December 2019 Clinical Advisor by The Clinical Advisor

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■ Nurse Burnout ■ Accuracy of EHRs ■ Rx for OUD ■ Autism in Rural Setting LEGAL ADVISOR

An Issue of Missed Diagnosis FEATURE

Clinical Review: Preventing HIV Infection in Men Who Have Sex With Men

DERMATOLOGY CLINIC

Raised Ringed Erythematous Plaque on Thigh

DERMATOLOGIC LOOK-ALIKES

Erythematous Facial Rash

DECEMBER 2019

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CANNABIS IN PRIMARY CARE

Spotlight on Cannabidiol: Overview of Current Product Development Are CBD products safe? Cannabis research is lagging behind public acceptance.

Director Nikki Kean nikki.kean@haymarketmedia.com Associate editor Madeline Morr Assistant editor Rita Aghjayan Production editor Kim Daigneau Group creative director, medical communications Jennifer Dvoretz Senior production manager Krassi Varbanov Director of audience insights Paul Silver National sales manager Alison McCauley, 973.224.6414 alison.mccauley @ haymarketmedical.com Associate account manager Michael Deverin, 732.343.4921 michael.deverin@haymarketmedia.com Publisher Kathleen Hiltz, 201.774.1078 kathleen.hiltz@haymarketmedia.com Vice president, content, medical communications Kathleen Walsh Tulley General manager, medical communications Jim Burke, RPh President, medical communications Michael Graziani CEO, Haymarket Media, Inc. Lee Maniscalco All correspondence to: The Clinical Advisor 275 7th Avenue, 10th Floor, New York, NY 10001 For advertising sales, call 646.638.6085. For reprints/licensing, email haymarketmedia@theygsgroup.com or call 800.290.5460. Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Features” are not the actual individuals mentioned in the articles. They appear for illustrative purposes only. The Clinical Advisor® (USPS 017-546, ISSN 1524-7317),Volume 22, Number 11. Published 11 times a year, by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001.

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Advisor Forum the color of the affected area was normal, the skin CLINICAL PEARLS felt quite thick and inflexible. These skin changes stopped abruptly at the collar line, below which POISON IVY PREVENTION the skin was entirely normal. Poison ivy season is starting! I recommend that Abundant evidence of sun damage — includ- people take an old pair of knee-high tube socks ing weathering, telangiectasias, solar lentiginosis, and cut off the foot part above the heel. Pull the and numerous actinic keratoses on prominent socks over the arms up to the start of their sleeve areas of his cheeks and ears — was noted. Similar (assuming they are wearing a T-shirt) and tuck changes were noted on the dorsa of both hands into gloves. Use the socks to protect arms when but were not present on his arms and trunk working in the yard or other high-risk poison because he wore long-sleeved shirts when in the ivy areas. They can be rolled off the arms and sun. Although he had worn a wide-brimmed hat thrown away, or washed and re-used. I remind while in the sun during his adult life, he had never people to always wear gloves, and to remove worn anything, such as a bandana, on his neck. the gloves before touching anything, including Always wear The posterior neck is especially susceptible door handles. This significantly reduces the gloves to to the effects of the sun, evidence of which fre- exposure area of skin to poison ivy. —JUDITH protect the quently manifests as it did in this patient. This MCINTOSH, MSN, Kokomo, Indiana skin from condition is called cutis rhomboidalis nuchae (CRN), which represents thickening and weathweath VERRUCA VULGARIS TREATMENT exposure to ering of the epidermis as well as solar elastosis I always recommend candida albicans skin anti- poison ivy, and of the underlying dermis caused by the sun. gen test injections for patients who are not remove them Although this condition is clear evidence of responding well to liquid nitrogen +/- paring for before touching chronic overexposure to the sun, CRN has no verruca vulgaris. A 0.1-mg injection every month anything. malignant potential, and treatment is neither for about 3 months creates an immune response required nor does it exist. against the warts. I have seen resolution of some Besides being common, CRN is unique in its recalcitrant cases that seemed most impossible! presentation, as well as in the patient population —SARAH LUP, PA-C, Chicago, Illinois it affects (eg, older patients with sun damage confined to the posterior neck), so the differen- RETHINKING PRESCRIBING tial is quite narrow. Punch biopsy would resolve DICLEGIS any confusion. Diclegis is the only FDA-approved prescription CRN puts this patient at higher risk for the medication for nausea and vomiting of pregdevelopmentThe of skin caused by sun expo- nancy that is classified as Category A (safe for se cancers are lette rssquamous sure, such asand basal cell carcinoma, cell mom and baby). Before writing a prescription, from prac successe titioconsider ners arou carcinoma, melanoma, and s,others. the price tag. Diclegis with a coupon obseThis nd the coun rvatpatient ions, andcosts approximately and others with similar histories require regular $345 try for 60 tablets. The pearls with who their to share their skin checks by a qualified dermatology provider most common dosagecolle is 2 tablets/dwan but tcan agues. We clinical chall at least once a year. Although this patient would be more. Some patients may obtain insurance invite you enges to participa be advised to protect himself from the sun, this coverage for this medication, but it will likely te. will do little to ward off any future skin cancers still cost something. Let’s break down Diclegis that will have been caused by sun overexposure CONSUL into its 2 active ingredients: doxylamine sucTAT occurring decades earlier. Application of sun- cinate IONand S pyridoxine hydrochloride (vitamin screen to his neck would prevent IRO worsening of B 6). Unless you are writing a prescription for N PILL 2. Cohen SM, Kwo PY, Lim, his CRN. a celebrity, recommend that your patients ON LIVE S AND THEIR JK. ACG clinical of abnorm Send us R ENZ al liver chemis ECT guideline: your purchase over-the-counter doxylamine YMESinsteadEFF Can takin evaluat tries. Am J Gastroe 3. Iron. ion g iron pills nterol. 2017;1 al Institute Reference letters with succinate and vitamin B 6 to take Nation at night elevate liver —AGNES 12:18-35. of Health nih.gov/Iron.h ques website. https:// enzymes? MURPHY, tm. Access for nausea. —AMBER PA-C, Bolognia JL, Jorizzo JL,tions Rapini RP. Dermatology. 1st ed. NewDEW, PCA and , Americus, livertox. ed April 3, commen 2019. Georgia Birmingham, Michigan York: Mosby, 2003;1380-1381. ts to: Liver enzym es Advisor Forum aspartate aminosuch as alanine amino , CASE FILE transfe The Clinica l Advisor, phatase are transferase (AST), and rase (ALT), S www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 45 275 7th Aven markers of alkaline phosfunction, and hepat ue, 10th CUTIS RHO should be referre ic injury, not hepat Floor, New Albumin, MBO ic York, d to as liver bilirubin, and chemistries. Contributed by Joe Monr IDALIS NY 10001 measures of prothrombin .You oe, MPAS, hepatocellu time are direct A 78-year-old may conta PA-C lar appropriately ct us heavily lined man presented characterized synthetic function and with thick e-mail at edito by skin on enzymes may are as “liver functio r@ be abnormal n tests.” Liver been present for an his posterior neck ened, clinicaladvis liver diseas that had even in patien indet or.com. Although e. The differe ts without the striking erminate period of Letters are ntial for elevat broad with time. skin chang tomatic, edited many be further define potential causative ed enzymes is insiste they were concerning es were asympfor length factors and and d that he be to his relativ d by the patien should risk factors. 1 clarity. The seen es who t’s by a medical histor The Clinical y and the patient had spent dermatology provider. Almost all Advisor’s policy nearl sun, farmi medications ng, ranching, y his whole life small risk of are associated is to print to his in elevat fishing, and the hepatotoxic 2 ed liver chemistries with at least a a histo property in rural tending author’s name Okla ity. Oral with ry homa or of witho iron skin cance . replacement with the letter r and claim He denied doses has little supplementation at typicaut good health. ed to be . liver or serum or No anony in The skin on enzyme elevati no adverse effects on l mous the patien or overdoses, the ons. However, contributio it in high doses lined and thickened t’s nuchal area was ns will of iron poison can cause acute hepato heavily . The multiple overla toxicity as a ing. be accepted. pping rhom lines joined to form result of ferrous sulfate Toxicity occurs after boidal shape ingestion of (approximat ≥3 g s. toxicity with Altho ely 10 tablets ugh aminotransf ). Severe the upper limit erases greate r overdoses and of normal typically than 25 times occurs with high initial larger serum iron dL). Mild levels to usually self-limmoderate cases of iron (>1000 ug/ whereas severe iting and resolve with poisoning are suppo KUSMIN cases become fatal rapidl 3 rtive care, SKY, PA-C y. —LAURA Referenc es

Advisor F

orum

Write us today.

1. Approach to the patient with abnorm and functio n tests. UptoD al liver bioche mical ate.com websit uptodate.com e. https://www. /contents/app roach-to-theabnormal-liver patient-with-biochemical -and-functionApril 2, 2019. tests. Access ed

44 THE CLINI

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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2019 1

CONTENTS DECEMBER 2019

NEWS 8

Newsline ■■Burnout a Concern Among Primary Care Nurses ■■Do Electronic Health Records Properly Capture ED Exams? ■■New Guideline for Use of Injectables for OUD ■■Autism Diagnostic Model Benefits Rural, Underserved Areas

41 Conference Roundup: CHEST 2019 Meeting 8 Burnout in Nurses

FEATURES 2 Spotlight on Cannabidiol: An Overview of Current 1 Product Development Because of increased interest, the Drug Enforcement Administration is improving access to research-grade cannabis.

24 Preventing HIV Infection

24 Clinical Review: Preventing HIV Infection in Men Who Have Sex With Men Comprehensive HIV prevention services, including counseling and the use of PrEP, can dramatically reduce the risk of HIV.

DEPARTMENTS

30 Hyperpigmented Lesion

39 Missed Diagnosis

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

Dermatology Clinic ■■Raised Ringed Erythematous Plaque on Thigh ■■Circumscribed Hyperpigmented Lesions on Hands

Dermatologic Look-Alikes Erythematous Facial Rash

Legal Advisor An Issue of Missed Diagnosis

MORE WAYS TO FIND US!

Like us on Facebook facebook.com/TheClinicalAdvisor Visit us on the web ClinicalAdvisor.com Download the app ClinicalAdvisor.com/App

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NEWS

FEATURES

ClinicalAdvisor.com/News

ClinicalAdvisor.com/Features

Ulcerative Colitis and Crohn Disease Linked to Increased Risk for Psychiatric Illnesses

Comorbidities in Atopic Dermatitis Atopic dermatitis, especially severe atopic dermatitis, is associated with allergic, autoimmune, and cardiovascular comorbidities.

Patients with inflammatory bowel disease have been shown to be at increased risk for psychiatric illnesses, although most studies have had limited patient populations.

AAP Recommendation for Bariatric Surgery in Obese Adolescents Substantial evidence has accumulated over the last decade to support the safety and efficacy of bariatric surgery in pediatric patients with severe obesity.

Optimizing Diagnosis and Management of PCOS in Adolescents Symptoms of PCOS typically manifest during the early pubertal years, though diagnosing this condition in adolescence remains a clinical challenge.

CASE STUDY

Official Blog of The Clinical Advisor ClinicalAdvisor.com/CaseStudy Brady Pregerson, MD Painful and Itchy Rash on Face, Torso, and Armpits A 42-year-old man presents for evaluation of a severe rash that mostly affects his face, torso, and armpits, the latter of which is the most severely affected area. The rash had occurred in the past and the patient’s physician prescribed a topical cream, but he does not recall what type of cream or any additional details about the condition. The rash is both painful and itchy. The patient has not had fever.

Telepsychiatry a Convenient Alternative for Older Vets Living in Rural Areas The majority of participants in the study reported liking or even preferring telehealth as a means of receiving psychiatric care.

HIV Drug Resistance Going Up Among Infected Infants Resistance to antiviral agents has increased among infants with HIV who live in a high prevalence setting where maternal antiretroviral therapy coverage has increased.

Weight Loss Maintenance Important for Cardiometabolic Risk Control in T2D The aim of this study was to assess the difference in cardiometabolic risk factors in individuals with T2D who either maintained weight loss or regained weight after a 1-year intensive lifestyle intervention.

THE WAITING ROOM

Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Jim Anderson, MPAS, PA-C, DFAAPA Provider Stigma in Treating Heroin Addiction: How Can We Eliminate It? Clinicians working with people with opioid use disorder can help to decrease the stigma and bias against these individuals. Continues on page 6

4 THE CLINICAL ADVISOR • DECEMBER 2019 • www.ClinicalAdvisor.com

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ClinicalAdvisor.com Advisor Dx

Interact with your peers by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit ClinicalAdvisor.com/AdvisorDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues. Check out some of our latest cases below!

DERM DX

Raised Hyperpigmented Lesions A 62-year-old black man presents for evaluation of a rash on his leg. The condition has been present for several months and is mildly pruritic. The patient currently takes oral medications for control of diabetes and hypertension, and he is positive for hepatitis C virus infection. Examination reveals scattered hyperpigmented annular lesions with slightly raised borders. CAN YOU DIAGNOSE THIS CONDITION?

• Granuloma annulare • Annular lichen planus

• Sarcoid • Discoid lupus

● See the full case at ClinicalAdvisor.com/DermDx_Dec19

ORTHO DX

In partnership with

Severe Chest Pain Following IV Drug Use A 32-year-old man presents with severe chest pain for the past week. He admits to a recent history of intravenous drug use but denies injury. Computed tomography shows erosive destruction of the medial cortex of the head of the left clavicle and adjacent sternum. Soft tissue swelling surrounding the sternoclavicular joint is also identified. WHICH IS THE BEST TREATMENT OPTION?

• • • •

Intravenous antibiotics Needle aspiration SC joint resection with intravenous antibiotics Complete sternectomy

● See the full case at ClinicalAdvisor.com/OrthoDx_Dec19

6 THE CLINICAL ADVISOR • DECEMBER 2019 • www.ClinicalAdvisor.com

TheJopa.org

Journal of Orthopedics for Physician Assistants

877.599.5327 / XLEAR.COM **

Newsline THE PREVALENCE OF burnout was found to be high among primary care nurses, especially younger nurses and those with higher levels of anxiety and depression, according to a study published in the International Journal of Environmental Research and Public Health. Researchers in Granada, Spain, conducted a cross-sectional study of 338 nurses (median age, 45.92 years; 58% women) by deploying a research questionnaire that analyzed sociodemographic and employment-related variables. Burnout was measured using the Maslach Burnout Inventory instrument and measured the frequency of certain dimensions on a Likert scale (from zero [never] to 6 [every day]). The revised NEO Personality Inventory was used to assess traits such as neuroticism, agreeableness,

and extraversion; an anxiety and depression questionnaire was also distributed to the participants. Approximately three-quarters (76.6%) of participants worked a fixed shift (morning, afternoon, or evening), and 86.8% performed on-call duties. Participants were employed for an average of 127.67 months in their respective positions and had an average of 273.66 months of professional seniority as nurses. A high level of burnout was seen in 40.24% of nurses; dimensions of emotional exhaustion and depersonalization were prominently found in participants with anxiety, depression, neuroticism, on-call duty, and professional seniority. Depersonalization was significantly associated with gender while emotional exhaustion correlated inversely with age.

Burnout a Concern Among Primary Care Nurses

A high level of burnout was seen in approximately 40% of nurses surveyed.

“This proﬁle of [primary health care] nurses that may be more prone to burnout syndrome should be taken into account by healthcare managers to establish preventive measures,” the authors concluded.“The implementation of measures to improve the working conditions of [primary health care] nurses would reduce levels of burnout and, therefore, enhance the quality of care provided.”

Do Electronic Health Records Properly Capture ED Exams? ELECTRONIC HEALTH records (EHRs) may not accurately represent physical examinations conducted by emergency department physicians, according to study results published in JAMA Network Open. The study found that the percentage of unsubstantiated documentation, described as inconsistencies between documentation and actual physical evaluation, was increased when information was less clinically relevant. To study how well EHRs reflect actual physical examinations, investigators reviewed 180 cases (mean [SD] age, 48.7 [20.0] years; 50.5% women) recorded by 9 resident physicians who were shadowed by 12 observers in 2 academic medical centers. Of these, 20 encounters (10 per physician/ site) were recorded, and the real-time observational data were compared with EHR data.

The outcomes were measured by the number of confirmed review of systems divided by the number of documented review of systems. The same measures were calculated for physical examination. For review of systems, audio recording data confirmed 38.5% of documented reviews, and concurrent observation confirmed 53.2% of documented physical examinations. “These results raise the possibility that some physician documentation may not accurately represent physician actions,” the investigators noted. “Further studies should be undertaken in other clinical settings to determine whether this occurrence is widespread. However, because such studies are unlikely to be performed owing to institution-level barriers that exist nationwide, payers should consider removing financial incentives to generate lengthy documentation,” concluded the investigators.

8 THE CLINICAL ADVISOR • DECEMBER 2019 • www.ClinicalAdvisor.com

Newsline New Guideline for Use of Injectables for OUD THE CANADIAN Research Initiative in Substance Misuse (CRISM) National Injectable Opioid Agonist Treatment Steering Committee has released a new guideline on the use of injectable opioid agonist treatment for opioid use disorder, particularly for patients with severe treatment-refractory opioid use disorder

ongoing illicit injection opioid use (quality of evidence, moderate; strength of recommendation, conditional). Evidence supports the efficacy of supervised injection of diacetylmorphine in combination with flexible doses of methadone over oral methadone for keeping patients with refractory opioid use disorder in treatment.

Treatment with injectable opioid agonists is recommended for patients with severe and treatment-refractory opioid use disorder, as well as those who still use illicit drugs. and concomitant opioid injection use. The full guideline was published in the Canadian Medical Association Journal. Treatment with injectable opioid agonists is recommended for patients with severe and treatment-refractory opioid use disorder, as well as for those with

Both diacetylmorphine and hydromorphone are deemed acceptable treatment options for patients who are considered for injectable opioid agonist therapy (quality of evidence, low; strength of recommendation, strong). Both treatments were found to be helpful for retaining patients

in treatment. The guideline also recommends providing injectable opioid agonist treatment as an open-ended treatment, with the option to switch to oral opioid agonist therapy after discussion between patient and provider (quality of evidence, low; strength of recommendation, strong). A limitation of many studies in which the use of injectable opioid agonist therapy in opioid use disorder is examined is the sole inclusion of participants who have previously received oral opioid agonist treatment (methadone, buprenorphine). “This guideline provides a framework for how to build a clinical practice of injectable opioid agonist treatment and recommends that this treatment should be considered for individuals with severe, treatment-refractory opioid use disorder and ongoing illicit injection opioid use,” concluded the guideline authors.

Autism Diagnostic Model Benefits Rural, Underserved Areas A DIAGNOSTIC model used at primary care clinics in rural and underserved communities helped to significantly decrease the time from first concern to a diagnosis of autism spectrum disorder (ASD), thus reducing wait times and potentially directing families to early interventions, according to study results published in the Journal of Developmental & Behavioral Pediatrics. A team of researchers conducted a study to expand on previous research supporting the use of a diagnostic model in primary care clinics to facilitate the early identification of young pediatric patients with ASD. The investigators collected data before and after the implementation of a streamlined model in primary care clinics providing health care in rural and underserved areas. The Screening Tool for Autism in Toddlers and Young Children, a playbased standardized assessment to detect

early social communication skills, was administered to 80 children (ages 19-47 months) across 5 different clinics to stimulate play, imitation, shared attention, and requesting. Patients were categorized as primary care (40 children) or nonprimary care (40 children); half of each population

A play-based screening tool reduced autism diagnosis time in rural areas.

10 THE CLINICAL ADVISOR • DECEMBER 2019 • www.ClinicalAdvisor.com

was seen either before or after the implementation of the streamlined model. After combining data for primary care and nonprimary care groups, use of the streamlined model resulted in a significant reduction in latency to diagnostic conclusion from an average of 144.7 to 49.9 days. Patients were more likely to experience greater decrease in wait times in primary care than in nonprimary care settings. Limitations to the study include the limited sample size, lack of data on family characteristics, and lack of information regarding increasing access to interventions and support services. “Implementation of a streamlined model for early identification of ASD dramatically improves wait times for diagnostic consultation and treatment plan within underserved and rural settings,” the investigators wrote. ■

FEATURE: MICHAEL T. ASBACH, MS, PA-C, PSY-CAQ

Spotlight on Cannabidiol: An Overview of Current Product Development Clinicians are routinely asked by their patients if CBD products are safe and effective, but research is lagging behind public acceptance.

ithin the past decade, cannabidiol (CBD) has become a fixture in the health supplement industry. CBD products are now easily found in retail settings and are associated with health claims ranging from analgesia to cancer prevention, often without scientific evidence to support the claims. Although legislative changes have removed legal restrictions on hemp and CBD, the legal framework within the United States remains complicated. However, despite legal ambiguity and uncertainty, cannabis sales are expected to reach $80 billion by 2030.1 A total of 33 states and the District of Columbia have legalized the medical use of cannabis; of these, 11 states and Washington, DC, have also legalized the recreational use of marijuana (Figure, page 14).2 The rapid expansion of over-the-counter CBD products has placed the primary care clinician in a difficult position. Patients routinely ask: “Are CBD products safe? Should I use CBD for my (fill in the blank) condition(s)?” In seeking the answers to these questions, clinicians are often provided with conflicting and confusing guidance. Cannabis vs Marijuana vs Hemp

The DEA has improved access to cannabis for research.

Cannabis is a generic term used to describe plants and products made from Cannabis sativa and Cannabis indica. Cannabis has been an agricultural fixture for more than 6000 years.3 Atakan reported in 2012 that at that time cannabis contained more than 400 chemical compounds of which Continues on page 14

12 THE CLINICAL ADVISOR • DECEMBER 2019 • www.ClinicalAdvisor.com

SPOTLIGHT ON CANNABIDIOL

Marijuana ■ Medical marijuana broadly legalized Legislation ■ Marijuana legalized for recreational use Status ■ No broad laws legalizing marijuana Source: Governing. State Marijuana Laws in 2019 Map.

FIGURE. Status of marijuana legalization in the US.2

approximately 60 were cannabinoids,3 and these numbers are growing. The 2 most-studied cannabinoids are CBD and Δ-9 tetrahydrocannabinol (THC). Cannabis is the preferred term when discussing medical products. Many medical cannabis products contain greater percentages of CBD than THC, while marijuana — which contains higher percentages of THC — usually refers to cannabis flowers or leaves that are used recreationally. Hemp is a variety of cannabis that has been cultivated for nonpharmacologic use and contains virtually no THC. Legally, hemp cannot contain more than 0.3% THC. Hemp fiber is often used in clothing and other industrial settings. CBD vs THC

While CBD and THC possess similar chemical structures, their effects are quite different and divergent (Table 1).3-6 Humans have 2 endogenous cannabinoid receptors: cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2). THC activates CB1, which is responsible for its psychoactive properties.6 CBD does not directly act on CB1 and carries a different pharmacologic profile.7 CBD appears to have a neuroprotective effect and mitigates the incidence of THC-induced anxiety, psychosis, and cognitive impairment.8,9 Murky Legal Status of Cannabis

As noted, the legal status of cannabis in the United States remains complicated. The 2018 Farm Bill changed the definition of marijuana to exclude hemp and legalized the production and sale of hemp plants and CBD preparations including “isomers, acids, salts, and salts of isomers, with a THC content

no more than 0.3% on a dry weight basis.”10 Any products with >0.3% THC, however, remain a Schedule I substance as per Drug Enforcement Administration (DEA) regulation.10 Federal prohibition of cannabis has made consistent procurement of pharmaceutical-grade cannabis products difficult. In August 2019, the DEA distributed a press release outlining its efforts to improve access to cannabis for research.“Over the last 2 years, the total number of individuals registered by DEA to conduct research with marijuana, marijuana extracts, derivatives, and THC has increased by more than 40% from 384 in January 2017 to 542 in January 2019,” noted the agency.11 Similarly, in the last 2 years, the DEA has more than doubled the production quota for marijuana each year based on increased use projections for federally approved research projects. Federally, CBD has been classified as a medicine, not a supplement.12 This does not equate to legality; instead, it communicates that oversight of CBD has shifted from the DEA to the US Food and Drug Administration (FDA).11 The FDA has determined that CBD is an investigational product and does not fall under the traditionally lax oversight afforded to dietary supplements. While the growth and sale of hemp is now legal, the FDA prohibits the sale and marketing of CBD with any associated health claims. At this time, the FDA has issued warning letters to but has not pursued prosecution of violators.13 Another pitfall of CBD legality is the mislabeling of THC content. Hemp often naturally contains a level of THC that exceeds the legal standard of 0.3%.While most plants are hermaphroditic, cannabis plants are male or female.When cannabis plants reproduce, dormant genes such as those that contribute to THC production may activate. Since pollination and TABLE 1. Comparison of THC and CBD Mechanism of Action and Effects3-6 THC

CBD

Mechanism of action

CB1 receptor binding

Mostly 5-HT1A and TRPV1 receptors

Psychoactive effects

Distortion of perception and time

None

Effect on anxiety

Anxiogenic

Anxiolytic

Sedating

Yes

None; may benefit sleep

Short-term memory impairment

Yes

None

Appetite

Increases appetite

None

CB1, cannabinoid receptor type 1; 5-HT1A, serotonin 1A receptor; TRPV1, transient receptor potential vanilloid 1

14 THE CLINICAL ADVISOR • DECEMBER 2019 • www.ClinicalAdvisor.com

reproduction results in less CBD production, most commercial hemp producers only use female plants to minimize the risk of sexual reproduction. However, hemp grown outside of a greenhouse remains susceptible to male pollen exposure, which can lead to THC production in previously CBD-only female plants.14 A retail CBD product that has not undergone rigorous lab testing may contain more THC than is considered legal (above the 0.3% limit set by the DEA). A recent study found that approximately 70% of CBD products are mislabeled, with many containing THC exceeding the legal standard of 0.3%.15 FDA-Approved Products and Clinical Data

The FDA has approved 4 cannabis-related products, including a cannabis-derived product (cannabidiol, Epidiolex®) that contains a purified form of CBD. In June 2018, the FDA approved Epidiolex for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients aged ≥2 years (Table 2).16-19 The most well-studied clinical use of CBD is in the treatment of epilepsy. The antiseizure activity of CBD has been examined in animals with research dating back to the 1970s.20 Outside of the standard drug approval process, prospective clinical data associated with CBD is scarce, making claims of efficacy in different therapeutic areas difficult. Khoury et al recently conducted a review of the clinical evidence supporting the use of CBD in psychiatric symptoms. Out of the 609 articles reviewed, the authors identified 6 case reports, 7 randomized clinical trials, and 21 registered clinical trials. Altogether, these studies included a total of only 201 subjects. The review concluded that the evidence is insufficient to support the use of CBD in psychiatric conditions.21 The lack of prospective clinical evidence regarding CBD should not lead to the conclusion that CBD lacks therapeutic potential. In addition to the studies leading to the approval of Epidiolex, extensive preclinical examination of CBD products has demonstrated promising therapeutic targets and speculation. One promising outcome of preclinical investigations is the potential for CBD to inhibit cancer.22 Researchers hypothesized that “through cannabinoid receptor and non-receptor signaling pathways, cannabinoids show specific cytotoxicity against tumor cells, while protecting healthy tissue from apoptosis.”22 Although the preclinical studies appear promising, clinical trials have yet to demonstrate efficacy of CBD in the treatment of cancer, and further research is required.23 Other preclinical studies suggest a therapeutic application in the treatment of addiction.24 Anxiety, insomnia, and analgesia are all conditions routinely associated with the medicinal use of cannabis, and these conditions have been examined thoroughly in preclinical studies.3-5, 8,9 In addition to the scarcity of clinical data, current preclinical and clinical studies have not identified a conclusive dosing range

TABLE 2. FDA-Approved Cannabis-Related Products16-19 Drug Name (generic)

Approval Date

Epidiolex® (cannabidiol)

2018

Treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients aged ≥2 years

Marinol® (dronabinol)

1985

Treatment of chemotherapy-related nausea and vomiting; AIDS-related anorexia

Syndros® (dronabinol)

2017

Treatment of chemotherapy-related nausea and vomiting; AIDS-associated anorexia

Cesamet® (nabilone)

1985

Treatment of chemotherapy-related nausea and vomiting

FDA-Approved Indication

for CBD. Currently, dosing of CBD ranges from 10 mg/d to 800 mg/d in studies, with tolerability observed in doses as high as 1500 mg/d.25 However, the CBD used in many studies was not a CBD-only product but rather a THC:CBD formulation. THC is potent at lower dosing and even a THC:CBD ratio of 1:25 may mask the effects of CBD by producing THC side effects.26 Due to decades of prohibition, medical cannabis was not subject to the traditional drug discovery process. As a result of the regulatory prohibition and subsequent liberalization of cannabis laws in just a few years, consumer availability and acceptance has outpaced clinical research efforts. Pharmacokinetics

CBD oil, a common formulation, is a concentrated extract dissolved in an edible oil.27 The use of solvents to extract the CBD varies among producers and can affect color, taste, and viscosity. Oil is favored among consumers due to the ease of ingestion, ability to receive high concentrated dosing, and avoidance of stigma that may be associated with smoking or vaping.27 However, CBD oil is poorly absorbed in the gastrointestinal tract, and oral bioavailability of CBD oil has been estimated at 6%.28 Aerosolized CBD has greater bioavailability than oral administration and rapid peak plasma concentrations.28 CBD is primarily metabolized through the liver; the 2 main cytochrome pathways involved are CYP3A4 and CYP2D6.29 More drugs are metabolized via CYP3A than any other P450 enzyme.30 The effects of CBD dose and absorption on drugdrug interaction requires further research. Safety

CBD consumption is not associated with risk of intoxication.31 Due to scarce clinical evidence, the available data on proper dosage, drug-drug interactions, and side effects are limited. In

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2019 15

SPOTLIGHT ON CANNABIDIOL

a review of the available evidence, CBD does not appear to change appetite or alter physiologic parameters, psychomotor functioning, or gastrointestinal transit time.27 Studies suggest chronic dosing of CBD up to 1500 mg/d is well tolerated.24 CBD does appear to affect hepatic drug metabolism and P-glycoprotein transporters.24 Pure CBD does not appear to have any recreational or abuse potential. In a World Health Organization report, the available literature reviewed demonstrated CBD to be well tolerated with a favorable safety profile.32 The FDA encourages clinicians to warn patients about purchasing CBD products online.“Selling unapproved products with unsubstantiated therapeutic claims — such as claims that CBD products can treat serious diseases and conditions — can put patients and consumers at risk by leading them to put off important medical care. Additionally, there are many unanswered questions about the science, safety, effectiveness and quality of unapproved products containing CBD,” said Acting FDA Commissioner Ned Sharpless, MD.33

POLL POSITION Which of the following is not a common side effect of cannabidiol (CBD)? 7.13% ■ Intoxication ■ Increased appetite ■ Sedation

8.79% 13.27%

70.81%

■ Memory loss

For more polls, visit ClinicalAdvisor.com/Polls.

CBD Drug Development Pipeline

Despite the availability of CBD in retail settings, CBD drug development is still an essential step toward the adoption and understanding of cannabis-based medicine. The rigorous drug development process provides valuable insight into the pharmacologic effects of a drug through phase 1, 2, and 3 studies. Drug development also provides a means of accountability for manufacturers through regulatory and peer-reviewed methods of oversight. To that end, several pure CBD drugs are currently in development (Table 3).34-38 Conclusion

CBD demonstrates promise in preclinical research, and numerous pharmaceutical companies are pursuing cannabis-based TABLE 3. CBD Drug Development Pipeline34-38 Company Name

Indication

Echo Pharmaceuticals (Netherlands)

Rett syndrome

Phase 1

Schizophrenia

Phase 1

Zynerba Pharmaceuticals

Fragile X and other epileptic neurologic indications

Phase 2

STI Pharmaceuticals (United Kingdom)

Marijuana-induced subjective effects

Phase 2

INSYS Pharmaceuticals

Infantile spasms

Phase 3

Prader-Willi syndrome

Phase 2

Childhood absence epilepsy

Phase 2

Neonatal hypoxic-ischemic encephalopathy

Phase 1

GW Pharmaceuticals

Status of Research

drug development. Recent regulatory changes have led to the explosion of CBD availability in retail and online markets. The quality and consistency of these CBD products are highly variable, which can lead to efficacy and safety concerns for consumers. In an ideal scenario, CBD products would not be available to consumers until they have been approved by the FDA; however, the genie is out of the bottle and clinicians are seeing an increase in the volume of questions from their patients regarding the use of CBD. While many issues remain unresolved, CBD appears to be well tolerated and safe. Clinicians must weigh the risks and potential benefits of CBD use in their patients. If clinicians choose to recommend CBD, they should ensure that their patients understand the importance of reputable product sourcing and the possibility of unreported THC content, which can cause positive drug testing among other potential unintended effects. Cannabis appears to be an exciting new frontier in drug development. The recent shift in public opinion and subsequent legalizations in various states have led to a rapid explosion of use and public adoption, with clinical research lagging behind. The lack of clinical research should not prompt clinicians to be pessimistic but rather cautiously acknowledge that the conclusive evidence is still pending. ■ Michael T. Asbach, MS, PA-C, Psy-CAQ is a physician assistant at DENT Neurologic Institute in Amherst, New York. Please go to ClinicalAdvisor.com/CBDFeature for a complete listing of references noted in this article.

16 THE CLINICAL ADVISOR • DECEMBER 2019 • www.ClinicalAdvisor.com

FEATURE: JEFFREY KWONG, DNP, MPH, ANP-BC, AAHIVS, FAANP

Clinical Review: Preventing HIV Infection in Men Who Have Sex With Men Providing culturally affirmative care and offering prophylaxis can help address the HIV epidemic in men who have sex with men. WORLD

AIDS DAY 12.1.19

n February 2019, the federal government announced a plan to reduce the number of new HIV infections in the United States by 75% within 5 years and by 90% within 10 years.1 In the United States, the burden of new HIV infections remains highest among men who have sex with men (MSM).2 The Centers for Disease Control and Prevention (CDC) estimates that of the 38,739 new cases of HIV reported in 2017, 70% were among MSM.2 Factors such as stigma, homophobia, poverty, violence, and racism have been identified as major contributors to the health disparities associated with the increased HIV prevalence among MSM.3 By providing MSM with culturally affirmative care and offering HIV prevention services, such as pre-exposure prophylaxis (PrEP) and non-occupational post-exposure prophylaxis (nPEP), nurse practitioners and physician assistants can help address the HIV epidemic among this population.

Assessing Risk: Asking the Right Questions

Clinicians can reassure patients of the confidential nature of the sexual history.

Providing comprehensive HIV prevention services begins with obtaining a thorough sexual history.4 Data have shown that many providers are not discussing sexual health with MSM, leading to missed opportunities for preventing HIV infection.4,5 Before taking a sexual history, clinicians should tell patients that the information being Continues on page 26

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PREVENTING HIV

Having an STI such as gonorrhea, chlamydia, or syphilis has been associated with greater risk of acquiring HIV in MSM. gathered is intended to ensure they are receiving appropriate care. Clinicians should reassure the patient of the confidential nature of the responses. A statement such as,“in order for me to provide you with appropriate care, I am going to ask you questions that I ask all of my patients. All of your answers will be kept confidential,” can help to inform the patient of the objective of the questioning and encourage cooperation. A pamphlet describing how to take a sexual history that includes asking the 5 “Ps”: partners, practices, past history of sexually transmitted infections (STIs), prevention of STIs, and plans for pregnancy is available on the CDC website.6 According to guidelines developed by the National Coalition of STD Directors and the National Network of STD Clinical Prevention Training Centers, the sexual history should be expanded to include a 6th “P” for pleasure, as comprehensive assessment of sexual history should include a discussion on sexual satisfaction and pleasure.4 Partners There are various ways to ask patients about their sexual partners. Some clinicians begin with a general screening question such as,“Do you have sex with men, women, or both?” Although this direct approach can be successful, another option is to use an open-ended request, such as,“Tell me about the gender of your partners.” This approach provides patients with an opportunity to define the gender of their partners. Not all MSM have sex exclusively with other men. Some MSM have sex with cisgender women, transgender men, and/or transgender women.7 Additionally, it is helpful to assess if they have a primary partner or if they have more than 1 partner. Some MSM may have a primary relationship that is sexually monogamous. Other individuals may have partners outside of their primary relationship. Understanding the gender of a patient’s partners and the number of partners can help determine the type of education, counseling, testing, and preventive health interventions that should be provided. Practices Once information about a patient’s partners has been obtained, clinicians should enquire about sexual practices. Does the patient engage in oral sex, anal sex, oral-anal sex (“rimming”)? Does the patient practice insertive sex (“top”), receptive sex (“bottom”), or both (“vers” or “versatile”)?8 Data have shown that physiologic changes in the rectal mucosa occur in MSM who engage in receptive anal sex, which places them at increased risk for HIV infection.9

Clinicians should enquire about other practices such as use of toys, fisting, and use of recreational drugs or substances while having sex. For the latter question, the clinician should ask about what type of drugs are used: for example, crystal methamphetamine (also known as “chemsex” or “party and play”), amyl nitrate (“poppers”), or alcohol.4 Answers to these questions can help provide a better assessment of risk for STIs, HIV prevention, need for extragenital screening, and/or other preventive health counseling or risk reduction interventions. History and Prevention of STIs Asking patients about prior STIs can provide information about the potential risk for HIV as well as risk for acquiring other STIs, such as gonorrhea, chlamydia, syphilis, or viral hepatitis. Clinicians should enquire about methods individuals use to prevent STIs, which may include condoms, other barrier methods, serosorting (a practice in which individuals only have sex with persons without HIV),10 or sexual positioning (being primarily the insertive partner or the receptive partner).4 Receptive anal intercourse has been associated with a higher probability of HIV infection compared with insertive anal intercourse (138/10,000 exposures vs 11/10,000 exposures, respectively).11 Condoms play a significant role in HIV and STI prevention. Condoms have been shown to reduce HIV infection by approximately 70% in MSM.12 The female condom can also be used by MSM as an alternative barrier method for receptive anal intercourse.4 Pregnancy Some MSM may also have sex with persons of childbearing potential. Clinicians should enquire about plans for pregnancy and need for contraception, if desired. Role of STIs and HIV Risk

Having an STI, such as gonorrhea, chlamydia, or syphilis, has been associated with increased risk of acquiring HIV in MSM.13 Sexually active MSM should be screened for STIs at least annually or more frequently based on risk.4 When screening for STIs, it is important for clinicians to remember that many oropharyngeal and rectal infections may be asymptomatic. Screening only for urethral gonococcal or chlamydial infection may miss asymptomatic infection in MSM.14 Therefore, clinicians should screen for oral and rectal STIs with the use of nucleic acid amplification testing (NAAT).4

26 THE CLINICAL ADVISOR • DECEMBER 2019 • www.ClinicalAdvisor.com

The CDC has reported that the use of daily PrEP has been shown to be more than 99% effective in preventing HIV infection. In 2019, the US Food and Drug Administration (FDA) approved NAAT for diagnosis of pharyngeal and rectal gonococcal and chlamydial infection.15 To obtain an oral NAAT specimen, clinicians can use a standard NAAT collection kit and swab the posterior pharynx, similar to the method employed for obtaining a strep culture. Obtaining a rectal NAAT specimen involves insertion of the collection swab gently into the anal canal slightly past the anal sphincter and rotating the swab for 5 to 10 seconds while the patient is in either a standing or lateral position.16 Lubricant should not be used as it can alter analysis of the specimen. Patients may also be instructed on self-collection of these specimens. Self-collection has been shown to be an effective method of obtaining specimens and can provide patients with greater privacy, if desired.17 Each specimen must be labeled according to the site of collection. Urine NAAT testing is appropriate for urethral STIs.4 Syphilis has been associated with an increased risk for future acquisition of HIV.13 Rates of syphilis among MSM have increased in the past several years.18 Testing for syphilis can be done via nontreponemal specific tests (eg, rapid plasma reagin [RPR]) or fluorescent treponemal antibody (FTA)specific tests.19 It is important for clinicians to remember that the FTA test will always be reactive in persons who have had syphilis previously. Screening for syphilis in sexually active MSM should be performed at least annually and more frequently based on reported risk.4 Sexually acquired hepatitis C virus (HCV) infection is seen more frequently among MSM, particularly among those living with HIV.20 Although HCV infection may be asymptomatic, clinicians should consider acute HCV infection in persons presenting with unexplained transaminitis, jaundice, or other signs and symptoms of hepatitis. The American Association for the Study of Liver Disease recommends baseline HCV testing in persons on PrEP and counseling all MSM about the risk of sexual HCV transmission with high-risk sexual and drug use practices.20 Vaccination should be offered to individuals not immune to hepatitis A or B virus.

fumarate (TDF) in combination with emtricitabine (FTC) (Truvada®) as the first oral agent for PrEP.23 Studies of Truvada in various populations (MSM, heterosexuals, and persons who inject drugs) have demonstrated efficacy in reducing HIV infection. The CDC has reported that the use of daily PrEP has been shown to be more than 99% effective in preventing HIV infection.24 In October 2019, the FDA approved a second PrEP option: tenofovir alafenamide (TAF)/FTC (Descovy ®).25 These 2 formulations are the only drug combinations approved for PrEP in MSM. Both formulations are HIV nucleoside reverse transcriptase inhibitors. The major difference between TDF/FTC and TAF/FTC is that TAF/FTC has been shown to have less effect on renal function and bone TABLE 1. Potential Candidates for HIV PrEP21,22 Men who have sex with men, who are sexually active, and who have one of the following characteristics: Engage in condomless sex with a partner whose HIV status is unknown, have untreated HIV, or have unsuppressed virus while on treatment for HIV Have had a recent sexually transmitted infection (STI) with syphilis, gonorrhea, or chlamydia Demonstrate inconsistent use of condoms during receptive or insertive anal sex Heterosexual women and men who are sexually active and have one of the following characteristics: Engage in condomless sex with a partner whose HIV status is unknown, have untreated HIV, or have unsuppressed virus while on treatment for HIV Demonstrate inconsistent use of condoms during sex with a partner whose HIV status is unknown and who is at high risk (eg, a person who inject drugs or a bisexual partner) Have had a recent STI with syphilis or gonorrhea

Pre-Exposure Prophylaxis

In 2019, the US Preventive Services Task Force recommended PrEP as a grade A recommendation for persons at high risk of acquiring HIV (Table 1).21,22 PrEP is an intervention that provides protection against HIV through the use of antiretroviral agents that are taken prior to sexual or drug-using encounters. In 2012, the FDA approved tenofovir disoproxil

Persons who inject drugs and have one of the following characteristics: Share drug injection equipment Are at risk of sexual acquisition of HIV

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2019 27

effective in preventing HIV infection.

PREVENTING HIV

TABLE 2. FDA Approved PrEP Therapies27,28 Tenofovir Alafenamide (TAF) / Emtricitabine (FTC)

Tenofovir Disoproxil Fumarate (TDF) / Emtricitabine (FTC)

Indications

Adults and adolescents weighing ≥35 kg who are HIV negative and at risk for sexually acquired HIV-1 infection, excluding individuals at risk from receptive vaginal sex

Adults and adolescents weighing ≥35 kg who are HIV negative and at risk for sexually acquired HIV-1 infection

Administration

One tablet daily with or without food

Dosing Restrictions

Discontinue if creatinine clearance <30 mL/min

Do not initiate if creatinine clearance <60 mL/min Discontinue if creatinine clearance <50 mL/min

TABLE 3. Pre-Prescription Laboratory Testing for PrEP or nPEP29,30 Laboratory Testing HIV antigen/antibody testinga Comprehensive metabolic panel Hepatitis A, B, and C serologies Screening for STIs • Gonorrhea and chlamydia (screen for infection in urethral, anal, and/or pharyngeal sites, as appropriate) • Syphilis Urinalysis a

For persons presenting with signs or symptoms of acute HIV infection (eg, fever, lymphadenopathy, mononucleosis-type illness), consider conducting HIV RNA testing.

TABLE 4. HIV nPEP Regimens30 Prescribe 28-day course of: TDF 300 mg/FTC 200 mg once daily WITH EITHER • Raltegravir 400 mg twice daily OR • Dolutegravir 50 mg once daily Additional Considerations Administer nPEP as soon as possible after exposure, up to 72 hours Repeat HIV antigen/antibody testing 4 to 6 weeks, 3 months, and 6 months after initial exposure At the conclusion of the 28 days of treatment, consider if patient may benefit from PrEP; if so, confirm HIV status and if uninfected, begin patient on PrEP

mineral density compared with TDF/FTC.26 Both medications are taken as one pill once daily (Table 2).27,28 Pre-Prescription Assessment

Specific pre-prescription laboratory testing should be performed prior to prescribing PrEP with either TAF/FTC or TDF/FTC (Table 3).29,30 Treatment of HIV infection requires a minimum of 2 different drug classes; therefore administering only TAF/FTC or TDF/FTC to a person with confirmed HIV infection can lead to drug resistance. This is one of the main reasons why it is important for clinicians to confirm a person’s HIV status prior to placing them on PrEP.23 An individual found to have HIV infection at baseline should be offered 1 of the recommended combination HIV antiretroviral therapy options based on the current CDC HIV treatment guidelines.23 The components of TAF/FTC and TDF/FTC have activity against hepatitis B virus (HBV).When persons with chronic HBV infection are prescribed TDF/FTC or TAF/FTC, these agents will also have an effect on HBV. Therefore, it is important to check the HBV status of any person with HIV prior to initiating therapy and monitor their liver function levels as there is risk for a flare of HBV infection following discontinuation of PrEP.23 Patients who are prescribed PrEP should be followed up at a minimum of every 3 months to monitor their HIV status. At each follow-up visit, clinicians should assess for any adherence issues, screen for STIs as appropriate, and periodically assess the need for ongoing PrEP. Renal function should also be assessed at least every 6 months in these patients.23 On-Demand or Event-Driven PrEP

For MSM who may not be at continuous risk for HIV but who still want to benefit from PrEP, the use of on-demand dosing (also known as “event-driven” or “2-1-1” dosing) may be considered.31 With on-demand dosing, individuals take 2 tablets of TDF/FTC between 2 and 24 hours prior to a sexual encounter and then continue taking an additional dose every 24 hours until there has been 2 consecutive days without sex. This regimen has been studied in several trials and is recommended by the World Health Organization, as well as the New York City and San Francisco Departments of Health.31-33 On-demand dosing is not recommended for individuals with chronic HBV infection. Non-Occupational Post-Exposure Prophylaxis

For individuals not on PrEP but who experience an exposure that puts them at risk for HIV infection, nPEP may be considered; nPEP should be started as soon as possible after exposure but not later than 72 hours after exposure.30

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right-hand column like this one does at the top

Baseline laboratory testing should be obtained and is similar to baseline testing for PrEP (Table 3). However, clinicians should not defer or delay starting nPEP if laboratory testing or results are not available prior to the first dose.30 Current guidelines for nPEP recommend a combination of TDF 300 mg/FTC 200 mg plus an integrase strand transfer inhibitor, either raltegravir 400 mg twice daily or dolutegravir 50 mg once daily (Table 4).30 The nPEP regimen should be taken for 28 days following an exposure. Clinicians should assess if individuals currently on nPEP would benefit from PrEP. If so, at the conclusion of the 28-day regimen, clinicians can transition individuals to PrEP with once-daily TDF/FTC or TAF/FTC.30 Follow-up antibody/antigen testing should be performed 4 to 6 weeks after initial exposure, with additional testing recommended 3 and 6 months post-exposure.30 If the person presents with signs or symptoms consistent with acute HIV infection (eg, fever, malaise, mononucleosis-like symptoms), the clinician should consider assessing HIV RNA viral load.34 All individuals on nPEP should be counseled to use additional protective barriers, such as condoms, until HIV status can be confirmed to avoid the possibility of transmission of HIV to others.30

screen for substance use and provide appropriate referrals or support for treatment. Interventions such as motivational interviewing and cognitive behavioral therapy have demonstrated some benefit in this setting.35 Persons who report ongoing substance use should be offered PrEP to minimize the risk of HIV infection.23 Conclusion

MSM remain a population at increased risk of acquiring HIV infection. One of the primary barriers to receiving appropriate HIV prevention services among MSM is a lack of culturally competent providers. Nurse practitioners and physician assistants can play a vital role in the assessment of these individuals, providing counseling about ways to minimize or prevent HIV and offering access to interventions proven to reduce the risk of acquiring HIV. By providing care that is culturally affirmative, clinicians can help address the disparity of HIV infection among MSM and help achieve the national goal of reducing the number of new HIV infections by 90% by 2030.1 ■ Jeffrey Kwong, DNP, MPH, ANP-BC, AAHIVS, FAANP, is a professor in the Division of Advanced Nursing Practice in the School of Medicine at Rutgers, The State University of New Jersey.

Substance Use

MSM who use substances, such as crystal methamphetamine, are at increased risk of acquiring HIV.34 Clinicians should

Please go to ClinicalAdvisor.com/HIVFeature for a complete listing of references cited in this article.

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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2019 29

Dermatology Clinic CASE #1

Raised Ringed Erythematous Plaque on Thigh CHRISTOPHER WONG, BA; ELEANOR JOHNSON, BA; CHRISTOPHER RIZK, MD

A 29-year-old white man presents with a 10-day history of a scaly, pruritic lesion on his right posterior thigh. His medical and family histories are unremarkable. On examination, the lesion is an annular erythematous plaque with trailing scale. The polycyclic plaque has a central clearing. Biopsy is performed, the results of which show a dense perivascular infiltrate and hyperkeratosis in the epidermis. Potassium hydroxide (KOH) test of the lesion is negative. What is your diagnosis? Turn to page 32

CASE #2

Circumscribed Hyperpigmented Lesions on Hands ALAY SHAH, BS; EMILY BURNS, BA; CHRISTOPHER RIZK, MD

A 10-year-old child presents for evaluation of a 5-day history of lesions on the hands. Examination reveals multiple circumscribed, hyperpigmented lesions. The lesions appeared 12 hours after the patient took oral ibuprofen for fever. Three months earlier, identical lesions appeared in the same locations after the patient took the same medication for 3 days. This first lesion healed after a few weeks, but some residual hyperpigmentation remained. What is your diagnosis? Turn to page 33 30 THE CLINICAL ADVISOR • DECEMBER 2019 • www.ClinicalAdvisor.com

Dermatology Clinic CASE #1

Erythema Annulare Centrifugum

Erythema annulare centrifugum (EAC), coined by Darier in 1916 and roughly translated as “centrifuged, ring-shaped redness,” is an uncommon chronic cutaneous eruption that presents as an outwardly expanding pink papule with an annular, arcuate, or polycyclic plaque.1 It is classified into a superficial variant, in which pruritic lesions have nonindurated borders and tend to desquamate, and a deep variant, in which lesions are typically nonpruritic and have firm, indurated borders without scaling.1,2 Limited epidemiologic data suggest that the condition can affect individuals of any race, sex, or age, but is seen with greater prevalence in adults, especially in the third and fourth decades of life.1 The etiology of EAC has not been elucidated, but it is thought that this condition is caused by a hypersensitivity reaction to infection, malignancy, systemic disease, medication, or pregnancy.1 In all of these cases, baseline physiology change is the recurring theme of disequilibrium in circulating immunologic factors or hormones. Therapeutic approaches

Due to its unknown etiology, erythema annulare centrifugum is often regarded as a diagnosis of exclusion. to EAC have therefore attempted to target the underlying disequilibrium that leads to dermatologic sequelae. In cases of EAC linked to cancer, for example, treatment of the neoplasm is correlated with resolution of the skin lesions, while relapse is associated with recurrence.1 Of the infectious risk factors, superficial dermatophytoses such as tinea pedis, onychomycosis, and tinea corporis have been noted in up to 40% of patients with EAC.2 Other associated infectious agents include but are not limited to Candida, mycobacteria, Molluscipoxvirus, herpes zoster, Epstein-Barr virus, and HIV.1,3 EAC can also present as a component of a paraneoplastic syndrome preceding the diagnosis of lymphoproliferative malignancies, breast carcinoma, and other cancers2,4,5 or as a concurrent condition in patients with liver, endocrine, or autoimmune disease.2,6 Induction of EAC has been reported with numerous drugs — including finasteride, azacitidine, rituximab, ustekinumab,

amitriptyline, gold sodium thiomalate, and ribavirin and pegylated interferon-α2a indicated for hepatitis C — with discontinuation of the drug leading to resolution of dermatologic symptoms.1 In addition, expectant mothers in the second and third trimesters of pregnancy have presented with EAC, albeit rarely; the lesions gradually fade shortly after delivery.1,7 The classic presentation of EAC is a patient who developed a pink papule on the buttock, thigh, or trunk that evolved into a larger plaque that has a lighter center with pronounced borders.1,2 While the diagnosis of EAC is primarily clinical, annular lesions that appear similar to it may be differentiated by histopathologic examination, particularly if they recur or are resistant to treatment. Classically, a dense infiltrate of lymphocytes, histiocytes, and eosinophils is distributed in a “coat-sleeve” pattern wrapped tightly around blood vessels.1 In the superficial type of EAC, changes are primarily restricted to the epidermal or upper dermal layers and may involve hyperkeratosis, parakeratosis, spongiosis, or vacuolar degeneration.1 In contrast, the deep type of EAC is associated with perivascular infiltrates along vascular plexuses in the upper and lower dermis with minimal, if any, disruption of the epidermis.1 The differential diagnosis of EAC includes infectious conditions such as erythema chronicum migrans (Lyme borreliosis) and tinea corporis, other hypersensitivity conditions such as annular urticaria and erythema multiforme, chronic conditions such as annular subacute cutaneous lupus erythematosus and annular psoriasis, and malignancies such as mycosis fungoides.1 Due to its unknown etiology and lack of distinctive clinical features, EAC is often regarded as a diagnosis of exclusion. A thorough and detailed patient history along with clinical findings should help eliminate other pathologies from the differential. In patients with a known or suspected diagnosis of infection, malignancy, or systemic disease, a full diagnostic workup should be performed to identify and optimize the management of underlying conditions that might precipitate the appearance of EAC. For patients who have recently started treatment with medications with reported associations to EAC, one should consider either alternative pharmacotherapies or symptomatic treatment of the skin lesion if the therapeutic benefit of the medication in question outweighs its dermatologic side effects. Pregnant patients presenting with EAC should be counseled regarding the natural progression and resolution of the disease, which is typically considered sufficient treatment due to the expected resolution of symptoms after delivery.1,7 In the absence of any risk factors or associated disease, EAC tends to follow a waxing-waning cycle in severity and may eventually disappear spontaneously.1,2 In a retrospective review, the duration of disease was found to be approximately 2 years,8

32 THE CLINICAL ADVISOR • DECEMBER 2019 • www.ClinicalAdvisor.com

with continuous lesions averaging 4.75 months.1,2 The superficial type of EAC tends to be more resistant to treatment and recurs at a higher rate, whereas exacerbations of the deep type tend to be of longer duration.1 Most treatments are targeted at symptomatic relief, rather than shortening the trajectory of the illness. Topical corticosteroids, topical vitamin D analogs, and oral antihistamines may be prescribed to alleviate pruritus. Oral steroids have been shown to fade plaques; however, rebound recurrence of EAC can occur with sudden cessation of treatment.1,2 More recently, antifungal agents and antibiotics including fluconazole, erythromycin, and metronidazole have demonstrated substantial benefit in a limited number of case studies.1,8-10 The paucity of robust clinical data suggests that one should only consider these treatment options if EAC is believed to be secondary to an underlying infectious cause or if the lesion has been resistant to other therapies. The patient in the case described decided against therapy, and his rash resolved after 6 months with supportive care. Christopher Wong, BA, and Eleanor Johnson, BA, are medical students at Baylor College of Medicine, and Christopher Rizk, MD, is a dermatologist at Elite Dermatology in Houston,Texas. References. 1. Ahn CS, Huang WW. Erythema annulare centrifugum and other figurate erythemas. In: Kang S, Amagai M, Bruckner AL, et al, eds. Fitzpatrick’s Dermatology. 9th ed. New York, NY: McGraw-Hill; 2019. 2. Kim KJ, Chang SE, Choi JH, Sung KJ, Moon KC, Koh JK. Clinicopathologic analysis of 66 cases of erythema annulare centrifugum. J Dermatol.

CASE #2

Fixed Drug Eruptions

First described in 1889 by Bourns, fixed drug eruptions (FDEs) are a common immune-mediated mucocutaneous reaction to the consumption of a variety of different medications.1 Typical presentation is an acute-onset lesion on the facial, labial, and/ or genital surfaces that can range from red-brown to violaceous in color with or without blistering.2,3 Morphologically, this drug-induced dermatosis may range from a round to oval erythematous macule to an edematous plaque.1,3 Lesions may be localized to 1 location or involve several areas of the body. FDEs rarely involve constitutional symptoms such as malaise, anorexia, or fever. Patients may report pruritus or a burning sensation associated with the lesion.1 The lesion will resolve eventually, usually within days to weeks, and leave residual pigmentation.2 The variable clinical manifestations of FDE broaden the differential, especially in the absence of a thorough history. The timeline for FDEs varies depending on the individual patient’s sensitivity to the offending drug, and FDEs may arise spontaneously after short- or long-term use of the medication. In addition, patients tend to forget or fail to mention use of over-the-counter drugs or drugs taken sporadically. Therefore, a thorough history is required for the diagnosis.

2002;29(2):61-67. 3. Chu C-H, Tuan P-K, Yang S-J. Molluscum contagiosum-induced erythema annulare centrifugum. JAMA Dermatol. 2015;151(12):1385-1386. 4. Chodkiewicz HM, Cohen PR. Paraneoplastic erythema annulare centrifugum eruption: PEACE. Am J Clin Dermatol. 2012;13(4):239-246. 5. Topal IO, Topal Y, Sargan A, et al. Erythema annulare centrifugum as present-

A distinguishing feature of fixed drug eruption is the tendency to recur at the same location after medication use.

ing sign of activation of breast cancer. An Bras Dermatol. 2015;90(6):925-927. 6. Chander R, Yadav P, Singh A, Nangia A. Systemic lupus erythematosus presenting as erythema annulare centrifugum. Lupus. 2014;23(11):1197-1200. 7. Chiang CH, Lai F-J. Pregnancy-associated erythema annulare centrifugum. J Formos Med Assoc. 2015;114(7):670-671. 8. Kruse LL, Kenner-Bell BM, Mancini AJ. Pediatric erythema annulare centrifugum treated with oral fluconazole: a retrospective series. Pediatr Dermatol. 2016;33(5):501-506. 9. Chuang F-C, Lin S-H, Wu W-M. Erythromycin as a safe and effective treatment option for erythema annulare centrifugum. Indian J Dermatol. 2015;60(5):519. 10. De Aloe G, Rubegni P, Risulo M, Sbano P, Poggiali S, Fimiani M. Erythema annulare centrifugum successfully treated with metronidazole. Clin Exp Dermatol. 2005;30(5):583-584.

A distinguishing feature of FDE is the tendency for the eruption to recur at the same location following medication use.4 The lips, genitalia, and upper extremities are some of the more common sites for FDEs.5-7 Medications implicated in this reaction include antibiotics such as trimethoprim-sulfamethoxazole1; nonsteroidal anti-inflammatory drugs such as ibuprofen, naproxen, and piroxicam1; analgesics such as acetaminophen1; antifungal agents such as fluconazole1 and cotrimoxazole6; uric acid reducers such as allopurinol1; phosphodiesterase type 5 inhibitors such as tadalafil4; and omeprazole,1 among many others. The broad range of offending agents, which continues to grow in number, is an additional challenge with regard to the differential diagnosis.

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Dermatology Clinic The incidence of FDE is variable and influenced by factors such as drug availability, typical use of drugs, medical literacy, and various social determinants of health.1 FDEs do not seem to predilect for either sex, as studies have observed slight male or female predominance.1,7 Additionally, FDE does not have a proclivity for a specific age group, although the majority of cases are found to to occur in people who have a history of FDEs.8 Patients taking higher-risk medications are susceptible to having an eruption. Although multiple hypotheses exist with regard to the pathogenesis of FDEs, histologic changes associated with FDEs have been described to occur in the epidermis and upper dermis, specifically involving degeneration of the basal layer. Inflammation and edema mediated by lymphocytes, neutrophils, histiocytes, and mast cells have been theorized. High-risk drugs may induce tumor necrosis factor-α (TNF-α)-dependent keratinocytes to express intercellular adhesion molecule-1 (ICAM-1), which would then serve as the stimulus for T-lymphocyte-driven damage. In particular, intraepidermal CD8+ T cells are the effectors that promote epidermal injury. After initial injury, CD8+ T cells are primed for future insult. Cytokines released by CD8+ T cells recruit further lymphocytes, which induce damage. This complex mechanism is further influenced by factors such as varying genetic susceptibility. More research is required to determine the exact cellular mechanism of FDEs.1,3 A thorough patient history and visual examination may narrow the differential diagnosis to Stevens-Johnson syndrome, hypermelanosis, discoid lupus erythematosus,7 localized

performed to check for lesion recurrence.11 The goal is to determine the medication that is responsible so as to discontinue its use. Finding the culprit can be difficult in patients taking multiple drugs or medications with more than 1 active agent.1 Patients should be provided a comprehensive list of trade and generic names of medications to avoid in the future. In addition to discontinuing the offending medication, further treatment depends on the location of the lesion. In nonmucosal areas, topical corticosteroid therapy can be applied to resolve active lesions.4 Mucosal lesions can be treated with gingival hyaluronic acid 0.2% gel.4 Oral antihistamines have also been used to reduce the pruritus associated with active lesions.9 In the case described above, suspicion of FDE caused by ibuprofen was confirmed by a provocation test to check for recurrence of the lesion in the same area. Once the association between the medication and the FDE was established, ibuprofen for fever management was discontinued and an alternative such as acetaminophen was recommended. The patient’s parents were also advised to monitor for FDEs with other medications. Corticosteroids and antihistamines were also prescribed to reduce acute inflammation. ■ Alay Shah, BS, and Emily Burns, BA, are medical students at Baylor College of Medicine, and Christopher Rizk, MD, is a dermatologist at Elite Dermatology in Houston,Texas. References 1. Sehgal VN, Srivastava G. Fixed drug eruption (FDE): changing scenario of incriminating drugs. Int J Dermatol. 2006;45(8):897-908. 2. Duarte de Sousa IC. Fixed drug eruption. New Engl J Med. 2011;365:e12.

A provocation test using oral or topical challenge can be performed to confirm the diagnosis of fixed drug eruption.

3. Shiohara T. Fixed drug eruption: pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol. 2009;9(4):316-321. 4. Bjekic M, Markovic M, Sipetic S. Fixed drug eruption caused by tadalafil – case report. An Bras Dermatol. 2013;88(4):617-619. 5. Jung J-W, Cho S-H, Kim K-H, Min K-U, Kang H-R. Clinical features of fixed drug eruption at a tertiary hospital in Korea. Allergy Asthma Immunol Res. 2014;6(5):415-420.

bullous pemphigoid, herpes simplex labialis, or nonpigmenting FDE.1 While diagnosis of FDE is typically made based on patient history and does not usually require histologic examination, a certain diagnosis of FDE involves a small punch biopsy to examine the epidermis and upper dermis.9 Biopsy may be indicated if the patient is uncertain about his or her medication history or has an unusual presentation. Histologic features of FDE include superficial and deep eosinophilic infiltrate, papillary dermal fibrosis, and basal layer hydropic change.10 To confirm this diagnosis with a less-invasive approach, a provocation test using oral or topical challenge can be

6. Ozkaya‐Bayazit E, Bayazit H, Ozarmagan G. Drug related clinical pattern in fixed drug eruption. Eur J Dermatol. 2000;10(4):288‐291. 7. Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol. 1998;379(11):833-838. 8. Jhaj R, Chaudhary D, Asati D, Sadasivam B. Fixed-drug eruptions: what can we learn from a case series? Indian J Dermatol. 2018;63(4):332-337. 9. Flowers H, Brodell R, Brents M, Wyatt JP. Fixed drug eruptions: presentation, diagnosis, and management. South Med J. 2014;107(11):724-727. 10. Elston DM, Stratman EJ, Miller SJ. Skin biopsy: biopsy issues in specific diseases. J Am Acad Dermatol. 2016;74(1):1-16. 11. Ozkaya E. Fixed drug eruption: state of the art. J Dtsch Dermatol Ges. 2008;6(3):181-188.

34 THE CLINICAL ADVISOR • DECEMBER 2019 • www.ClinicalAdvisor.com

Dermatologic Look-Alikes Erythematous Facial Rash CLAIRE JORDAN WIGGINS, BS; MICHELLE EUGENE LEE, BA; CHRISTOPHER RIZK, MD

CASE #1

CASE #2

A 14-year-old girl is brought to the dermatology clinic by her mother for evaluation of a rash on her face and back that has not improved despite washing her face daily. On physical examination, the patients has a number of open and closed comedones with scattered erythematous papules and mild scarring. The girl’s skin feels oily to the touch and is not itchy. The patient has no other relevant medical or social history. She has not tried any treatment regimens.

A 25-year-old woman presents to the dermatology clinic complaining of an intermittent red rash on her face. She experiences worsening redness when she eats spicy foods or when she is stressed at work. She notices flares during the summer and winter months, although she reports them as occurring more frequently in the summer. The rash burns but does not itch. Upon examination, there are telangiectasias around the nose with few erythematous pustules on the lateral cheeks and central face.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2019 35

Dermatologic Look-Alikes CASE #1

Acne Vulgaris

Acne vulgaris is a chronic inflammatory condition of the cutaneous pilosebaceous unit. It is among the most common dermatologic complaints, affecting approximately 9% of the world’s population,1 and it has been recognized as a treatable condition since the time of the ancient Greek physicians Aristotle and Hippocrates.2 The phrase “acne vulgaris” is likely derived from the ancient Egyptian terms aku-t, which means boil, pustule, or inflamed swelling, and vulgaris, meaning “common” in Latin.2,3 Factors such as bacterial colonization by Propionibacterium acnes, hormone-related sebum production, aberrant keratinization, and local inflammatory response play a role in the pathogenesis of acne, although how these factors interact is incompletely understood.4,5 The microcomedone, the precursor lesion in acne, forms from follicle obstruction due to dysfunction in epithelial desquamation. Excessive androgen-induced sebum production creates a favorable anaerobic environment for P acnes to flourish, resulting in an inflammatory reaction and keratinocyte proliferation.6

The goals of treating acne are to prevent future outbreaks, resolve existing lesions, and limit scarring. Acne can present as comedones, papules, nodules, and/or cysts. Although acne can affect individuals of all ages, prevalence is highest during puberty, with as many as 80% to 95% of adolescents affected. Facial scarring due to acne occurs in approximately 20% of teenagers, and perseverance of acne into adulthood is not uncommon.4,7 Acne affects both genders equally.8 Clinical manifestations of acne can range from mild to severe and most commonly affect the face, back, and chest, where sebaceous glands are most concentrated. Family history, supported by twin studies, and environmental factors, such as climate and pollution exposure, have been shown to contribute to the development of acne, but the relation of diet and smoking with acne is less clear.7 Several studies have linked intake of refined carbohydrates and certain dairy products to acne.9,10 A diagnosis of acne is made by identifying the characteristic lesions on physical examination, with further classification based on type and severity of lesions. Comedonal acne is

noninflammatory and contains dilated follicles with keratin, sebum, and bacteria. Whiteheads are closed comedones, while blackheads are open comedones filled with debris. Papulopustular acne is a type of inflammatory acne characterized by pustules containing a center of purulent material and pink or red papules measuring 2 mm to 5 mm in diameter. Nodular acne involves raised inflammatory lesions measuring >5 mm in diameter. Acne can be described as mild, with less than 30 total lesions; moderate, with 30 to 125 lesions; and severe, with more than 125 lesions or more than 5 nodules.11 Histologically, acne is defined by the dilation of normal sebaceous glands, forming comedones. Perifollicular inflammatory infiltrate, excess keratin, and the presence of P acnes may also be noted.4 Other dermatologic lesions may resemble acne but do not present with comedones. Differential diagnosis includes keratosis pilaris, milia, rosacea, periorificial dermatitis, molluscum contagiosum, flat warts, tuberous sclerosis, pseudofolliculitis barbae, and medication reaction. A thorough history and physical examination, including medication review, are important for reaching the correct diagnosis. Aggravating and relieving factors and family history may be helpful during evaluation. Acne in young children may warrant an endocrinology workup.11 The goals of treating acne are to prevent future outbreaks, resolve existing lesions, and limit scarring. Depending on the severity of lesions, comorbid conditions, patient preferences, and goals of care, a variety of medications can be used. Targets of acne medication include hormonal, antibacterial, sebum production, and keratinization. Topical retinoids are vitamin A derivatives that reduce follicular occlusion by regulating keratinization, thereby decreasing acne-related hyperpigmentation and scarring. As topical retinoids increase sun sensitivity, they should be used along with sunscreen. Topical antimicrobials such as benzoyl peroxide, erythromycin, and clindamycin target P acnes, thereby reducing associated inflammation. Oral antibiotics are used in more severe cases of inflammatory acne or when the chest and/or back are affected. Macrolides and tetracyclines are often used for oral treatment but are not intended for long-term use. Minocycline is preferred over tetracycline by many providers due to its speedier resolution of inflammatory acne.12 Oral isotretinoin is used for severe cases of acne and has been shown to induce apoptosis in sebaceous glands. Women undergoing treatment with oral isotretinoin must use an effective method of birth control due to the teratogenic nature of this medication, and liver enzymes and lipids must be monitored in all patients.11 Other common side effects of treatment with oral isotretinoin include dry skin and lips.13 For comedonal acne, treatment with topical retinoids, salicylic acid, or azelaic acid represent a suitable first step. The addition

36 THE CLINICAL ADVISOR • DECEMBER 2019 • www.ClinicalAdvisor.com

of a topical antimicrobial agent may help in individuals with mild pustular or papular types. Individuals with moderate papular or pustular acne may benefit from oral antibiotics, topical retinoids, and benzoyl peroxide. For those with nodular or severe acne, oral isotretinoin may be considered.Women with moderate to severe acne may consider antiandrogen therapy, and oral contraceptives may be beneficial if the timing of acne outbreaks coincides with menses.11 Although acne is not a life-threatening condition, morbidity from acne can have a significant psychological impact, especially in the adolescent population. The peak of acne prevalence coincides with major physical, social, and emotional development in these patients, magnifying the psychosocial effects of even mild cases of acne. Patients with acne have higher rates of depression and suicidal ideation and lower rates of pride and self-worth.14 Timely and appropriate treatment, therefore, can limit this psychosocial impairment in the short term by limiting acute lesions and in the long term by preventing scar formation. The patient presented in this case was given topical retinoids and oral doxycycline. The patient started to see resolution of her acne within 2 to 3 weeks and has been maintained on only a topical retinoid.

CASE #2

Rosacea

Rosacea is a chronic, progressive inflammatory disease of the pilosebaceous unit, classically presenting with pustules, papules, or telangiectasias on the face. These paroxysmal flares of lesions are accompanied by underlying erythematous, sensitive skin. Patients often complain of flushing, itching, and burning skin with outbreaks. Rosacea is most common in middle-aged and elderly populations, with higher prevalence in countries with more lighter-skinned individuals.15 Rosacea may appear differently in different races, with papules and pustules more commonly seen in lighter-skinned individuals than in those with darker skin.16 Although the specific pathogenesis of rosacea is unknown, it appears to occur when those with a genetic predisposition are exposed to certain environmental factors.16 Overproduction of antimicrobial peptides, reaction to skin mites, inappropriate cytokine release and B-cell response, overproduction of toll-like receptors, and abnormal vasomotor and nervous response have

all been implicated in the pathogenesis of rosacea.15 Although multifactorial in inheritance, twin studies suggest that half of the risk for developing rosacea is genetic, including patterns in major histocompatibility complex (MHC) class II genes and BPTK3 genes.17 Only in Haber syndrome, where rosacea is one of many classic symptoms, is rosacea directly inherited in an autosomal-dominant manner.15,18 Triggering factors for rosacea include topical agents, smoking, oral medications, weather or temperature changes, certain foods, and emotional changes.19 The role of Helicobacter pylori in triggering rosacea is still being debated.20 Rosacea due to chronic sun damage as well as long-term topical or oral steroid use has also been observed. There are several classifications systems for rosacea. One is based on phenotype, with the subtypes of telangiectasias, phyma, transient and persistent erythema, and inflammatory papules or pustules. An older system of classification describes subtypes: I (erythematotelangiectatic rosacea), II (papulopustular rosacea), III (phymatous rosacea), and IV (ocular rosacea). In subtype I, the central area of the face, especially the nose and cheeks, becomes erythematous and edematous due to chronically dilated capillaries. Differential diagnosis for subtype I includes systemic lupus erythematosus, menopausal hot flashes, dermatomyositis, polycythemia vera, atopic eczema, phototoxic reactions, and pheochromocytoma. Subtype II is classified by inflammatory papules and pustules, and the differential diagnosis often includes papulopustular acne, contact dermatitis, granulomatous rosacea, cutaneous sarcoidosis, and eosinophilic folliculitis. Subtype III involves sebaceous gland hyperplasia, typically on the nose, which results in rhinophyma. The differential diagnosis includes chilblain lupus, angiosarcoma, and eosinophilic granuloma. In subtype IV, there is ocular involvement resulting in symptoms such as eye dryness, irritation, conjunctivitis, and blepharitis. Bacterial, allergic, or viral conjunctivitis should also be considered in the differential diagnosis.15, 20 A thorough clinical examination, history, and medication review are essential for the correct diagnosis of rosacea, especially as it can take several different forms. Features indicative of rosacea include centrofacial erythema, phymatous growths, and papules and pustules, whereas skin thickening, scarring, scaling, or unilateral symptoms would indicate a different pathology. Diagnosis is usually clinical; however, biopsy can be performed to rule out lupus erythematosus and life-threatening angiosarcoma. On biopsy, rosacea will appear as dilated blood vessels in the middle and upper dermis, often with a perivascular or perifollicular lymphocytic infiltrate. Extensive histologic changes are not characteristics of subtype I rosacea, whereas spongiotic changes and intrafollicular neutrophils are seen in subtype II. The histology of subtype III is characterized by cysts, granulomas, and hyperplastic sebaceous glands.15

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Dermatologic Look-Alikes Although treatment for rosacea is not curative, both topical and oral agents are used to help control symptoms. As there are many factors that contribute to rosacea, no one clear target for treatment has been well established. Topical antibiotics, such as clindamycin, erythromycin, and metronidazole, and topical vitamin A act as anti-inflammatory agents. Other topical agents such as sulfacetamide-sulfur and azelaic acid are routinely prescribed, although they can be more irritating to the skin than topical antibiotics. Topical vitamin C has shown benefit in some studies, suggesting that free-radical damage plays a role in rosacea. Oral tetracycline is often used in combination with topical therapy. If tetracycline use in contraindicated, such as during pregnancy, penicillin, erythromycin, amoxicillin, or ampicillin may be prescribed. Oral isotretinoin, spironolactone, ondansetron, cyclooxygenase-2 inhibitors, and prednisone have been effective for treating rosacea. Nonmedical treatment (photo or laser therapy, sun avoidance, sunscreen use, regular moisturizer use, and avoidance of triggering factors) are important for preventing outbreaks.20 Rosacea can be a disfiguring disorder, and satisfactory results may not be attainable even with multiple treatments. Psychological screening is advised for individuals with rosacea, with appropriate counseling of the disease course.20

The patient was advised to avoid the triggers of spicy foods when possible. She was also prescribed doxycycline 40 mg/d. The patient was also counseled on sun avoidance and sunscreen use. ■ Claire Jordan Wiggins, BS, and Michelle Eugene Lee, BA, are medical students at Baylor College of Medicine, and Christopher Rizk, MD, is a dermatologist at Elite Dermatology in Houston,Texas. References 1. Tan JKL, Bhate K. A global perspective on the epidemiology of acne. Br J Dermatol. 2015;172(Suppl 1):3-12. 2. Mahmood NF, Shipman AR.The age-old problem of acne. Int J Womens Dermatol. 2017;3(2):71-76. 3. Grant RN.The history of acne. Proc R Soc Med. 1951;44(8):647-652. 4.Williams HC, Dellavalle RP, Garner S. Acne vulgaris. Lancet. 2012;379(9813):361-372. 5. Schnopp C, Mempel M. Acne vulgaris in children and adolescents. Minerva Pediatr. 2011;63(4):293-304. 6. Webster GF.The pathophysiology of acne. Cutis. 2005;76(2 Suppl):4-7. 7. Rzany B, Kahl C. Epidemiology of acne vulgaris. J Dtsch Dermatol Ges. 2006;4(1):8-9. 8. Hunter J, Savin J, Dahl M. Clinical Dermatology. 3rd ed. Oxford, England, United Kingdom: Wiley-Blackwell; 2002. 9. Mahmood SN, Bowe WP. Diet and acne update: carbohydrates emerge as the main culprit. J Drugs Dermatol. 2014;13(4):428-435. 10.Veith WB, Silverberg NB.The association of acne vulgaris with diet. Cutis.

Acne Vulgaris vs Rosacea1-8,15-19

Dermatologic Presentation

Associations

Etiology

2011;88(2):84-91.

Acne Vulgaris

Rosacea

Comedones (blackheads, whiteheads), papules, pustules, deep painful cysts

Papules, pustules, telangiectasias, redness in the center of the face, ocular symptoms; no comedones present

Teenagers and young adults, androgen-induced sebum production

Adults aged 30-50 years, sensitive skin, flushing

Pilosebaceous unit dysfunction

Neurovascular, immune, and pilosebaceous unit dysfunction

11. Botros PA,Tsai G, Pujalte GGA. Evaluation and management of acne. Prim Care. 2015;42(4):465-471. 12. Leyden JJ, Del Rosso JQ. Oral antibiotic therapy for acne vulgaris: pharmacokinetic and pharmacodynamic perspectives. J Clin Aesthet Dermatol. 2011;4:40-47. 13. McLane J. Analysis of common side effects of isotretinoin. J Am Acad Dermatol. 2001;45(5): S188-S194. 14. Dalgard F, Gieler U, Holm JØ, Bjertness E, Hauser S. Self‐esteem and body satisfaction among late adolescents with acne: results from a population survey. J Am Acad Dermatol. 2008;59(5):746-751. 15. Anzengruber F, Czernielewski J, Conrad C, et al. Swiss S1 guideline for the treatment of rosacea. J Eur Acad Dermatology Venereol. 2017;31(11):1775-1791. 16. Juliandri J, Wang X, Liu Z, Zhang J, Xu Y, Yuan C. Global rosacea treatment

Characteristic Location

Face, back, chest

Face

Histology

Keratin, sebum, and bacteria within cyst-like lumen, with perifollicular inflammation

Enlarged blood vessels with perivascular lymphocytic infiltrates

17. Aldrich N, Gerstenblith M, Fu P, et al. Genetic vs environmental factors

History and physical examination

18. Binet O, Audefray D, Beltzer‐Garelly E, Gauchy O, Cesarini JP. Haber’s syn-

Topical and/or oral agents depending on severity

Topical and/or oral agents depending on severity, avoidance of known triggers, phototherapy

19. Scheinfeld N, Berk T. A review of the diagnosis and treatment of rosacea.

Diagnosis Treatment

guidelines and expert consensus points: the differences. J Cosmet Dermatol. 2019;18(4):960-965. that correlate with rosacea: a cohort‐based survey of twins. JAMA Dermatol. 2015;151(11):1213-1219. drome. First French family (2 cases). Ann Dermatol Venereol. 1986;113(1):43-50. Postgrad Med. 2010;122(1):139-143. 20. Kutlubay Z, Zara T, Engin B, et al. Helicobacter pylori infection and skin disorders. Hong Kong Med J. 2014;20(4):317-324.

38 THE CLINICAL ADVISOR • DECEMBER 2019 • www.ClinicalAdvisor.com

LEGAL ADVISOR CASE

An Issue of Missed Diagnosis Three trips to the ED fail to diagnose compartment syndrome in a young boy.

BY ANN W. LATNER, JD

Joe, a 7-year-old boy, caught his foot in a trampoline at a birthday party. The next day, his father took him to urgent care where a physician diagnosed the child with a sprained ankle. When Joe’s pain persisted the following day, his mother took him to the emergency department (ED) of a local hospital. In the ED, Joe was first seen by Nurse A, who gave the child a cursory evaluation. He was then evaluated by Physician Assistant 1 (PA1), who ordered radiographic examination. No fracture or dislocation was identified. Joe was diagnosed with a foot sprain and discharged. The patient remained in pain, and the following day his father took him back to the ED. At that time, he was seen by Nurse B, the triage nurse. “Joey was restless and crying for most of the night,” the father told the nurse. “He also had a fever.” Nurse B noted that Joe presented with foot pain and swelling, but she failed to assess the foot any further. She did not take the child’s blood pressure, but she did note that his heart

Despite repeated trips to an emergency department, a young patient experiences a tragic outcome related to an incorrect diagnosis.

rate was elevated at 160 beats per minute. He did not have a fever at that time. Nurse A saw the child again on this visit but did not assess his leg. Joe was evaluated again by PA1, who applied a splint to the child’s leg and provided him with crutches. The patient was again discharged with a diagnosis of foot sprain. That night, Joe could not sleep and was in a great deal of pain. His mother gave him an analgesic, which did not provide any relief. At 3:00 AM, the parents took Joe back to the same ED for the third time. This time he was assessed by Nurse C, who completed a pain assessment and recorded Joe’s pain level (6 out of 10). She performed gastrointestinal, genitourinary, integumentary, neurologic, and respiratory assessments, but she did not note any skin or sensation assessment, or perform a pulse check on Joe’s lower leg. Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

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LEGAL ADVISOR A different physician assistant (PA2) evaluated Joe on this visit. While performing a physical examination, she noted tenderness of the left foot with mild swelling and ecchymosis of the lateral and medial aspects. She reapplied the splint and wrote a prescription for ibuprofen for pain, as needed. The child was discharged at approximately 6:00 AM with a diagnosis of foot sprain. That same morning, Joe’s mother took him with her to work. In the bathroom, she saw that Joe’s leg had turned purple. She called his pediatrician, who told her to take him immediately to a different hospital. Upon arrival, Joe was noted to be pale, fussy, and uncomfortable. His left leg was cyanotic and cold to the touch. A Doppler ultrasound showed no pulses in his lower left leg, and ultrasound examination revealed deep vein thrombosis (DVT). The child was diagnosed with compartment syndrome and taken into surgery for a fasciotomy. Following surgery, Joe developed septic shock and went into respiratory failure requiring ventilator support. This led to a lifesaving above-the-knee leg amputation. The boy’s parents sought the advice of an attorney and sued the nurses, PAs, and the supervising physicians at the first hospital. Legal Background

During the discovery process, several expert medical reports were filed by the plaintiffs pointing out the substandard care the child received from the nurses, PAs, and physicians responsible for his treatment at the first hospital. Among these was a report by an expert nurse stating that the defendant

A proper nursing assessment should provide the data needed to confirm or rule out DVT or compartment syndrome. nurses had deviated from the accepted standards of emergency nursing practice by failing to properly assess and document findings of Joe’s complaint of lower leg pain and swelling, as well as failing to communicate the findings of that assessment to the physician or physician assistant. Another expert testified that the PAs had deviated significantly from the standard of care by, among other things, failing to ensure that the nursing assessments were adequately performed. The expert concluded that the failure of the PAs and supervising physicians to ensure that every nursing assessment was adequately completed contributed to the patient’s ultimate outcome.

Finally, a third expert stated that had the appropriate testing been done, Joe would have been correctly diagnosed on his second visit to the ED, and the DVT would not have occurred, avoiding the leg amputation. During discovery, the PAs and supervising physicians, who were employed by another company (not the first hospital), settled the case out of court, leaving just the nurses and the hospital as defendants. The defense attorney made a motion to dismiss the case against them, objecting to the expert testimony and claiming that no expert had directly tied the nursing deviations to the proximate cause of the amputation. The lower court agreed and dismissed the case against the nurses and the hospital. The plaintiffs appealed. On appeal, the higher court reversed the lower court’s decision and found that there were grounds for a negligence case against the nurses and the hospital. The case has been remanded to the lower court for a trial. Protecting Yourself

In its decision, the court faulted the nurses for not conducting a proper assessment of the child’s leg. “The patient’s nursing expert’s opinion is that the [ED] nurses’ negligence delayed a correct diagnosis,” wrote the court in its decision. “Although the child was brought in several times for severe persistent pain in his injured foot and ankle, no nursing assessment of the lower extremity was ever performed. The nurses should have done a visual exam of the foot and ankle, noted the color of the skin, felt for the temperature of the skin and checked the pulses and capillary refill. An x-ray ordered by a [PA] showed no fractures, but it did not rule out vascular damage in the lower extremity. During three visits to the [ED] the nurses never saw to it that the boy was examined by a physician,” the court reported. These errors led to a delay in diagnosis such that a bad outcome was inevitable. A proper nursing assessment of a lower extremity injury should provide the data needed to confirm or to rule out DVT or compartment syndrome. The treating physician will need the nurses’ assessment of skin condition, capillary refill, and pulse, as well as the patient’s report of sensation and pain. The only information gathered in this instance were the parents’ reports of the child’s extreme pain, which should have alerted the clinicians that something was seriously wrong. ■ Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, New York.

40 THE CLINICAL ADVISOR • DECEMBER 2019 • www.ClinicalAdvisor.com

Conference Roundup CHEST 2019 Meeting

LUNG CANCER SCREENING GUIDELINES SUBOPTIMAL FOR IDENTIFYING AT-RISK WOMEN Current US Preventive Services Task Force (USPSTF) guidelines are not applicable to most women at risk for lung cancer, according to research presented at CHEST 2019, held October 19 to 23, 2019, in New Orleans, Louisiana. While USPSTF guidelines identify age and smoking history as prerequisites for lung cancer screening, 20% of lung cancers in the United States are not attributed to tobacco, and the smoking prevalence in women is approximately one-fifth of that in men. Researchers hypothesized that a gender gap in lung cancer mortality may develop in the near future. Therefore, they conducted a retrospective cohort study of 294 women who were treated for lung cancer between 2005 and 2015 at Los Angeles County Hospital and Norris Comprehensive Cancer Center. Demographic data including smoking status, family history of cancer, and lung cancer subtype were collected. More than 80% of the women (n=237) did not meet USPSTF lung cancer screening criteria at the time of diagnosis. Reasons for exclusion included age (too young, 27.4%) and smoking status (75.1% had smoked <30 pack-years). In addition, the researchers noted that race and ethnicity may have been a factor because certain ethnicities tend to have a higher rate of nonsmoking-related lung cancers with genomic mutations (37.5% of the patients

were Asian and 28.0% were Hispanic). A total of 83.5% of women who did not meet the screening criteria had lung cancers that were adenocarcinoma in histology and 48.1% had a family history of cancer.

COMMUNITY-ACQUIRED BACTERIAL PNEUMONIA IN PATIENTS WITH RENAL INSUFFICIENCY Delafloxacin may provide an antibiotic monotherapy option for the treatment of community-acquired bacterial pneumonia (CABP) in patients with renal impairment, according to research presented at CHEST 2019. Delafloxacin is an anionic fluoroquinolone antibiotic available in both oral and intravenous (IV) formulations. Of note, unlike the other members of this class of medication, delafloxacin does not have QT restrictions; it is approved for the treatment of serious skin infections in the United States. Researchers conducted a phase 3, multicenter, randomized, double-blind trial of adults with CABP and renal insufficiency to compare the safety and effectiveness of delafloxacin with that of moxifloxacin. A total of 447 patients were randomly assigned in a 1:1 ratio to receive either delafloxacin or moxifloxacin for 5 to 10 days. Patients were switched from IV to oral therapy after 3 days at physician’s discretion. Clinical end points were investigator assessment of clinical success at test of cure visit (5-10 days after the end of treatment) and all-cause mortality at day 28.

Results demonstrated that 32.6% and 29.7% of patients with renal insufficiency in the delafloxacin and moxifloxacin groups, respectively, had more than 1 treatment-emergent adverse event. The most common adverse events associated with delafloxacin were gastrointestinal or hepatic in nature, and none led to the discontinuation of treatment. However, serious adverse events did lead to discontinuation of treatment in 6 patients in the delafloxacin group compared with 3 in the moxifloxacin group. There were no preclinical signs of QT prolongation in patients who received delafloxacin; of note, this finding was validated in a challenge study.

The American College of Chest Physicians New Orleans, Louisiana

Delafloxacin may be a feasible option for treating CABP in patients with renal impairment.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2019 41

Conference Roundup

THE RISING COST OF THE EPIPEN: EFFECT ON PATIENTS AND PROVIDERS Rising EpiPen wholesale acquisition cost was associated with increased emergency department (ED) visits and increased in-hospital length of stay between 2007 and 2014, according to data presented at CHEST 2019. Researchers from Howard University Hospital in Washington, DC, utilized the Nationwide Emergency Department Sample and National Inpatient Sample databases to extract data relating to demographics, type of insurance, ED disposition, in-hospital length of stay, in-patient mortality, intubation, and use of mechanical ventilation. The wholesale acquisition cost of the EpiPen was defined as the manufacturer’s list price for the drug to wholesalers or direct purchasers in the United States. A total of 47,008 patients with anaphylaxis were included in the study; average patient age was 42 years and insurance coverage included Medicare (19.31%),

Rise in EpiPen cost has been associated with increased ED visits and length of hospital stay.

Medicaid (16.35%), private insurance (48%), and self-pay (10.95%). The rising cost of the EpiPen was associated with increased ED visits and increased length of hospital stay. After implementation of the Affordable Care Act (ACA), the rising cost of ED visits and inpatient management did not change; however, there was a decline in the length of hospital stay and the requirement for mechanical ventilation. The total number of ED visits increased despite implementation of the ACA, but there was no change in mortality. “With ACA implementation, despite increased [whole acquisition cost], there was a steady decline in mean [length of stay], mortality and ventilation requirement,” the researchers concluded. “[Emergency department] visit cost and inpatient hospital cost continued to increase from 2007 to 2014.”

SELEXIPAG MAINTAINS, IMPROVES WHO FUNCTIONAL CLASS IN PULMONARY ARTERIAL HYPERTENSION Twice-daily selexipag was associated with improvements in 6-minute walk distance (6MWD) and potential maintenance or improvement in World Health Organization functional class (WHO FC) in patients with pulmonary arterial hypertension (PAH), according to findings from the SPHERE trial reported at CHEST 2019. The SPHERE trial is a multicenter, prospective registry that began in November 2016. Patients with PAH who were actively treated with selexipag (either newly starting selexipag ≤60 days before enrollment or previously receiving selexipag at enrollment with a documented titration regimen) were enrolled. Although the enrollment target is set at 800 patients, a total of 250 patients at data cutoff

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(December 20, 2018) were included in these results. Clinical assessments were conducted at time of selexipag initiation and were compared with assessments performed 18 months later. During the median follow-up time of 17.8 months, 191 of the first 250 patients discontinued the study: 137 patients discontinued because of study completion, 22 patients discontinued for other reasons, and 32 patients died. A total of 97% of patients had PAH at time of diagnosis (WHO Group 1), with idiopathic and connective tissue disease-associated etiologies representing the most common PAH types (54% and 30%, respectively). WHO FC 2 or 3 disease was reported in 28% and 55% of patients, respectively. The median time receiving selexipag before enrollment in the 76% of patients who previously started the drug was 9.2 months (interquartile range [IQR], 6.0-11.7 months). Overall, the median on-study treatment duration was 15.7 months (IQR, 7.8-17.8 months). The median time to reach the twice-daily median maintenance dose of 1200 μg selexipag (IQR, 800-1600 μg) was 8.1 weeks (IQR, 5.6-10.8 weeks). Of the 117 patients with available FC data at 18 months, approximately 62% of patients maintained their WHO FC, and 25% had improvements in FC. Approximately 13% of patients had worsened FC at 18 months. The median 6MWD was 315 meters (IQR, 211-406 m; n=207), with a change of +7 meters (IQR, -30 to 38 m) in the median 6MWD at 18 months from time of selexipag initiation. Newly initiated patients had a higher rate of discontinuation because of adverse events compared with previously initiated patients (34% vs 16%, respectively). Disclosure: Several study authors declared affiliations with the pharmaceutical industry.

ASTHMA, COPD, AND ASTHMA-COPD OVERLAP DIFFERENTIATED USING SPUTUM CELL COUNT Sputum cell count, as measured by a simplified method, provided data to allow differentiations between asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap, according to data presented at CHEST 2019. Researchers from the Shizuoka General Hospital in Japan retrospectively evaluated 195 patients between July 2015 and November 2017 who had either asthma (n=95), COPD (n=61), or asthma-COPD overlap (n=39). Sputum samples were treated with a mucolytic agent and then centrifuged at 500 g for 5 minutes and the precipitates were transferred to a plain glass slide. The particles were crushed with a rotary motion using another clean glass slide. The resultant material was spread evenly over the slide for staining and counting as percentages. Sputum cell counts were compared between the diseases and the relationship with clinical variables was examined. The researchers constructed a receiver operating characteristic (ROC) curve analysis to assess whether the blood eosinophil count would predict a sputum eosinophil count ≥3%. Patients with COPD had significantly lower sputum eosinophil counts, as well as higher neutrophil counts, during the stable period compared with patients with asthma and asthma-COPD overlap (mean eosinophil and neutrophil counts: asthma, 17.4% and 78.8%, respectively; COPD, 1.8% and 95.6%, respectively; and asthma-COPD overlap, 11.8% and 84.2%, respectively). However, during a period of exacerbation, there were no differences between the 3 diseases (mean eosinophil and neutrophil counts: asthma, 15.0% and 83.3%, respectively; COPD, 4.8% and 86.4%, respectively; and asthma-COPD overlap, 17.7% and 79.9%, respectively).

A new method of measuring sputum eosinophil counts helps in the diagnosis of asthma and COPD.

There were significant correlations between sputum and blood eosinophil counts among all patients during both the stable (rho=0.492) and the exacerbation periods (rho=0.529). In addition, the ROC curve analysis demonstrated that the blood eosinophil count predicted the sputum eosinophil count 3% during the stable period (AUC, 0.75 [95% CI, 0.66-0.84]; cutoff, 235 µL; sensitivity, 75.4% and specificity, 71.3%) and during the exacerbation period (AUC, 0.80 [95% CI, 0.66-0.94]; cutoff, 351 µL; sensitivity, 61.1% and specificity, 97.1%).

HOSPITAL READMISSION FOR PNEUMONIA COMMON IN PATIENTS WITH COMORBIDITIES Thirty-day readmission following hospitalization for pneumonia is common in patients with underlying comorbidities such as chronic obstructive pulmonary disease (COPD), kidney and heart diseases, and dementia, according to research presented at CHEST 2019.

Researchers conducted a retrospective, observational, noninterventional chart review of adult patients to evaluate the clinical, radiologic, and physiologic risk factors for pneumonia. Patients were admitted to the Brooklyn Hospital Center between June 2016 and June 2018. Nearly 16% of the 349 patients hospitalized secondary to pneumonia were readmitted within 30 days for all causes. Among all readmissions, 83.4% were due to pneumonia, 3.47% were due to other respiratory diseases, and 13.13% were due to all other causes. Compared with non-readmissions, patients who were readmitted were more likely to have comorbidities including COPD (31% vs 20%), kidney disease (40% vs 35%), heart disease (51% vs 40%), dementia (35% vs 17%), and other respiratory diseases such as bronchiectasis (44% vs 34%; P <.05 for all). Patients who were enrolled in either Medicare or Medicaid also had a significantly increased readmission risk (P <.05). Patients who were intubated or received noninvasive positive pressure ventilation, or who had issues with mobility, dysphagia, CURB65 scores of 1 and 2, or healthcare-associated pneumonia risk also had increased rates of hospital readmission (P <.05). Additionally, the researchers noted that a change in antibiotic treatment during the initial hospital admission or hospital admissions within the past year were risk factors for 30-day readmission. “The results of our study suggest that there are specific underlying comorbidities, patient demographics, and admission details that can predict patients who are at an increased risk of 30-day all-cause readmission due to pneumonia,” the researchers concluded. “Early identification of high-risk patients can [include] more vigilant monitoring of pneumonia resolution, increased conscientiousness of patient education and discharge follow-up to potentially reduce readmissions.”

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2019 43

Conference Roundup

Combination therapy was associated with a 47% reduction in mean PVR .

MACITENTAN AND TADALAFIL COMBINATION IMPROVES PVR IN PAH Combination therapy consisting of once-daily macitentan and tadalafil was associated with reductions in pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH), according to research presented at CHEST 2019. Patients in the prospective, multicenter, single-arm, open-label, phase 4 OPTIMA study had newly diagnosed PAH, were in World Health Organization functional class 2 and 3, and had no history of prior PAH therapy. Treatment consisted of once-daily macitentan 10 mg and oncedaily tadalafil 20 mg, with the tadalafil dose increasing to 40 mg after 8±3 days. The primary end point included reduction in mean PVR, which was assessed at week 16. Safety was also assessed for 16 weeks until study termination. During the trial, median duration of exposure to macitentan and tadalafil was 605.5 days. In the 46 patients who were enrolled and treated in OPTIMA, there was a 47% reduction in the mean PVR

at 16 weeks compared with baseline (geometric mean ratio, 0.53; 95% CI, 0.47-0.59; p2.5 L/min/m2; mean right atrial pressure, 440 m; NT-proBNP, 65%). There was also a substantial increase in the percentage of patients meeting at least 3 low-risk criteria from baseline to week 16 (23.9% to 68.2%, respectively). The majority of patients (93.5%) experienced at least 1 adverse event (AE), with 28.3% (n=13) of patients reporting serious AEs. A total of 3 patients discontinued treatment due to AEs, and 3 patients died during the trial. Causes of mortality included cardiac arrest, heart failure, and multiorgan failure with sepsis. The most frequently occurring AEs included peripheral edema (n=13), headache (n=11), diarrhea (n=9), dyspnea (n=7), anemia (n=6), and asthenia (n=6). Study limitations included the small sample size, short follow-up duration, and lack of a comparator group. Disclosure: Several study authors declared affiliations with the pharmaceutical industry.

USE OF FEV1/FEV6 RATIO MAY LEAD TO UNDERDIAGNOSIS OF COPD IN WOMEN There is significant disparity in the ratios for postbronchodilator forced expiratory volume in 1 second (FEV1)/FEV6 and FEV1/forced vital capacity (FVC) %, and this disparity is very pronounced in women, without any differences in age, body mass index, total lung capacity (TLC) or carbon monoxide diffusing capacity (DLCO) to account for the disparity, according to new research results presented at CHEST 2019. Because many patients find FVC a difficult maneuver, FEV6 has been proposed as an alternative way of diagnosing chronic obstructive pulmonary disease (COPD). The current study examined the influence of gender in a real-world community-based setting on the discrepancy

44 THE CLINICAL ADVISOR • DECEMBER 2019 • www.ClinicalAdvisor.com

between FEV1/FEV6 and FEV1/FVC for the diagnosis of airflow obstruction. Preand postbronchodilator spirometry, total lung volumes, and DLCO based on standard American Thoracic Society criteria using body plethysmography were used to assess airflow obstruction. To be eligible for participation, patients had postbronchodilator FEV1/FVC ratios <70% and were either smokers presently or in the past. Nonsmokers and patients with a history of asthma or other pulmonary conditions were excluded. Concordance between the 2 diagnostic ratios was compared as the difference in absolute percentage between postbronchodilator FEV1/FVC and FEV1/FEV6, using standard statistical tests to derive comparisons. Of 600 consecutive patients, a total of 83 (42 men and 41 women) met the study inclusion criteria. The mean difference between postbronchodilator FEV1/ FVC % and postbronchodilator FEV1/ FEV6 % was 7.9%±4.7%. When men and women were compared, a consistently greater disparity in values was seen between the genders (5.8%±4.2% for men vs 10%±4.2% for women). Men and women were comparable in age (70±7 years vs 71± 8 years) and body mass index (26.2±9 vs 27±5; P =.35). No differences in lung volumes were seen between the genders in terms of TLC % (110%±23% vs 103%±18%; P =.18) and DLCO measurements (50%±22% vs 50%±23% P =.8). Using postbronchodilator FEV1/ FEV6 (ratio <0.7), 24% of women would have been classified as normal compared with only 7% of men (P =.03) The researchers concluded, “Routine use of FEV1/FEV6 ratio may lead to a significant degree of underdiagnosis of COPD in [women]. The physiology underlying these differences in spirometric characteristics needs to be better understood.” ■ Disclosure: One study author declared affiliations with the pharmaceutical industry.

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