June 2019 Clinical Advisor by The Clinical Advisor

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■■ Intussusception Risk, Rotavirus Vaccine ■■ USPSTF Lead Screening Guidelines CONFERENCE ROUNDUP

2019 AAN Annual Meeting LEGAL ADVISOR

RN Fired for Blowing Whistle

FEATURE

Fournier Gangrene: A Rare Flesh-Eating Soft Tissue Infection

DERMATOLOGIC LOOK-ALIKES

Macules With Irregular Borders

JUNE 2 019

| www.ClinicalAdvisor.com

INFECTIOUS DISEASE

Emerging Tickborne Illnesses: Looking Beyond Lyme Disease The lone star tick transmits the pathogen that causes erlichiosis.

XARELTO® (rivaroxaban) tablets Prophylaxis of DVT Following Hip or Knee Replacement Surgery The combined analysis of the RECORD 1-3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous thromboemboli in this population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Avoid the use of XARELTO in patients with CrCl <30 mL/min. Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD Patients with Chronic Kidney Disease not on Dialysis Patients with a CrCl <15 mL/min at screening were excluded from COMPASS, and limited data are available for patients with a CrCl of 15-30 mL/min. In patients with CrCl ≤30 mL/min, a dose of 2.5 mg XARELTO twice daily is expected to give an exposure similar to that in patients with moderate renal impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information], whose efficacy and safety outcomes were similar to those with preserved renal function. Patients with End-Stage Renal Disease on Dialysis No clinical outcome data is available for the use of XARELTO with aspirin in patients with ESRD on dialysis since these patients were not enrolled in COMPASS. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 2.5 mg twice daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in moderate renal impaired patients in the COMPASS study [see Clinical Pharmacology (12.2, 12.3) in Full Prescribing Information]. It is not known whether these concentrations will lead to similar CV risk reduction and bleeding risk in patients with ESRD on dialysis as was seen in COMPASS. Hepatic Impairment In a pharmacokinetic study, compared to healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B). The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy. OVERDOSAGE Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not dialyzable [see Warnings and Precautions and Clinical Pharmacology (12.3) in Full Prescribing Information]. Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products. An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Product of Germany Finished Product Manufactured by: Janssen Ortho LLC Gurabo, PR 00778 or Bayer AG 51368 Leverkusen, Germany Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Licensed from: Bayer HealthCare AG 51368 Leverkusen, Germany

Director Laura Kusminsky, PA-C laura.kusminsky@haymarketmedia.com Associate editor Madeline Morr Assistant editor Rita Aghjayan Production editor Kim Daigneau Group art director, Haymarket Medical Jennifer Dvoretz Senior production manager Krassi Varbanov Assistant manager, audience development Ashley Noelle 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 6, Published 12 times a year, monthly, by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. For Advertising Sales & Editorial, call (646) 638-6000 (M–F, 9am–5pm, ET). The Clinical Advisor is available on a paid subscription basis at the following annual rates: $75 USA, $85 Canada, $110 for all other foreign, in U.S. dollars, Single copy price: USA $20, Foreign $30. To order or update a paid subscription visit our website at www. ClinicalAdvisor.com or call (800) 436-9269. Periodicals postage rate paid at NewYork, NY, and additional mailing offices. Postmaster: Send changes of address to The Clinical Advisor, c/o Direct Medical Data, 10255 W. Higgins Rd., Suite 280, Rosemont, IL 60018.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2019 7

CONTENTS JUNE 2019

NEWS 14

Newsline ■■Low Risk for Intussusception With Rotavirus

Vaccine ■■Lead Screening in Children, Pregnant Women:

Updated USPSTF Guidelines 14 No Rotavirus Vaccine, Intussusception Link

16 Conference Roundup: 2019 AAN Annual Meeting ■■Anxiety, Depression Linked to Levodopa-Responsive Freezing of Gait in Parkinson Disease ■■Pimavanserin and Quetiapine Comparable for Psychosis in Parkinson Disease ■■Adverse Events Associated With Lasmiditan for Acute Migraine ■■Smoking Increases MS Severity ■■Diazepam Nasal Spray for Breakthrough Seizures in Epilepsy

18 Smoking and MS Severity

FEATURES 20 Fournier Gangrene: A Rare Flesh-Eating Soft Tissue Infection Fournier gangrene is now widely understood to be a fulminant necrotizing fasciitis of the genitals, perineum, and perianal regions requiring rapid recognition and early surgical intervention. 37 Bright Red Vascular Tumors

Continues on page 10

47 Nurse Fired for Whistle-Blowing

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CONTENTS JUNE 2019

FEATURES (cont’d) Emerging Tickborne Illnesses: Looking Beyond Lyme Disease Because of increased education and recognition, most healthcare providers are familiar with the symptoms of Lyme disease, but coinfection with other tickborne illnesses such as babesiosis, human granulocytic anaplasmosis, and human monocytic ehrlichiosis is becoming more prevalent.

DEPARTMENTS 12

41 47

Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com Dermatology Clinic ■ Brown Macules on the Face and Trunk ■ Bright Red, Dome-Shaped Papules Dermatologic Look-Alikes Macules With Irregular Borders Legal Advisor RN Fired for Blowing Whistle

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■ Intussusception Risk, Rotavirus Vaccine ■ USPSTF Lead Screening Guidelines CONFERENCE ROUNDUP

2019 AAN Annual Meeting

JUNE A PEER 2 019 - R E V|I Ewww.ClinicalAdvisor.com W E D F O RU M F O R N U R S E PAR AC PEER-REVIEWED T I T I O N E R S | FORUM M AY 2 01FOR 9 | NURSE www.ClinicalAdvisor.com PRACTITIONERS | APRIL 2 019

INFECTIOUS NEWSLINE DISEASE

■ Dietary Cholesterol, CVD ■ Primary HPV Screening ■ No Link Between MMR Vaccine, Autism ■ IVF and Maternal Morbidity

| www.ClinicalAdvisor.com

NEWSLINE INFECTIOUS DISEASECARDIOLOGY

■ Exercise and Cognitive Function ■ CRC Screening Outreach ■ Screen Time and Children

Emerging Tickborne The Art of Administering Case Clinic: A 67-YearIllnesses: Looking a Tuberculin Skin Old Man With Atrial Beyond Lyme DiseaseTest: Wheal Does Matter Risk Factors Fibrillation FEATURE

CASE STUDY

LEGAL ADVISOR

Gynecomastia in an Elderly Man

RN Fired for Blowing Whistle

LEGAL ADVISOR

RN Fired Over Social Media Post

The Counseling Connection

The Healthcare Practitioner’s Guide to Atopic Dermatitis

The lone star tick LEGAL ADVISOR transmits the pathogen Careful Note-Taking that causes Wins Case erlichiosis.

The vast majority of clinics use the Mantoux test to screen for cases of tuberculosis.

Atrial fibrillation is the most common type of cardiac arrhythmia.

FEATURE

Fournier Gangrene: A Rare Flesh-Eating Soft Tissue Infection

FEATURE

Implementation of a Screening Questionnaire for OSA in the EMR

DERMATOLOGIC LOOK-ALIKES

DERMATOLOGY CLINIC

Macules With Irregular Borders

Inflamed, Hyperpigmented Axillary Plaque

DERMATOLOGIC LOOK-ALIKES

Multiple Erythematous, Scaly Plaques

FREE CME COURSE

Dietary Interventions for the Management of Obesity

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“It’s their big annual event — the Run for the Roses.”

EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com

NEWS ClinicalAdvisor.com/News

Recommendations for the Evaluation, Management of Recurrent UTI in Women Released A new clinical guideline includes 16 recommendations that cover evaluation, testing, treatment, and follow-up of women experiencing recurrent UTI.

FDA Launches “Remove the Risk” Campaign for Safe Disposal of Unused Opioids The campaign involves reducing exposure to opioids to prevent addiction, supporting the treatment of opioid use disorder, fostering the development of novel pain medications; and improving drug enforcement.

Increased Disability, Reduced Quality of Life in Pediatric Patients Receiving Infusion Therapy for Migraine Children and adolescents undergoing infusion therapy for migraine were found to have higher levels of functional disability and a lower quality of life compared with patients who do not seek infusion therapy.

THE WAITING ROOM

Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Jim Anderson, MSPAS, PA-C, DFAAPA Credential Alphabet Soup: Great for the Resume but Confusing to the Patient While medical credentials are meaningful to both patient and provider, they can also cause confusion.

FEATURES ClinicalAdvisor.com/Features Exploring the Use of Cupping in Dermatology Cupping involves creating suction on the skin using a glass, ceramic, bamboo, or plastic cup. The ancient practice dates as far back as 1500 BC.

PRACTICE MANAGEMENT ClinicalAdvisor.com/MyPractice ACP Recommendations to Achieve Universal Health Care Insurance Coverage Based on initial gains in access to health care from the passage of the 2010 Patient Protection and Affordable Care Act, the American College of Physicians offers recommendations on how to improve the law and achieve universal health care coverage.

CLINICAL CHALLENGE ClinicalAdvisor.com/CaseStudy Brady Pregerson, MD Progressive Abdominal Pain A 46-year-old man with no significant medical history presents to the emergency department with progressive, right-sided abdominal pain of 3 days’ duration. He states that the pain is constant and worsens with walking or deep breathing. He denies nausea, vomiting, fever, diarrhea, dyspnea, or other complaints. See the full case at: ClinicalAdvisor.com/CaseJun19

12 THE CLINICAL ADVISOR • JUNE 2019 • www.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

Multiple Itchy Plaques on the Trunk and Extremities An 87-year-old man presents for evaluation of an itchy rash affecting his trunk and extremities. The eruption has continued to intensify despite an intramuscular steroid injection. The patient recently had begun taking combination memantine and donepezil hydrochloride for treatment of early stage dementia; discontinuation of this medication had no effect on the dermatitis. CAN YOU DIAGNOSE THIS CONDITION?

• Erythema multiforme • Drug eruption

• Nonbullous pemphigoid • Granuloma annulare

● See the full case at ClinicalAdvisor.com/DermDx_Jun19

ORTHO DX

In partnership with

TheJopa.org

Journal of Orthopedics for Physician Assistants

Worsening Foot Pain in a Boy An 8-year-old is brought to the office with right foot pain that has persisted for 1 month. The pain seems to have worsened over the past week when his parents noticed him limping. The patient’s symptoms intensify with running and other athletic activities. WHICH IS THE BEST TREATMENT OPTION?

• Observation without restrictions • Immobilization in a walking boot • Immediate bone biopsy • Revascularization with a vascular bone graft ● See the full case at ClinicalAdvisor.com/OrthoDx_Jun19

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2019 13

Newsline SIGNIFICANT RISK FACTORS for intussusception in infants include acute gastroenteritis 2 weeks prior to hospitalization and the use of infant formula with or without breastfeeding; however, the risk related to rotavirus vaccination was undetectable as a result of low vaccine coverage and limited statistical power, according to a study published in Vaccine. This case-control study investigated the risk of intussusception in infants age <1 year with systematic inclusion of all suspected intussusception cases in infants in emergency departments in eastern France from April 2008 to March 2012. All level 1 cases were matched with 4 hospital controls (115 cases, 457 controls). Exposure windows examined were exposure to first rotavirus vaccine dose within the first 7 days of and 14

days prior to intussusception occurrence. The average rotavirus vaccine coverage rate was 8.6% over the 4 years of the study. The vaccine was not significantly associated with the occurrence of intussusception in the 7 or 14 days after vaccine administration. Infant formula given alone or in combination with breastfeeding was associated with a significant risk of intussusception (OR 2.74; 95% CI, 1.10-6.79) as was a history of gastroenteritis within 2 weeks before hospitalization (OR 2.24; 95% CI, 1.07-4.67). Study limitations included a lack of statistical power as a result of poor vaccine coverage rates and the potential for residual confounding. Recent gastroenteritis occurrence and infant formula were both significantly associated with increased risk of

Low Risk for Intussusception With Rotavirus Vaccine

This risk for intassusception was not linked to rotavirus vaccination.

intussusception in infants. Although a small, insignificant increase in intussusception risk was seen after rotavirus vaccination, study investigators concluded that “[t]he limited statistical power and the low vaccine coverage likely preclude detection of a significant increase in the risk of [intussusception] related to rotavirus vaccination.”

Lead Screening in Children, Pregnant Women: Updated USPSTF Guidelines AN UPDATED US Preventive Services Task Force (USPSTF) recommendation states that the current evidence is insufficient to assess the benefits and harms of screening for elevated blood lead levels in asymptomatic children age ≤5 years at average and increased risk, as well as in pregnant women. The guidelines were published in JAMA. Researchers sought to update the 2006 USPSTF screening recommendations, as elevated blood lead levels may be associated with neurologic effects in children and organ failure and preeclampsia in pregnant women. Capillary blood testing was confirmed as the method to accurately identify children with elevated blood lead levels compared with venous blood testing. Questionnaires and other clinical predication tools were found to be inaccurate in identifying elevated levels

in asymptomatic children or communities at highest risk, while no determination could be made regarding the accuracy of these tools in identifying elevated levels in asymptomatic pregnant women. The USPSTF found inadequate evidence on the effectiveness of screening for or treatment of elevated blood lead levels in asymptomatic children age ≤5 years or pregnant women. In an accompanying editorial published in JAMA Pediatrics, author Michael Weitzman, MD, concludes, “The inconclusive findings of the new USPSTF recommendation does not mean that screening children for elevated lead levels is not necessary, nor does it shed light on whether screening should be targeted to children at high risk or whether it should be universally done. Only more rigorously conducted research will provide evidence-based answers to these questions.” ■

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

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AGA=American Gastroenterological Association. References: 1. Schiller LR, Emmett M, Santa Ana CA, Fordtran JS. Osmotic effects of polyethylene glycol. Gastroenterology. 1988;94(4):933-941. 2. Hammer HF, Santa Ana CA, Schiller LR, Fordtran JS. Studies of osmotic diarrhea induced in normal subjects by ingestion of polyethylene glycol and lactulose. J Clin Invest. 1989;84(4):1056-1062. 3. Survey of 672 consumers, August 2017, Bayer Consumer Health. 4. Bharucha AE, Dorn SD, Lembo A, Pressman A; American Gastroenterological Association. American Gastroenterological Association medical position statement on constipation. Gastroenterology. 2013;144(1):211-217.

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Conference Roundup 2019 AAN Annual Meeting American Academy of Neurology Philadelphia, PA

ANXIETY, DEPRESSION LINKED TO LEVODOPARESPONSIVE FREEZING OF GAIT IN PARKINSON DISEASE Depression and anxiety are associated with levodopa-responsive freezing of gait (FOG) in patients with Parkinson disease (PD) but not with levodopaunresponsive FOG, according to research presented at the 2019 American Academy of Neurology Annual Meeting, held May 4-10, 2019, in Philadelphia, Pennsylvania. A cohort of 125 patients with PD were assessed for depression and anxiety. One of 3 FOG subtypes was determined: no freezing, levodopa-responsive freezing (RFOG), and levodopa-unresponsive freezing (URFOG).

Of the total sample, 14% of patients presented with RFOG, 11% with URFOG, and 18% with depression/ anxiety. Current depression was associated with significantly increased odds of RFOG (OR, 4.84). In a similar fashion, a marginally significant association was identified for current anxiety and RFOG (OR, 3.90). Associations between depression or anxiety and URFOG were not significant. “These results suggest that anxiety or depression may be differentially associated with [RFOG]. [URFOG] may reflect distinct underlying pathophysiology with potentially less interaction with limbic cortico-basal ganglia pathways,” the investigators concluded. Reference McKay J, Goldstein F, Factor S. Anxiety and depression are associated with levodopa-responsive, but not levodopa-unresponsive, freezing of gait in

This retrospective cohort study included 91 participants with Parkinson disease or dementia with Lewy bodies. Time to medication discontinuation constituted the primary outcome, while secondary outcomes included psychosis improvement, reason for discontinuation, and mortality. Among those taking quetiapine, 22% discontinued; among those taking pimavanserin, 33% discontinued. Significantly more participants discontinued quetiapine than pimavanserin due to side effects (70% vs 13.3%, respectively). Discontinuation due to inefficacy was more common in the pimavanserin vs quetiapine group (53.3% vs 10% respectively). Mortality rates were 15% and 7% in the quetiapine and pimavanserin groups, respectively. Hallucinations improved comparably in both the quetiapine and pimavanserin cohorts (65.2% vs 75.6%, respectively).

Parkinson’s disease. Presented at: 2019 American Academy of Neurology Annual Meeting; May 4-10;

Reference

Philadelphia, PA. Abstract P2.8-031.

Horn S, Dahodwala N. Pimavanserin versus quetiapine for the treatment of psychosis in Parkinson’s

IMAGES: TOP, BOTTOM: © GETTY IMAGES

disease and dementia with Lewy bodies. Presented

Freezing of gait may occur when individuals start to walk or need to turn.

PIMAVANSERIN AND QUETIAPINE COMPARABLE FOR PSYCHOSIS IN PARKINSON DISEASE No significant differences between pimavanserin and quetiapine in time to discontinuation, mortality, or psychosis improvement were noted among individuals with Parkinson disease or Lewy body dementia, according to research presented at AAN 2019.

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

at: 2019 American Academy of Neurology Annual Meeting; Philadelphia, PA. Abstract P2.8-037.

ADVERSE EVENTS ASSOCIATED WITH LASMIDITAN FOR ACUTE MIGRAINE Lasmiditan for the treatment of acute migraine is associated with quickonset, self-limiting, mild to moderate

Conference Roundup treatment-emergent adverse events, according to research presented at AAN 2019. Data were taken from the double-blind, phase 3 SPARTAN and SAMURAI studies. A total of 4439 participants with migraine were assigned to lasmiditan 50 mg (n=654), 100 mg (n=1265), 200 mg (n=1258), and placebo (n=1262). Participants were instructed to take the dose within 4 hours of the start of a migraine attack. A total of 7 participants distributed equally across all groups reported serious adverse events; no deaths were reported. At least 1 treatment-emergent adverse event occurred in 13.5% of placebo, 25.4% of lasmiditan 50-mg, 36.2% of lasmiditan 100-mg, and 40.3% of lasmiditan 200-mg groups. Most treatment-emergent adverse events in the lasmiditan groups were of mild or moderate severity, with the most significant being dizziness, paresthesia, drowsiness, fatigue, nausea, weak muscles, and hypoesthesia. The events had a median onset time of 0.50 to 0.85 hours and a median duration of 1.00 to 4.75 hours. Reference Krege JH, Liffick E, Doty EG, Dowsett SA, Wang JN, Buchanan AS. Safety findings from the phase 3 studies (SAMURAI, SPARTAN) of lasmiditan for acute treatment of migraine. Presented at: 2019 American Academy of Neurology Annual Meeting;

May 4-10, 2019; Philadelphia, PA. Abstract P1.10-009.

SMOKING INCREASES MS SEVERITY Cigarette smoking increased disease severity in patients with multiple sclerosis (MS) with severity scores remaining unchanged when considering smoking load and smoking cessation, according to research presented at AAN 2019. In this cross-sectional study, investigators sought to evaluate the impact of cigarette smoking and smoking cessation on disease severity in individuals with MS. Patients with MS completed a lifestyle

on multiple sclerosis severity: a cross-sectional study. Presented at: 2019 American Academy of Neurology Annual Meeting; May 4-10, 2019; Philadelphia, PA. Abstract P4.6-008.

Investigators concluded that smoking was associated with greater MS severity.

questionnaire from which their lifetime cigarette smoking load was estimated and then categorized into 2 groups: low smoke load and high smoke load. Disease severity was assessed using the MS Severity Score (MSSS). Of 351 patients included in the study, 190 were ever-smokers (92 current and 98 former) and 161 were never-smokers. Ever-smokers had a higher median MSSS than never-smokers (3.21 vs 2.33; P =.02) and were more likely to fall into the upper tertile of MSSS distribution when adjusted for age and gender. There was no statistically significant difference in median MSSS between current and former smokers (3.14 vs 3.25) nor between ever-smokers with low smoke loads vs high smoke loads (3.44 vs 3.10; P =.98). The investigators concluded that these results confirm the association of cigarette smoking with greater disease severity in MS. Among ever-smokers, low smoke loads and smoking cessation were not significant factors affecting MS severity.

DIAZEPAM NASAL SPRAY FOR BREAKTHROUGH SEIZURES IN EPILEPSY Diazepam nasal spray was found to be safe and well tolerated in patients with epilepsy who experience frequent breakthrough or acute repetitive seizures, according to research presented at AAN 2019. In this interim analysis, investigators assessed the long-term safety of diazepam after repeat doses were administered to patients with epilepsy who experienced frequent breakthrough seizures or acute repetitive seizures over 12 months. Doses (5 mg, 10 mg, 15 mg, or 20 mg) were based on age and body weight and were modified as needed; participants documented time and duration of seizures in patient diaries, along with any outcome events. The safety population included 109 patients who received at least 1 dose of diazepam. A total of 1585 seizure episodes were treated with diazepam over the study period. In 1457 (92%) episodes, a single dose of diazepam was adequate to stop the seizure. Overall, 67 patients reported at least 1 adverse event, and 19 experienced adverse events that were considered related to treatment.The most frequent treatment-related adverse events were nasal discomfort, epistaxis, and headache. Adverse events that were considered serious were reported by 18 patients; none were considered treatment related. ■ Reference Sperling M, Hogan R, Biton V,Tarquinio D, Carrazana E. A 12-month, open-label, repeat-dose safety study of Valtoco™ (NRL-1 diazepam nasal spray) in patients

Reference

with epilepsy: interim report. Presented at: 2019

Ivashynka A, D’Alfonso S, Copetti M, et al. Effects

American Academy of Neurology Annual Meeting;

of cigarette smoking and smoking cessation

May 4-10, 2019; Philadelphia, PA. Abstract P1.5-028.

18 THE CLINICAL ADVISOR • JUNE 2019 • www.ClinicalAdvisor.com

FEATURE: MARA KOHLS, PA-C; CHRISTOPHER M. HOWELL, DSC, MSC, MPAS, PA-C, MBA, FAAPA

Fournier Gangrene: A Rare Flesh-Eating Soft Tissue Infection Prompt identification of Fournier gangrene is essential, as the condition can have numerous life-threatening complications.

escribed first by Jean-Alfred Fournier in 1883 as an idiopathic condition, Fournier gangrene (FG) is now widely understood to be a fulminant necrotizing fasciitis of the genitals, perineum, and perianal regions.1-3 FG is a rare and potentially fatal form of necrotizing fasciitis requiring rapid recognition and early surgical intervention.1,2,4-8 Necrotizing soft tissue infections can progress rapidly and can affect any or all the layers of soft tissue from the dermis through the fascial and muscle compartments.8 Failing to promptly identify FG is regarded as one of the greatest impediments to management, as this process can possess an array of early nonspecific symptoms such as tachycardia, erythema, and focal tenderness.2,4,8 However, as the disease progresses, findings may include pain disproportionate to appearance, hemorrhagic bullae, tense edema, and crepitus in the perineum.8 Due in large part to the ambiguous nature of this spectrum of disease progression, a high index of suspicion is required for diagnosis and begins with knowledge of high-risk patient populations.8 Population

Early surgical intervention can reduce mortality associated with Fournier gangrene.

20 THE CLINICAL ADVISOR • JUNE 2019 • www.ClinicalAdvisor.com

FG most commonly affects patients with complex comorbidities, such as diabetes mellitus, chronic substance abuse (eg, alcohol, tobacco, and/or intravenous [IV] drug use), obesity, hypertension, or immunosuppression (Table 1).1,6,7,9,10 Although most often presenting in men in the

right-hand column like this one does at the top

fifth and sixth decades of life, FG is not a gender- or agespecific disease.4,6 In fact, emerging research has concluded that when women develop FG, the clinical course is often protracted and more critical than in men. As a result, it can manifest as prolonged hospital stays, increased ventilator times, and dependence on dialysis during expanded recovery.3,6 Etiology

Generally arising from the gastrointestinal, genitourinary, and integumentary systems, the spectrum of FG causes is vast, ranging from idiopathic to iatrogenic surgical events.1,2,7-9,11-13 Frequently cited etiologies include appendicitis, diverticulitis, colorectal cancer, complicated nephrolithiasis and its sequelae, and urogenital and perineal abscesses.9,11,14 Trauma from indwelling catheter placement, rectal or prostate biopsies, diathermy for genital warts, constriction rings for erectile dysfunction, coital injury, genital trauma, hemorrhoidectomy, and hysterectomies have also been implicated.9,11,14 Of note, the clinical course of FG is dictated not only by host immune defense and the route of opportunistic infection but also by the organism involved.8 Pathogenesis

Pathogenesis of FG is multifactorial and commonly begins as cellulitis or an untreated purulent infection that progresses through enzymatic and platelet reactions, eventually culminating in microthrombotic changes within local subcutaneous veins.2,4,8 This in turn causes an alteration in the delivery of oxygen to the tissues, which allows for development of irreversible necrosis.2,4 FG is able to progress rapidly in these conditions in which ischemic changes result from microvascular constriction in susceptible disease states.4 FG is frequently a polymicrobial infection, and the microbes most commonly implicated in its development are Escherichia coli and Bacteroides, and clostridial, staphylococcal, and streptococcal species.2,4,7,8 Streptococcal and staphylococcal species are known to produce enzymatic reactions that alter host immunity, resulting in degradation of the host’s connective tissue structures and a more rapidly progressive disease state.8,10 Anaerobic bacteria, though more rare than their aerobic counterparts, thrive in this oxygen-deficient environment and create a synergistic effect that perpetuates the fulminant progression of the disease.10,11 These anaerobic organisms subsequently release their own characteristic enzymes that increase intravascular coagulation, resulting in progressive ischemia.9,10,11 As the infectious process progresses from the initial site of inoculation, FG classically traverses the planes of Colles fascia and the perineum with predictable ease and may ultimately affect the distal thighs and abdominal wall.2,4 Infrequent cases

of extension to the clavicles have been reported in instances when the disease was able to progress undetected until late stages.2,9,11,13 The testicles are often spared in the progression of necrosis due to a separate blood supply from the aorta.9,11 Signs and Symptoms

Associated with a myriad of symptoms, FG can easily remain clinically elusive. It has been reported that patients with FG can present early in the course of the disease with nonspecific symptoms of mild, focal swelling and pain in the groin and perineum.7,8,15 Systemic symptoms of fever and nausea are often lacking in early disease. In late stages, pain often becomes more pronounced; men may complain of swelling, and patients may report systemic symptoms such as fever.7,8,10,15 However, the systemic symptoms are unreliable, with fever being present in 20% of confirmed cases of FG. Its absence therefore does little to rule out early- through late-stage disease.15 Physical Examination

Early stages of FG can begin as a focal area of erythema within the perineum and groin with often limited systemic response. Although tachycardia has been observed, findings most consistent with uncomplicated cellulitis typically are present.7,8,9-11,16 As the disease progresses, it becomes more consistent with expanding erythema, hemorrhagic bullae overlying tense skin with palpable crepitus (when gasproducing organisms are present), pain out of proportion to clinical findings or anesthesia, fever, and signs of septic shock including hypotension and tachycardia (Figures 1A, 1B).2,7-9,13 As with symptoms of FG, these physical examination findings TABLE 1. Risk Factors for Fournier Gangrene1,7,9,15 Advanced age

Hypertension

Alcohol abuse

Lymphoproliferative diseases

Chronic steroid use

Malignancy

Cytotoxic drugs

Malnutrition

Defective phagocytosis

Obesity (BMI >30 kg/m2)

Diabetes mellitus

Poor hygiene

Diabetic neuropathy

Tobacco use

HIV

Vascular compromise

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right-hand column like this one does at the top

FOURNIER GANGRENE

FIGURES 1A, 1B. Fournier gangrene of the scrotum.

are more specific than sensitive, being present in <40% of cases, so their absence does not preclude the presence of disease.8,11,16 During the final stages of FG, patients may develop multiorgan failure, including acute respiratory distress syndrome and disseminated intravascular coagulopathy.11 Therefore, it is incumbent upon clinicians to consider FG in all patients with risk factors even in the absence of notable physical examination findings, in particular those that are refractory to conservative outpatient treatment.2,10 Diagnostics

No laboratory markers specific for FG exist, although some serum studies assist in determining the extent of systemic involvement and provide biomarkers for prognosis, including: a comprehensive metabolic panel (which may reveal hyponatremia) and elevations of white blood cells, C-reactive protein, erythrocyte sedimentation rate, and lactate.4,7,8,13 Some studies have discussed that a white blood cell count >15,400 cells/µL and serum sodium <135 mEq/L significantly increase the likelihood of necrotizing infections, with the recognition that these laboratory studies have greater negative predictive value than positive predictive yield.8 Some providers therefore advocate the use of various scoring instruments, of which

laboratory analysis is of great significance. One such instrument is the laboratory risk indicator for necrotizing fasciitis (LRINEC), which is used to distinguish between necrotizing and non-necrotizing soft tissue infections by assigning points to laboratory findings in patients with suspected severe soft tissue infections to create a score that stratifies risk (Table 2). The utility of the score is dependent on a clinician’s high index of suspicion.8 When FG is suspected, blood and wound cultures should be obtained early so that appropriate antibiotics may be selected according to the susceptibility of the causative organism(s). Computed tomography (CT) with IV contrast is the preferred modality to confirm diagnosis across specialties, owing in large part to its availability and reliability in guiding surgical management.11,17,18 CT with IV contrast is able to reveal the path of disease, extent of inflammation, fascial thickening, formation of emphysema, fluid collection, and fat stranding.11,17,18 While magnetic resonance imaging with IV contrast offers benefits similar to CT, many clinicians regard this imaging modality as impractical in the emergent setting given resource limitations and challenges in obtaining reliably. It has been proposed that diagnosis of FG may be confirmed with bedside ultrasound, which can reveal the presence of subcutaneous gas. However, this is neither specific nor sensitive, as the absence of subcutaneous emphysema does not rule out FG and has the added limitation of being examiner dependent when used at the bedside.11 Treatment

FG historically has been a urologic emergency, with early surgical intervention being the cornerstone of mortality reduction.7,9,10 Conventional practice has allowed an interdisciplinary approach that includes both plastic and general surgery. Considering multiple provider consultations in the management of FG is essential to success and may include supportive inpatient medical management by a hospitalist and an infectious disease specialist.2,3,11 A number of antibiotic regimens that can halt disease progression may be administered preoperatively, although they are not meant to substitute for or delay surgical intervention.7,10 Generally, the regimen should cover polymicrobial sources including grampositive, gram-negative, aerobic, and anaerobic organisms, with consideration for emerging multidrug-resistant strains.2,10,15 Suitable regimens might include a combination of some or all of the following: an aminoglycoside, metronidazole, piperacillin/tazobactam, clindamycin, vancomycin, and/or a third-generation cephalosporin (Table 3).2,10 Clindamycin remains one of the preferred first-line agents, due in large part to its role in reduction of mortality through coverage against toxin-producing organisms including streptococcal

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right-hand column like this one does at the top

and clostridial species.15 Those with progressive disease, including septic shock, will require fluid restoration and vasopressors. Hyperbaric therapy has been proposed for management of FG to improve oxygenation to the tissues and increase healing times.2,7,9

TABLE 2. Laboratory Risk Indicator for Necrotizing Fasciitis* Laboratory Value

Points

C-reactive protein (mg/L) <150 >150

0 4

White blood cell count (cells/µL) <15 15-25 >25

0 1 2

Hemoglobin (g/dL) <11 11-13.5 >13.5

0 1 2

Sodium (mEq/L) ≥135 <135

0 2

Creatinine (mg/dL) ≤1.6 >1.6

0 2

Glucose (mg/dL) ≤180 >180

0 1

Prevention

*The LRINEC scoring system is used only for those patients with a suspected or diagnosed soft tissue infection. A total score >6 implies intermediate- and high-risk patients.8

TABLE 3. Common Antimicrobial Agents for Treatment of Fournier Gangrene10,12 Drug Class

Name

Brand Name

Third-generation cephalosporins

Ceftriaxone

Rocephin

Aminoglycosides

Amikacin

Amikin®

Nitroimidazoles

Metronidazole

Flagyl®

β-lactamase inhibitors

Piperacillin-tazobactam

Zosyn®

Lincosamides

Clindamycin

Cleocin®

Many of the risk factors associated with FG are preventable. Of the common comorbidities, alcohol use and hyperglycemia remain those most associated with morbidity and mortality.2,9,11 Simple measures of glycemic and hypertension control along with weight loss have been proposed as key factors for prevention. Numerous studies have been conducted to determine the role of the most common comorbidities in provoking FG, especially those deemed largely preventable.4,6,12 For example, some studies determined that glycosylated hemoglobin levels >7% or uncontrolled diabetes present the greatest risk.4,6,12,18 Similar studies were unable to consistently substantiate the correlation between uncontrolled diabetes and mortality, instead favoring other prognostic indicators such as chronic kidney disease (CKD), in particular CKD requiring hemodialysis.19-22 Despite these findings, strict conventional glycemic control as a means of risk reduction is strongly recommended. Prevention of FG should not be limited to outpatient strategies alone. During the course of the patient’s hospital stay and recovery, further care should be taken to reduce the hazards of additional trauma from procedures that could result in FG, particularly those to the gastrointestinal and genitourinary tracts.9,10,11 If trauma to the perineum has occurred, patients and healthcare professionals should be encouraged to clean the affected sites frequently, continue proper hand washing techniques, and remain vigilant for any signs of disease.23 Patients should be informed that if signs of infection manifest, prompt recognition and management should be sought.23 Prognosis

Some researchers and clinicians have advocated the use of scoring systems, such as the Fournier Gangrene Severity Index (FGSI), as a prognostic tool for patient mortality once the disease is confirmed.4 Although its academic merits are without question, the clinical utility of FGSI in early management is debatable.6 FGSI is meant to predict a patient’s likely mortality risk associated with the disease, not to guide clinical decision-making. FGSI analyzes temperature, heart rate, respiratory rate, white blood cell count, hematocrit, serum sodium, serum creatinine, and bicarbonate levels to create a value to predict patient mortality.15 A score from the FGSI >9 Continues on page 29

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2019 23

FOURNIER GANGRENE

3. Sorensen M, Kriegar J. Fournier’s gangrene: epidemiology and outcomes in

POLL POSITION

the general US population. Urol Int. 2016;97(3):249-259. 4. Sen H, Bayrak O, Erturhan S, Borazan E, Koc MN. Is hemoglobin A1c level effective in predicting the prognosis of Fournier gangrene? Urol Ann.

Which of the following is the cornerstone of mortality reduction in Fournier gangrene?

2016;8(3):343-347. 5. Eke N. Fournier’s gangrene: a review of 1726 cases. Br J Surg. 2000;87(6):718-728. 6. Yim SU, Kim SW, Ahn JH, et al. Neutrophil to lymphocyte and platelet to

2.43%

lymphocyte ratios are more effective than the Fournier’s gangrene sever-

■ Early surgical intervention ■ An interdisciplinary approach ■ Appropriate antibiotic coverage

ity index for predicting poor prognosis in Fournier’s gangrene. Surg Infect

9.44%

(Larchmt). 2016;17(2):217-223. 26.03%

62.10%

7. Norton KS, Johnson L, Perry T, Perry K, Sehon J, Zibari G. Management of Fournier’s gangrene: an eleven year retrospective analysis of early recognition, diagnosis, and treatment. Am Surg. 2002;68(8):709-713.

■ Glycemic control

8. Anaya DA, Dellinger EP. Necrotizing soft-tissue infection diagnosis and management. Clin Infect. Dis. 2007;44(5):705-710. 9. Thwaini A, Khan A, Malik A, et al. Fournier’s gangrene and its emergency

For more polls, visit ClinicalAdvisor.com/Polls.

management. Postgrad Med J. 2006;82(970):516-519. 10. Smith GL, Bunker C, Dinneen M. Fournier’s gangrene. Br J Urol. 1998;81(3):347-355. 11. Chennamsetty A, Khourdaji I, Burks F, Killinger KA. Contemporary diagno-

is associated with high likelihood of mortality, and a score <9 is associated with a greater likelihood of survival.4,9,13,15

sis and management of Fournier’s gangrene. Ther Adv Urol. 2015;7(4):203-215. 12. Saber A, Bajwa TM. A simplified prognostic scoring system for Fournier’s gangrene. Urol Nephrol Open Access. 2014;1(3):00018.

Conclusion

13. Wróblewska M, Kuzaka B, Borkowski T, Kuzaka P, Kawecki D,

Although rare, FG may be associated with significant risk for morbidity and mortality especially if recognition and treatment are delayed, which is common due to ambiguous history and physical examination findings. Although risks can be reduced significantly with preventive health management of key comorbid conditions, namely those associated with immunodeficiency, disease cannot always be prevented. If FG develops despite these preventive efforts, prompt identification and management, including early antibiotic administration and surgical intervention, are the foundations of mortality reduction and require a high index of suspicion on the part of the examiner. ■

Radziszewski P. Fournier’s gangrene–current concepts. Pol J Microbiol. 2014;63(3):267-273. 14. Zaba R, Grzybowski A, Prokop J, Zaba Z, Zaba C. Fournier’s gangrene: historical survey, current status, and case description. Med Sci Monit. 2009;15(2):CS34-CS39. 15. Chia L, Crum-Cianflone NF. Emergence of multi-drug resistant organisms (MDROs) causing Fournier’s gangrene. J Infect. 2018;76(1):38-43. 16. Levenson RB, Singh A, Novelline R. Fournier gangrene: role of imaging. Radiographics. 2008;28:519-528. 17. Sharif HS, Clark D, Aabed M, et al. MR imaging of thoracic and abdominal wall infection: comparison with other imaging procedures. AJR Am J Roentgenol. 1990;154:989-995. 18. Verma S, Sayana A, Kala S, Rai S. Evaluation of the utility of the Fournier’s

Mara Kohls, MPAS, PA-C, is a physician assistant with Qualified Emergency Specialists, Inc. and the Department of Emergency Medicine of the University of Cincinnati in Cincinnati, Ohio. Christopher M. Howell, DSc, MSc, MPAS, PA-C, MBA, FAAPA, is an associate professor at Kettering College in Kettering, Ohio, and practices in Indiana and Ohio in addiction and emergency medicine.

gangrene severity index in the management of Fournier’s gangrene in North India: a multicentre retrospective study. J Cutan Aesthet Surg. 2012;5(4):273-276. 19. Jeong HJ, Park SC, Seo IY, Rim JS. Prognostic factors in Fournier gangrene. Int J Urol. 2005;12:1041-1044. 20. Nisbet AA, Thompson I. Impact of diabetes mellitus on the presentation and outcomes of Fournier’s gangrene. Urology. 2002;60(5):775-779.

References

21. Ersoz F, Sari S, Arikan S, et al. Factors affecting mortality in Fournier’s gan-

1. Tarchouli M, Bounaim A, Essarghini M, et al. Analysis of prognostic factors

grene: experience with fifty-two patients. Singapore Med J. 2012;53:537-540.

affecting mortality in Fournier’s gangrene: a study of 72 cases. Can Urol Assoc J.

22. Lin TY, Ou CH, Tzai TS, et al. Validation and simplification of Fournier’s

2015;9(11-12):E800-804.

gangrene severity index. Int J Urol. 2014;21(7):696-701.

2. Faria SN, Helman A. Deep tissue infection of the perineum: case report and

23. Taviloglu K, Yanar H. Necrotizing fasciitis: strategies for diagnosis and

literature review of Fournier gangrene. Can Fam Physician. 2016;62(5):405-407.

management. World J Emerg Surg. 2007;2:19.

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

FEATURE: KIMBERLY DAMATO, PA-C; DANIELLE KRUGER, PA-C, MS ED

Emerging Tickborne Illnesses: Looking Beyond Lyme Disease Although most providers are familiar with the symptoms of Lyme disease, coinfection with other tickborne illnesses is becoming more prevalent.

Tickborne diseases in the United States are a significant health problem.

ickborne diseases in the United States are a significant public health problem, and in the past 50 years scientists have detected at least a dozen new such infections.With more than 30,000 cases diagnosed each year, Lyme disease is the most commonly reported vector-borne illness in the United States, and in 2015 it was the sixth most common nationally notifiable disease.1 Due to increased education and recognition, most practitioners are familiar with the symptomatic presentation of Lyme disease. In stage 1, patients usually exhibit the classic erythematous expanding annular “bulls-eye” rash known as erythema migrans, and approximately 50% experience constitutional flu-like symptoms. In stages 2 and 3, or disseminated Lyme disease, patients may present with Bell’s palsy or other cranial nerve deficits, arthritis, peripheral neuropathies, and cardiac manifestations such as transient heart block and carditis. Borrelia burgdorferi, the spirochete that causes Lyme disease, is not the only pathogen spread by the deer tick Ixodes scapularis in the northeastern United States: Babesia microti, the agent of babesiosis, and Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis (HGA; formerly human granulocytic ehrlichiosis) are asserting a presence in similar geographic regions. Coinfection with these organisms is possible. Human monocytic ehrlichiosis (HME), caused by Ehrlichia chaffeensis, is another emerging tickborne disease with similar geography to HGA. Continues on page 32

30 THE CLINICAL ADVISOR • JUNE 2019 • www.ClinicalAdvisor.com

Daily Gut-Health GardTM

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Cash BD, Epstein MS, Shah SM. Patient satisfaction with IBS symptom relief using a novel peppermint oil delivery system in a randomized clinical trial and in the general population. Int J Dig. Dis. 2016;2(2). doi:10.4172/2472-1891.100027. Cash BD, Epstein MS, Shah SM. IBgard: a novel small intestine targeted delivery system of peppermint oil results in significant improvement in severe and unbearable IBS symptom intensity. Results from the U.S.-based, 4-week, randomized, placebo-controlled, multi-center IBSREST™ trial. Poster presented at DDW, May 2015. Cash BD, Epstein MS, Shah SM. A novel delivery system of peppermint oil is an effective therapy for irritable bowel syndrome symptoms. Dig Dis Sci. 2016;61(2):560-571. 4 Ford AC, Moayyedi P, Chey WD et al. American College of Gastroenterology Monograph on Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2018 Jun;113(Suppl 2):1-18. 5 Lacy BE. A Caraway Oil/l-Menthol Combination Improves Functional Dyspepsia (FD) Symptoms within 24 hours: Results of a Randomized Controlled Trial which Allowed Usual FD Treatments. Poster presented at DDW 2017. 6 Chey W. Rapid relief of functional dyspepsia symptoms with a novel formulation of caraway oil and l-Menthol: outcomes from a self-reported patient outcomes study. Presented at American College of Gastroenterology Annual Conference; 2017; Orlando, FL. 7 Micka A, et al. Effect of consumption of chicory inulin on bowel function in healthy subjects with constipation: a randomized, double-blind, placebo-controlled trial. International Journal of Food Sciences and Nutrition. Aug 2017 68:1, 82-89. 8 Lacy B, Epstein M, Shah S, Corsino P. Improved regularity with a chewable inulin fiber (CIF): results from a Patient Reported Outcomes (PRO) study. Presented at American College of Gastroenterology Annual Conference - Philadelphia, PA.; 2018. 9 Brodner DC, Shah SM. REM Absorption Kinetics Trial: A Randomized, Crossover, Pharmacokinetics Evaluation of a Novel Continuous Release and Absorption Melatonin Formulation versus a Same Strength Immediate-Release Formulation in Healthy Adults (Abstract 0396). Poster presented at: SLEEP 2017; June 3-7, 2017; Boston, MA. 10 Brodner C, Seiden DJ, Shah SM. Improvement in Sleep Maintenance and Sleep Quality with Ion Powered Pump Continuous Release and Absorption Melatonin: Results from a Self-Reported Patient Outcomes Study (Abstract 0419). Poster presented at: SLEEP 2018, June 2018, Baltimore MD. † Among gastroenterologists who recommended peppermint oil for IBS. Alpha ImpactRx ProVoice survey (September 2018). ‡ Among gastroenterologists who recommended herbal products for Functional Dyspepsia. Alpha ImpactRx ProVoice survey (June 2018). †† Among gastroenterologists who recommended a chewable prebiotic fiber brand. Alpha ImpactRx ProVoice survey (May 2018). CA_0619T § ©2019 IM HealthScience® Among primary care physicians with a certification in sleep disorders who recommended a brand of modified release melatonin. QuintilesIMS ProVoice survey (July-Sept. 2017). 1

*THESE STATEMENTS HAVE NOT BEEN EVALUATED BY THE FOOD AND DRUG ADMINISTRATION. THIS PRODUCT IS NOT INTENDED TO DIAGNOSE, TREAT, CURE, OR PREVENT ANY DISEASE.

EMERGING TICKBORNE ILLNESSES

The incidence of babesiosis, human granulocytic anaplasmosis, and HME is increasing, and the geographic areas for their tick vectors are expanding. The incidence of babesiosis, HGA, and HME is increasing, and the geographic areas for their tick vectors are expanding. HME and HGA can be serious infections with high rates of hospitalization and complications, particularly when diagnosis or treatment is delayed. Epidemiology

Incidence

Incidence of all 3 of these tickborne illnesses is steadily increasing. In 2014, 1744 cases of babesiosis were reported in the United States, according to the Centers for Disease Control and Prevention (CDC).2 The geographic region and number of cases of babesiosis have steadily increased since it became a reportable illness in 1986.3 More than 4600 cases of babesiosis in New York alone have been reported since 1986, of which 3500 were reported between 2006 and 2015.3 From 2000 to 2008, cases of ehrlichiosis quadrupled from 200 to 961,with 4613 cases reported from 2008 to 2012.4,6 Anaplasmosis is more frequently reported than HME in the United States. Incidence of anaplasmosis climbed from 348 to 1761 cases between 2000 to 2008, and the number of reported cases increased 52% between 2009 and 2010.4,7 These numbers likely underestimate the actual incidence of these diseases as many cases are not confirmed by laboratory testing and current surveillance systems, and the majority of patients with these

Babesia microti is the predominant protozoan cause of babesiosis in the United States; occasional sporadic cases of babesiosis caused by other species have been reported. Babesiosis is transmitted by the bite of an infected I scapularis (commonly known as the black-legged or deer tick) (Figure 1), usually in the nymphal or adult stage.The primary carrier of Babesia are white-footed mice, although it is found in other small mammals.Although white-tailed deer are the most important food source for the adult stage of the tick, deer are not infected with B microti.2 Babesia is rarely transmitted by blood transfusion, organ transplant, or vertically during pregnancy.The incidence of transfusion-transmitted babesiosis in the United States is 1.1 cases per million red blood cell units distributed.3 HME is caused by Ehrlichia chaffeensis, an obligate intracellular gram-negative species of rickettsial bacteria that grows within membrane-bound vacuoles in human and animal leukocytes.4,5 Less commonly, human disease is caused by E ewingii, the organism responsible for canine granulocytic ehrlichiosis. The principal vector of E chaffeensis is the lone star tick (Amblyomma americanum). Other ticks occasionally have been found to contain DNA of E chaffeensis, but their

role in transmission is unlikely.4 The white-tailed deer is the main competent reservoir for E chaffeensis, although domestic goats, dogs, raccoons, and coyotes may also carry the bacterium. HGA is caused by the gram-negative bacterium Anaplasma phagocytophilum, which is transmitted by I scapularis, the same vector of Lyme disease and babesiosis. I pacificus, the western black-legged tick (Figure 2), is the primary vector of HGA in the western United States. Also similar to Lyme disease, deer and the white-footed mouse are the principal animal hosts for HGA.

FIGURE 1. Ixodes scapularis, also known as the deer tick or black-legged tick.

FIGURE 2. Ixodes pacificus, also known as the western blacklegged tick.

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

As many as two-thirds of patients with babesiosis experience concurrent Lyme disease, and one-third experience concurrent HGA. infections remain asymptomatic. Additionally, babesiosis was only reportable for surveillance in 31 states in 2014.2 Distribution of vector-borne disease is determined by complex demographic, environmental, and social factors. For many vector-borne diseases, climate change and warming temperatures make transmission seasons longer or more intense or spread vectors so that disease can emerge in different geographic locations. Expanding deer and tick populations, swelling human population density, urbanization and deforestation, and human activities and recreation in wooded areas with exposure to ticks are surmised to relate to this increasing incidence. Most patients acquire babesiosis, HME, and HGA between May and September with reported spikes in June and July.3,6,7 Approximately 75% of cases of babesiosis are diagnosed from June through August.3 Age groups with high incidence for these 3 diseases are similar; the ranges include persons aged 60 to 69 years, 60 to 64 years, and ≥65 years and older for babesiosis, ehrlichiosis,6 and anaplasmosis, respectively.2,7

Cases

0 ■ 1-5 ■ 6-10 ■ 11-20 ■ >20 ■ Not reportable

FIGURE 3. Number of reported cases of babesiosis by US county of residence, 2014.

Geography DC

Cases per million

0 ■ 0.1-0.7 ■ 0.7-3.1 ■ 3.1-136

FIGURE 4. Incidence of anaplasmosis by region in the US, 2010.

Coinfection

As many as two-thirds of patients with babesiosis experience concurrent Lyme disease, and one-third experience concurrent HGA.3 One study demonstrated that the frequency of

Cases per million

0 ■ 0.03-1.0 ■ 1.0-3.3 ■ 3.3-26

FIGURE 5. Incidence of ehrlichiosis by region in the US, 2010.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2019 33

MAPS COURTESY OF THE US CENTERS FOR DISEASE CONTROL AND PREVENTION

The CDC reports that 90% of cases of babesiosis and anaplasmosis occur in only 7 states with concentrations in the Northeast (Massachusetts, Connecticut, Rhode Island, NewYork, and New Jersey) and the upper Midwest (Minnesota and Wisconsin).2,3,7 In the Northeast, babesiosis occurs in both inland and coastal areas (ie, Nantucket and Martha’s Vineyard in Massachusetts; Block Island in Rhode Island; and Shelter Island, Fire Island, and eastern Long Island in New York) (Figures 3 and 4). This also corresponds to the known geographic distribution of Lyme disease as all of these diseases share the same Ixodes tick vector. HME is most frequently reported in the Southeastern, South Central, and Mid-Atlantic regions of the United States. Approximately 35% of infections of E chaffeensis were reported in Oklahoma, Missouri, and Arkansas in 20105 (Figure 5). Of note, from 2009 to 2011 a novel Ehrlichia species closely related to E muris in Europe and Asia was identified among patients in the upper Midwest (Wisconsin and Minnesota).4 Since then, more than 67 cases have been identified.6 This epidemiologic shift is important as ehrlichiosis had not been previously described in that geographic area and studies suggest that the tick vector has expanded to include I scapularis.4

EMERGING TICKBORNE ILLNESSES

Most patients acquire babesiosis, human monocytic ehrlichiosis, and HGA between May and September with reported spikes in June and July. ticks infected with B microti is higher when they feed on mice that are coinfected with B burgdorferi and B microti, rather than with B microti alone.8 In studies of I scapularis from different locales, 2.2% to 26% were coinfected with B burgdorferi and A phagocytophilum; in fact, 3% to15% of patients in Connecticut and Wisconsin were found to be coinfected.4 Disease concomitance is important to recognize as patients who are coinfected tend to have increased duration and severity of infection, and treatment of B microti is different from the other disorders.9 Pathophysiology, Clinical Manifestations, and Associated Laboratory Features

In babesiosis, sporozoites are delivered to the dermis within 36 to 72 hours of tick attachment.Therefore, removal of the tick during the first 24 to 36 hours of attachment greatly minimizes risk of transmission, similar to Lyme disease. In a process similar to the actions of protozoa that cause malaria, the Babesia sporozoites migrate to the bloodstream where they invade erythrocytes, mature into merozoites, and lyse the host cell to be released back into the bloodstream to invade new erythrocytes. The host’s splenic macrophages play a critical role in clearing Babesia-infected erythrocytes. Clinical manifestations of babesiosis range from asymptomatic to flu-like symptoms, but patients with asplenia, those aged >50 years, or those with immune system compromise (ie, from HIV/AIDS, malignancy, chemotherapy, radiation, or immunosuppressant therapy) are at risk for severe, life-threatening babesiosis.3,10 The release of merozoites into the circulation stimulates the host’s inflammatory response involving pyrogenic cytokines (ie, tumor necrosis factor-alpha, interleukin-6), which induce symptoms characteristic of a viral-like illness such as fever, chills, diaphoresis, headache, anorexia, myalgia, fatigue, nausea, and vomiting. The lysis of erythrocytes results in hemolytic anemia with associated jaundice, and hemoglobinuria may cause resultant renal injury. This anemia is compounded by Babesia-induced generation of reactive oxygen species, loss of erythrocyte membrane integrity, and opsonization, all of which promote clearance of erythrocytes by splenic macrophages. Hepatosplenomegaly may be noted on physical examination. The same cytokines may contribute to complications associated with severe babesiosis such as acute respiratory distress syndrome and disseminated intravascular coagulation (DIC).10 The pathology of babesiosis is reflected in laboratory findings that may include hemolytic anemia with reticulocytosis and unconjugated hyperbilirubinemia, thrombocytopenia, lymphopenia, and elevated aminotransferases.

Ehrlichia species preferentially infect peripheral leukocytes, with E chaffeensis associated with human monocytic cells (ie, monocytes and macrophages); infection of neutrophils with E ewingii has been reported. Multiorgan involvement is known to occur, with organisms detected in the spleen, lymph nodes, bone marrow, and peripheral blood. A phagocytophilum preferentially infects granulocytes, particularly neutrophils. HME and HGA typically present as similar acute illnesses; however, a wide spectrum of disease exists from subclinical and self-limited to subacute or chronic infection. It is likely that symptoms are due to the host inflammatory response rather than to direct damage caused by the bacteria.5 Ehrlichia has an incubation period of 1 to 2 weeks, but a shorter period may be seen. In a study of 18 adults with HGA, symptoms appeared an average of 5.5 days after tick bite.4 Constitutional symptoms such as fever, chills, headache, malaise, and myalgia occur in the majority of patients, while nausea, vomiting, arthralgia, and cough occur in 25% to 50%.4,11 In HME, cough and respiratory symptoms are more common in adults than in children.5 A minority of patients (up to 36%) with HME may present approximately 5 days into illness with a nonpruritic, erythematous rash that may be macular, maculopapular, or petechial and is more frequent in children.4,5 Rash is not typical in anaplasmosis. In both HME and HGA, laboratory evaluation demonstrates thrombocytopenia, leukopenia, and increased aminotransferase levels. Although HME and HGA have similar clinical manifestations, HME is often more serious, with hospitalization occurring in 50% of patients and increased risk of sepsis or shock-like presentations, particularly in immunosuppressed hosts and the elderly.4 Central nervous system involvement occurs in 20% of patients, and symptoms may progress to acute respiratory distress syndrome or coagulopathy.5 The CDC reports mortality rates of 1% to 3% in patients who present for medical care of ehrlichiosis.5 In HGA, 5% to 7% of patients require intensive care, and at least 7 deaths associated with delayed diagnosis and treatment and development of opportunistic infections have been identified. In HGA, infection diminishes CD4 and CD8 counts and impairs phagocytosis, antibody responses, neutrophil emigration, and intracellular killing.11 An intact immune system is important for recovery from HGA, and HGA further antagonizes immune dysfunction.11 Other complications of HME and HGA include acute abdominal syndrome, rhabdomyolysis, myocarditis, acute renal failure, and demyelinating polyneuropathies and/or cranial nerve palsies.

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Avoidance of tick bites remains the mainstay of prevention, and patients should be educated to use insect repellents as directed. Diagnosis

Patients who remain asymptomatic following a tick bite do not require evaluation as there is no prophylaxis for babesiosis, HME, or HGA, and treating asymptomatic individuals even if they test positive for these diseases is not recommended by the Infectious Diseases Society of America (IDSA).Antibiotic prophylaxis for Lyme disease is generally not recommended by IDSA, except under certain circumstances.12 Due to limitations in diagnostic testing, clinical diagnosis that takes into consideration epidemiologic, geographic, and laboratory features is most practical. For example, exposure to ticks in an endemic area during spring or summer in a patient who develops febrile illness, leukopenia, or thrombocytopenia is strongly suggestive of HME and is sufficient justification for treatment.4 Testing for Lyme disease should be considered in patients diagnosed with babesiosis and HGA as coinfection with the Ixodes tick vector is common. In symptomatic individuals, the standard to diagnose babesiosis, HME, and HGA is light microscopy of Giemsa-stained peripheral blood smears. Babesia can be seen within erythrocytes in its ringform trophozoite and tear drop-shaped merozoite stages, which classically but rarely appear as a “Maltese-cross” tetrad. The observation of extracellular ring forms is also suggestive of Babesia.10 The presence of characteristic intracytoplasmic morulae (membrane-bound vacuoles with irregular edges containing clustered purple or blue colonies of gram-negative bacteria) on buffy coat examination are highly suggestive of HME (if in monocytes) or HGA (in granulocytes). Absence of morulae does not rule out infection as they are present in 1% to 20% of patients with HME and in 20% to 80% of patients with HGA.4 If initial smears are negative but clinical suspicion is high, subsequent smears may be obtained over a period of days to increase yield. Polymerase chain reaction (PCR) testing is available for Babesia, HME, and HGA. It is more sensitive than microscopy so is useful when parasitemia is very low; it can also distinguish between Babesia species.3 The reported sensitivity of PCR for HGA varies from 60% to 70% and from 52% to 87% for HME.4 If symptoms persist but microscopy has been negative, repeat blood smear and PCR testing should be performed. Of note, parasite DNA may be detectable by PCR for several months following completion of antibiotic therapy and resolution of symptoms.3 The preferred and most widely available method of diagnosis of HME and HGA is the indirect fluorescent antibody (IFA) test that can be obtained through state health departments.4 The IFA test is 94% to 100% sensitive if the second

sample is obtained 2 weeks after the onset of symptoms; a 4-fold rise is considered positive.4 An important limitation of the test is that antibodies first become detectable 2 to 3 weeks after the onset of the illness. Enzyme-linked immunosorbent assay (ELISA) testing is also available. Serology is of limited use in acute disease but provides retrospective evidence of infection; a 4-fold rise in titers confirms recent infection. Because serologic cross reactivity can occasionally occur between E chaffeensis and A phagocytophilum, it is not possible to reliably differentiate between these 2 infections with a single serologic assay.4 Treatment

The preferred treatment of babesiosis for adults is azithromycin 500 mg orally on day 1, followed by 250 mg orally plus atovaquone 750 mg orally every 12 hours to complete 7 to 10 days of therapy. The therapy is weight-based for children.An alternative regimen includes clindamycin plus quinine, which has the same efficacy but with a higher side effect profile. Symptoms usually begin to improve within 48 hours of initiating antimicrobial therapy and resolve within 1 to 2 weeks. Management of severe babesiosis consists of hospitalization, antimicrobial therapy, and, in some cases, red blood cell exchange transfusion for parasitemia >10%, severe hemolysis, or organ failure.4 Treatment should be initiated in all patients suspected of having HME or HGA.The medication of choice in all patients, including children and pregnant women, is doxycycline.This is also the preferred therapy for spotted fever rickettsiosis, the disorder most frequently confused with HME and Lyme disease.4 Doxycycline can be given orally or intravenously at 100 mg twice daily for 10 days or for 3 to 5 days after fever abates.4 Patients who have intolerance or allergy to tetracyclines can be treated with rifampin 300 mg twice daily for 7 to 10 days. Prognosis

Mild to moderate babesiosis in immunocompetent patients is usually associated with <4% parasitemia and does not require hospital admission.3 Severe babesiosis is often associated with parasitemia ≥4% and is more likely to lead to complications and/or persistent or relapsing disease. Of 34 cases of babesiosis on Long Island, acute respiratory failure and DIC proved to be the 2 most common complications, occurring in 7 out of 34 cases and 6 out of 34 cases, respectively.13 In HME and HGA, delay in treatment with doxycycline was associated with increased rates of mechanical ventilation and prolonged hospitalization.3 Estimated mortality rates have been 2% to 5% for HME and as high as 7% to 10% for HGA.4 Life-threatening

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right-hand column like this one does at the top

EMERGING TICKBORNE ILLNESSES

infection is more common in the immunocompromised population and secondary opportunistic infections were common in patients who died.4

References 1. Lyme Disease. Data and surveillance. Centers for Disease Control and Prevention. https://www.cdc.gov/lyme/stats/index.html. Published November 13, 2017. Accessed April 9, 2019.

Conclusion

2. Parasites: babesiosis. Centers for Disease Control and Prevention.

Tickborne diseases in the United States will continue to be a significant public health problem, and ongoing expansion of these vectors emphasizes the need for effective prevention methods. Surveillance of expansion of vectors over the past 20 years has shown an overall 277% increase from 69 to 260 counties in highincidence areas for Lyme disease.1 This is likely a surrogate marker for the expansion of other tick populations. Avoidance of tick bites remains the mainstay of prevention, and patients should be educated to use insect repellents as directed. Products with higher percentages of DEET [N,N-diethyl-meta-toluamide] are preferred and are directly applied to exposed skin and clothing. The product label includes details about how and where to apply the repellent, how often to reapply, and how to use it safely on children. For those patients wary of DEET, a newer odorless, nongreasy repellant known as picaridin has been available in the United States since 2005. Created by Bayer from plant extract, picaridin is the best-selling insect repellant in Europe and Australia, is equal in efficacy to DEET, and does not dissolve plastics or other synthetics.The United States Environmental Protection Agency has a website tool14 that provides guidance on which insect repellant is most appropriate based on duration of exposure and which insects it repels, season, and region. Additionally, permethrin products can be applied to clothing and shoes, but not to skin, to kill ticks on contact. It is usually effective through several washings. Patients should be educated to avoid high-risk areas if possible, especially wooded and brushy areas, overgrown grasses, and leaf litter. Hikers and those who enjoy recreational outdoor activities should walk in the center of cleared trails, cover exposed skin (ie, tuck pant legs into socks), and perform thorough tick checks immediately after engaging in outdoor activities to increase likelihood of prompt removal. Clinicians should be comfortable identifying specific tick vectors and be familiar with endemic geographic regions for disease exposure. Prompt recognition and treatment of isolated infection or coinfection with babesiosis, HME, and HGA improves outcomes. Information on other tick-borne infections in the United States, including spotted fever rickettsioses, southern tick-associated rash illnesses, and tickborne viruses (ie, Colorado tick fever, Powassan) is available from the CDC.15 ■

https://www.cdc.gov/parasites/babesiosis/. Published May 24, 2016. Accessed April 9, 2019. 3. Krause PJ, Vannier EG. Babesiosis: microbiology, epidemiology, and pathogenesis. UpToDate website. https://www.uptodate.com/contents/babesiosismicrobiology-epidemiology-and-pathogenesis?search=babesiosis&source= search_result&selectedTitle=3~69&usage_type=default&display_rank=3. Published May 7, 2018. Accessed April 9, 2019. 4. Sexton DJ, McClain MT. Human ehrlichiosis and anaplasmosis. UpToDate website. https://www.uptodate.com/contents/human-ehrlichiosis-andanaplasmosis?search=human ehrlichiosis&source=search_result&selectedTit le=1~150&usage_type=default&display_rank=1. Published August 15, 2016. Accessed April 9, 2019. 5. Snowden J, Simonsen KA. Ehrlichiosis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2018. 6. Ehrlichiosis: signs and symptoms. Centers for Disease Control and Prevention. https://www.cdc.gov/ehrlichiosis/symptoms/index.html. Updated January 17, 2019. Accessed April 9, 2019. 7. Anaplasmosis: signs and symptoms. Centers for Disease Control and Prevention. https://www.cdc.gov/anaplasmosis/symptoms/index.html. Updated January 11, 2019. Accessed April 9, 2019. 8. Dunn JM, Krause PJ, Davis S, et al. Borrelia burgdorferi promotes the establishment of Babesia microti in the northeastern United States. PLoS ONE. 2014;9(12):e115494. 9. Knapp KL, Rice NA. Human coinfection with Borrelia burgdorferi and Babesia microti in the United States. J Parasitol Res. 2015;2015:587131. 10. Brennan-Krohn T. Nothing new under the sun: detecting Babesia as it reemerges. American Society for Microbiology website. https://www. asm.org/index.php/clinmicro-blog/item/6790-nothing-new-under-the-sundetecting-babesia-as-it-reemerges. Published September 5, 2017. Accessed April 9, 2019. 11. Dumler JS, Choi KS, Garcia-Garcia JC, et al. Human granulocytic anaplasmosis and Anaplasma phagocytophilum. Emerg Infect Dis. 2005; 11(12):1828-1834. 12. Tickborne diseases of the United States: tick bites/prevention. Centers for Disease Control and Prevention. https://www.cdc.gov/ticks/ tickbornediseases/tick-bites-prevention.html. Updated January 10, 2019. Accessed February 9, 2019. 13. Akel T, Mobarakai N. Hematologic manifestations of babesiosis. Ann Clin Microbiol Antimicrob. 2017;16(1):6. 14. Find the repellent that is right for you. United States Environmental

Kimberly Damato, PA-C, is a physician assistant in neurosurgery at Brookdale University Hospital and Medical Center, in Brooklyn, NewYork. Danielle Kruger, PA-C, MS Ed, is an associate professor in the physician assistant program at St. John’s University, in New York City.

Protection Agency. https://www.epa.gov/insect-repellents/find-repellent-rightyou. Updated June 14, 2017. Accessed April 9, 2019. 15. Tickborne diseases of the United States. Centers for Disease Control and Prevention. https://www.cdc.gov/ticks/diseases/index.html. Updated January 10, 2019. Accessed April 9, 2019.

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Dermatology Clinic CASE #1

Brown Macules on the Face and Trunk SAIRA E. ALEX, BS; MCKENNA E. BOYD, BS; CHRISTOPHER RIZK, MD

A 60-year-old man presents with brown macules on his face, arms, hands, and back. He reports that the spots first appeared after he moved to California 20 years ago, and he has been noticing new spots ever since. He denies pruritus or fading of the spots during winter. The patient previously worked as a lifeguard at a local beach. He does not have significant medical or family history. Examination reveals numerous 1-cm, well-defined, dark brown, evenly pigmented, flat macules over his face, arms, hands, and back. What is your diagnosis? Turn to page 38

CASE #2

Bright Red, DomeShaped Papules JUNRU YAN, BA; MCKENNA E. BOYD, BS; CHRISTOPHER RIZK, MD

A 62-year-old man with gastric adenocarcinoma for which he has been receiving chemotherapy for 4 weeks presents to his internist with new lesions on his trunk. He noticed approximately 30 bright red, smooth, dome-shaped papules measuring 2 to 5 mm that appeared suddenly on his arms, chest, and back. He denies any other recent illnesses or fevers. The patient is concerned that the spots are a sign that his cancer is worsening. Punch biopsy is obtained, revealing erythrocytes filling endothelial cell-lined dilated vascular channels in the mid to upper dermis. What is your diagnosis? Turn to page 39 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2019 37

Dermatology Clinic CASE #1

Solar Lentigines

Solar lentigines (SLs) are stable, hyperpigmented patches or macules that increase in number with age in sun-exposed areas.1,2 Also known as liver spots or aging spots, SLs occur due to proliferation of melanocytes and consequent accumulation of melanin.1 The main risk factors for developing these lesions include fair skin, chronic sun exposure, age, and diabetes.1-4 These lesions are diagnosed clinically, although histology, immunohistochemistry, and electron microscopy features have been described.1 Solar lentigines are confused most often with ephelides, as both types of lesions are used to describe sun-induced freckling; however, distinction can be made based upon size, seasonal pigmentation changes, and age at onset. While treatment is not necessary, several physical and topical therapies exist for cosmetic purposes. The etiology and pathogenesis of SLs are largely associated with skin damage from chronic exposure to ultraviolet (UV) radiation.1-9 When exposed to UV light, keratinocytes release reactive oxygen species that can induce genetic and/ or epigenetic changes within keratinocytes.1 Melanocytes serve to protect the skin by producing the pigment melanin, which absorbs these radicals.1-3 Melanocytes, arising from the neural crest, differentiate in the basal epidermis to create dendritic contacts with surrounding keratinocytes.1 Through these connections, melanocytes transfer melanin, which in turn pigments the skin. Intense and chronic UV exposure overpowers this physiologic system and genetic damage occurs, thus inducing formation of SLs.1,3 Specific gene mutations have been associated with the development of SLs, namely inactivating mutations in MC1R.3 Other associated genes include SLC45A2, GFR3, and PIK3CA.1 Additional studies have shown that malfunction of Notch 1-dependent keratinocytes leads to the hyperpigmentation seen in SLs.2 Several factors increase the risk of developing SLs, namely chronic sun exposure, increased age, and lighter skin tones.2,3,6 A recent study of white women determined additional risk factors to include frequent sunburns, chronic sun exposure, tanning, intake of oral contraceptives, and progesterone treatment.5 Interestingly, diabetes mellitus is an independent risk factor, possibly due to the effects of diminished glucose metabolism in skin.4 The presence of SLs and lentigine density have been associated with increased risk of melanoma.1,3,6 SLs vary from light yellow to dark brown in color, have

well-defined borders, are measured in millimeters to centimeters, and are stable under varying amounts of sunlight.1,3 Lesions are most commonly found on the hands and other sun-exposed areas such as the face, trunk, and arms.1,2,4,8 Histologically, SLs appear with epidermal thickening and hyperplasia, a hyperpigmented basal layer, functionally active melanocytes, and extended epidermal ridges.1,2,6 Of note, melanocyte size and melanosome size and number are normal in SLs.1 Other distinctive features have been noted on immunohistochemistry and electron microscopy.1 Immunohistochemical studies have shown an increased number of melanocytes, increased tyrosine kinase receptor expression in melanocytes, increased melanoblasts in

Solar lentigines are stable, hyperpigmented patches or macules that increase in number with age in sun-exposed areas. hair follicular infundibulum, and increased melanocyte stem cells in the bulge of hair follicles. Electron microscopy studies have shown microinvaginations into keratinocytes, a welldeveloped endoplasmic reticulum, increased mitochondria density, disorganized and disrupted dermal-epidermal junction, and a thin lamina densa. The differential diagnosis for SLs includes ephelides, seborrheic keratoses, lentigo maligna, lentigo maligna melanoma (LMM), and psoralens and ultraviolet A (PUVA) lentigines.1,3 Patient history and physical examination findings are sufficient to narrow the diagnosis. Briefly, seborrheic keratoses are genetically predisposed and present with palpable lesions and horn cysts.3 Patients with lentigo maligna have macular lesions with irregular borders of varying size and pigmentation; LMM has a similar presentation except these lesions are palpable. Lastly, PUVA lentigines are induced by PUVA light therapy as opposed to the sun in SLs. Freckles are colloquially used to describe both ephelides and SLs. Both lesions are characterized as benign spots induced by sun exposure most commonly seen in Asian and white populations; however, ephelides and SLs can be distinguished based on size and temporal pigmentation changes.1,5,6 Ephelides are small, 1- to 2-mm macules that appear around age 2Â years, and these red- to light brown-colored spots increase in pigmentation with increased sun exposure. On the other hand, SLs are larger, darker, appear most commonly in sun-exposed areas, and do not present with seasonal variation.While SLs increase in number as patients age, ephelides peak during adolescence and regress with age.

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SLs do not require treatment but are often treated for cosmetic reasons.7 Of note, as these lesions are induced by chronic sun exposure, all patients should be counseled about sun protection.3 If patients wish to pursue treatment, 2 broad methods exist: physical and topical treatments.7 Physical treatments include cryotherapy, laser treatments, intense pulsed lights, and chemical peeling.7,8 Of all the treatment options available, cryotherapy with liquid nitrogen is the preferred method.3,7 In patients with darker skin types III and IV, pulsed-dye laser was shown to be superior to cryotherapy for lightening SLs; this difference was not seen for patients with lighter skin tones.7 Combination of picosecond-switched lasers and biophotonic therapy has produced successful results.8 Compared with these physical therapies, topical therapies require extended treatment but are associated with fewer risks.7 The most common of these options include hydroquinone and tretinoin.7 Lastly, recent studies have shown a modest whitening effect of lotions with L-ascorbate-2-phosphate trisodium salt.9 The 60-year-old patient mentioned in the case was diagnosed with solar lentigines. No treatment was administered since he did not want a cosmetic procedure. The patient was advised to apply sunscreen daily and wear protective gear to prevent further photodamage. He was also advised to return for evaluation if his lentigines changed in size or color. Saira E. Alex, BS, is a medical student; McKenna E. Boyd, BS, is a medical student; and Christopher Rizk, MD, is a dermatology fellow at Baylor College of Medicine, in Houston,Texas. References 1. Praetorius C, Sturm RA, Steingrimsson E. Sun-induced freckling: ephelides and solar lentigines. Pigment Cell Melanoma Res. 2014;27(3):339-350. 2. Barysch MJ, Braun RP, Kolm I, et al. Keratinocytic malfunction as a trigger for the development of solar lentigines. Dermatopathology (Basel). 2019;6(1):1-11. 3. Goldstein BG, Goldstein AO. Overview of benign lesions of the skin. UpToDate. https://www.uptodate.com/contents/overview-of-benign-lesionsof-the-skin?search=solar%20lentigo%20treatment&source=search_ result&selectedTitle=2~24&usage_type=default&display_rank=2#H1101421390. Updated February 19, 2019. Accessed March 19, 2019. 4. Moazzami B, Razavi N, Babaei M, Haghparast M, Bayani MA. The association between solar lentigines and type-2 diabetes. Caspian J Intern Med. 2017;8(4):317-320. 5. Ezzedine K, Mauger E, Latreille J, et al. Freckles and solar lentigines have different risk factors in Caucasian women. J Eur Acad Dermatol Venereol. 2013;27(3):e345-e356. 6. Bastiaens MT, Westendorp RG, Vermeer BJ, Bavinck JN. Ephelides are more related to pigmentary constitutional host factors than solar lentigines. Pigment Cell Res. 1999;12(5):316-322.

7. Seirafi H, Fateh S, Farnaghi F, Ehsani AH, Noormahammadpour N. Efficacy and safety of long-pulse pulsed dye laser delivered with compression versus cryotherapy for treatment of solar lentigines. Indian J Dermatol. 2011;56(1):48-51. 8. Scarcella G, Dethlefsen MW, Nielson MCE. Treatment of solar lentigines using a combination of picosecond laser and biophotonic treatment. Clin Case Rep. 2018;6(9):1868-1870. 9. Ishikawa Y, Niwano T, Hirano S, Numano K, Takasima K, Imokawa G. Whitening effect of L-ascorbate-2-phosphate trisodium salt on solar lentigos. Arch Dermatol Res. 2019;311(3):183-191.

CASE #2

Cherry Angioma

Cherry angiomas are also known as Campbell de Morgan spots, cherry hemangiomas, and senile angiomas. These lesions are the most common benign vascular tumors affecting primarily older, paleskinned individuals.1,2 Cherry angiomas are well-demarcated, blanchable, bright red, domeshaped papules and pinpoint macules most commonly found on the trunk and arms measuring several millimeters in diameter.1 The number and size of lesions increase with age with prevalence increasing from approximately 5% in adolescents to approximately 75% in adults aged >75 years.1,2 Diagnosis is based on patient history and clinical presentation. Lesions do not require treatment although several cosmetic therapies exist. The etiology and pathogenesis of cherry angiomas are poorly understood.1,2 For a time it was even unclear if these lesions should be classified as vascular tumors or vascular malformations. Recent studies have shown the cytoplasmic expression of Wilms tumor protein 1, a marker of endothelial plasticity, in cherry angioma tumor cells.3 This evidence thus classifies cherry angiomas as vascular tumors given the proliferative nature of the contained endothelial cells. Other studies have attempted to discover somatic mutations associated with cherry angiomas. One such study found that mutations in genes GNAQ and GNA11 were found to be present in 50% of cherry angioma samples taken (n=10); these are the same mutations present in port wine stains and Sturge-Weber syndrome.4 Of note, pathogenesis of cherry angiomas may be associated with malignancy as sudden appearance is often associated with systemic internal malignancy.3

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Dermatology Clinic Several risk factors for the development of cherry angiomas exist. Lesions are most commonly found in the third to fourth decade of life in pale-skinned individuals.1,3 A cross-sectional study found older age, chronic immunosuppression, skin tumors, and nonskin tumors to have an increased association with the appearance of cherry angiomas.2 In addition, the appearance of cherry angiomas has been associated with pregnancy, human herpesvirus 8, chronic graft-vs-host disease, and chemical compounds including mustard gas, bromides, and cyclosporine.1,2

Cherry angiomas are also known as Campbell de Morgan spots, cherry hemangiomas, and senile angiomas. Cherry angiomas typically present in an eruptive fashion on the upper extremities and trunk.1,2 Lesions can be found on any skin surface but are found less commonly on the hands, feet, face, and open space mucosal surfaces.1,3 Cherry angioma can also arise as a singular lesion or in fewer numbers; this presentation is more commonly associated with earlier onset and genetic predisposition.2 Important considerations for the differential diagnosis include petechiae, pyogenic granulomas, amelanotic melanomas, strawberry hemangioma, Kaposi sarcoma, and bacillary angiomatosis.1,5 Petechiae arise due to bleeding under the skin in the context of low platelet levels. Pyogenic granulomas typically are benign skin or mucosal-vascular tumors that grow rapidly and bleed profusely after minimal injury, usually with a more friable appearance and lobular pattern than cherry angiomas.5,6 An amelanotic melanoma has the features of melanoma without the typical pigmentation; thus, irregular borders and large size should help distinguish it from cherry angioma. Strawberry hemangiomas, or capillary hemangiomas, arise in infants and regress with age. Kaposi sarcoma and bacillary angiomatosis often are associated with immunosuppression due to infection with human herpesvirus 8 and Bartonella henselae, respectively. In cases when diagnosis cannot be made based on presentation and history, histologic analysis typically is recommended. When malignancy is suspected, excision of the lesion prior to histologic analysis is preferred. Histologically, cherry angiomas are true capillary hemangiomas, consisting of an amalgamation of newly formed capillaries within the papillary dermis.1 Intravascular changes such as hyalinization of collagen fibers and edema can also be seen.1,3

Cherry angiomas do not require treatment since they are self-limited, non-life-threatening, and can be managed with observation. However, patients may choose to treat these lesions for cosmetic purposes. Currently, no existing medical therapies exist; however, several surgical options ranging from destructive treatments to less-invasive targeted laser therapies are available. Destructive treatments include shave excision and electrodesiccation and curettage.1 Invasive targeted laser therapies are also quite effective since cherry angiomas contain oxygenated hemoglobin, which can be targeted and vaporized with laser wavelengths of 418, 542, and 577 nm.7 Cherry angiomas are destroyed when the vascular lumen is obliterated. Pulsed-dye laser as well as potassium titanyl phosphate laser have been shown to minimize risk of treatment-associated textural change or scarring.8 The patient in this case was reassured that these spots were cherry angiomas and likely related to his continued immunosuppression. These lesions were unlikely a sign that his cancer was worsening. The spots themselves were benign lesions that did not affect his mortality and did not require immediate medical or surgical treatment. The patient deferred elective management. ■ Junru Yan, BA, is a medical student; McKenna E. Boyd, BS, is a medical student; and Christopher Rizk, MD, is a dermatology fellow at Baylor College of Medicine, in Houston,Texas. References 1. Kim JH, Park HY, Ahn SK. Cherry angiomas on the scalp. Case Rep Dermatol. 2009;1(1):82-86. 2. Borghi A, Minghetti S, Battaglia Y, Corazza M. Predisposing factors for eruptive cherry angiomas: new insights from an observational study. Int J Dermatol. 2016;55(11):e595-e608. 3. Fernandez-Flores A, Colmenero I. Campbell de Morgan spots (cherry angiomas) show endothelial proliferation. Am J Dermatopath. 2018;40(12):894-898. 4. Klebanov N, Lin WM, Artomov M, et al. Use of targeted next-generation sequencing to identify activating hot spot mutations in cherry angiomas. JAMA Dermatol. 2019;155(2):211-215. 5. Cheah S, Dekoven J. Pyogenic granuloma complicating pulsed-dye laser therapy for cherry angioma. Australas J Dermatol. 2009;50(2):141-143. 6. Bovée JVMG. Practical soft tissue pathology: a diagnostic approach. Virchows Arch. 2018;473(6):785-786. 7. Rohrer TE, Geronemus RG, Berlin AL. Vascular lesions. In: Goldberg DJ, ed. Laser and Lights, Volume 1. 2nd ed. Philadelphia, PA: Saunders Elsevier: 2009. 8. Collyer J, Boone SL, White LE, et al. Comparison of treatment of cherry angiomata with pulsed-dye laser, potassium titanyl phosphate laser, and electrodesiccation. Arch Dermatol. 2010;146(1):33-37.

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Dermatologic Look-Alikes Macules With Irregular Borders ELEANOR G. JOHNSON, BA; MCKENNA E. BOYD, BS; CHRISTOPHER RIZK, MD

CASE #1

CASE #2

A 45-year-old man presents to your office because he is concerned about a mole on his arm that has been changing over the past several months. He has no significant medical history, but he has been a patient of yours for the past 10 years since his mother was diagnosed with skin cancer. As a teenager, he frequently visited tanning salons and reports experiencing numerous severe sunburns. He has fair skin, blue eyes, and many freckles. The mole measured 4 mm in diameter during his last visit. Today it measures 8 mm, is brown and black in color, and has an irregular border.

A 50-year-old man presents to your office because he recently noticed a mole on his right cheek. He is unsure how long the lesion has been present or if it has grown in size. The borders are slightly irregular, and a central black region among various shades of brown is noted.You estimate the mole to measure approximately 6 mm in diameter. The patient states that the lesion does not itch or bleed and is not painful. His medical history includes diabetes mellitus, and his social history includes 30 packyears of smoking. He has worked on construction sites since age 18 years.

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Dermatologic Look-Alikes CASE #1

Melanoma

René Théophile Hyacinthe Laennec first lectured on melanoma and coined the term “melanose,” meaning “black” in Greek, in 1804. Between 1829 and 1842, his colleague, Jean Cruveilhier, published articles on melanoma of the hand, foot, and vulva, as well as on metastases to the heart.1 Melanoma is the most dangerous skin cancer, accounting for 80% to 90% of deaths from skin cancer, even though it represents only 4% of all dermatologic cancers.2-5 Like many dermatologic pathologies, this malignancy is thought to develop after repeated exposure to intense sunlight.2 Clinical appearance may vary, but the most common presentation is an asymmetric macule that may slowly develop into a papule, with an irregular border and variable pigmentation.2,3 Several other conditions mimic melanoma, including dysplastic nevi — a benign condition that may be a precursor to malignant melanoma.6,7 If diagnosed at an early stage, melanoma can be cured with resection, but cancers stage III and greater require treatment with adjunctive therapy, lymph node resection, and potentially chemotherapy and radiation.3,5 Incidence of melanoma ranges widely by region but is highest in New Zealand and Australia.5 Rates are also high in the European Union and North America, as the condition predominantly affects fair-skinned populations.3,5 Melanoma is in the top 10 most common malignancies for both men and women in the United States.5 It can occur anywhere on the body but is most commonly found in sun-exposed areas, including the trunk, head, neck, face, and lower legs.3,8 Onset is dependent on the subtype of melanoma; superficial spreading is most common and diagnosed on average between the ages of 40 and 60 years.9 The elderly and men tend to have lower survival rates, but generally melanoma has a high 5-year survival rate of approximately 92% in the United States.5 Melanoma is a malignancy of melanocytes that develops from a series of mutations.2,9 The Clark model outlines a potential method of step-wise pathogenesis.2 First, melanocytes proliferate to form a nevus, which then continues via dysplasia and hyperplasia to form a dysplastic nevus, and then finally invades and undergoes metastasis in the form of malignant melanoma. Signaling pathways commonly mutated include MAPK (including BRAF) and PTEN (PI3K), which regulate growth and proliferation; WTN, which regulates differentiation; and MC1R-MITF, which is associated with a melanocyte-specific receptor.2,9 Additionally, the loss of E-cadherin and expression

of N-cadherin marks the progression to vertical growth and thus increased Breslow depth.2,3 This transformation into melanoma is influenced by many factors, most notably exposure to ultraviolet (UV) radiation.2,5 Sun exposure induces genetic changes in the skin, forms DNA-damaging reactive oxygen species, and alters the local immune system and growth factors.2 The skin’s defense mechanism is to produce more melanin to absorb and dissipate damaging rays. With chronic, low-grade exposure the skin is able to shield itself against this process. This physiologic defense mechanism is overrun, however, with intermittent exposure to intense UV radiation, resulting in genetic damage and potential progression to skin cancer.2 Risk factors for the development of melanoma include a history of intermittent, intense sun exposure, frequent sun burns, personal or family history of melanoma, multiple benign or atypical nevi, fair skin, and immunosuppression.2,5,8 Despite identification of several genes associated with melanoma (eg, CDKN2A and MC1R), genetic testing has failed to show

Melanoma is in the top 10 most common malignancies for both men and women in the United States. clinical benefit.2,5,9 Although the risk of transformation of a single benign or atypical nevus to melanoma is low, 1 in thousands and 1 in hundreds of individuals, respectively, with many nevi have been noted to have higher rates of melanoma.9 This is potentially because of increased sun exposure or an underlying condition such as dysplastic nevus-melanoma syndrome.9,10 Phenotypic characteristics including fair hair, eye, and skin colors and the tendency to freckle increase an individual’s susceptibility to UV-induced damage.3,9 Classic clinical characteristics of melanoma include asymmetry, irregular borders, color variability, and diameter >5 mm. This is easily remembered by the ABCD rule.8 The lesion may be itchy, tender, ulcerated, and/or bleeding. When the malignancy enters its rapid vertical growth phase, the original macule may transform into a papule or nodule.9 The main subtypes of melanoma include superficial spreading, lentigo maligna (malignant melanoma in situ), nodular, and acrallentiginous.5,9 Superficial spreading is the most common variant; in women, it is found most commonly on the legs and in men, on the trunk.9 In the initial clinical evaluation, dermoscopy is useful in detection of melanoma. While this technique is user dependent, it is up to 90% effective.5 On

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Dermatologic Look-Alikes histologic examination, markedly atypical melanocytes are seen in nests in the epidermis. These nests may be confluent and vary in size. Melanocytes may also be scattered above the dermal-epidermal junction and within the dermis.9 The differential diagnosis for melanoma is extremely broad. Various nevi — including dysplastic, combined, congenital, blue, black, and halo — can clinically mimic melanoma. Reticulated lentigo, seborrheic keratosis, dermatofibroma, and plantar warts are benign conditions on the differential. Malignant conditions to consider include pigmented basal cell carcinoma, pigmented actinic keratosis, and extramammary Paget disease.9 The first step in differentiating melanoma from similar-appearing conditions is dermoscopy to determine if the lesion is melanocytic in origin; various algorithms including the ABCD rule, Menzies method, and the 7-point checklist can then be used to decide if a biopsy should be performed.8,9 Diagnosis is made clinically and confirmed by excisional biopsy and histopathologic examination. Breslow thickness is the most important prognostic factor. Other prognostic factors include location, ulceration, gender, and mitotic activity.5 Classification is determined by tumor thickness (T stage; Breslow staging), involvement of lymph nodes (N stage), and presence of metastasis (M stage).3,5 After diagnosis is made, the lesion should be re-excised. Margins range from 0.5 cm for malignant melanoma in situ to 2 cm if the tumor is >2 mm thick.5 As discussed previously, the tumor should be staged and lymph node involvement should be assessed. Lymph node biopsies are recommended if the tumor is >1 mm thick. Computed tomography or magnetic resonance imaging should be performed to determine if distant metastasis is present if evidence of metastasis is noted.5,9 For those with melanoma stage III and greater, adjunctive therapy is recommended, and chemotherapy may be needed to treat metastases.3,5,9 Immunotherapy such as PD-1 inhibitors and anti-CTLA-4 antibodies stimulates the patient’s immune system to more effectively attack the malignant cells. Ipilimumab, nivolumab, and pembrolizumab are immunotherapy options approved to treat melanoma.3,4 BRAF gene mutations are the ones most commonly seen in melanoma and are found in 40% to 50% of tumors.4 Individuals with BRAF mutations can be treated with either a kinase inhibitor such as vemurafenib or dabrafenib, or the reversible MEK1 and MEK2 kinase inhibitor trametinib.4 These drugs can be given alone or in combination. The American Cancer Society lists many possible chemotherapy regimens including dacarbazine, temozolomide, nab-paclitaxel, paclitaxel, cisplatin, carboplatin, and vinblastine.11 The American Cancer Society also states that adding immunotherapy drugs (interferon-alfa and/or interleukin-2) to chemotherapy may be more effective than chemotherapy alone.

Follow-up is important to identify recurrence, but recommendations on the frequency of these visits vary depending on a patient’s particular case. Because 90% of all metastases occur within the first 5 years, it is recommended that more frequent visits occur during this time period.3 For individuals with melanoma stages I to II, screening every 3 months with the goal of detecting local recurrence is recommended. Biopsy was performed on the lesion in this case, with pathologic evaluation revealing atypia and melanocyte nests.The patient was diagnosed with melanoma and returned for re-excision with 1-cm margins. Breslow thickness measured 0.6 mm; therefore, lymph node dissection was not recommended. The patient returned for regular screening and did not develop recurrence.

CASE #2

Dysplastic Nevi

In 1978, Wallace Clark first introduced the term dysplastic nevus in the context of “B-K mole syndrome”; since then, its definition has been debated and its name has changed multiple times.10,12 Despite recommendations by the National Institutes of Health Consensus Development Conference to change the name to atypical mole, dysplastic nevus and dysplastic nevus syndrome are the most commonly used terms in the literature.10 The condition causes debate because it exists in the gray area between common nevi and melanoma.13 The prevalence of dysplastic nevi is estimated to be anywhere from 2% to18%.10 Dysplastic nevi significantly increase a patient’s risk for developing melanoma; accordingly, patients with a history of melanoma have a higher prevalence of dysplastic nevi ranging from 34% to 59%.6,10,12 While this association exists, most dysplastic nevi themselves do not transform into melanoma.6,10,12 Since they are associated with sun exposure, dysplastic nevi begin to appear in puberty or adolescence and can either further develop or regress throughout adulthood.14 A patient may have just 1 or multiple heterogeneous dysplastic nevi. Sun-exposed areas such as the trunk and upper back are the most common locations for dysplastic nevi to develop.3,6,12 Dysplastic nevi can develop de novo or from previously normal-appearing nevi.6 As mentioned previously, exposure to UV-radiation induces numerous changes in the skin. It can damage DNA, which allows cells to acquire mutations

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that allow for uncontrolled cell growth. Currently, dysplastic nevi are thought to be precursors to melanoma.7 Common risk factors for developing atypical nevi include fair, sun-sensitive skin types and a history of blistering sunburns lasting more than 2 days.6 Another risk factor is dysplastic nevus-melanoma syndrome, which is a condition that can occur spontaneously or be inherited in an autosomaldominant fashion.6,7 With this syndrome, patients classically have a triad of a minimum of 100 nevi, 1 nevus ≥8 mm in diameter, and 1 nevus with clinically atypical features.6 Clinically, dysplastic nevi look very similar to melanoma. They were originally defined as symmetric moles ≥5 mm in length with irregular, fuzzy borders and color variability.6,10,14 The current definition of dysplastic nevi states that they are macular lesions with a majority of the following features: pigment irregularity, an ill-defined or irregular border, background erythema, and size >5 mm.10 Several subtypes of dysplastic nevi are known.The lentiginous variant is flat with evenly distributed dark brown to black

pigmentation.10 The “fried-egg” or sunnyside-up variant has a raised or flat center with pigmentation different from its flat peripheral border.6,10 The targeted variant presents as variable pigmentation in a concentric pattern.10 The seborrheic keratosis–like variant presents as a dark brown verrucous lesion.10 The erythematous type is pink to red in color.6,10 Finally, the melanoma-stimulant subtype resembles melanoma and thus is not determined to be a dysplastic nevus until histologic examination of the biopsied lesion has been performed.10 Dysplastic nevi are characterized by several histologic features. These include architectural disorder without symmetry, papillary dermis fibroplasia, perivascular lymphocytic infiltrate, bridging of rete ridges, and lentiginous melanocytic hyperplasia.12,15 Additionally, dysplastic nevi may show melanocyte atypia confined to the dermal-epidermal junction.15 The differential diagnosis for dysplastic nevi includes malignant melanoma, congenital nevus, and recurrent nevus. Compared with melanoma, dysplastic nevi are more symmetric and have well-defined lateral borders.12 One study found

TABLE. Characteristics of Melanoma and Dysplastic Nevi Melanoma1-5

Dysplastic Nevi6-10

Dermatologic Presentation

• Asymmetric • Irregular borders • Color variability • Diameter <6 mm

• Symmetric or asymmetric • Irregular, fuzzy borders • Color variability • Background of erythema

Associations

• Intense, intermittent sun exposure • Family history • Fair complexion • Multiple dysplastic nevi

• Dysplastic nevus-melanoma syndrome • Intense, intermittent sun exposure

Etiology

Malignancy of melanocytes

Precursor lesion on the spectrum between benign nevus and melanoma

Characteristic Location

Sun-exposed areas • Women: legs • Men: trunk

Can occur anywhere but favor sun-exposed areas

Histology

• Atypical melanocytes in nests that coalesce • Melanocytes may be scattered above the dermalepidermal junction and within the dermis

• Architectural disorder without symmetry • Subepidermal fibroplasia • Lentiginous melanocytic hyperplasia with spindle or epithelioid melanocytes aggregating in nests of variable size and forming bridges between adjacent rete ridges

Diagnosis

Biopsy

Physical examination with dermoscopy

Treatment

• Re-excisional biopsy • Lymph node evaluation, if recommended • Computed tomography/magnetic resonance imaging, if recommended • Adjunctive chemotherapy and/or radiation

• Excision of severely dysplastic nevi • Continued monitoring of mild to moderate dysplastic nevi • Close follow-up • Prophylactic removal not recommended

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Dermatologic Look-Alikes that pathologists misdiagnosed dysplastic nevi as melanoma approximately 21% of the time and that the reverse occurred approximately 12% of the time.10 In order to improve diagnostic accuracy, scientists are developing tools that use nuclear image analysis in conjunction with next-generation sequencing.15 Specific markers for discrimination between melanoma and dysplastic nevi are scarce. One study found 4 (Bim, BRG1, Cul1, and ING4) out of 12 immunohistochemical markers that could differentiate melanoma from dysplastic nevi with nearly 95% sensitivity.16 In contrast, congenital nevi and recurrent nevi cannot be clinically differentiated from dysplastic nevi; the differentiation is made with histologic examination.13

2. Miller AJ, Mihm MC. Melanoma. N Eng J Med. 2006;355(1):51-65. 3. Garbe C, Peris K, Hauschild A, et al. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline - Update 2016. Eur J Cancer. 2016;63:201-217. 4. Lee CS, Thomas CM, Ng KE. An overview of the changing landscape of treatment for advanced melanoma. Pharmacotherapy. 2017;37(3):319-333. 5. Schadendorf D, van Akkooi ACJ, Berking C, et al. Melanoma. Lancet. 2018;392(10151):971-984. 6. Naeyaert JM, Brochez L. Clinical practice. Dysplastic nevi. N Engl J Med. 2003;349(23):2233-2240. 7. Goldstein AM, Tucker MA. Dysplastic nevi and melanoma. Cancer Epidemiol Biomarkers Prev. 2013;22(4):528. 8. McEnroe-Petitte MD. Melanoma. Nursing. 2011;41(5):45.

The differential diagnosis for dysplastic nevi includes malignant melanoma, congenital nevus, and recurrent nevus.

9. Bolognia J, Jorizzo JL, Schaffer JV, eds. Dermatology. 4th ed. Philadelphia: Elsevier Saunders; 2012:1885-1914. 10. Farber MJ, Heilman ER, Friedman RJ. Dysplastic nevi. Dermatol Clin. 2012;30(3):389-404. 11. American Cancer Society. Treating melanoma skin cancer. American Cancer Society. https://www.cancer.org/cancer/melanoma-skin-cancer/ treating.html. Published 2018. Accessed April 22, 2019. 12. Clarke LE. Dysplastic nevi. Clin Lab Med. 2011;31(2):255-265. 13. Duffy K, Grossman D. The dysplastic nevus: from historical perspective to management in the modern era: Part II. Molecular aspects and clinical management. J Am Acad Dermatol. 2012;67(1):19.e11-19.e12. 14. Halpern AC, Guerry D, Elder DE, Trock B, Synnestvedt M, Humphreys T. Natural history of dysplastic nevi. J Am Acad Dermatol. 1993;29(1):51-57. 15. Hanna M, Liu C, Rohde G, Singh R. Predictive nuclear chromatin characteristics of melanoma and dysplastic nevi. J Pathol Inform. 2017;8(1):15. 16. Zhang G, Li G. Novel multiple markers to distinguish melanoma from dysplastic nevi (biomarker in differential diagnosis of melanoma). PLoS One. 2012;7(9):e45037.

Eleanor G. Johnson, BA, is a medical student; McKenna E. Boyd, BS, is a medical student; and Christopher Rizk, MD, is a dermatology fellow at Baylor College of Medicine, in Houston,Texas. References 1. Denkler K, Johnson J. A lost piece of melanoma history. Plast Reconstr Surg. 1999;104(7):2149-2153.

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Diagnosis of dysplastic nevi is made clinically; thus, biopsy is unnecessary except in cases of suspected melanoma.10 The likelihood of dysplastic nevi progressing to melanoma is very low, and removing the mole does not significantly lower the risk of developing melanoma.6,10 Dysplastic nevi can be graded as mild, moderate, or severe. Mild and moderate dysplastic nevi can be monitored; however, severely dysplastic nevi should be excised, as they might represent an overlap with melanoma in situ. Patients diagnosed with dysplastic nevi should be followed closely. Recommendations vary, but annual visits are a general guideline, with more frequent visits if the patient prefers.6,10 Patients with familial dysplastic nevi should be seen every 3 months.6 When screening patients during these visits, clinicians should reassess the nevus for concerning changes such as growth, color change, or papule formation within the lesion. Patients should be cautioned to avoid sun exposure as much as possible and to wear protective clothing when outdoors.10 In this case, it was determined that the lesion showed signs of atypia upon examination with dermoscopy. Biopsy of the lesion was performed, the results of which revealed mild atypia; thus it was monitored for changes during future visits. ■

LEGAL ADVISOR CASE

RN Fired for Blowing Whistle A nurse was wrongfully terminated for reporting improper medication storage practices. BY ANN W. LATNER, JD

Ms N stood on the curb outside of the nursing facility where until 10 minutes ago she had been employed. The registered nurse had called a friend to pick her up after she was terminated from her position. Ms N had never been fired before, and she was surprised how affected she felt by the event. She had started working at the nursing facility 7 years ago, and the job seemed like a good fit. Ms N enjoyed her work, and her reviews after her first few years were extremely positive. Her only problem was that she began suffering from debilitating migraine headaches, which often affected her ability to work. Her employer, however, was understanding and allowed her to use flex time to adjust her schedule when the headaches prevented her from working. After 3 years, Ms N was promoted to the position of minimum data set coordinator, which required her to evaluate the condition and needs of nursing home residents following admission to the facility. Ms N was pleased with the promotion and the additional responsibility and threw herself into the job. Things were fine for a couple of years until she began noticing something disturbing — on more

Be sure to keep records of your performance reviews, especially if they reflect a change from prior to reporting an incident compared with after.

than 1 occasion, she saw narcotic medication being left out in the office of the director of nursing, Mr D. Concerned, Ms N reported the issue to the assistant director and then to the head of the facility, Mrs H. Ms N was surprised at how long it took anyone to look into the issue. Eventually, Mrs H conducted an investigation and ordered drug testing for some employees. Mrs H reprimanded Mr D and another employee for not storing medication properly after 2 pills were discovered missing, but no additional action was taken. Ms N was disappointed with how the situation was handled, but she hoped that the reprimand would encourage the rest of the staff to take the storage of medication more seriously. A few months later, Ms N was demoted from her position as minimum data set coordinator. She was told that it was because a state review of the facility had identified deficiencies in Ms N’s 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 performance of her duties, but Ms N knew that she had only ever made minor clerical errors. Meanwhile, Ms N noticed that medication was still not being stored properly, despite Mrs H’s reprimand. Ms N wrote to Mrs H about her ongoing concerns. A second investigation ensued as a result of Ms N’s letter, and the facility hired a nurse consultant who identified issues related to medication storage and the system used for medication management. However, the nurse never spoke with Ms N as part of the investigation, and when Ms N discussed the investigation with coworkers, she was written up for allegedly breaching the confidentiality of the investigation by discussing it with colleagues.

Although a number of laws have been established to protect whistle-blowers, protection can only go so far. “But no one told me I couldn’t talk about the investigation,” she told the director of nursing and human resources manager. “You should know that this can’t be discussed,” was the reply. Things continued to steadily get worse for Ms N. Soon after the second investigation, she was told that she could no longer use flex time when she developed a migraine. “We’ve changed our policy,” said Mr D. A few months later, Ms N was inexplicably switched to working the night shift, making her headaches more problematic because of the change in her sleep schedule. She was ultimately called into human resources and told that she was being terminated because of errors that she had made. Ms N shared this situation with her friend who had arrived at the nursing facility. “You need to speak to an attorney,” she advised Ms N.

The case went to trial during which the nursing facility claimed that Ms N’s work was subpar, even though her reviews prior to reporting the medication mismanagement had been excellent. Ms N’s attorney was able to show a pattern of behavior on the part of the nursing facility that appeared to punish Ms N for reporting a valid issue. The case went to the jury, who found in favor of Ms N and awarded her $46,000 in actual damages and $1 million in punitive damages. Protecting Yourself

This situation is known as a whistle-blower case, in which an employee is fired and/or faces social stigma, legal action, or even criminal charges in retaliation for reporting illegal or improper actions by an employer. Although a number of laws have been established to protect whistle-blowers, protection can only go so far. Would your job be at risk if you were to report something like improper storage of medication? It shouldn’t be — everyone should have the same interest in managing medication safely. However, as Ms N discovered, reporting concerns can sometimes be viewed as a hostile action by an employer. Does this mean you shouldn’t report issues? Of course not. If there are issues, you should keep a log of what you noticed and when, who you reported them to, and what action was taken. Additionally, be sure to keep records of your performance reviews, especially if they reflect a change from prior to reporting an incident compared with after.While you may not be able to protect yourself from being fired if your employer wants to retaliate, you will have a good foundation for a legal case if you document the situation well. ■ Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, New York.

Ms N consulted with an attorney and explained the situation. The attorney was able to obtain her employment records, which showed she had done nothing more serious than commit a few minor clerical errors. “I think the reason cited for firing you was a smokescreen created to get rid of you after you reported the improper medication storage,” said the attorney. The attorney filed a lawsuit against the nursing facility, alleging wrongful discharge and disability discrimination based on the unwillingness of the facility to continue to offer flex time scheduling to Ms N to accommodate her recurrent migraine condition. 48 THE CLINICAL ADVISOR • JUNE 2019 • www.ClinicalAdvisor.com

Legal Background

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