detecting hepatic steatosis, compared with histology. Its sensitivity and specificity for this purpose were similar to those of computed tomography (CT) and magnetic resonance imaging (MRI).10 The CAP, which may be reported as part of VCTE (FibroScan®), also has demonstrated high sensitivity, specific, and positive and negative predictive values for detecting steatosis (91.9%, 85.7%, 85.0% and 92.3%, respectively).18 Choosing therapy

There are more than 6 HCV DAA regimens approved by the US Food and Drug Administration (FDA), which are currently available for persons who have never been treated for hepatitis C (treatment-naive). In general, these DAA regimens can be classified as genotype-specific (active against certain HCV genotypes but not others) or pangenotypic (active against all HCV genotypes). Genotype-specific regimens include ledipasvir/sofosbuvir, paritaprevir/ritonavir/ombitasvir + dasabuvir and elbasvir/grazoprevir; these regimens are not active against HCV genotypes 2 and 3. Pangenotypic regimens include sofosbuvir/velpatasvir, sofosbuvir + daclatasvir, and glecaprevir/pibrentasvir.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2018 37

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TABLE 1. AASLD/IDSA recommended and alternative regimens for treatment-naive genotype 3 patients without cirrrhosis.1 Recommended

Duration

Rating

Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg)a

8 weeks

I, A

Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)

12 weeks

I, A

Alternative

Duration

Rating

12 weeks

I, A

Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) b

AASLD, American Association for the Study of Liver Diseases; HCV, hepatitis C virus; IDSA, Infectious Diseases Society of America. his is a 3-tablet coformulation. Please refer to the prescribing information. T The dose of daclatasvir may need to increase or decrease when used cocomitantly with cytochrome P450 3A/4 inducers and inhibitors, respectively.

For the management of persons with HCV genotype 3 infection who are treatment-naive and do not have cirrhosis, the American Association for the Study of Liver Diseases/ Infectious Diseases Society of America (AASLD/IDSA) HCV guidelines panel recommends either sofosbuvir/ velpatasvir (1 tablet daily for 12 weeks) or glecaprevir/ pibrentasvir (3 tablets for 8 weeks). After the FDA approval of glecaprevir/pibrentasvir in August 2017, the Panel changed the level of recommendation for sofosbuvir plus daclatasvir (12 weeks) to an alternative regimen (Table 1).1 This decision was made largely because this regimen includes 2 distinct DAAs, which may be associated with increased cost.

*Listed alphabetically.

Patients with SVR 12 (%)

FIGURE 3. Glecaprevir/pibrentasvir in treatmentnaive noncirrhotic genotype 3: SVR 12 by treatment duration and regimen19 100

80 60 40 20 0

222/233

111/115

149/157

GLE-PIB

SOF + DCV

GLE-PIB

12-week regimens

8-week regimen

DCV, daclatasvir; GLE-PIB, glecaprevir-pibrentasvir; ITT, intent-to-treat; SOF, sofosbuvir; SVR, sustained virologic response

FIGURE 4. Sofosbuvir/velpatasvir: SVR rates in HCV genotype 321 Sustained virologic response (%)

RAS testing At the time of publication, the AASLD/IDSA guidance states that testing for RASs is not required for treatmentnaive, noncirrhotic individuals with genotype 3 being considered for therapy with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir.1 However, some experts have recommended consideration of testing for the A30K RAS prior to treatment with glecaprevir/pibrentasvir.

100

Sofosbuvirvelpatasvir

Sofosbuvirribavirin

40 20 0

160/163

141/156

No cirrhosis No previous treatment

Bars represent 95% confidence intervals.

Treatment options Glecaprevir/pibrentasvir. This therapy, which was approved by the FDA in August 2017, demonstrated noninferiority to 12 weeks of daclatasvir/sofosbuvir in genotype 3, treatment-naive, noncirrhotic patients whether given for 8 or 12 weeks. This finding comes from the results of a phase 3 trial reporting similar sustained virologic response (SVR) rates for each glecaprevir/pibrentasvir regimen and for daclatasvir/sofosbuvir. (Figure 3).19 In an integrated analysis of noncirrhotic persons with genotype 3 infection treated with glecaprevir/pibrentasvir in phase 2 and 3 trials, the SVR rate was 95% following 8 or 12 weeks of treatment and did not vary by patient or virus characteristics.20 Sofosbuvir/velpatasvir. This regimen was approved by the FDA in June 2016: 12 weeks of treatment with sofosbuvir/velpatasvir was found to be superior to sofosbuvir and ribavirin for 24 weeks in patients with HCV genotype 3 with and without cirrhosis. The SVR rate was 98% for treatment-naive, noncirrhotic patients with genotype 3 (Figure 4).21 Similar response rates have been reported in real-world studies. 22,23 One study of the first 105 patients receiving sofosbuvir/velpatasvir in a single center in Germany reported SVR rates of 100% with sofosbuvir/velpatasvir

38 THE CLINICAL ADVISOR • JANUARY 2018 • www.ClinicalAdvisor.com

in genotype 3 patients who completed therapy and for whom data were available at SVR4 (27/27). Most patients (75%; 79/105) treated with this therapy were infected with genotype 3.23 Injection drug use and HCV treatment Because IDU is an efficient mode of HCV transmission, many persons with HCV infection have a previous or current history of IDU. In a series of 1000 consecutive patients treated during the interferon era (2002-2012), historical IDU did not affect rates of adherence or response to HCV therapy. Nonadherence rates did not differ significantly between those with a recent, remote, or current history of IDU, and those with no history of IDU (8.4% and 6.8%; IDU history and no history, respectively; relative risk [RR], 1.23, 95% confidence intervals [CI] 0.76 ± 1.99). SVR rates also did not differ significantly (64.1% and 60.9%, IDU history and no history, respectively; RR 1.05; 95% CI 0.95 ± 1.17).24 Since the introduction of DAAs, SVR rates have been similarly high in study participants with and without opiate use disorders, including those taking concurrent opiate agonist therapy (OAT).25,26 In 1 study that enrolled 301 persons with HCV genotype 1, 4, or 6 infection who were taking OAT—including those actively using drugs—12 weeks of treatment with elbasvir/grazoprevir was highly effective (SVR in ~90%). Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy. However, HCV reinfection after SVR occurred in 6 study participants.27 Taken together, these observations demonstrate that HCV treatment with DAA is highly effective in persons who use drugs; however, patients and clinicians must be cognizant of the risk of HCV reinfection following cure and incorporate harm reduction strategies into their management plan. Making the choice The provider considered that glecaprevir/pibrentasvir is a shorter course of therapy; however, this newly approved medication was not on the patient’s insurance formulary. He prescribed sofosbuvir/velpatasvir, directing Jay to return in 4 weeks for laboratory work (HCV RNA and hepatic function panel).1 He counseled Jay about the importance of treatment adherence to achieve cure. The patient was instructed not to use acid-reducing agents during treatment with sofosbuvir/velpatasvir, in accordance with the prescribing information. Acid suppression can reduce exposure to velpatasvir.28

Evaluating patients with HCV infection A rapid hepatitis C virus (HCV) antibody test is appropriate for screening individuals whose past and current HCV infection status are unknown. Antibody testing does not distinguish prior, resolved infection from current, active infection. The Centers for Disease Control and Prevention (CDC) recommends that all persons who are HCV-antibody positive undergo confirmatory testing for active HCV infection as evidenced by the detection of any HCV RNA level in blood, which identifies currently infected individuals.1 Patients should undergo quantitative HCV RNA testing prior to starting antiviral therapy, along with genotype and subtype.2 In some settings, reflex testing for HCV RNA on blood specimens found to be positive for HCV antibody is available and prevents the need for a return visit and additional phlebotomy to confirm active viremia. Other pretreatment measures include2: • Complete blood count (CBC), including platelet count and international normalized ratio (INR) • Hepatic function panel (albumin, total and direct bilirubin, alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase) • Creatinine and calculated glomerular filtration rate (GFR) • Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) • Human immunodeficiency virus (HIV) antibody • Hepatitis A antibody total (to confirm immunity) • HCV genotype • Fibrosis staging • Right upper quadrant ultrasound in persons found to have advanced fibrosis (stage 3 fibrosis or stage 4 cirrhosis)3 A history and physical examination also should be performed, and a list of medications gathered to identify possible drug interactions with anti-HCV therapy. 1. Testing for HCV infection: an update of guidance for clinicians and laboratorians. MMWR Morb Mortal Wkly Rep. 2013;62(18):362-365. 2. American Association for the Study of Liver Diseases, Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. Published April 12, 2017. http://www.hcvguidelines.org. Accessed July 5, 2017. 3. Kanwal F, Bacon BR, Beste LA, et al. Hepatitis C virus infection care pathway—a report from the American Gastroenterological Association Institute HCV Care Pathway Work Group. Gastroenterology. 2017;152(6):1588-1598.

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HCV, HBV, and HIV co-infection All persons with active hepatitis C virus (HCV) infection should be screened for hepatitis B and human immunodeficiency virus (HIV) infection, as these conditions share many of the same modes of transmission with HCV.1 Persons should also be screened for immunity to hepatitis A. Hepatitis A virus (HAV). Acute infection with hepatitis A in persons with hepatitis C can lead to serious and even life-threatening illness; testing for HAV antibody total should be performed and, if negative, vaccination against hepatitis A is recommended. Hepatitis B virus (HBV). Active HBV infection, as indicated by positive hepatitis B surface antigen (HBsAg), is associated with a worse prognosis in persons with HCV. It should be treated with antivirals.2 Further, patients with active (HBsAg positive) or prior HBV infection (positive for antihepatitis B core antibody (IgG or total) may be at risk for HBV reactivation during HCV treatment with direct acting antivirals (DAAs). These patients should be monitored or, in some cases, treated with antivirals for HBV during and after HCV treatment.1 Human immunodeficiency virus (HIV). Co-infection with HIV increases the rate of liver fibrosis progression in HCV, and all persons with HIV should be treated with antiretrovirals.3 In addition, the Centers for Disease Control and Prevention (CDC) recommends that everyone between the ages of 13 and 64 years be tested for HIV at least once, and annual HIV screening is recommended in persons with ongoing with risk factors.4 1. American Association for the Study of Liver Diseases, Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. Published April 12, 2017. http://www.hcvguidelines.org. Accessed July 5, 2017. 2. Shi J, Zhu L, Liu S, Xie WF. A meta-analysis of case-control studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma in China. Br J Cancer. 2005;92(3):607-612. 3. Hernandez MD, Sherman KE. HIV/HCV coinfection natural history and disease progression, a review of the most recent literature. Curr Opin HIV AIDS. 2011;6(6):478-482. 4. Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep. 2006;55(RR-14):1-17

On-treatment monitoring

4-week follow-up visit Jay’s HCV RNA level was undetectable at less than 15 IU/mL, indicating an excellent HCV response. His liver enzymes had normalized. He reported no issues with taking the 1 pill once daily. He said he has started the warehouse job that required the physical exam and is happy to be working. He was directed to return in 8 weeks, at the end of treatment.

End of therapy visit (12-week posttreatment initiation) Jay’s HCV RNA remained undectectable at the end of treatment. His laboratory findings were normal. He was scheduled to return for laboratory testing in 12 weeks. 12-week posttherapy visit Jay’s HCV RNA was detectable, with a viral load of 787,000 IU/mL. In discussion with the physician, he reported that he had missed some doses of sofosbuvir/velpatasvir, particularly in the first month. He also reported that he took over-the-counter omeprazole during the second and third month of therapy because he had developed heartburn. He also admitted the he had slipped a couple of times and injected heroin with friends after completing treatment; however, he quickly got back into his program and resumed treatment with buprenorphine/naloxone. HCV genotype testing confirmed that the pretreatment HCV genotype was present; additional testing revealed the NS5A Y93H RAS. Virologic relapse

In the phase 3 study of sofosbuvir/velpatasvir, the overall rate of HCV recurrence after stopping 12 weeks of treatment was only 4% (11 of 276 patients); most patients with HCV relapse had evidence of cirrhosis and/or prior treatment with peginterferon/ribavirin. Of the 11 study participants with HCV recurrence, 1 patient had reinfection with HCV genotype 1a at the time of recurrence. Of the 10 patients with HCV relapse, 4 had the Y93H RAS prior to treatment, and all 10 had evidence of the Y93H RAS at the time of HCV rebound. Only 1 treatment-naive, noncirrhotic patient experienced HCV relapse in the ASTRAL-3 study; this individual had the Y93H RAS at baseline and at the time of relapse.21 In accordance with the AASLD/ IDSA guidance, Jay did not have NS5A RAS testing prior to treatment. Missed doses may have contributed to his treatment failure. Recommended retreatment The first step in Jay’s case was to determine if his recurrent HCV was the result of reinfection or HCV relapse. The finding of the same HCV genotype/subtype and the presence of an expected NS5A RAS, Y93H, suggest that this likely represents relapse. The next step was to discuss the potential negative impact of nonadherence and the use of the proton-pump inhibitor omeprazole with Jay. These represent correctable treatment factors that should be addressed prior to retreatment. Sofosbuvir (400 mg)/velpatasvir (100 mg)/

40 THE CLINICAL ADVISOR • JANUARY 2018 • www.ClinicalAdvisor.com

voxilaprevir (100 mg), a fixed-dose combination, 1-tablet, once-daily therapy taken with food for 12 weeks, is the only FDA-approved and guideline-recommended regimen for patients previously treated with an NS5A inhibitor.1 It received FDA approval in July 2017 for treatment of patients with genotypes 1 to 6, no cirrhosis or compensated cirrhosis, and prior DAA treatment including NS5A inhibitors. It also is approved for those with genotype 1a or 3 who have been treated with sofosbuvir but no NS5A inhibitor.29 In a study of patients with NS5A inhibitor experience, 95% (74/78) of genotype 3 patients attained SVR.30 All 4 relapsed patients had cirrhosis, and the presence of Y93H did not impact the likelihood of SVR.1,30 Headache, fatigue, and diarrhea were the most common side effects with active therapy and with placebo.30 Retreatment After counseling and education regarding adherence and the need to avoid acid-suppressing agents such as proton-pump inhibitors, Jay was retreated with sofosbuvir/velpatasvir/ voxilaprevir (1 tablet daily for 12 weeks). His HCV RNA was not detected at the end of treatment, and Jay reported that he did not miss a single dose of therapy. At 12 weeks after treatment, his HCV RNA remained undetected. His PCP was very pleased to inform him that he has been cured of chronic hepatitis C. The benefits to his health include no elevated risk of liver disease. SVR is defined as a cure, given that less than 1% of patients relapse after achieving this milestone.31-34 Compared to patients with ongoing infection, SVR has been associated with reduced risk of death from all causes, liver-related death, HCC, variceal bleeding, and the need for liver transplantation. 31,33,35,36 Regression of fibrosis and inflammation also has been documented.35,36 The physician reminded Jay that he will remain HCV antibody positive and that this test should not be repeated. His HCV RNA is expected to remain undetectable, however. Studies of patients treated with DAAs have demonstrated a very low risk of HCV relapse in persons who are HCV RNA not detected at 12 weeks after stopping treatment. In 1 study of 1393 noncirrhotic persons who were followed for a median 2.5 years after achieving HCV cure with DAAs, only 1 individual experienced late HCV relapse. However, 6 persons developed HCV reinfection (as determined by sequencing).37 Jay’s risk of reinfection is quite low if he remains abstinent from IDU; however, patients with opiate use disorders remain at risk for relapse into drug use. Based on his relatively recent drug use, Jay should remain

Hepatic fibrosis Evaluation of hepatic fibrosis prior to therapy is important as it identifies patients who require screening for hepatocellular carcinoma (HCC) and can affect treatment choice. Liver biopsy, long considered the gold standard, is rarely performed since the advent of noninvasive therapies for assessing fibrosis. Besides its invasiveness, recognized problems with biopsy include high cost, sampling error, observer variability, and generally minor but sometimes serious complications.1,2 In addition, in the current era of highly effective HCV treatments, the primary goal of pretreatment liver disease assessment is to determine the presence or absence of cirrhosis. This is because management recommendations for treatment regimens and posttreatment monitoring differ based on the presence of cirrhosis. Many noninvasive methods for indirect fibrosis assessment have been developed. Vibration-controlled transient elastography (VCTE), a measure of liver stiffness, has correlated well with biopsy and predicts clinical outcomes. A study of VCTE in patients with chronic hepatitis B or C reported sensitivity and specificity of 58% and 75%, respectively, for detection of fibrosis (METAVIR stage ≥2 [F2]), and higher values (76% sensitivity and 85% specificity) for detecting cirrhosis (F4).3 A meta-analysis also reported high levels of accuracy for fibrosis staging with elastography. Performance was rated as good to excellent for assessing significant fibrosis and excellent for diagnosis of severe fibrosis and cirrhosis.4 The serum biomarkers FibroTest® (Europe)/FibroSure® (USA) and serum-AST-to-platelet ratio (APRI) are among the most widely used and validated options of their type.5 The American Association for the Study of Liver Diseases (AASLD) HCV guidance recommends combining VCTE with serum biomarkers to assess fibrosis stage, with liver biopsy performed in the event of discordant findings.1 1. American Association for the Study of Liver Diseases, Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. Published April 12, 2017. http://www.hcvguidelines.org. Accessed September 27, 2017. 2. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003;38(6):1449-1457. 3. Afdhal NH, Bacon BR, Patel K, et al. Accuracy of fibroscan, compared with histology, in analysis of liver fibrosis in patients with hepatitis B or C: a United States multicenter study. Clin Gastroenterol Hepatol. 2015;13(4):772-779.e1-e3. 4. Herrmann E, de Ledinghen V, Cassinotto C, et al. Assessment of biopsy-proven liver fibrosis by 2D-shear wave elastography: an individual patient data based metaanalysis. Hepatology. 2017. Epub ahead of print. 5. Chou R, Wasson N. Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection: a systematic review. Ann Intern Med. 2013;158(11):807-820.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2018 41

CME

FEATURED COURSE

Counseling to reduce risk of liver injury and HCV transmission Patients with HCV infection should abstain from alcohol consumption due to the risk of further liver damage. They should also be informed that HCV is transmitted through contact with infected blood and advised to refrain from injection drug use (IDU), or to avoid sharing or reusing needles if they engage in IDU. Other practices to minimize the risk of HCV transmission include not sharing toothbrushes, dental, or shaving equipment; covering any bleeding wound; and cleaning any HCV-infected person’s blood from surfaces with diluted bleach (1:9 bleach to water). Persons with multiple sexual partners or sexually transmitted infections should use barrier protection to prevent sexual transmission.1 Alcohol consumption of more than 50 g per day has been associated with an increased rate of liver fibrosis progression2 and hepatocellular carcinoma (HCC).3,4 A standard drink contains 14 g of alcohol. 5 Even light-to-moderate alcohol use has been shown to raise the risk of HCC in patients with HCV infection and cirrhosis.6 Continued alcohol consumption or IDU should not be used as a basis to exclude patients from therapy, however.2 Additionally, recording specific remote risk factors that do not affect HCV treatment or transmission serves no medical purpose and risks stigmatizing the patient. 1. American Association for the Study of Liver Diseases, Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. Published April 12, 2017. http://www.hcvguidelines.org. Accessed September 27, 2017. 2. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349(9055):825-832. 3. Khan KN, Yatsuhashi H. Effect of alcohol consumption on the progression of hepatitis C virus infection and risk of hepatocellular carcinoma in Japanese patients. Alcohol. 2000;35(3):286-295. 4. Safdar K, Schiff ER. Alcohol and hepatitis C. Semin Liver Dis. 2004;24(3):305-315. 5. National Institute on Alcohol Abuse and Alcoholism (NIAAA). Rethinking Drinking website. Drink size calculator. https://www.rethinkingdrinking.niaaa.nih.gov/tools/ Calculators/drink-size-calculator.aspx. Accessed August 9, 2017. 6. Vandenbulcke H, Moreno C, Colle I, et al. Alcohol intake increases the risk of HCC in hepatitis C virus-related compensated cirrhosis: a prospective study. J Hepatol. 2016;65(3):543-551.

use and maintain a normal BMI to prevent future risk of alcoholic or nonalcoholic steatohepatitis.31 Conclusion

Patients with recent drug use can be successfully treated; most achieve SVR with DAAs but a small proportion do not. A new treatment is available for patients who did not attain SVR with DAAs, increasing the proportion of individuals who can be cured of HCV. PWIDs, including those receiving OAT, attain SVR at high rates. In the absence of an effective vaccine, HCV reinfection can occur after treatment-induced SVR. Patients at risk, including PWIDs, should be educated about harm reduction strategies and monitored for reinfection. n References 1. American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Updated September 21, 2017. Accessed September 24, 2017. 2. Testing for HCV infection: an update of guidance for clinicians and laboratorians. MMWR Morb Mortal Wkly Rep. 2013;62(18):362-365. 3. Suryaprasad AG, White JZ, Xu F, et al. Emerging epidemic of hepatitis C virus infections among young nonurban persons who inject drugs in the United States, 2006-2012. Clin Infect Dis. 2014;59(10):1411-1419. 4. Viral Hepatitis Surveillance—United States, 2015. US Centers for Disease Control and Prevention. https://www.cdc.gov/hepatitis/ statistics/2015surveillance/pdfs/2015HepSurveillanceRpt.pdf. Accessed September 11, 2017. 5. Zibbell JE, Iqbal K, Patel RC, et al. Increases in hepatitis C virus infection related to injection drug use among persons aged </=30 years - Kentucky, Tennessee, Virginia, and West Virginia, 2006-2012. MMWR Morb Mortal Wkly Rep. 2015;64(17):453-458. 6. Patrick SW, Bauer AM, Warren MD, Jones TF, Wester C. Hepatitis C virus infection among women giving birth—Tennessee and United States, 2009-2014. MMWR Morb Mortal Wkly Rep. 2017;66(18):470-473. 7. Campbell CA, Canary L, Smith N, et al. State HCV incidence and policies related to HCV preventive and treatment services for persons who

in active care for treatment of his addiction. In addition, the AASLD/IDSA guidance recommends that persons at risk for reinfection undergo HCV RNA testing at least annually. Fortunately, Jay’s HCV infection was successfully treated before he developed significant liver fibrosis, and he is not at risk for subsequent liver-disease progression or HCC. He does not require liver imaging studies in the future. Nonetheless, he should be advised to avoid alcohol

inject drugs - United States, 2015-2016. MMWR Morb Mortal Wkly Rep. 2017;66(18):465-469. 8. Gordon SC, Trudeau S, Li J, et al. Race, age, and geography impact hepatitis C genotype distribution in the United States. J Clin Gastroenterol. 2017 July 21. Epub ahead of print. 9. Peters PJ, Pontones P, Hoover KW, et al. HIV infection linked to injection use of oxymorphone in Indiana, 2014-2015. N Engl J Med. 2016;375(3):229-239.

42 THE CLINICAL ADVISOR • JANUARY 2018 • www.ClinicalAdvisor.com

10. Hernaez R, Lazo M, Bonekamp S, et al. Diagnostic accuracy and

Association for the Study of the Liver; April 19-23, 2017; Amsterdam,

reliability of ultrasonography for the detection of fatty liver: a meta-

The Netherlands.

analysis. Hepatology. 2011;54(3):1082-1090.

24. Elsherif O, Bannan C, Keating S, et al. Outcomes from a large

11. Modaresi Esfeh J, Ansari-Gilani K. Steatosis and hepatitis C.

10 year hepatitis C treatment programme in people who inject drugs:

Gastroenterology Report. 2016;4(1):24-29.

No effect of recent or former injecting drug use on treatment adherence

12. Leandro G, Mangia A, Hui J, et al. Relationship between steatosis,

or therapeutic response. PLoS One. 2017;12(6):e0178398.

inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of

25. Grebely J, Dore GJ, Zeuzem S, et al. Efficacy and safety of sofosbuvir/

individual patient data. Gastroenterology. 2006;130(6):1636-1642.

velpatasvir in patients with chronic hepatitis C virus infection receiving

13. Roingeard P. Hepatitis C virus diversity and hepatic steatosis. J Viral

opioid substitution therapy: analysis of phase 3 ASTRAL trials. Clin Infect

Hepat. 2013;20(2):77-84.

Dis. 2016;63(11):1479-1481.

14. Castera L, Hezode C, Roudot-Thoraval F, et al. Effect of antiviral

26. Foster GR, Grebely J, Sherman KE, et al. Safety and efficacy of

treatment on evolution of liver steatosis in patients with chronic hepatitis

glecaprevir/pibrentasvir in patients with chronic hepatitis C genotypes 1-6

C: indirect evidence of a role of hepatitis C virus genotype 3 in steatosis.

and recent drug use. Hepatology. 2017;66(1 Suppl):636A-637A.

Gut. 2004;53(3):420-424.

27. Dore GJ, Altice F, Litwin AH, et al. Elbasvir-grazoprevir to treat

15. Kanwal F, Kramer JR, Ilyas J, et al. HCV genotype 3 is associated with

hepatitis C virus infection in persons receiving opioid agonist therapy:

an increased risk of cirrhosis and hepatocellular cancer in a national sample

a randomized trial. Ann Intern Med. 2016;165(9):625-634.

of U.S. Veterans with HCV. Hepatology. 2014;60(1):98-105.

28. Epclusa [package insert] Foster City, CA; Gilead Sciences, Inc: 2017.

16. Goolsby Hunter A, Rosenblatt L, et al. Clinical characteristics,

29. Vosevi [package insert]. Foster City, CA; Gilead Sciences, Inc: 2017.

healthcare costs, and resource utilization in hepatitis C vary by genotype.

30. Bourliere M, Gordon SC, Flamm SL, et al. Sofosbuvir, velpatasvir,

Curr Med Res Opin. 2017;33(5):829-836.

and voxilaprevir for previously treated HCV infection. N Engl J Med.

17. McCombs J, Matsuda T, Tonnu-Mihara I, et al. The risk of long-term

2017;376(22):2134-2146.

morbidity and mortality in patients with chronic hepatitis C: results from

31. Jacobson IM, Lim JK, Fried MW. American Gastroenterological

an analysis of data from a Department of Veterans Affairs Clinical Registry.

Association Institute clinical practice update—expert review: care

JAMA Intern Med. 2014;174(2):204-212.

of patients who have achieved a sustained virologic response after

18. Jun BG, Park WY, Park EJ, et al. A prospective comparative assessment

antiviral therapy for chronic hepatitis C Infection. Gastroenterology.

of the accuracy of the FibroScan in evaluating liver steatosis. PLoS One.

2017;152(6):1578-1587.

2017;12(8):e0182784.

32. Nahon P, Bourcier V, Layese R, et al. Eradication of hepatitis C virus

19. Foster GR, Gane E, Asatryan A, et al. ENDURANCE-3: Safety and

infection in patients with cirrhosis reduces risk of liver and non-liver

efficacy of glecaprevir/pibrentasvir compared to sofosbuvir plus daclatasvir

complications. Gastroenterology. 2017;152(1):142-156.e2.

in treatment-naïve HCV genotype 3-infected patients without cirrhosis.

33. Pearlman BL, Traub N. Sustained virologic response to antiviral therapy

Abstract GS-007. Presented at: European Association for the Study of the

for chronic hepatitis C virus infection: a cure and so much more. Clin Infect

Liver; April 21, 2017, 2017; Amsterdam, The Netherlands.

Dis. 2011;52(7):889-900.

20. Flamm S, Wyles D, Asatryan A, et al. Efficacy and safety of glecaprevir/

34. Morgan RL, Baack B, Smith BD, et al. Eradication of hepatitis

pibrentasvir for 8 or 12 weeks in treatment-naïve patients with chronic hcv

C virus infection and the development of hepatocellular carcinoma: a

genotype 3: an integrated phase 2/3 analysis. Abstract 62. Presented at:

meta-analysis of observational studies. Ann Intern Med. 2013;158(5 pt

Americation Association for the Study of Liver Diseases; October 20-24,

1):329-337.

2017; Washington, DC.

35. van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between

21. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and

sustained virological response and all-cause mortality among patients

velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med.

with chronic hepatitis C and advanced hepatic fibrosis. JAMA.

2015;373(27):2608-2617.

2012;308(24):2584-2593.

22. Buggisch P, Atanasov P, Wursthorn K, et al. Real-world effectiveness

36. George SL, Bacon BR, Brunt EM, et al. Clinical, virologic, histologic, and

and cost per SVR of sofosbuvir/velpatasvir chronic hepatitis C treatment.

biochemical outcomes after successful HCV therapy: a 5-year follow-up of

Presented at: European Association for the Study of the Liver; April 19-23,

150 patients. Hepatology. 2009;49(3):729-738.

2017; Amsterdam, The Netherlands.

37. Bourlière M, Gane EJ, Jacobson IM, et al. Long-term follow up of

23. Christensen S, Ingiliz P, Schewe K, et al. Does sofosbuvir (SOF)/

patients with chronic HCV and no or minimal fibrosis shows low risk for

velpatasvir (VEL) with or without ribavirin (RBV) change the landscape

liver-related morbidity and mortality after achieving SVR with

of therapy in chronic hepatitis C genotype 3 (GT 3) infection? - Results

DAA-based therapy: results from the Gilead SVR registry. Hepatology.

from the GErman hepatitis C COhort (GECCO). Presented at: European

2017;66(1 Suppl):518A-519A.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2018 43

CME

POSTTEST Expiration date: November 30, 2018

A statement of credit will be issued only upon receipt of a completed preassessment test, activity evaluation form, and posttest with a score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/Jan18feature. CREDITS: 0.50 | A 29-year-old man with a history of injected drug use

1. The incidence of new, acute hepatitis C virus (HCV) infection has increased dramatically since 2006—and injection drug use (IDU) is the most common reported risk factor for HCV. Which of the following statements regarding this association is correct? a. Increased HCV infection rates associated with IDU are most dramatic among minority groups in the nation’s urban areas. b. Increased HCV infection rates associated with IDU are most dramatic among baby boomers (ie, people born from 1945-1965). c. Women represent a high proportion of young people with HCV infection who inject drugs. d. Adherence and response to treatment are significantly worse among patients with a history of IDU, even if in the remote past. 2. Which of the following statements regarding HCV genotypes is correct? a. All HCV genotypes display similar pathogenic mechanisms. b. HCV genotype 3 affects hepatic lipid metabolism indirectly (eg, via diabetes, higher body mass index [BMI], ongoing alcohol use). c. Hepatic steatosis typically resolves after HCV cure in all HCV genotypes. d. HCV genotype 3 is associated with higher rates of, and faster progression to, cirrhosis.

3. Which of the following direct-acting antiviral (DAA) regimens is classified as genotype-specific (that is, not active against HCV genotypes 2 and 3)? a. Elbasvir/grazoprevir b. Glecaprevir/pibrentasvir c. Sofosbuvir/velpatasvir d. Sofosbuvir + daclatasvir 4. Which of the following statements regarding pangenotypic (ie, active against all HCV genotypes) DAA regimens is correct? a. Sofosbuvir/velpatasvir is ineffective in genotype 3 patients with cirrhosis. b. Glecaprevir/pibrentasvir should be given for a minimum of 12 weeks in genotype 3 HCV. c. Real-world studies indicate that response rates with these regimens in genotype 3 are generally about half what has been reported in controlled trials. d. Most patients who experience virologic relapse have evidence of cirrhosis and/or had prior treatment with peginterferon/ribavirin.

TO TAKE THE POSTTEST please go to: ClinicalAdvisor.com/Jan18feature

44 THE CLINICAL ADVISOR • JANUARY 2018 • www.ClinicalAdvisor.com

What Should You Consider

Before Recommending an Over-the-Counter (OTC) Analgesic? Pain is one of the top reasons patients seek care from a healthcare provider (HCP).1

The right OTC analgesic recommendation matters.

In a survey of US adults,

58% of patients

discussed OTC medications with their physicians.2

Consider a Few Important Factors for Safe and Efficacious Pain Management

Assess coexisting medical conditions According to the Centers for Disease Control and Prevention,

133 million Americans have at least one

• 6.2% of US adults are undergoing therapy for ulcers4 • Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), may promote ulcer formation and bleeding5 • Acetaminophen is recommended as an alternative to NSAIDs in patients with gastrointestinal (GI) risks6 More than 26 million people (13%) in the United States have chronic kidney disease (CKD), and most are undiagnosed. Another 20 million are at increased risk for CKD.7

RENAL

• Acetaminophen is recommended as the analgesic of choice for patients with kidney disease8 • NSAIDs may cause kidney disease if taken long term and may increase the risk of sudden kidney failure8

An estimated 85.6 million US adults (>1 in 3) have ≥1 type of cardiovascular (CV) disease.7

HEPATIC

81% of 2590

US adults surveyed

claimed to have used at least one medication in the prior week.12

chronic illness or disease.3

Some OTC analgesic options may exacerbate the risk of adverse events in patients with certain coexisting medical conditions.

Assess concomitant medications

• 18.7% of US adults are undergoing therapy for hypertension4 • NSAIDs may increase blood pressure9 • Acetaminophen and aspirin are both recommended as the least risky pain medications for patients with CV risks9; however, any existing GI and renal concerns should also be considered • Although most people take acetaminophen appropriately,10 exceeding the recommended dose of acetaminophen poses a risk of liver damage11

OTC Analgesic Concomitant Medication Risk NSAID

• May cause GI bleeding when taken with anticoagulants6 • May cause GI bleeding when taken with steroids6 • May cause GI bleeding when taken with other NSAIDs6 • May interact with and decrease the efficacy of certain antihypertensive agents9

Acetaminophen

• May increase hepatic risk when taken with other acetaminophen-containing products

Ibuprofen

• May decrease the benefit of low-dose aspirin heart therapy9

Ensure patient understanding In a survey of pharmacy customers,

53.2%

were not aware of potential interactions between their prescription and OTC medications.13 It is important to help your patients understand all factors involved in making a safe and appropriate OTC analgesic choice. They need to know that your recommendations for an OTC analgesic are influenced by their coexisting medical conditions as well as current prescription and OTC medications. Each recommendation should be specific to a unique patient profile.

GetReliefResponsibly.com has more information for HCPs and patients. References: 1. Prunuske JP, et al. Opioid prescribing patterns for non-malignant chronic pain for rural versus non-rural US adults: a population-based study using 2010 NAMCS data. BMC Health Serv Res. 2014;14:563. 2. Sleath B, et al. Physician–patient communication about over-the-counter medications. Soc Sci Med. 2001;53(3):357-369. 3. Centers for Disease Control and Prevention. Chronic diseases and health promotion. http://www.cdc.gov/chronicdisease/overview/ index.htm. Updated August 13, 2012. Accessed March 12, 2014. 4. Aitken M, et al. Declining Medicine Use and Costs: For Better or Worse? A Review of the Use of Medicines in the United States in 2012. Parsippany, NJ: IMS Institute for Healthcare Informatics; May 2013. 5. Bhatt DL, et al; American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. 2008;118(18):1894-1909. 6. American College of Gastroenterology. Ulcers and gastrointestinal bleeding: protecting your health: what you should know about the safe and appropriate use of common pain medications. http://s3.gi.org/patients/pdfs/ulcerprotect.pdf. Accessed January 28, 2015. 7. Mozaffarian D, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131(4):e29-e322. 8. National Kidney Foundation. Pain medicines (analgesics). http://www.kidney.org/atoz/content/painMeds_Analgesics.cfm. Reviewed June 2009. Accessed January 28, 2015. 9. Antman EM, et al; American Heart Association. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007;115(12):1634-1642. 10. Kaufman DW, et al. Prevalence and correlates of exceeding the labeled maximum dose of acetaminophen among adults in a U.S.-based internet survey. Pharmacoepidemiol Drug Saf. 2012;21(12):1280-1288. 11. Bower WA, et al. Population-based surveillance for acute liver failure. Am J Gastroenterol. 2007;102(11):24592463. 12. Kaufman DW, et al. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002;287(3):337-344. 13. Indermitte J, et al. Prevalence and patient awareness of selected potential drug interactions with self-medication. J Clin Pharm Ther. 2007;32(2):149-159. © Johnson & Johnson Consumer Inc. 2016

YOUR COMMENTS REFERRAL TO A PSYCHIATRIC PROVIDER This nurse practitioner [Legal Advisor, “A patient commits murder,” November 2017, page 58] did not err by failing to consult with her partner. She erred by not referring this patient to a psychiatric provider. If her MSN program was anything like the one I attended, FNPs get one 3-hour class on mental health treatment. Prescribing a single antidepressant is fine in a primary care setting. The regimen she used is appalling.—RACHEL BOOKER, PMHNP-BC, Bangor, Maine (231-1)

MY MOST MEMORABLE PATIENT SIGNS OF PHYSICAL ABUSE IN A PATIENT I have been a physician assistant for more than 20 years now, but I encountered one of my most memorable patients in my Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 275 7th Avenue, 10th Floor, New York, NY 10001.You may contact us by e-mail at 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.

first year in practice. I was working at the women’s clinic for a county health department. A new patient came in for her routine annual Pap smear examination. She had her young son with her. During the exam, I noticed some suspicious bruises on her arms and asked her how she got the bruises. She said that she did not recall, but I could tell by the look on her face that she knew. I told her I was concerned for her safety and asked her if she was being abused. She said, “no.” I still shared with her resource information and phone numbers and encouraged her to seek help if she ever felt that she and/or her son were in danger. She thanked me and walked out of the clinic. About 6 months later, I received a letter from this patient. She thanked me for recognizing her abuse. She said that I was the first person to ever ask her about her bruises (which she frequently had), and my asking her about them made her realize that she could not hide the abuse and be in denial anymore. She informed me that a few weeks after her appointment with me she had found the strength and courage to leave her abusive husband. She and her son had moved out of state, were living with family, and were safe! This patient taught me a very valuable lesson. Sometimes it is hard to ask our patients personal questions. We don’t want to assume the worst or offend our patients. But if we aren’t asking them, who is? We have to be the strong ones and be advocates for our patients. It’s our job, and they are depending on us.—LINDA NEW, PA-C, DeBary, Fla. (231-2)

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.

46 THE CLINICAL ADVISOR • JANUARY 2018 • www.ClinicalAdvisor.com

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.

CASE FILES PULSATILE TINNITUS: A POUNDING SOUND INSIDE THE EAR Contributed by Sherril Sego, FNP-C, DNP (See photo at bottom of this page for more information about Dr. Sego.) A 72-year-old man presented to his primary care provider with a complaint of a pounding sound that he described as inside his right ear. An examination of the ear did not reveal any abnormality. The patient had mild hearing loss from years of working around machinery, but otherwise the ear itself was normal. Upon further examination, he was found to have a significant bruit in the right carotid artery. Carotid Doppler and magnetic resonance angiography (MRA) revealed significant vascular flow impediment throughout his cerebrovascular system. The sound he was hearing is referred to as pulsatile tinnitus. The condition is considered serious because it indicates that the patient is at high risk for a catastrophic event such as a stroke. In this case, the patient not only subsequently had a stroke 2 years later, but he also required coronary artery bypass surgery within 5 years. (231-3)

CONSULTATIONS TREATMENT FOR A PATIENT WITH AN EPIDIDYMAL CYST An 18-year-old male presents with sudden inguinal pain that did not result from an injury or lifting. A physical examination demonstrates no bulging at the inguinal canal. There is moderate tenderness, the testicle does not rise or fall with

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.

temperature change, and there is no erythema or swelling. The patient is not sexually active, his urine is negative, and there is no discharge or fever. A sonogram reveals a 9-mm epididymal cyst. The urologist is not concerned. How do you treat this patient?—PATRICIA SCHROEDER, FNP-C, Abilene, Texas Epididymal cysts are an incidental finding in approximately 30% of asymptomatic males. I am wondering about the location of the epididymal cyst found on ultrasound. The location of the cyst gives a helpful clue in defining the cyst. A spermatocele is a cyst that usually arises from the head of the epididymis. Its sac contains spermatozoa and is most often asymptomatic. A hydrocele usually arises from the anterolateral area of the testicle. Typically, it causes swelling of one or both testicles. A varicocele is a cluster of dilated veins arising from the spermatic cord. The patient often reports pain associated with physical exertion and relief upon rest. From the information you have provided, it sounds like this may be a spermatocele. These cysts are typically self-limiting. NSAIDs are recommended for discomfort. However, if the patient’s discomfort persists, then perhaps he should return to the urologist for re-evaluation. On occasion, surgical intervention such as spermatocelectomy or sclerotherapy is indicated.—Laura A. Foster, CRNP, FNP (231-4) n References 1. Crawford P, Crop JA. Evaluation of scrotal masses. Am Fam Physician. 2014;89:723-727. 2. Weerakkody Y, et al. Epididymal cyst. Available at: https://radiopaedia. org/articles/epididymal-cyst (Accessed December 27, 2017). 3. Pais VM, Kim ED. Spermatocele. Available at: https://emedicine. medscape.com/article/443432-overview (Accessed December 27, 2017).

Claire O’Connell, MPH, PA-C,

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

Katherine Pereira, DNP, FNP,

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

Sherril Sego, FNP-C, DNP,

is an independent consultant in Kansas City, Mo.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2018 47

Dermatology Clinic CASE #1

Papules on the soles of the feet of an infant LARAIB SAFEER, BS, CHRISTOPHER RIZK, MD

A 6-month-old infant presents with 2 weeks duration of erythematous papules on the soles of both feet and in the toe web spaces. On examination, a single burrow is visible on the left sole. Multiple family members also complain of a pruritic rash that has been bothering them for several months. The family members have tried multiple over-thecounter creams and remedies without success. The patient has no other medical problems or relevant family history. What is your diagnosis? Turn to page 50

CASE #2

A painless and non-itchy rash on a woman’s lower leg KAREN RESNICK, BA, DAVID RIZK, BA, CONNIE WANG, MD

A 53-year-old woman presents with a rash on her left lower extremity that has been present for several weeks. The patient is a native of Brazil and immigrated to the United States in the past month. She states that the rash is painless and does not itch. On examination, the patient has multiple, raised, hyperpigmented papules on the left lower extremity. There is a large, atrophic, hypopigmented patch on her lower shin, at the site of a previous large ulcer. The superior lesion is the newest, and is beginning to ulcerate. She has no other medical problems. What is your diagnosis? Turn to page 51 48 THE CLINICAL ADVISOR • JANUARY 2018 • www.ClinicalAdvisor.com

Dermatology Clinic CASE #1

Scabies

Scabies is caused by the Sarcoptes scabiei mite and is typically transmitted by direct contact.1 The intense pruritus with which it typically presents can be so debilitating that the disease is embedded in historic accounts, from the Ancient Greek physicians to the French revolutionaries, who supposedly had “the itch.”2 Although it is primarily a cutaneous infection, the potential for secondary bacterial skin infection links scabies to further complications such as lymphadenopathy, acute poststreptococcal glomerulonephritis, and rheumatic fever.3 The prevalence of scabies is higher in children than in adolescents and adults.4 The Global Burden of Disease Study of 2010 estimated a worldwide prevalence of 100 million cases, with the high disease burden in the Pacific region.4 Few quality, population-based studies are available despite the high disease burden; scabies was added to the World Health Organization’s list of neglected tropical diseases in 2013.3,4 Populations at increased risk include children, the elderly, and immunocompromised individuals.1,4 Scabies is also associated with malnutrition, reduced access to health care, poverty, and domestic crowding.1,4

Topical treatment with 5% permethrin, 10% or 25% benzyl benzoate, or 1% benzene hexachloride is effective for scabies. Clinically, patients have an intense pruritus that typically spares the head and neck.5 The pruritus can occur within 4 to 6 weeks of a first infestation, or within 24 hours of a reinfestation.5 A hyperinfestation of scabies may indicate an immunocompromised state.5 Lesions occur at the sites of mite infestation but can also result from hypersensitivity to mites or secondary to chronic rubbing and scratching.5 Lesions typically appear as erythematous papules (and sometimes pustules) and burrows. Intraepidermal burrows and papules may be visible as linear or serpiginous ridges commonly found in the finger webs, wrist flexures, elbows, or armpits, or on the breasts or in the genital region, and in the palms and soles of infants.1,5 Patients may be aware of similar symptoms in other household members.5

Histologically, primary lesions are characterized by epidermal hyperkeratosis, acanthosis, spongiotic edema, and vesiculation.6 Dermal perivascular and diffuse cell infiltrates are mainly composed of mononuclear cells and sometimes eosinophilic granulocytes.6 Secondary lesions have acanthuses and a perivascular inflammatory infiltrate composed of mononuclear cells.6 The number of circulating eosinophils and serum immunoglobulin E concentrations may correlate with the severity of the skin lesions.6 However, the most diagnostic and specific findings are the visualization of the mites, ova, or scybala (mite feces) in the stratum corneum. The differential diagnosis is broad and ranges from localized or generalized pruritus to eczema, delusions of parasitosis, adverse drug reactions, allergic contact dermatitis, or pruritus secondary to a metabolic condition.5 The intense pruritus can lead to excoriation and secondary bacterial infection, resulting in impetigo.1 Diagnosis is reached clinically and can be confirmed by visualization of the mites, mite eggs, or mite feces through microscopy (this can be easily and cheaply performed in any office setting with a basic light microscope).5 Microscopy can be performed by lightly scraping an area of burrows with a #15 blade, wiping the blade on a glass slide containing a layer of mineral oil, placing a coverslip over the slide, and viewing it under the microscope. An evidencebased diagnostic criteria is currently being formulated by the International Alliance for the Control of Scabies (Melbourne, Australia).4 Several treatment options are effective; the standard is to treat individuals and household members at the same time.4 Topical treatment with 5% permethrin, 10% or 25% benzyl benzoate, or 1% benzene hexachloride is effective, although drawbacks include expense of the medication and compliance with application over extensive body surface areas.4,5 In most areas, the first-line therapy is topical treatment with 5% permethrin. Permethrin should be applied on all skin from the neck down, and should not be washed off for at least 12 hours; this routine should be repeated 7 days later. Alternatively, 2 doses of oral ivermectin (200 mg/kg) can also be effective (first dose on day 1 and second dose on day 14).5 Mass administration of a topical treatment or oral medication such as ivermectin to an entire community has been effective in treating outbreaks in remote areas and localized outbreaks in institutions.4 However, treatment expense remains a drawback and the lack of safety data for ivermectin prevents use in young children and pregnant women.4 Pruritus can persist for several weeks after mite eradication.5 The rate of reinfestation through community or

50 THE CLINICAL ADVISOR • JANUARY 2018 • www.ClinicalAdvisor.com

household contacts remains high and control measures such as laundering all bed linen must be implemented.4 In this case, scabies was suspected because multiple family members appeared to have the same rash. A skin scraping was performed, and a mite was visualized under microscopy. The patient and all household members were treated with permethrin, which led to the resolution of the rash. Laraib Safeer, BS, is a medical student at the Baylor College of Medicine, and Christopher Rizk, MD, is a dermatology resident at the Baylor College of Medicine in Houston. References 1. Banerji A. Scabies. Paediatr Child Health. 2015;20:395-402. 2. Weisshaar E, König A, Diepgen TL, Eckart WU. About itching and scabies. Pruritis in medical history—from the ancient world to the French revolution [article in German]. Hautarzt. 2008;59:1000-1006. 3. Thomas J, Peterson GM, Walton SF, Carson CF, Naunton M, Kavya EB. Scabies: an ancient global disease with a need for new therapies. BMC Infect Dis. 2015;15:250. 4. Romani L, Steer AC, Whitfeld MJ, Kaldor JM. Prevalence of scabies and impetigo worldwide: a systematic review. Lancet Infect Dis. 2015;15:960-967. 5. Wolff K, Johnson RA, Saavedra AP, Roh EK, eds. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology. 8th ed. New York, NY: McGraw-Hill Education; 2017. 6. Falk ES, Eide TJ. Histologic and clinical findings in human scabies. Int J Dermatol. 1981;20:600-605.

CASE #2

Cutaneous leishmaniasis

Cutaneous leishmaniasis is a disease of the skin caused by an infection of the protozoa Leishmania.1,2 Though clinical presentations are diverse, cutaneous leishmaniasis commonly begins as a small papule that grows over time into a nodule before ulcerating.1-3 The disease affects individuals worldwide, with an estimated prevalence of 12 million cases.2 Over 90% of cases are seen in the Middle East, Brazil, and Peru; however, the disease has also been reported in Central Asia, Sub-Saharan Africa, India, and the United States.1 Cutaneous leishmaniasis is divided into two categories—Old World and New World—based on the geographic location

of infection. This distinction is important, as the 2 categories differ in Leishmania species, sandfly genus, clinical presentation, and prognosis.1 Old World leishmaniasis, or infections endemic to the Middle East, Northern Africa, Asia, and the Mediterranean, are caused by the L tropica complex (eg, L major, L tropica, L aethiopica). New World leishmaniasis, or infections endemic to Central and South America, and Texas, are caused by the L mexicana complex (eg, L mexicana, L amazonesis, L pifanoi, L venezuelensis) as well as the L Vianna complex (eg, L panamensis, L guyanensis, L braziliensis).3,4 The Leishmania protozoa is primarily transmitted through the bite of female sandflies; there are over 20 diverse species that cause disease.1 When an individual is bitten by an infected sandfly, promastigotes are injected into the skin. Promastigotes are taken up by macrophages and transform into amastigotes. Amastigotes burst out of the macrophage to infect fellow macrophages. Histologically, amastigote-filled macrophages are a clear sign of disease.3 In acute lesions, these cells are seen alongside lymphocytes, epithelioid cells, plasma cells, and giant cells. The parasites are identified by their round shape, basophilic nature, and organization along the periphery of the macrophages in a “marquee sign.” With time, the number of infected macrophages drops, with a simultaneous increase in giant cells, epithelioid cells, and histiocytes.4 Clinically, all cases present with a small papule 1 to 2 weeks after the patient is bitten by an infected sandfly. The subsequent development of the papule depends on the infecting Leishmania species. Most patients present with 1 or 2 papules that enlarge before developing an ulceration at their center.5 These lesions typically maintain a thick and raised margin and remain painless unless secondary infection occurs. Ulceration is typical for the New World and Old World species, L major.2 However, for Old World species L aethiopica and L tropica infection, instead of ulcerating, the papule may develop into a nodule or become hyperkeratotic.5 Most forms of cutaneous leishmaniasis resolve over time; however, exceptions include leishmaniasis recidivans, diffuse cutaneous leishmaniasis, mucocutaneous leishmaniasis, and post kala-azar dermal leishmaniasis.2 Leishmaniasis recidivans, commonly caused by L tropica and L braziliensis, presents with recurrent papules around the edges of a healed lesion. Diffuse cutaneous leishmaniasis is a severe form of infection in which L amazonesis or L aethiopica parasites spread to create multiple lesions that can manifest indefinitely. This rare form typically does not occur unless an individual is already immunocompromised. Mucocutaneous leishmaniasis is caused when infection from the L vianna complex infects the mucosal membranes. Lesions form on the lips, and in the

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2018 51

Dermatology Clinic nose and mouth, and can lead to degradation of cartilage. Post kala-azar dermal leishmaniasis is a skin eruption following the resolution of visceral leishmaniasis. It consists of a hypopigmented maculopapular rash.1,2 The clinical presentation of cutaneous leishmaniasis is often confused with infected insect bites, tropical ulcers, traumatic ulcers, pyoderma, foreign body granuloma, mycobacterial infections, fungal infections, malignant ulcers, and myiasis.5 Therefore, the diagnosis of cutaneous leishmaniasis relies on the appearance of amastigote-filled macrophages on a skin biopsy or tissue smear, or growth of the parasite in culture. New lesions are ideal for biopsy because chronic lesions have fewer parasites. In some cases, parasites may not be visible. Punch biopsies are recommended because they yield enough sample for a smear, histologic examination, culture, and polymerase chain reaction (PCR) analysis. PCR tests are sensitive when there are low numbers of parasites and are specific to different species of Leishmania.1-3 A serologic test

function test results. As such, bloodwork and regular followup may be recommended.1,2 New oral medications such as miltefosine have also been shown to be efficacious. Additional treatments include local heat therapy, cryotherapy, curettage, topical paromomycin, and oral imidazole drugs. However, studies demonstrate varying levels of efficacy.2 The patient in this vignette was diagnosed with New World cutaneous leishmaniasis. She was immediately referred to the local infectious disease experts for treatment. She was treated with sodium stibogluconate which led to the resolution of her infection. n Karen Resnick, BA, is a medical student at the Baylor College of Medicine, David Rizk, BA, is a medical student at the University of South Alabama, and Connie Wang, MD, is a dermatology resident at the Baylor College of Medicine in Houston. References 1. Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed.

The clinical presentation of cutaneous leishmaniasis is often confused with infected insect bites and tropical ulcers.

Philadelphia, PA: Elsevier Saunders; 2012. 2. Bailey MS, Lockwood DN. Cutaneous leishmaniasis. Clin Dermatol. 2007;25:203-211. 3. Reithinger R, Dujardin JC, Louzir H, Pirmez C, Alexander B, Brooker S. Cutaneous leishmaniasis. Lancet Infect Dis. 2007;7:581-596. 4. Patterson JW, ed. Weedon’s Skin Pathology. 4th ed. London, UK: Churchill Livingstone; 2016. 5. Hepburn NC. Cutaneous leishmaniasis. Clin Exp Dermatol. 2000;25:363-370.

52 THE CLINICAL ADVISOR • JANUARY 2018 • www.ClinicalAdvisor.com

“Not Chicken a la King again!”

called the leishmanin skin test exists; however, it may not be useful for diagnosis because the test does not distinguish between past and present infection.1,5 Treatment for cutaneous leishmaniasis varies by species of infection. Most Old World species, including L major and L tropica, resolve without treatment within 2 to 4 months or 6 to 15 months, respectively.1 Conversely, most New World lesions, with the exception of L mexicana complex infections, require treatment to avoid development of mucocutaneous leishmaniasis.2 Regardless, once the diagnosis of leishmaniasis is made, the patient should be referred to a leishmaniasis expert for treatment. Treatment is usually handled by infectious disease physicians in conjunction with the Centers for Disease Control and Prevention (Atlanta, GA). The main systemic treatment for cutaneous leishmaniasis and mucocutaneous leishmaniasis are parenteral pentavalent antimonial agents. First-line treatment for most New World lesions is intravenous or intramuscular sodium stibogluconate, 20 mg/kg/d for 20 days; doses should be lower for Old World lesions.5 A single course of sodium stibogluconate cures over 90% of New World leishmaniasis.5 Adverse effects have been noted with injected antimonial use, including elevated amylase or lipase levels, and elevated liver

Dermatologic Look-Alikes A bilateral, itchy rash McKENNA BOYD, BA, EMMA WEISS, BA, CHRISTOPHER RIZK, MD

CASE #1

CASE #2

A 40-year-old Hispanic man presents with a bilateral rash on his arms that has been present for several weeks. The patient says that the rash itches and appears to be getting worse. On examination, he has ill-defined erythematous patches and papules on his dorsal and ventral forearms, bilaterally. The patient has a past medical history of hypertension and diabetes. He works as a dishwasher in a restaurant and switched jobs approximately 2 months ago.

A 35-year-old white man presents for examination with a bilateral rash on his legs. The patient says that his rash has been present for several months and that it itches intensely. He has been applying copious amounts of over-the-counter hydrocortisone. The patient says that this helps a little, but it does not get rid of the rash. On examination, the patient has multiple circular, erythematous papular patches on his legs, but he has no other relevant medical history.

www.ClinicalAdvisor.com â&#x20AC;˘ THE CLINICAL ADVISOR â&#x20AC;˘ JANUARY 2018 53

Dermatologic Look-Alikes CASE #1

Contact dermatitis

Contact dermatitis is a localized inflammatory skin disease caused by the host’s reaction to exogenous irritants or allergens.1 It is further divided into irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD). ICD results from direct cytotoxic effect of a physical or chemical irritant upon initial or repeated contact. This reaction results in localized cytokine release,2 but does not induce an adaptive T-cell response. It typically presents with localized burning and stinging within 48 hours after exposure.3 In contrast, ACD is an allergic reaction in an individual previously sensitized to the allergen.1 Re-exposure to the allergen activates memory T cells to elicits a delayed (type IV) hypersensitivity reaction at the cutaneous site of contact.1,4 ACD typically presents with localized or patchy areas of erythema and pruritus.3 ICD is the most prevalent form of contact dermatitis and represents approximately 80% of occupational dermatitis.1 Individuals in professions necessitating prolonged exposure to wet conditions, such as food handling, healthcare professions, and cleaning, are particularly at risk for ICD.5 Mechanistically, prolonged exposure to water results in swelling of the stratum corneum, lipid disruption, and increased skin permeability.6 Other risk factors for ICD include female sex5 and history of atopic dermatitis.7 Common irritants include water, solvents, detergents, cleaning agents, and physical factors such as extreme temperature, humidity, or pressure.5 ACD has an estimated prevalence of 15% to 20%,8 and represents 20% of contact dermatitis cases.1 Risk factors for ACD include occupation, age,8 and (potentially) history of atopic dermatitis.9 Those in high-risk occupations include healthcare workers, florists, construction workers, and cosmetologists, due high exposure to allergic agents such as latex, resins, acrylics, and hair dyes.10 Although individuals of all ages are affected by ACD11, older adults show higher rates of ACD, likely due to increased exposure to potential allergens.12 Common allergens include poison ivy, metals, topical antibiotics, preservatives, paraphenylenediamine, hair care products, fragrances, and rubber.13,14 The pathogenesis of contact dermatitis begins with exposure to an exogenous substance. In ICD, this exposure results in epidermal barrier disruption that increases skin

permeability and transepidermal water loss. In response to cellular damage, keratinocytes release cytokines that ultimately recruit mononuclear and polymorphonuclear cells.15 This process results in symptoms within a few hours of irritant exposure. In contrast, ACD results in the activation of antigen-specific helper T cells.16 During the sensitization phase of ACD, dendritic cells migrate from the skin to lymph nodes and present captured antigens to effector T cells. Once activated, T cells proliferate, migrate to cutaneous tissues, and are primed to stimulate antigenspecific inflammation. The initial sensitization process take a few weeks to develop, but results in rapid inflammation with 48 hours upon re-exposure to the allergen. Clinically, patients with acute contact dermatitis present with localized erythema, dry skin, edema, oozing, crusting, and vesicular lesions.1 As the disease progresses, scales, hyperpigmentation, and acanthosis may appear.16 Chronic cases often present with lichenification and fissuring.1

Clinically, patients with acute contact dermatitis present with localized erythema, dry skin, edema, oozing, and crusting. Histologic changes in acute contact dermatitis include eosinophilic spongiosis and mononuclear infiltration.14 ACD cases may also present with lymphocytic infiltrate. Necrosis, neutrophilic infiltrate, and acanthosis may also be seen in severe cases of acute ICD. Histology of chronic stages may show chronic spongiotic dermatitis and lichenification. Diagnosis of contact dermatitis requires a detailed history of exposures, and occupational and recreational risk factors. Clinical features of ICD include (1) rapid postexposure onset of symptoms, (2) localized symptoms of pain, burning, and stinging, (3) erythematous, scalded epidermis or chronic features of hyperkeratosis, scaling, or lichenification, and (4) a negative patch test result.17 In contrast, ACD may present will a slower onset of symptoms dominated by pruritus and greater potential for diffuse or patchy distribution and/or spreading beyond the original contact site.1 In addition to a thorough history and physical examination, patch testing can be used to diagnose ACD.16 For this test, dilutions of chemicals are applied to the patient’s back and evaluated after 2 to 3 days. A positive test result is indicative of ACD; however, this diagnosis cannot be ruled out with

54 THE CLINICAL ADVISOR • JANUARY 2018 • www.ClinicalAdvisor.com

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Dermatologic Look-Alikes a negative test result, because not all potential allergens are represented. For both ICD and ACD, skin biopsy is not a routine diagnostic technique. The differential for contact dermatitis includes other forms of dermatitis (such as atopic dermatitis), psoriasis, seborrheic dermatitis, and fungal infection. Treatment of contact dermatitis begins with identification of the offending agent and subsequent avoidance of that irritant or allergen.1 If symptoms persist, treatment turns to limiting inflammation. First, barrier creams are used to limit irritant diffusion. Second, moisturizers or emollients limit water loss and restore epidermal barrier function. These should be applied several times a day and especially after bathing. Topical corticosteroids are an effective treatment for ACD in the short term, but should not be used extensively. Evidence is unclear if topical corticosteroids are effective for treatment of ICD. Topical calcineurin inhibitors, such as pimecrolimus cream or tacrolimus ointment, are second-line treatment options for ACD. The patient in this vignette was diagnosed with ICD. The patient was advised to wear full-arm gloves while washing dishes and to avoid excessive contact with soaps and water. With the use of gloves, his rash resolved within 1 month.

CASE #2

Atopic dermatitis (eczema)

Atopic dermatitis, commonly known as eczema, is a chronic pruritic inflammatory disease of endogenous origin.19 It typically manifests in children, but it may affect adults as well. Symptoms include pruritus, erythema, dry skin, exudate, crusting, and lichenification. Patients often present with a family history of atopy, the tendency to develop allergic diseases such as atopic dermatitis, asthma, and allergic rhinitis, and elevated serum immunoglobulin E (IgE) levels.19 Atopic dermatitis is more common in children than adults. Nearly 11% of American children are diagnosed with eczema.20 Most of these cases resolve; however, the disease may persist into adulthood.21 Persistence is associated with female sex, increased disease severity (higher levels of xerosis, pruritus, and impact on daily living), and age of onset between 6 and 11 years of age.22 During infancy, boys

show a higher prevalence of atopic dermatitis; interestingly, however, this prevalence switches to girls after puberty.23 Prevalence is also higher in developed countries1 and in patients with a family history of atopy.23 The cause of atopic dermatitis is complex, involving a combination of genetic, environmental, and immunologic factors that result in a defective skin barrier. In healthy skin, the stratum corneum consists of layers of dead cells, corneocytes, within a matrix of ceramides, cholesterol, free fatty acids, and filaggrin breakdown products, namely natural moisturizer factor (NMF).24 Disruption of this protective

Patients with acute atopic dermatitis present with pruritic papules and serous exudate that crust with scratching. barrier can lead to the excessive transepidermal water loss and increased susceptibility to microbial infection such as Staphylococcus aureus seen in atopic dermatitis.19,25 Loss-offunction mutations in the filaggrin gene result in defective barrier function and are associated with the development of atopic dermatitis.24 Reduced barrier function is also associated with unrestricted protease activity, abnormal tight junctions, microbes, and proinflammatory cytokines.25 Immune dysregulation has also been associated with atopic dermatitis. For example, the strong IgE response common to atopic dermatitis may be due to overexpression of type 2 helper T cells (Th2); however, the exact role of IgE is yet to be determined.26 Clinically, patients with acute atopic dermatitis present with erythematous, pruritic papules and serous exudate that crust with scratching.14,19 As the disease progresses, the skin becomes dry and scaly, and chronic stages are characterized by lichenification and hyperpigmentation.14 The typical presentation varies with age.19 Before 2 years of age, atopic dermatitis presents in acute stages on extensor surfaces, cheeks, and the scalp. In patients between 2 and 16 years, the disease typically presents in a flexural distribution, specifically the antecubital and popliteal fossae, neck creases, ankles, and wrists. During adulthood, atopic dermatitis becomes more localized, especially to flexures and often the face, and lichenification is common. Additional sites for adult eczema include the hand and eyelids. Histologically, acute atopic dermatitis presents with mild spongiosis, lymphocytic infiltrate, and parakeratosis.14 Later stages are characterized

56 THE CLINICAL ADVISOR â&#x20AC;˘ JANUARY 2018 â&#x20AC;˘ www.ClinicalAdvisor.com

by hyperkeratosis, parakeratosis, and acanthosis. Serology typically shows elevated IgE levels and eosinophilia. Diagnosis of atopic dermatitis relies upon patient history, clinical features, and morphology and distribution of skin lesions. Several diagnostic criteria have been created, namely the Hanifin and Raika criteria19 and the UK Working Party’s Diagnostic criteria for atopic dermatitis.27 The UK criteria defines atopic dermatitis as pruritic skin plus 3 of the following: (1) skin crease involvement, (2) history of asthma or hay fever, (3) dry skin within the past year, (4) symptoms before the age of 2 years, and (5) dermatitis of the flexural areas if >4 or dermatitis of the cheeks, forehead, or extensor surfaces if <4. Furthermore, several disease severity scales exist that assess factors such

area of skin affected, amount of itching, impact on sleep, and impact on daily living.28 Skin biopsy is not a routine diagnostic measure. The differential diagnosis for atopic dermatitis includes contact dermatitis, seborrheic dermatitis, and scabies.19 A patient with contact dermatitis presents with a history of irritant or allergen exposure and a localized inflammatory reaction. A patch test can be performed to determine a diagnosis of allergic contact dermatitis. Infants with seborrheic dermatitis present with greasy scales, salmon colored skin, and scalp involvement, and pruritus will not be a prominent symptom. Patients with scabies present with secondary eczematous changes in volar regions and skin folds. Detection of mites and eggs confirm a diagnosis of scabies.

Contact Dermatitis

DERMATOLOGIC PRESENTATION

Irritant

Allergic

Atopic Dermatitis

• Localized sites characterized by burning and stinging

• Localized or patchy sites characterized by erythema and pruritus

• Pruritic, erythematous plaques with acute exudation leading to crusting and eventual lichenification

• Acute: xerosis, crusting, vesicular lesions • Chronic: hyperpigmentation, acanthosis, lichenification ASSOCIATIONS

• Any age, but incidence increases with age • Any age, but incidence increases with age • Personal or family history of atopy • Personal or family history of atopy may often present be present • Female sex • Occupations with allergen exposure • Wet-work occupations (health care, (health care, cosmetologist, florist) food handling, cleaning)

• Disease typically presents in childhood, but may persist into adulthood • Personal or family history of atopy • High serum immunoglobulin E • Food allergies common • Cutaneous infections common

ETIOLOGY

• Direct cytotoxic effect of exogenous physical or chemical irritant

• Immunogenic (T-cell mediated) • Delayed type IV hypersensitivity to exogenous allergen

• Complex, involving genetic, environmental, and immunologic factors that result in a defective skin barrier

CHARACTERISTIC LOCATION

• Localized to site of contact

• Localized to site of contact, but may spread distally

• 0-2 y: face and extensors surfaces • 2-16 y: flexures • Adults: flexures and face

HISTOLOGY

DIAGNOSIS TREATMENT

• Acute: eosinophilic spongiosis with mononuclear infiltrate • Chronic: lichenification • Necrosis and neutrophilic infiltrate

• Lymphocytic infiltrate

• Acute: mild spongiosis, lymphocytic infiltrate, and parakeratosis • Chronic: hyperkeratosis, acanthosis, and lichenification

• History and physical examination • Negative patch test result

• History and physical examination • Positive patch test result

• History and physical examination • One of several atopic dermatitis criteria

• Identification and avoidance of irritant or allergen • Moisturizers, emollients, and barrier creams • Short-term topical corticosteroids (unclear effectiveness)

• Short-term topical corticosteroids • Second-line topical calcineurin inhibitors

• Minimize exacerbating factors • Moisturizers, emollients, and prescription moisturizers • Topical corticosteroids (mild-potency for maintenance and medium to highpotency for flares) • Topical calcineurin inhibitors • Sedating antihistamines • Phototherapy and/or dupilumab in severe cases

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Dermatologic Look-Alikes No cure exists for atopic dermatitis; however, several treatment options exist for symptom management. All patients should minimize exacerbating factors such as overheating skin, prolonged bathing, low humidity environments, food allergens, emotional stress.25,29 It is also important to maintain skin hydration, particularly after bathing, through use of creams, ointments, and prescription moisturizers containing natural moisturizer factor and ceramide, natural components of the epidermal matrix.25,30 Topical anti-inflammatory agents are enlisted if symptoms persist.25 Acute flares are managed with medium- to high-potency corticosteroids, but for maintenance it is recommended to use low-potency corticosteroids, especially when treating children.25,31 In addition, topical calcineurin inhibitors, such as pimecrolimus cream or tacrolimus ointment, are nonsteroidal immunomodulators used to limit inflammation in patients older than 2 years.19,25 To promote sleep

References 1. Rashid RS, Shim TN. Contact dermatitis. BMJ. 2016;353:i3299. 2. De Jongh CM, Verberk MM, Withagen CE, Jacobs JJ, Rustemeyer T, Kezic S. Stratum corneum cytokines and skin irritation response to sodium lauryl sulfate. Contact Dermatitis. 2006;54:325-333. 3. Ahmed S. Contact dermatitis. InnovAiT. 2015;8:653-659. 4. Saint-Mezard P, Berard F, Dubois B, Kaiserlian D, Nicolas JF. The role of CD4+ and CD8+ T cells in contact hypersensitivity and allergic contact dermatitis. Eur J Dermatol. 2004;14:131-138. 5. Dickel H, Kuss O, Schmidt A, Kretz J, Diepgen TL. Importance of irritant contact dermatitis in occupational skin disease. Am J Clin Dermatol. 2002;3:283-289. 6. Warner RR, Boissy YL, Lilly NA, et al. Water disrupts stratum corneum lipid lamellae: damage is similar to surfactants. J Invest Dermatol. 1999;113:960-966. 7. Dickel H, Bruckner TM, Diepgen TL, Schmidt A. Impact of atopic skin diathesis on occupational skin disease incidence in a working population. J Invest Dermatol. 2003;121:37-40.

Patients should minimize exacerbating factors such as prolonged bathing, food allergans, and emotional stress.

8. Peiser M, Tralau T, Heidler J, et al. Allergic contact dermatitis: epidemiology, molecular mechanisms, in vitro methods and regulatory aspects. Current knowledge assembled at an international workshop at BfR, Germany. Cell Mol Life Sci. 2012;69:763-781. 9. Thyssen JP, Linneberg A, Engkilde K, Menné T, Johansen JD. Contact sensitization to common haptens is associated with atopic dermatitis: new insight. Br J Dermatol. 2012;166:1255-1261.

and control pruritic symptoms, antihistamines are used; however, efficacy is unclear.31 One study did show sedating antihistamines to be superior to nonsedating antihistamines at controlling pruritus.32 For severe cases of atopic dermatitis, the addition of phototherapy1 or dupilumab19,33 may be indicated. Dupilumab is a human monoclonal antibody targeting the interleukin 4 receptor-α. It was approved for use in March, 2017, for moderate to severe atopic dermatitis not sufficiently controlled with topical options, and has shown large improvements in controlling pruritic symptoms. Therapeutic trials assessing its safety and efficacy are ongoing in the pediatric population.34 In addition, anti-infective measures should be taken, as these patients have a higher risk of infection.25 The adult in this vignette was diagnosed with nummular eczema, a type of atopic dermatitis that commonly presents as circular eczematous patches in adults. The patient was prescribed triamcinolone, 0.1% ointment twice daily. The rash was completely clear at the patient’s 1-month follow-up. n

10. Mowad CM, Anderson B, Scheinman P, Pootongkam S, Nedorost S, Brod B. Allergic contact dermatitis. J Am Acad Dermatol. 2016;74:1029-1040. 11. Simonsen AB, Deleuran M, Johansen JD, Sommerlund M. Contact allergy and allergic contact dermatitis in children – a review of current data. Contact Dermatitis. 2011;65:254-265. 12. Prakash AV and Davis MD. Contact dermatitis in older adults: a review of the literature. Am J Clin Dermatol. 2010;11:373-381. 13. Wentworth AB, Yiannias JA, Keeling JH, et al. Trends in patch-testing results and allergen changes in the standard series: a Mayo clinic 5-year retrospective review (January 1, 2006 to December 31, 2010). J Am Acad Dermatol. 2014;70:269-275. 14. Wu H, Brandling-Bennett HA, Harrist TJ. Noninfectious vesiculobullous and vesiculopustular disease. In: Elder DE, ed. Lever’s Histopathology of the Skin. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins;2015:237-240. 15. Spiekstra SW, Toebak MJ, Sampat-Sardjoepersad S, et al. Induction of cytokine (interleukin-1alpha and tumor necrosis factor-alpha) and chemokine (CCL20, CCL27, and CXCL8) alarm signals after allergen and irritant exposure. Exp Dermatol. 2005;14:109-116.

McKenna Boyd, BA, is a medical student, Emma Weiss, BA, is a medical student, and Christopher Rizk, MD, is a dermatology resident at the Baylor College of Medicine in Houston.

16. Kostner L, Anzengruber F, Guillod C, Recher M, Schmid-Grendelmeier P, Navarini AA. Allergic contact dermatitis. Immunol Allergy Clin North Am. 2017;37:141-152.

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17. Rietschel RL. Clues to an accurate diagnosis of contact dermatitis. Dermatol Ther. 2004;17:224. 18. Boehncke W-H, Schön MP. Psoriasis. Lancet. 2015;386:983-994. 19. Weidinger S, Novak NN. Atopic dermatitis. Lancet. 2016;387:1109-1122. 20. Shaw TE, Currie GP, Koudelka CW, Simpson EL. Eczema prevalence in the United States: data from the 2003 National Survey of Children’s Health. J Invest Dermatol. 2011:131:67-73. 21. Vinding GR, Zarchi K, Ibler KS, Miller IM, Ellervik C, Jemec GB. Is adult atopic eczema more common than we think?—a population-based study in Danish adults. Acta Derm Venereol. 2014;94:480-482. 22. Kim JP, Chao LX, Simpson EL, Silverberg JI. Persistence of atopic dermatitis (AD): a systematic review and meta-analysis. J Am Acad Dermatol. 2016;75:681-687. 23. Pyun BY. Natural history and risk factors of atopic dermatitis. Allergy Asthma Immunol Res. 2015;7:101-105. 24. Sandillands A, Sutherland C, Irvine AD, McLean WH. Filaggrin

“Of all the wet cement, in all the towns, in all the world, she walks into mine.”

in the frontline: role in skin barrier function and disease. J Cell Sci. 2009;122:1285-1294. 25. Leung DY. New insights into atopic dermatitis: role of skin barrier and immune dysregulation. Allergol Int. 2013;62:151-161. 26. Fallon PG, Sasaki T, Sandilands A, et al. A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nat Genet. 2009;41:602-608. Party’s Diagnostic Criteria for Atopic Dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol. 1994;131:383-396. 28. Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care for the management of atopic dermatitis. J Am Acad Dermatol. 2013;70:338-351. 29. Langan SM, Bourke JF, Silcocks P, Williams HC. An exploratory prospective observational study of environmental factors exacerbating atopic eczema in children. Br J Dermatol. 2006;154:979-980.

The old man, the sea, and the well-meaning neighbor.

30. Miller DW, Koch SB, Yentzer BA, et al. An over-the-counter moisturizer is as clinically effective as, and more cost-effective than, prescription barrier creams in the treatment of children with mild-tomoderate atopic dermatitis: a randomized, controlled trial. J Drugs Dermatol. 2011;10:531-537. 31. Strathie Page S, Weston S, Loh R. Atopic dermatitis in children. Aust Fam Physician. 2016;45:293-296. 32. Nuovo J, Ellsworth AJ, Larson EB. Treatment of atopic dermatitis with antihistamines: lessons from a single-patient, randomized clinical trial. J Am Board Fam Pract. 1992;5:137-142. 33. Beck LA, Thaci D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371:130-139. 34. Hamilton JD, Ungar B, Guttman-Yassky E. Drug evaluation review: dupilumab in atopic dermatitis. Immunotherapy. 2015;7:1043-1058.

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27. Williams HC, Burney PG, Hay RJ, et al. The U.K. Working

LEGAL ADVISOR CASE

A dosage change over the phone

BY ANN W. LATNER, JD

Dr H, 53, an internist, and her nurse practitioner, Ms B, 45, had been working together for several years at a large practice affiliated with a hospital. The clinicians worked well together, and Dr H relied on Ms B to handle things in the office when she was needed at the hospital. One of their patients was Mrs A, an 80-yearold widow who had numerous medical conditions, including chronic pulmonary emboli (for which she was taking warfarin), hypertension, coronary artery disease, congestive heart failure, chronic restrictive lung disease, chronic kidney disease, and severe osteoarthritis in her right hip. Despite her ailments, Mrs A was cheerful and upbeat, preferring to walk rather than use her wheelchair when possible. When Mrs A first came to the practice, about a year ago, Dr H noted that the patient was able to clearly relay her medical problems, knew what medications she was on, and was able to understand her treatment. At the first appointment, the physician took a blood test to check Mrs A’s INR level and found it to be low, at 1.5. She called the patient the next day to increase her dose of warfarin.

A clinician makes a dosage change for a patient during a telephone call, which leads to a lawsuit. The plaintiffs claimed that the patient was not competent to understand the directions and that the clinicians should have contacted a family member.

60 THE CLINICAL ADVISOR • JANUARY 2018 • www.ClinicalAdvisor.com

The physician explained to Mrs A that her optimal INR level was 2.0 to 3.0 and that Dr H would increase or decrease the warfarin dose as necessary to keep the INR at the right level. This was not new information to Mrs A, as her previous physicians had modified her warfarin prescription numerous times over the years. During the past year, the patient was seen frequently by both Dr H and Ms B and had her warfarin dosage modified at least five times by the clinicians. In January, Mrs A had a short hospitalization, and at the time of discharge her dosage was increased to 5 milligrams of warfarin daily at bedtime. At her follow-up appointment a week later on a Thursday evening, she met with Dr H. The patient brought all of her medication with her, including the warfarin, and asked questions about them. The physician ordered a blood test 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.

that evening to check the patient’s INR level. A follow-up appointment was scheduled for two weeks later, in early February. The blood work came back that night and revealed an elevated INR of 3.7. The physician knew she would be in the hospital the following day, so she emailed Ms B late that night, asking her to contact the patient and reduce the warfarin from 5 milligrams daily to 5 milligrams on Tuesday, Thursday, Saturday, and Sunday, and 4 milligrams on Monday, Wednesday, and Friday. The next day, Friday, Ms B received the email from the physician and contacted the patient. She reached Mrs A by phone that afternoon and explained the new dosage. “From now on, you’ll be taking 4 milligrams on Monday, Wednesday, and Friday, and you’ll be taking 5 milligrams on Tuesday, Thursday, Saturday, and Sunday,” she told the patient. She asked Mrs A if she understood the directions, and the patient said that she did. Ms B asked the patient to repeat the directions, and Mrs A was able to do so. After getting off the phone with the patient, Ms B called the prescription into the pharmacy and noted her conversation with the patient in the patient’s chart. She also emailed Dr H to advise her that the conversation had taken place. The follow-up appointment was left for the same date in February. Although the prescription was called in on Friday, Mrs A did not pick it up until Monday. Two days later, the patient was admitted to the hospital with extremity weakness, shoulder pain, limited arm motion, and an inability to feel or move her legs. Her INR was 5.36 and increasing. She developed a spontaneous bleed on her spinal cord, causing paralysis of her lower extremities. Despite the best efforts at the hospital, Mrs A continued to decline over the next several months until she died. After her death, the patient’s daughter retained an attorney and sued Dr H and Ms B, alleging that they failed to properly communicate the dosage decrease and improperly monitored her warfarin levels, leading to her death. Legal background

The case went to trial and ultimately hinged on the testimony of the medical experts and the documentation in the patient’s chart. The plaintiffs claimed that the patient was not competent to understand the directions and that the clinicians should have contacted a family member as well. However, the records showed that the patient had managed dosage changes with no problem in the past, even when it involved cutting pills in half. It would not have been appropriate to contact

the family because the patient had not given permission to do so, and her medications were confidential information. The plaintiffs claimed that an earlier follow-up appointment should have been scheduled after Mrs A’s dose was changed, but this would not have affected the outcome, and the experts admitted that a 7- to 14-day window for retesting INR was fine. The plaintiffs then argued that the dosage instructions on the 5-milligram warfarin bottle said, “take daily” and on the new 4-milligram bottle said “take on Monday, Wednesday, and Friday,” leading to the probability that Mrs A accidently took both a 5- and 4-milligram pill on the Monday she picked up the prescription. They argued that Ms B should have specifically told the patient not to take the 5-milligram pill on those days. The defense experts, however, testified that Ms B had met the standard of care by clearly explaining the change in dosage, and that it was being lowered (not raised), and having the patient repeat back the instructions, which she was able to do. After deliberating, the jury ultimately found the defendants not liable. Protecting yourself

Although you cannot always protect yourself from being sued, you can increase your odds of not being found liable by taking good notes, as the clinicians did here. The notes documenting the various changes in warfarin dosage, combined with new INR numbers showing that the patient was taking her medications correctly during the past year, set a foundation that the patient was competent, able to understand directions, and able to adjust her dosage. The documentation by Ms B of the patient’s last warfarin adjustment made it clear that the patient understood the change and was able to convey the new directions back to the clinician. Dosage changes, particularly in patients with chronic diseases, sometimes need to be made over the phone. While face-to-face conversations are always preferable, they cannot always happen. If you need to change a dosage via the phone, be sure that the patient understands the dosage change, can recite the change back, and understands the underlying reason for the dosage change. Do not rush these conversations, and consider asking the patient to write down, then read back, the new instructions. n Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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