A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS
■■Cough, Cold Medicine ■■Sesame Allergy ■■Autonomy for PAs in MO ■■Postmenopausal Testosterone ■■Cognition in Schizophrenia ■■Childhood Cancer Risk LEGAL ADVISOR
Negligence and Mistaken Identity
Rough, Scaly, Red Plaques
New Onset of Verrucous Papules
Eosinophilic Esophagitis: A Chronic Allergic Inflammatory Disease The prevalence of EoE is approaching that of Crohn disease and ulcerative colitis.
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Advisor Forum the color of the affected area was normal, the skin CLINICAL PEARLS felt quite thick and inflexible. These skin changes stopped abruptly at the collar line, below which POISON IVY PREVENTION the skin was entirely normal. Poison ivy season is starting! I recommend that Abundant evidence of sun damage — includ- people take an old pair of knee-high tube socks ing weathering, telangiectasias, solar lentiginosis, and cut off the foot part above the heel. Pull the and numerous actinic keratoses on prominent socks over the arms up to the start of their sleeve areas of his cheeks and ears — was noted. Similar (assuming they are wearing a T-shirt) and tuck changes were noted on the dorsa of both hands into gloves. Use the socks to protect arms when but were not present on his arms and trunk working in the yard or other high-risk poison because he wore long-sleeved shirts when in the ivy areas. They can be rolled off the arms and sun. Although he had worn a wide-brimmed hat thrown away, or washed and re-used. I remind while in the sun during his adult life, he had never people to always wear gloves, and to remove worn anything, such as a bandana, on his neck. the gloves before touching anything, including Always wear The posterior neck is especially susceptible door handles. This significantly reduces the gloves to to the effects of the sun, evidence of which fre- exposure area of skin to poison ivy. —JUDITH protect the quently manifests as it did in this patient. This MCINTOSH, MSN, Kokomo, Indiana skin from condition is called cutis rhomboidalis nuchae weath- VERRUCA VULGARIS TREATMENT exposure to (CRN), which represents thickening and weath ering of the epidermis as well as solar elastosis I always recommend candida albicans skin anti- poison ivy, and of the underlying dermis caused by the sun. gen test injections for patients who are not remove them Although this condition is clear evidence of responding well to liquid nitrogen +/- paring for before touching chronic overexposure to the sun, CRN has no verruca vulgaris. A 0.1-mg injection every month anything. malignant potential, and treatment is neither for about 3 months creates an immune response required nor does it exist. against the warts. I have seen resolution of some Besides being common, CRN is unique in its recalcitrant cases that seemed most impossible! presentation, as well as in the patient population —SARAH LUP, PA-C, Chicago, Illinois it affects (eg, older patients with sun damage confined to the posterior neck), so the differen- RETHINKING PRESCRIBING tial is quite narrow. Punch biopsy would resolve DICLEGIS Diclegis is the only FDA-approved prescription any confusion. CRN puts this patient at higher risk for the medication for nausea and vomiting of pregdevelopmentThe of skin caused by sun expo- nancy that is classified as Category A (safe for se cancers are lette rssquamous sure, such asand basal cell carcinoma, cell mom and baby). Before writing a prescription, from prac successe titioconsider ners arou carcinoma, melanoma, and s,others. the price tag. Diclegis with a coupon obseThis nd the coun rvatpatient ions, andcosts approximately and others with similar histories require regular $345 try for 60 tablets. The pearls with who their to share their skin checks by a qualified dermatology provider most common dosagecolle is 2 tablets/dwan but tcan agues. We clinical chall at least once a year. Although this patient would be more. Some patients may obtain insurance invite you enges to participa be advised to protect himself from the sun, this coverage for this medication, but it will likely te. will do little to ward off any future skin cancers still cost something. Let’s break down Diclegis that will have been caused by sun overexposure CONSUL into its 2 active ingredients: doxylamine sucTAT occurring decades earlier. Application of sun- cinate IONand S pyridoxine hydrochloride (vitamin screen to his neck would prevent IRO worsening of B 6). Unless you are writing a prescription for N PILL 2. Cohen SM, Kwo PY, Lim, his CRN. a celebrity, recommend that your patients ON LIVE S AND THEIR JK. ACG clinical of abnorm Send us R ENZ al liver chemis ECT guideline: your purchase over-the-counter doxylamine YMESinsteadEFF Can takin evaluat tries. Am J Gastroe 3. Iron. ion g iron pills nterol. 2017;1 al Institute Reference letters with succinate and vitamin B 6 to take Nation at night elevate liver —AGNES 12:18-35. of Health nih.gov/Iron.h ques website. https:// enzymes? MURPHY, tm. Access for nausea. —AMBER PA-C, Bolognia JL, Jorizzo JL,tions Rapini RP. Dermatology. 1st ed. NewDEW, PCA and , Americus, livertox. ed April 3, commen 2019. Georgia Birmingham, Michigan York: Mosby, 2003;1380-1381. ts to: Liver enzym es Advisor Forum aspartate aminosuch as alanine amino , CASE FILE transfe The Clinica l Advisor, phatase are transferase (AST), and rase (ALT), S www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 45 275 7th Aven markers of alkaline phosfunction, and hepat ue, 10th CUTIS RHO should be referre ic injury, not hepat Floor, New Albumin, MBO ic York, d to as liver bilirubin, and chemistries. Contributed by Joe Monr IDALIS NY 10001 measures of prothrombin .You oe, MPAS, hepatocellu time are direct A 78-year-old may conta PA-C lar appropriately ct us heavily lined man presented characterized synthetic function and with thick e-mail at edito by skin on enzymes may are as “liver functio r@ be abnormal n tests.” Liver been present for an his posterior neck ened, clinicaladvis liver diseas that had even in patien indet or.com. Although e. The differe ts without the striking erminate period of Letters are ntial for elevat broad with time. skin chang tomatic, edited many be further define potential causative ed enzymes is insiste they were concerning es were asympfor length factors and and d that he be to his relativ d by the patien should risk factors. 1 clarity. The seen es who t’s by a medical histor The Clinical y and the patient had spent dermatology provider. Almost all Advisor’s policy nearl sun, farmi medications ng, ranching, y his whole life small risk of are associated is to print to his in elevat fishing, and the hepatotoxic 2 ed liver chemistries with at least a a histo property in rural tending author’s name Okla ity. Oral with ry homa or of witho iron skin cance . replacement with the letter r and claim He denied doses has little supplementation at typicaut good health. ed to be . liver or serum or No anony in The skin on enzyme elevati no adverse effects on l mous the patien or overdoses, the ons. However, contributio it in high doses lined and thickened t’s nuchal area was ns will of iron poison can cause acute hepato heavily . The multiple overla toxicity as a ing. be accepted. pping rhom lines joined to form result of ferrous sulfate Toxicity occurs after boidal shape ingestion of (approximat ≥3 g s. toxicity with Altho ely 10 tablets ugh aminotransf ). Severe the upper limit erases greate r overdoses and of normal typically than 25 times occurs with high initial larger serum iron dL). Mild levels to usually self-limmoderate cases of iron (>1000 ug/ whereas severe iting and resolve with poisoning are suppo KUSMIN cases become fatal rapidl 3 rtive care, SKY, PA-C y. —LAURA Referenc es
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1. Approach to the patient with abnorm and functio n tests. UptoD al liver bioche mical ate.com websit uptodate.com e. https://www. /contents/app roach-to-theabnormal-liver patient-with-biochemical -and-functionApril 2, 2019. tests. Access ed
44 THE CLINI
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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2019 1
CONTENTS OCTOBER 2019
Newsline ■■Pediatric Cough and Cold Medicine Recommendations ■■US Sesame Allergy Incidence and Severity ■■Legislation Passed in Missouri Increases Autonomy for PAs ■■Testosterone for Postmenopausal Low Libido ■■Long-Term Cognitive Decline in Schizophrenia and
8 Cough, Cold Medicine Recommendations
■■Association Between Maternal Obesity and Childhood Cancer
FEATURE 13 Eosinophilic Esophagitis: A Chronic Allergic Inflammatory Disease The increased prevalence of EoE may be due to the rising incidence of allergic diseases in general, as well as by increased recognition of the disease. 31 Enlarging, Erythematous Lesions
Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com. Dermatology Clinic ■■Rough, Scaly, Red Plaques ■■Erythematous, Scaly, Pruritic Lesions
35 New Onset of Waxy, Brown Papule
35 Dermatologic Look-Alikes New Onset of Verrucous Papules 41 Legal Advisor Negligence and Mistaken Identity
41 A Case of Mistaken Identity
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Lifestyle Counseling Improves Diabetes Outcomes
Ending the HIV Epidemic Starts With HIV Screening A recently released CDC report indicates that HIV testing is well below where it needs to be in the United States, even in areas with a high burden of HIV and among populations known to be at high risk, which highlights the importance of screening to reduce new HIV infections.
Patients with diabetes who received more lifestyle counseling were at a reduced risk for cardiovascular events or mortality compared with those who received less lifestyle counseling.
Residence Change in Early Pregnancy Linked to Adverse Birth Outcomes Moving to a new residence during the first trimester of pregnancy may be associated with low birth weight, preterm birth, and small for gestational age.
Later Puberty Associated With Lower BMD Puberty represents a period of rapid skeletal growth and bone remodeling, and late onset may be associated with lower BMD and an increased risk for osteoporosis later in life.
GOLD Board of Directors Calls for More Serious Action on COPD The GOLD board noted that more awareness, earlier diagnosis, and more effective and earlier treatment of COPD are urgently needed.
ACP Releases New Policy on DOI, COI Management for Authors The American College of Physicians endorses the necessity of a comprehensive process for disclosure of potential conflicts of interest to ensure the integrity of clinical guidelines and guidance statements.
PRACTICE MANAGEMENT ClinicalAdvisor.com/MyPractice Out-of-Network Billing Common for Privately Insured Patients Receiving In-Network Care Little is known about the frequency and financial repercussions of out-of-network billing, despite frequent news in the media about surprise medical bills.
THE WAITING ROOM
Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom
Pediatric Cough and Cold Medicine Recommendations, 2002-2015 A 14-year analysis revealed that the number of physicians recommending either opioid-containing or nonopioid cough and cold medicines has declined significantly.
Jim Anderson, MPAS, PA-C, DFAAPA To Hug or Not to Hug: Identifying Physical Boundaries in Patient Encounters While some providers may think hugging patients provides comfort during challenging times, others may feel hugging a patient is unprofessional. Continues on page 6
4 THE CLINICAL ADVISOR â€˘ OCTOBER 2019 â€˘ www.ClinicalAdvisor.com
EXCLUSIVE TO THE WEB AT
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!
Rash on the Leg Following Outdoor Activity A 42-year-old man requests a dermatologic evaluation by emailing an image of an asymptomatic rash on his leg. The patient developed the rash approximately 2 weeks ago and was diagnosed with cellulitis at a local urgent care center. Despite 10 days of cephalosporin therapy, the rash has persisted, and new “blotches” have appeared on his back and arms. He states that he recently spent a significant amount of time outdoors but denies observing a tick bite. CAN YOU DIAGNOSE THIS CONDITION?
• Erythema migrans • Erythema dyschromicum perstans
• Erythema multiforme • Measles
● See the full case at ClinicalAdvisor.com/DermDx_Oct19
In partnership with
Draining Wound on the Ankle A 65-year-old man with poorly controlled type 1 diabetes presents with a draining wound on the medial side of his right ankle. He underwent open reduction and internal fi xation 3 months ago for a closed fracture of the distal tibia and fibula. He reports continued pain over the right leg that is made worse with weight bearing. WHICH PREOP TEST IS MOST ACCURATE FOR DIAGNOSIS OF AN INFECTED NONUNION?
• Superficial wound culture • CBC, ESR, and C-reactive protein
• Bone scan • Blood cultures
● See the full case at ClinicalAdvisor.com/OrthoDx_Oct19
6 THE CLINICAL ADVISOR • OCTOBER 2019 • www.ClinicalAdvisor.com
Journal of Orthopedics for Physician Assistants
Newsline SINCE 2002, there has been a steady decrease in the number of physician recommendations for cough and cold medicines for children, especially in children aged <2 years, according to a research letter published in JAMA Pediatrics. In 2008, the US Food and Drug Administration released a public health advisory recommending that children aged <2 years should not take overthe-counter cough and cold medicines. Shortly after, the American Academy of Pediatrics recommended that children aged <6 years should avoid cough and cold medicines. Investigators analyzed the trends of physician recommendations for cough and cold medicines and compared these trends with recommendations for antihistamines in the US pediatric population.
Measures for cough and cold medicines were categorized by the presence of opioid ingredients; codeine monotherapy was also recorded for visits with respiratory diagnoses. Of the 3.1 billion pediatric visits over the 14-year analysis, 95.7 million cough and cold medicines were ordered by physicians; 12% of these medicines contained opioids. Compared with rising recommendations for antihistamines, recommendations for both opioid-containing and nonopioid cough and cold medicines declined significantly. Compared with older children, opioid-containing and nonopioid cough and cold medicine recommendations declined even more for children aged <2 years and <6 years, respectively. The researchers noted, “our findings suggest that physicians’ recommendations
© ROSS WHITAKER / GETTY IMAGES
Pediatric Cough and Cold Medicine Recommendations
Cough and cold medicines should be avoided in children younger than 6 years.
of these medicines have steadily declined in the United States since 2002. … However, trends in the recommendations of nonopioid [cough and cold medicine] for children ages 2 to 6 years did not change after 2008 despite changes in labeling and the American Academy of Pediatrics’ effort to limit such use.”
US Sesame Allergy Incidence and Severity SESAME ALLERGY in the United States affects >1 million individuals and is linked to severe reactions and food allergy-associated use of healthcare services, according to study results published in JAMA Network Open. Using data from food allergy questionnaires, investigators conducted a cross-sectional study to characterize demographic and allergic characteristics of sesame allergy, including relative frequency, severity, distribution, and associated clinical qualities. The main outcomes were self-reported
sesame allergy (allergies were plausible if consistency was observed between sesame allergy reactions and immunoglobulin E [IgE]-mediated reactions), diagnostic history of certain allergens, and the use of food allergy-related healthcare services. A total of 40,443 adults and 38,408 children were included in the study; 273 adults and 206 children reported sesame allergy. Using survey responses, the researchers estimated that 0.49% of the US population reported sesame allergy, 0.23% met the symptom-report criteria for plausible IgE-mediated
8 THE CLINICAL ADVISOR • OCTOBER 2019 • www.ClinicalAdvisor.com
sesame allergy, and an additional 0.11% reported receiving a diagnosis of sesame allergy by a physician, but they did not report reactions that matched symptoms listed in the questionnaire. Of the participants who had convincing IgE-mediated sesame allergy, about 23.6% to 37.2% had experienced a severe sesame-related allergic reaction before. In addition, 81.6% of these patients had at least 1 other convincing food allergy; 33.7% of these participants self-reported using epinephrine to treat their sesame allergy.
Newsline Legislation Passed in Missouri Increases Autonomy for PAs A NEW LAW passed in Missouri will allow physician assistants (PAs) to practice with more autonomy and mirrors the collaboration requirements for PA-physician teams with those for nurse practitioner-physician teams.The enactment of Senate Bill 514 (SB 514) will replace all references of physician “supervision” with “collaboration.” The bill, signed by Governor Michael Parson on July 11, 2019, will make Missouri the 11th state to use a term other than supervision to describe PA practice. The legislation will eliminate the requirement that a physician practice at the same facility as the PA for 4 hours every 2 weeks. Any other direct supervision language added through regulation could be met through telemedicine
capabilities. Additionally, the legislation will remove the mandate that a PA practice at a location where the collaborating physician routinely sees patients. Finally, the bill eliminates the requirement that a PA practice at the same location as a
“The [Missouri Academy of Physician Assistants] leadership and I are ecstatic about the passage of SB 514,” stated Paul Winter, PA-C, president of the organization. “With the enactment of this legislation PAs will practice under
The new legislation will eliminate the requirement that a physician practice at the same facility as the physician assistant for 4 hours every 2 weeks. physician for 30 days before the PA is able to practice in a remote setting. Instead, the decision regarding how much time the PA and physician must practice at the same location before the PA begins working remotely will be made at the practice level.
a model that more accurately describes the PA-physician team and moves toward parity for PAs and [nurse practitioners].” The passing of the legislation will enhance the PA practice in Missouri as well as increase patient access to care. The law will become effective on August 28, 2019.
NON-ORAL TESTOSTERONE is effective for increasing low sex drive that causes concern in naturally and surgically postmenopausal women, according to study results published in The Lancet. Investigators conducted a systematic review and meta-analysis of randomized
Participants receiving testosterone reported improvement in sexual function.
controlled trials and drug registration applications to evaluate the risks and benefits associated with testosterone therapy in women with low libido. Primary outcomes included the effects of testosterone on sexual function, cardiometabolic outcomes, cognitive measures, and musculoskeletal health. Data collected from 8480 participants suggested that compared with placebo or a comparator, testosterone significantly increased the following sexual functions in postmenopausal women: satisfactory sexual event frequency (average difference, 0.85), sexual desire (standardized average difference, 0.36), pleasure (average difference, 6.86), arousal (standardized average difference, 0.28), orgasm (standardized average difference, 0.25), responsiveness (standardized average difference, 0.28), and self-image (average difference, 5.64). Results revealed a reduction in sexual concerns (average
10 THE CLINICAL ADVISOR • OCTOBER 2019 • www.ClinicalAdvisor.com
difference, 8.99) and distress (standardized average difference, −0.27). The oral administration of testosterone resulted in a significant rise in lowdensity lipoprotein cholesterol levels and a fall in total cholesterol, high-density lipoprotein cholesterol, and triglycerides, which was not observed in women taking non-oral testosterone. Treatment was associated with weight gain and a significantly greater chance of reporting acne and hair growth. Effects on body composition, musculoskeletal outcomes, or cognitive measures were not reported. The investigators noted that this study “provides robust support for a trial of testosterone treatment, using a dose appropriate for women, when clinically indicated in postmenopausal women.The absence of any approved testosterone formulations for women in any country, however, is a major treatment barrier.”
© WESTEND61 - WEST / GETTY IMAGES
Testosterone for Postmenopausal Low Libido
© WILDPIXEL / GETTY IMAGES
Long-Term Cognitive Decline in Schizophrenia and Other Psychoses
Patients with schizophrenia were found to have a small decline in cognitive function.
OVER A 10-year period, patients with schizophrenia and other psychoses had a cognitive decline in memory, verbal learning, and vocabulary according to a study published in the American Journal of Psychiatry. Researchers assessed baseline cognitive function using data obtained from the Aetiology and Ethnicity in Schizophrenia and Other Psychoses study of first-episode psychosis. Follow-up neuropsychological assessments were performed on 106 of these patients with a diagnosis of schizophrenia (n=65) or other psychoses (n=41). The average follow-up duration was 109.3 months (SD 29.5) for patients and 102.9 months (SD 34.1) for controls. Cognitive decline was assessed by subtracting followup from baseline assessments. Data were analyzed using analysis of covariance models with planned orthogonal comparisons. Patients with schizophrenia had cognitive impairment at both initial and follow-up diagnoses. A small, but significantly larger decline in intelligence quotient was measured in schizophrenic patients after approximately 10-year follow-up (effect=-0.28; 95% CI, -0.47 to -0.09; P =.003). Other psychoses did
not show significant decline in intelligence quotient (effect=-0.09; 95% CI, -0.30 to 0.11; P =.37). In terms of cognitive function, memory declined to a greater extent in schizophrenic patients when compared with the comparison group. Specific functions, including verbal learning (P =.001), immediate recall, delayed recall, and vocabulary (P =.003) were reduced.Verbal learning was found to decline with other psychoses as well. There was no decline in processing speed, executive function, working memory, or visual-spatial ability over time when compared with comparison participants in both schizophrenic and other psychoses groups. Treatment with first-generation vs both first- and second-generation antipsychotics did not affect intelligence quotient decline, nor did treatment duration. No association was found between initial symptom severity and change in cognitive function. This study had several limitations, including the sample size, which made subanalysis of psychoses not possible. Additionally, the fixed follow-up time point did not allow for a detailed study of the time-course for cognitive decline. Potential confounding contributors to cognitive decline, such as smoking, drug use, victimization, physical health problems, and education after initial follow-up were not controlled for. In conclusion, after an approximately 10-year period, the researchers found a small but significant decline in the intelligence quotient of patients with schizophrenia. Interestingly, cognitive decline was not global, but found to target verbal knowledge and memory. Other psychoses demonstrated cognitive decline but were more limited in scope. This study helps clarify the effects of schizophrenia on long-term cognitive function.
12 THE CLINICAL ADVISOR • OCTOBER 2019 • www.ClinicalAdvisor.com
Association Between Maternal Obesity and Childhood Cancer MATERNAL OBESITY before pregnancy is associated with a higher risk for childhood cancer, particularly leukemia, but not with birth size, according to study results published in the American Journal of Epidemiology. Investigators also found a link between maternal weight gain and higher risk for neuroblastoma. In a prospective cohort analysis, researchers used maternal and infant data to evaluate the link between trends in maternal weight before pregnancy and at delivery and the risk of developing any childhood cancer and leukemia. The mediation effect of newborn size on the association between maternal obesity and risk for childhood cancers was also studied. All diagnoses of any cancer, and specifically of leukemia, were made by age 14 years in 2352 and 747, respectively, of the 1,827,875 infants included in the study. The risk for leukemia was 57% greater in children born to mothers with a body mass index ≥40.0 kg/m2 and 84% greater in neonates who weighed ≥30% than expected at birth. Older maternal age was linked to an increased risk for any childhood cancer and leukemia, although no association between maternal height and gestational weight gain was found. In addition, nonwhite race was associated with lower risk. “Future studies are warranted to elucidate the underlying biological mechanisms of early-life exposure through maternal obesity or manifestation of large or small infant size in the development of childhood cancer,” the authors noted.” ■
FEATURE: ALISON MILLER, MPAS, PA-C; ALICIA ELAM, PHARMD; SETH MARCUS, MD, MSCI
Eosinophilic Esophagitis: A Chronic Allergic Inflammatory Disease Eosinophilic esophagitis is marked by an inflammatory cascade that leads to subepithelial fibrosis and esophageal dysmotility.
© PHOTOS: INSET COURTESY OF NEW ENGLAND JOURNAL OF MEDICINE; HANK GREBE / SHUTTERSTOCK
osinophilic esophagitis (EoE) is a chronic allergic disease of the esophagus characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominate esophageal inflammation. Aggregation of eosinophils within the esophagus is caused by exposure to food allergens, leading to a cytokine response of T helper type 2 (Th2) cells mediated by interleukin (IL)-4, IL-5, and IL-13.1 This eosinophilic accumulation results in an inflammatory cascade, which leads to remodeling of the esophageal mucosa and potential subsequent subepithelial fibrosis. Eosinophilia and fibrosis prevent appropriate esophageal function and cause symptoms associated with esophageal dysmotility.1
Trachealization is a typical endoscopic finding in eosinophilic esophagitis.
EoE has been described as the most common cause of dysphagia and food impaction in the emergency department setting.2 With a 10-fold increase in patients living with EoE over the past 30 years, the prevalence of EoE is approaching that of Crohn disease and ulcerative colitis,3 which may be due to the rising incidence of allergic diseases in general but also may be influenced by an increased recognition of the disease. Recent studies have suggested a genetic predisposition to EoE. Hoboken et al found a positive family history (ie, first-degree relatives) of EoE in up to 10% of pediatric patients.1 Approximately two-thirds of patients with EoE have a family history of atopy including seasonal
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2019 13
Food impaction in the esophagus should trigger consideration of eosinophilic esophagitis in the emergency department setting. allergies, IgE-mediated food allergies, or asthma.4 EoE has been described in both children and adults, and nearly all studies on EoE have demonstrated a predominance in white men.2 History and Physical Examination
The classic presentation of EoE consists of recurrent attacks of dysphagia and/or food impaction. Dysphagia is 3 times more likely to occur in an adult with EoE than heartburn, dyspepsia, and chest pain combined.2 Symptoms in children vary by age and include poor eating (infants), abdominal pain and vomiting (school-aged children), and reflux symptoms and/or dysphagia in teenagers (Figures 1A and 1B).1,2 Subtle and subclinical symptoms of dysphagia often can include eating small portions of food slowly and requiring large amounts of liquid to lubricate the esophagus.4 Patients with EoE may avoid ingesting breads and meats and have difficulty swallowing pills. Food impaction in the esophagus should trigger consideration of EoE in the emergency department setting. One clinical series reported that 18 of 54 patients presenting to the emergency department with food impaction would ultimately be diagnosed with EoE.2
Other atopy-associated diseases linked to EoE include atopic dermatitis (eczema), allergic rhinitis, and allergic and/or nonallergic asthma. When atopy is present, serum immunoglobulin E (IgE) may be elevated as a response to allergic diseases of the skin, lungs, or extraesophageal mucous membranes; however, EoE alone has not been associated with an increase in serum IgE.2,3 The physical examination of a patient with EoE is usually unremarkable, although weight loss from dysphagia and undereating may be present. Diagnostic Methods
Three diagnostic criteria define EoE: the presence of agespecific symptomatology, ≥15 eosinophils per high-power field (hpf ) on histologic examination, and the exclusion of alternative etiologies of esophageal eosinophilia such as gastroesophageal reflux disease (GERD).1 Classic endoscopic findings of EoE include edema, strictures, trachealization (circular rings resembling the trachea), white exudates, and linear furrowing (deep creases along the length of the esophagus).2 Continues on page 22
Mean age (y)
40 30 20 10 0
Failure to thrive
Proportion of patients with EoE
FIGURE 1B ■ Adults (≥18 y) ■ Children (<18 y)
40 20 0
20% 4% Failure to thrive
18% Abdominal pain
55% 39% 17%
FIGURES 1A, 1B. Comparison of symptoms of eosinophilic esophagitis in children and adults.1,2 14 THE CLINICAL ADVISOR • OCTOBER 2019 • www.ClinicalAdvisor.com
Patients with eosinophilic esophagitis may avoid ingesting breads and meats and have difficulty swallowing pills. Until recently, the diagnostic criteria for EoE included histologic evidence from an esophagogastroduodenoscopy (EGD) only after a failed 2-month trial of high-dose acid suppressive therapy. However, a subset of EoE identified as proton pump inhibitor-responsive EoE (PPI-REE) has been classified. Patients with this diagnosis respond to PPIs and may not exhibit histologic or endoscopic evidence of the disease if taking a PPI when EGD is performed.With this new information, it is imperative that patients discontinue treatment with PPIs for 3 to 4 weeks before endoscopy to avoid misdiagnosis.5 Therapeutic Modalities
The 3 main treatments for EoE are medication, dietary therapy, or mechanical dilation of the esophagus. Patients should be evaluated individually to address their most problematic complaints first, and therapy should be tailored based on patient preference. Debate exists among the medical community whether therapeutic goals should be defined by clinical or histologic remission with various reported thresholds of permissible esophageal eosinophilia. Pharmacotherapy Treatment with PPIs can be effective in up to 50% of patients when used as primary therapy for EoE, particularly in those with PPI-REE.4,6 Although some researchers believe this diagnosis is defined by the presence of both GERD and EoE, more investigation is necessary to find its etiology. Swallowed topical steroids are often considered as first-line therapy for EoE. Both swallowed fluticasone propionate (aerosolized) and budesonide (mixed with a thickener and sweetening agents) have been shown to be effective and well tolerated.7,8 These medications target the inflammatory response locally as they travel down the esophagus after ingestion. In a double-blind, placebo-controlled trial, fluticasone propionate was found to be 90% effective in pediatric patients.7 In another randomized, double-blind, placebo-controlled trial, oral budesonide for 15 days significantly decreased the number of eosinophils in the esophageal epithelium (from 68.2 eosinophils/hpf to 5.5 eosinophils/hpf) compared with placebo (from 62.3 eosinophils/hpf to 56.5 eosinophils/hpf).8 Although generally safe and tolerated, potential side effects from these medications can include development of Candida esophagitis, growth delay, adrenal insufficiency, reduced bone density, and cataracts, particularly with fluticasone.7 Oral systemic steroids (eg, prednisone) are effective for EoE but are used sparingly due to their systemic side effect profile. In
general, topical steroid therapy is effective for treating EoE, but medication duration is indefinite, as the root of the disease (ie, food allergy) has not been addressed. Dietary Interventions Dietary treatments for EoE include targeted elimination therapy, elimination therapies, and elemental dietary therapy. Targeted elimination therapy, also known as skin test-directed elimination, aims to exclude from a patient’s diet only the foods for which allergy testing is positive. Empiric elimination therapies can be further categorized into a milk elimination diet, 2-food group elimination diet, 4-food group elimination diet, and 6-food group elimination diet. Milk elimination, in which patients avoid milk protein without having previously tested positive for a milk protein allergy, is one of the newest empiric approaches to treating EoE.9 In a retrospective study assessing the effect of a cow’s milk elimination diet on children with EoE, Kagalwalla et al reported clinical and histologic remission in 65% of the sample population.10 The 2-food, 4-food, and 6-food group elimination diets consist of initially removing the respective number of food proteins from the diet including those derived from milk, eggs, soy, wheat, peanuts/tree nuts, and/or seafood, which are the proteins most commonly associated with the development of food allergies and most commonly reported to cause esophageal injury in patients with EoE.9 In a step-up dietary treatment approach, patients who do not have a clinicohistologic response to a 2-food group elimination diet (eg, milk and gluten) are then offered to step up to a 4-group and subsequent 6-group elimination diet if necessary.9 Once patients achieve remission on any of the empiric diet therapies, they reintroduce an eliminated food group and then undergo re-evaluation via endoscopy and biopsy. Depending on the eosinophil count of the esophageal biopsy, a food group is deemed either tolerated and then retained in the diet or labeled as a trigger and removed from the patient’s diet indefinitely. Finally, the elemental dietary therapy uses formulas containing exclusively proteins that have been hydrolyzed into their simplest form, amino acids. These formulas are often associated with diet nonadherence in both children and adults who have previously tolerated a regular diet as they are often unpalatable and expensive. The use of the elemental dietary therapy in young children may provide the dual benefit of remission from EoE as well as complete nutrition for a short period; however, long-term use in this population may eventually impede oromotor function.11
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Continues on page 24
right-hand column like this one does at the top
POLL POSITION Which of the following is considered first-line therapy for eosinophilic esophagitis? 0.97% ■ Swallowed topical steroids ■ Proton pump inhibitors ■ Elimination diets
■ Esophageal dilation
For more polls, visit ClinicalAdvisor.com/Polls.
With each of these diets, the goal is to methodically and sequentially advance a patient’s diet until achieving the one that is the least restrictive while maintaining clinical and histologic remission of EoE.When comparing each of these dietary therapies for pediatric EoE, Henderson et al found the following: the elemental diet was the most effective with a 96% remission rate, the empiric 6-food elimination diet had an 81% remission rate, and the skin test-directed diet had a 65% remission rate.12 In the adult population, Peterson et al found a 75% histologic remission rate with an elemental diet but no symptom improvement and high drop-out rates.13 A 94% clinical response and a 70% histologic response were noted in an adult population with EoE tried on the 6-food elimination diet in a prospective study by Gonsalves et al.14 Adults with EoE were shown to have 68% improvement in symptoms and a 32% histologic response in a retrospective cohort study performed by Wolf et al.15 Dietary therapy ultimately identifies the root cause of EoE disease and often is preferred by patients reluctant to use medications indefinitely. Mechanical Dilation Esophageal dilation, a procedure during which a balloon is used to expand the diameter of the esophagus to allow for immediate symptomatic relief, is the least desirable means of treating EoE. However, it is the only treatment for narrow esophageal strictures. Due to the risk of chest pain, deep mucosal tears, esophageal perforation, and increased postendoscopic pain, dilation is not preferred as initial therapy. The goal of treating EoE early with medication or dietary therapy is to prevent
fibrosis and strictures from occurring, thereby reducing the need for dilation therapy. Regardless of the treatment implemented, one of the most challenging aspects of EoE from a patient’s perspective is the need for frequent endoscopies to monitor therapeutic efficacy, as this is time-consuming, costly, and associated with procedural risks. As such, judicious use of these procedures is recommended. Finding a noninvasive screening method to monitor treatment efficacy would be highly advantageous for patients. Prognosis
EoE is a chronic relapsing and remitting disease without cure requiring long-term, routine therapy to prevent recurrence. Straumann et al followed 30 adult patients with EoE for 7 years and found that only 10% of patients experienced resolution of the disease.1 To make an important distinction from chronic GERD, EoE has not been associated with risk for esophageal cancer, nor is there evidence linking EoE to increased mortality. However, cases have been reported in which patients with EoE were also diagnosed with Barrett esophagus, a disease that predisposes patients to esophageal cancer.2 The risk of further stricture formation and narrowing of the esophagus causing subsequent food impaction should be considered when weaning or discontinuing a patient’s medication as the recurrence of esophageal symptoms is expected if treatment is discontinued. In fact, studies have reported clinical and histologic recurrence in up to 90% among adult patients with EoE within 13 months of discontinuing topical steroid therapy.1 Although the entity of EoE is still in its early stages of clinical and scientific exploration, researchers aim to find more curative treatment options in the future. Conclusion
The presentation of EoE can be similar to other gastrointestinal disorders, but the therapies that provide symptomatic and histologic remission are dissimilar. Therefore, it is important for medical practitioners to consider EoE in the differential diagnosis when evaluating dysphagia. Although the diagnostic criteria for EoE are straightforward, the various maintenance therapies and the need for frequent endoscopies can make disease management challenging for both patients and providers. ■ Alison Miller, MPAS, PA-C, is a physician assistant, and Seth Marcus, MD, MSCI, is a pediatric gastroenterologist at GI Care for Kids, in Atlanta, Georgia; Alicia Elam, PharmD, is an associate professor in the physician assistant department of Augusta University, in Augusta, Georgia.
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8. Straumann A, Conus S, Degen L, et al. Budesonide is effective in adoles-
1. Wallace MB, Aquel BA, Lindor KD, Devault KR. Practical Gastroenterology
cent and adult patients with active eosinophilic esophagitis. Gastroenterology.
and Hepatology Board Review Toolkit. 2nd ed. Hoboken, NJ: John Wiley & Sons;
9. Arias Á, González-Cervera J, Tenias JM, Lucendo AJ. Efficacy of dietary
2. Richter JE, Castell JE. The Esophagus. 5th ed. Hoboken, NJ: John Wiley &
interventions for inducing histologic remission in patients with eosino-
philic esophagitis: a systematic review and meta-analysis. Gastroenterology.
3. Greenberger NJ, Blumberg RS, Burakoff R. Eosinophilic esophagitis. In:
Current Diagnosis & Treatment Gastroenterology, Hepatology, & Endoscopy. 2nd
10. Kagalwalla AF, Amsden K, Shah A, et al. Cow’s milk elimination: a novel
ed. New York: McGraw Hill Medical; 2012:183-186.
dietary approach to treat eosinophilic esophagitis. J Pediatr Gastroenterol Nutr.
4. Lucendo AJ, Molina-Infante J, Arias Á, et al. Guidelines on eosinophilic
esophagitis: evidence-based statements and recommendations for diagnosis
11. Wechsler J, Schwartz S, Amsden K, Kagalwalla A. Elimination diets in the
and management in children and adults. United European Gastroenterol J.
management of eosinophilic esophagitis. J Asthma Allergy. 2014;7:85-94.
12. Henderson CJ, Abonia JP, King EC, et al. Comparative dietary therapy
5. Odiase E, Schwartz A, Souza RF, Martin J, Konda V, Spechler SJ. New
effectiveness in remission of pediatric eosinophilic esophagitis. J Allergy Clin
eosinophilic esophagitis concepts call for change in proton pump
inhibitor management before diagnostic endoscopy. Gastroenterology.
13. Peterson KA, Byrne KR, Vinson LA, et al. Elemental diet induces histologic
response in adult eosinophilic esophagitis. Am J Gastroenterol. 2013;108(5):759–766.
6. Molina-Infante J, Katzka DA, Gisbert JP. Review article: proton pump
14. Gonsalves N, Yang G-Y, Doerfler B, Ritz S, Ditto AM, Hirano I. Elimination
inhibitor therapy for suspected eosinophilic oesophagitis. Aliment Pharmacol
diet effectively treats eosinophilic esophagitis in adults; food reintroduction
identifies causative factors. Gastroenterology. 2012;142(7):1451-1459.e1.
7. Konikoff MR, Noel RJ, Blanchard C, et al. A randomized, double-blind,
15. Wolf WA, Jerath MR, McConville S, Shaheen NJ, Dellon ES. Su1842 dietary
placebo-controlled trial of fluticasone propionate for pediatric eosinophilic
elimination therapy is an effective option for adults with eosinophilic esopha-
esophagitis. Gastroenterology. 2006;131(5):1381-1391.
gitis. Gastroenterology. 2013;144(5):S-488.
© The New Yorker Collection 2019 from cartoonbank.com. All Rights Reserved.
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2019 25
Dermatology Clinic CASE #1
Rough, Scaly, Red Plaques JAY M. PATEL, BS; MCKENNA E. BOYD, BS; CHRISTOPHER RIZK, MD
A 65-year-old retired mailman with a history of squamous cell carcinoma presents to the dermatology clinic for his routine total body skin examination. He reports finding 2 gritty, red spots on his scalp. On examination, you notice multiple telangiectasias on his cheeks and nose, areas of depigmentation, and excessive wrinkles with leathery-appearing skin. Two rough, scaly, red plaques are noted on the scalp. What is your diagnosis? Turn to page 32
Erythematous, Scaly, Pruritic Lesions MARY B. KIM, BA; MICHELLE EUGENE LEE, BA; CHRISTOPHER RIZK, MD
A 24-year-old white man presents with a 4-week history of multiple enlarging, erythematous lesions with associated itching and burning on the lower abdomen, thighs, and pubic area. He tried topical steroid cream prescribed at an outside clinic that worsened the symptoms. The patient denies a history of skin changes in family members or experiencing any systemic symptoms including fever. He started working on a poultry farm 6 months ago. On examination, erythematous, scaly rings with central clearing and active borders are noted. What is your diagnosis? Turn to page 33 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2019 31
Dermatology Clinic CASE #1
Actinic keratoses (AKs), also known as solar or senile keratoses, are cutaneous neoplasms caused by exposure to ultraviolet (UV) radiation that induces the development of abnormal epidermal keratinocytes.1 AKs are precancerous lesions that have the potential to develop into squamous cell carcinoma (SCC).2 Conceptually presented first in the late 1800s by Dubreuilh, these lesions were later characterized and termed actinic keratosis by Pinkus in 1958.1,3 AKs are the second most common reason for a dermatology consultation after acne, with almost universal occurrence in adults aged >80 years.1,4,5 The estimated cost of treating AKs in the United States reaches >$1 billion annually.4 The greatest risk factors for AKs are exposure to UV radiation and increasing cumulative sun exposure, the latter of which is evidenced by the increased incidence of AKs from 10% in white adults aged 20 to 29 years to 80% in white adults aged 60 to 69 years.6 Other risk factors include older age, male gender, lighter-colored hair and eyes, and fair skin that easily burns and develops freckles.1,6 Rarer risk factors include immunosuppression and certain genetic syndromes such as
Actinic keratoses are precancerous lesions that have the potential to develop into squamous cell carcinoma. albinism and xeroderma pigmentosum.1,6 It is important to note that cumulative exposure to UV radiation results not only from sunlight but also from tanning bed use, and many variables can affect the amount of exposure to UV light, such as a patient’s occupation or place of residence. The greater the cumulative exposure to UV rays, the greater the prevalence of AKs.1,6 AKs arise from UV radiation that damages and induces mutations in the DNA of keratinocytes, which can lead to hyperproliferation and tumor formation. UV radiation can also damage DNA in a way that prevents the immune system from recognizing the tumor, thereby allowing it to progress to SCC. The tumor suppressor gene p53 has been implicated in the initiation of AKs, and mutated p53 can lead
to unrestricted growth of skin cells.7,8 With increasing UV radiation-induced DNA damage, a progression from AKs to SCC can occur.7,8 Patients with AKs are often older, lighter-skinned, and have had significant exposure to the sun that results in burns and freckles.1 Most often found on sun-exposed body sites, AKs can present with bleeding, crusting, pruritus, burning, or stinging pain.1,6 Erythematous AKs are the most common subtype, presenting as 3- to 6-mm erythematous, flat, gritty, rough, scaly papules or plaques.1 Other clinical subtypes of AKs include hypertrophic, inflamed, pigmented, proliferative, conjunctival, spreading pigmented, actinic cheilitis, and cutaneous horn.1,6 Histologic findings reveal AKs to be confined to the epidermis with atypical, pleomorphic keratinocytes in the basal cell layer of the skin and protrusions that bud into the papillary dermis.1,8 Several histologic findings near these abnormal keratinocytes include irregular acanthosis (hyperproliferation of skin cells), hyperkeratosis (increasing skin thickness due to excess keratin production), and parakeratosis (retention of nuclei in the stratum corneum layer of the epidermis).1,8 Variations in the histology of AKs mimic the aforementioned clinical subtypes, including large amounts of hyperkeratosis for hypertrophic AKs and increased melanin production in pigmented AKs. Clinically, AKs are diagnosed by visual inspection; however, the accuracy of such a diagnosis is not well known since most AKs are not confirmed with histologic examination.1,2,6 Differential diagnoses of AKs include, but are not limited to, psoriasis, seborrheic dermatitis, verruca vulgaris, benign lichenoid keratosis, and lentigo maligna. The most important differential that must be distinguished from AKs is SCC. Signs that indicate SCC include larger size, pain, induration, bleeding, fast growth, and recurrence after treatment.1,5,7 Because of the risk of AKs transforming to SCC, most dermatologists recommend either field treatment or targeted destruction of individual lesions, the latter of which is the most commonly used method.2,6 Liquid nitrogen cryotherapy is the most common type of targeted destruction due to its ease and efficiency; hand-held cryostats can be carried easily between patient rooms, and the ideal freeze time is only 10 to15 seconds.9 Side effects of cryotherapy include pain, blisters, hypopigmentation, scarring, and alopecia in treated areas.9 Other therapies for individual lesions of AKs include curettage and shave excision.1 Field therapies are used to treat large areas of skin that contain numerous AK lesions and are categorized into medical and procedural modalities. Medical therapies for generalized AKs include topical 5-fluorouracil (5-FU), imiquimod,
32 THE CLINICAL ADVISOR • OCTOBER 2019 • www.ClinicalAdvisor.com
and diclofenac.1 Of these, 5-FU is the most common treatment and is available in a variety of formulations and strengths, with an effectiveness of up to 75%.1,5,10 Side effects of 5-FU include discomfort, crusting, pruritus, scabbing, and erythema.1,10 Counseling patients on dosage, proper application, and side effects is essential when treatment with 5-FU is initiated to improve adherence and maximize efficacy. Procedural field therapies include cryopeeling, dermabrasion, and chemical peels.1 It is important to remember that AKs are caused by UV damage and have the potential to develop into malignant
4. Bickers DR, Lim HW, Margolis D, et al; American Academy of Dermatology Association; Society for Investigative Dermatology. The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J Am Acad Dermatol. 2006;55(3):490-500. 5. Siegel JA, Korgavkar K, Weinstock MA. Current perspective on actinic keratosis: a review. Br J Dermatol. 2017;177(2):350-358. 6. Frost CA, Green AC. Epidemiology of solar keratoses. Br J Dermatol. 1994;131(4):455-464. 7. Grossman D, Leffell DJ. The molecular basis of nonmelanoma skin cancer: new understanding. Arch Dermatol. 1997;133(10):1263-1270. 8. Pillon A, Gomes B, Vandenberghe I, et al. Actinic keratosis modelling in mice:
Medical therapies for generalized actinic keratoses include topical 5-fluorouracil, imiquimod, and diclofenac.
a translational study. PloS One. 2017;12(6):e0179991. 9. Thai K-E, Fergin P, Freeman M, et al. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. Int J Dermatol. 2004;43(9):687-692. 10. Segatto MM, Dornelles SIT, Silveira VB, Frantz G de O. Comparative study of actinic keratosis treatment with 3% diclofenac sodium and 5% 5-fluorouracil. An Bras Dermatol. 2013;88(5):732-738.
lesions. Recently, an effort has been made to reclassify AKs as malignant neoplasms since they represent an essential initial stage in the evolution to SCC.1,6 AKs also represent an important clinical lesion since their presence is a strong predictor for the development of either melanoma or nonmelanomatous skin cancers. Thus, patients with AKs should undergo long-term monitoring for cutaneous malignancies and implementation of early interventions.1,6 The patient in this case was treated with liquid nitrogen cryotherapy to destroy the 2 AKs on his scalp. He was counseled on the importance of undergoing routine skin examinations every 6 to12 months and to follow up sooner if he noticed a concerning lesion during a skin self-examination. Jay M. Patel, BS, and McKenna E. Boyd, BS, are medical students at Baylor College of Medicine, in Houston,Texas. Christopher Rizk, MD, is a dermatologist with Elite Dermatology, in Houston,Texas. References 1. Duncan KO, Geisse JK, Leffell DJ. Chapter 113. Epithelial precancerous lesions. In: Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: The McGraw-Hill Companies; 2012. 2. Criscione VD, Weinstock MA, Naylor MF, Luque C, Eide MJ, Bingham SF; for the Department of Veteran Affairs Topical Tretinoin Chemoprevention Trial. Actinic keratoses: natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009;115(11):2523-2530. 3. Pinkus H. Keratosis senilis; a biologic concept of its pathogenesis and diagnosis based on the study of normal epidermis and 1730 seborrheic and senile keratoses. Am J Clin Pathol. 1958;29(3):193-207.
Tinea is a name that refers to cutaneous fungal infections, and the clinical classification is based on the area of the body affected: tinea capitis (head), tinea faciei (face), tinea manuum (hand), tinea cruris (groin), tinea pedis (foot), tinea unguium (nail), and tinea corporis (body). Tinea corporis manifests as a dermatophyte infection on the body that is not present on the face, hands, groin, or feet. Tinea infections are categorized as anthropophilic, zoophilic, or geophilic based on host colonization preference and whether transmission occurs via humans, animals, or the soil.1 Tinea corporis usually develops after skin-to-skin contact, with an infected area developing on 1 of the involved individuals.2 It can also be transmitted through contact with infected farm animals or pets, and various animals are vectors for different types of fungi.3 The causative dermatophytes of tinea infection are Microsporum, Trichophyton, and Epidermophyton.1 Tinea corporis and tinea capitis are the most common infections seen in children, whereas tinea cruris, tinea pedis, and tinea unguium are more frequently seen in adolescents and adults.2 Predisposing factors for tinea infection
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2019 33
Dermatology Clinic include geographic, social, and individual health conditions. Dermatophytes thrive particularly well in hot and humid weather. As such, intertriginous areas with increased sweat production, skin breakdown, and alkaline environments provide favorable conditions for fungal proliferation.4 Social factors such as overcrowding and low socioeconomic status also predispose individuals to dermatophyte infection, and patients with diabetes mellitus, lymphoma, immunocompromised states, and Cushing syndrome are particularly susceptible.4,5 Tinea corporis, more commonly referred to as “ringworm,” manifests as a scaly rash in the shape of a ring with central clearing and a raised, erythematous border; it most commonly presents on the torso with associated pruritus. Single
The causative dermatophytes of tinea infection are Microsporum, Trichophyton, and Epidermophyton. or multiple rings ranging from 1 to 5 cm in diameter may develop with any episode of infection. However, larger lesions can result from the convergence of these rings.2 When the diagnosis is unclear from the history and physical examination, a potassium hydroxide (KOH) preparation is often used for confirmation. The active, raised border of the annular rash should be scraped to obtain the highest number of dermatophytes. A positive scraping reveals branching, hyaline, and septate hyphae.6 False-negative tests may occur due to inadequate scrapings. Preparations of KOH are quick and simple tests that can be conducted at the bedside, and cultures are typically not necessary for a definitive diagnosis of tinea corporis. For patients with persistent symptoms, skin biopsy with periodic acid-Schiff stain may be warranted.2 Differential diagnosis of tinea corporis includes nummular eczema, psoriasis, tinea versicolor, erythema multiforme, lupus erythematosus, pityriasis rosea, and granuloma annulare. Psoriasis and eczema often are associated with a family history, and erythema multiforme and granuloma annulare typically do not present with scales on the rash. The herald patch of pityriasis rosea can mimic the ringed shape of tinea corporis, but the subsequent rash eruption in pityriasis rosea exhibits a characteristic dermatomal “Christmas tree” distribution.2,7 To distinguish between these conditions and tinea corporis, it is important to obtain a detailed history and conduct a thorough physical examination. Patients with tinea corporis are often prescribed topical steroids due to a misdiagnosis of cutaneous lupus or eczema. In such cases, the patient
will experience an exacerbation of symptoms after use of topical steroids, which should prompt the consideration of tinea corporis.2 First-line treatment for tinea corporis includes topical antifungals such as azoles, allylamines, butenafine, ciclopirox, and tolnaftate. In particular, 2 allylamines — topical terbinafine and naftifine — were tested and confirmed in a randomized controlled trial for their efficacy in treating tinea corporis and tinea cruris.8 Oral antifungals such as terbinafine and itraconazole should be considered for systemic treatment in patients for whom topical treatment failed or those with immunocompromised states or extensive disease. Oral ketoconazole and nystatin are not recommended for treatment of tinea infection due to risk for hepatic toxicity and widespread resistance, respectively. Combination products containing steroids, such as betamethasone/clotrimazole, can exacerbate fungal infections. No prophylaxis for tinea corporis is needed for asymptomatic household members or close contacts.2 The patient in this case did not have any systemic symptoms indicative of a complication of tinea corporis, nor was he in an immunocompromised state. Therefore, the patient was prescribed topical terbinafine and instructed to apply this medication to the affected area for 2 weeks. At his 1-month follow-up visit, his symptoms had resolved. ■ Mary B. Kim, BA, and Michelle Eugene Lee, BA, are medical students, at Baylor College of Medicine. Christopher Rizk, MD, is a dermatologist with Elite Dermatology, in Houston,Texas. References 1. De Hoog GS, Dukik K, Monod M, et al. Toward a novel mutilocus phylogenetic taxonomy for the dermatophytes. Mycopathologia. 2017;182(1-2):5-31. 2. Ely JW, Rosenfeld S, Seabury Stone M. Diagnosis and management of tinea infections. Am Fam Physician. 2014;90(10):702-711. 3. Kim J, Tsuchihashi H, Hiruma M, Kano R, Ikeda S. Tinea corporis due to Trichophyton erinacei probably transmitted from a hedgehog: the second case report from Japan. Med Mycol J. 2018;59(4):E77-E79. 4. Sahoo AK, Mahajan R. Management of tinea corporis, tinea cruris, and tinea pedis: a comprehensive review. Indian Dermatol Online J. 2016;7(2):77-86. 5. Oke OO, Onayemi O, Olasode OA, Omisore AG, Oninla OA. The prevalence and pattern of superficial fungal infections among school children in Ile-Ife, South-Western Nigeria. Dermatol Res Pract. 2014;2014:842917. 6. Zarei Mahmoudabadi A, Yaghoobi R. Tinea corporis due to Trichophyton simii – a first case from Iran. Med Mycol. 2008;46(8):857-859. 7. Kelly BP. Superficial fungal infections. Pediatr Rev. 2012;33(4):e22-e37. 8. El-Gohary M, van Zuuren EJ, Fedorowicz Z, et al. Topical antifungal treatments for tinea cruris and tinea corporis. Cochrane Database Syst Rev. 2014;(8):CD009992.
34 THE CLINICAL ADVISOR • OCTOBER 2019 • www.ClinicalAdvisor.com
Dermatologic Look-Alikes New Onset of Verrucous Papules RACHEL E. GRAUBARD, BSA; MCKENNA E. BOYD, BS; CHRISTOPHER RIZK, MD
A 42-year-old white man presents for his annual skin check with complaints of a waxy, brown papule on his back. He reports that he scratched it off on several occasions recently, but it returned each time. He states that the lesion is a nuisance, but it does not itch, bleed, or cause pain. He recalls that his mother has several of the same lesions on her back. He denies a family history of melanoma or other skin cancer. On examination, you notice 2 similar lesions on his chest and above his clavicle.
A 19-year-old man presents to the clinic with his mother with concerns about a new lesion on his hand.The man first noticed a bump on his right palm 2 months ago. His mother observed him picking at the lesion to remove it; however, it returned, and now he has additional lesions on his right thumb and left index and middle fingers. On examination, dome-shaped, flesh-colored, rough papules with evidence of mild trauma and residual pin-point bleeding are noted.
www.ClinicalAdvisor.com â€˘ THE CLINICAL ADVISOR â€˘ OCTOBER 2019 35
Dermatologic Look-Alikes CASE #1
One of the most common benign skin tumors, seborrheic keratoses (SKs) are the result of epithelial proliferation associated with increasing age and chronic exposure to ultraviolet (UV) light. The lesions can vary in size and color but classically manifest as pigmented plaques or papules with a waxy, verrucous surface and a characteristic “stuck on” appearance.1,2 Because SKs are benign lesions, they do not require therapeutic removal; however, features such as dark coloration and irregular borders may prompt a biopsy to exclude life-threatening diagnoses such as melanoma.2-4 The prevalence of SKs increases with increasing age, with lesions occurring in most adults aged >50 years.4 The number of individual lesions also increases with age, usually appearing in large numbers in older individuals. Despite occurring more frequently in the elderly, SKs have also been identified in younger patients, and the condition affects both men and women equally.2 SKs are most prevalent among white individuals with fair skin, while their variant, dermatosis papulosa nigra, is more common among those of African or Asian descent with darker skin tones. Although the etiology of SKs remains unknown, many lesions reveal mutations in the FGFR3 gene, which regulates cell proliferation, angiogenesis, and wound repair.5 Mutated FGFR3 typically is associated with congenital skeletal dysplasias, but the gene also is expressed in the keratinocytes of wounded skin.4 Benign skin tumors, particularly SKs, have been shown to express increased numbers of FGFR3 mutations, which may be the result of the cumulative effects of exposure to UV light with increasing age.5 In addition to age and chronic exposure to UV radiation, family history may be a risk factor for SKs.1,5 Due to the classic verrucous appearance of SKs, human papillomavirus (HPV) has also been suggested as a potential etiology; however, recent studies have not yet confirmed viral involvement.1,24 The diagnosis of SK usually is based on distinct clinical presentations. Lesions present as well-demarcated, round or oval plaques that vary in size and color, ranging from flesh-tone to brown and occasionally black, often with a rough and oily surface.Although the majority of SKs are found on the face and trunk, they can be found almost anywhere on the body, except the palms, soles, and mucous membranes.1,2 Dermoscopy can be useful when diagnosis is uncertain. The most widely
recognized diagnostic criteria for SKs demonstrated by dermoscopy are pseudofollicular openings resembling comedones as well as keratin-filled pits that form invaginations on the surface of lesions, known as horn pseudocysts.2 Additional features that may improve the accuracy of diagnosis and decrease the need for biopsy include a “moth-eaten border” and clusters of hairpin blood vessels.6 If the diagnosis remains unclear after dermoscopy, biopsy should be performed to definitively differentiate SK from a malignancy. Lesions can be further classified into subtypes based on the wide variety of histologic features, the most common of which include acanthosis, papillomatosis, and hyperkeratosis.2 Although SKs are benign neoplasms of epidermal cells, they may resemble malignant melanoma, which should be included in the differential diagnosis. Melanoma typically appears as an isolated lesion, whereas multiple SKs are commonly found at initial presentation, especially with increasing age.1,2 Malignant lesions evolve in appearance and size as they progress; in contrast, SKs have a greasy surface,
The prevalence of seborrheic keratoses increases with increasing age, with lesions occurring in most adults aged >50 years. appear stuck on the skin, and rarely display changes over time.3 The histologic appearance of SKs reveals a noninvasive, benign process, whereas melanoma is characterized by marked cellular atypia and infiltration.3 Other lesions with a similar clinical presentation to SKs of pigmented or rough plaques include actinic keratoses, melanocytic nevi, lentigo, or manifestations of HPV infection, such as verruca vulgaris or condyloma acuminatum.2 A rapid increase in size and number of symptomatic, pruritic SKs, a manifestation known as the Leser-Trélat sign, may indicate an underlying malignancy, most commonly adenocarcinoma of gastrointestinal origin, and requires an extensive diagnostic investigation.7 Because SKs are benign lesions, no therapy is necessary; however, they are removed frequently due to cosmetic concerns or if significant irritation occurs.1 Features of SKs such as bleeding, ulceration, and inflammation require further evaluation to rule out malignancy. Lesions are removed with a variety of operative techniques including cryotherapy, curettage, and shave excision.2 Cryotherapy is a convenient and commonly used treatment method, although this technique is the most likely to leave a residual lesion.1 In contrast, shave
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Continues on page 38
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Dermatologic Look-Alikes excisions and curettage exchange more complete removal for increased risk for scar formation. The patient in the case presented was reassured that the lesions were benign SKs. He was told that no intervention was necessary, but the patient requested removal of the lesion on his back. The lesion was initially treated with cryotherapy, but the patient opted for a shave excision after recurrence. The biopsy revealed horn pseudocysts consistent with an initial diagnosis of SK.
Verruca vulgaris, also known as the common wart, is a benign cutaneous lesion caused by human papillomavirus (HPV) infection of the skin and mucosa and is most commonly seen in children and adolescents.8 Common warts are caused by a large group of the hundreds of identified HPV genotypes, most frequently types 1, 2, 27, and 57.8 Although warts are asymptomatic in immunocompetent patients, lesions have the potential to undergo malignant transformation in immunosuppressed patients due to impaired cell-mediated immunity and infection clearance.9 HPV is a nearly universal infection that is eventually cleared by the immune system of healthy individuals. This ubiquitous infectious agent can give rise to a wide variety of clinical manifestations, including cutaneous or anogenital warts and malignancies of both the male and female reproductive tracts. HPV represents one of the most common causative agents of cutaneous infections in patients of all ages, with the greatest prevalence of verruca vulgaris occurring in primary school-aged children.10 Increased incidence of warts is also reported among immunocompromised patients and handlers of meat or fish, an occupation in which the skin of the hands is continuously exposed to moisture.10,11 Verruca vulgaris occurs as a result of viral inoculation of the epidermis through direct skin-to-skin contact or contact with contaminated surfaces.11,12 Individuals are increasingly susceptible to HPV infection if the barrier function of the skin is compromised by disruption or injury. Once the DNA virus has infected the basal epithelial layer, viral proteins use the host’s replication machinery to proliferate within the more superficial layers of the skin, creating benign growth.12
Children regularly spread the virus both through contact with others and autoinoculation, especially when putting their fingers in their mouths, which results in localized expansion of lesions.11 Risk factors involve contact with infected individuals, occupational contact with meat or fish, and immunosuppressed states, including HIV infection or after organ transplantation. Plantar infection may also occur by walking barefoot on contaminated surfaces, such as in communal showers.13 Verruca vulgaris presents as fleshy or pink papules of varying size with a verrucous surface. Common warts can develop on any part of the body, including mucous membranes, palms, and the soles as plantar warts.The most common distribution occurs along the fingers or dorsal surface of the hands.10 Warts caused by HPV serotype 1 have a characteristic presentation, often arising on the plantar surfaces in children aged <12 years.8 Typically, fewer than 4 lesions arise, and resolution usually occurs in <6 months. The pathognomonic feature of HPV on histopathologic examination are koilocytes, which are squamous epithelial cells surrounded by a perinuclear halo.10 The common wart appears largely benign on histologic examination, with prominent keratohyaline granules and dermal hypertrophy, leading to striking acanthosis and papillomatosis.11
Human papillomavirus is a nearly universal infection that is eventually cleared by the immune system of healthy individuals. The differential diagnosis of HPV includes other benign lesions that may present with a hyperkeratotic or verrucous papule, such as seborrheic keratoses, keratoacanthomas, or fibrokeratomas. Other cutaneous manifestations of viral infections, such as molluscum contagiosum caused by poxvirus, lead to similar skin lesions that are spread through skin-toskin contact; however, verruca vulgaris lacks the central umbilication seen in poxvirus papules.14 Warts that coalesce along the nail beds may also resemble onychomycosis, so fungi should be cultured to distinguish the diagnosis.Verruca vulgaris may resemble malignant lesions, such as verrucous carcinoma or squamous cell carcinoma, and an excisional biopsy should be performed if the diagnosis is unclear based on clinical presentations alone or lesions are refractory to standard treatments.15 When a patient presents with 1 or multiple well-demarcated, fleshy papules on the fingers, hands, elbows, or knees, the
38 THE CLINICAL ADVISOR • OCTOBER 2019 • www.ClinicalAdvisor.com
Seborrheic Keratosis vs Verruca Vulgaris Seborrheic Keratosis2-9
• Pigmented plaques or papules with a verrucous, greasy surface and a characteristic “stuck-on” appearance • Typically present in individuals >50 y and increase with age
• Flesh-colored or pink papules with a verrucous surface • Typically presents in children and adolescents
• Increasing age • Chronic exposure to ultraviolet light • Possible role of FGFR3 gene mutations
• Human papillomavirus infection • May undergo malignant transformation in immuno compromised patients
Unknown; thought to be related to cumulative exposure to ultraviolet light with increasing age, which may lead to development of FGFR3 gene mutations
Human papillomavirus infects the basal epithelial layer of the epidermis, leading to viral replication in the superficial skin layers
• Most commonly occurs on the face and trunk • Can occur anywhere on the body but spares the palms, soles, and mucous membranes
• Most commonly occurs on the fingers and hands • Can occur anywhere on the body, including the palms, soles, and mucous membranes
• Variety of histologic presentations depending on subtype • Most common characteristics include hyperkeratosis, papillomatosis, and acanthosis • Horn pseudocysts: keratin-filled invaginations
• Koilocytes: squamous epithelial cells surrounded by a perinuclear halo • Prominent keratohyaline granules • Acanthosis and papillomatosis as a result of hypertrophy of the dermis
• History and physical examination • Dermoscopy or excisional biopsy may provide additional information if diagnosis is unclear and to rule out malignant processes
• History and physical examination • Polymerase chain reaction to detect human papillomavirus DNA or excisional biopsy may provide additional information if diagnosis is unclear and to rule out malignant processes
• No therapy required • Problematic lesions can be removed with cryotherapy, shave excision, or curettage
• Majority resolve spontaneously • Topical salicylic acid is first-line therapy
diagnosis of verruca vulgaris traditionally is made based on established diagnostic criteria.16 However, in the case of an atypical lesion that cannot be readily diagnosed on examination, the lesion should be sampled for polymerase chain reaction (PCR) to detect viral DNA or a histopathologic examination should be performed.10 After the diagnosis is established, warts that do not spontaneously regress can be treated with a variety of therapeutic options, supported by limited clinical data. Topical salicylic acid, a keratinolytic agent that eradicates infected cells, is often used as first-line treatment for HPV.15 Other forms of immunotherapy such as topical dinitrochlorobenzene, or ablation with cryotherapy are only associated with a moderate increase in resolution
compared with placebo.15 The 3 available vaccinations against HPV aim to provide protection against the serotypes of the virus with the greatest risk of progression to malignancy of the genital tracts (6, 11, 16, and 18) but do not protect against the most common types associated with cutaneous infection. Some studies suggest that vaccination with the nonavalent HPV vaccine, which provides the greatest coverage, can aid in the treatment of diffuse verruca vulgaris in immunocompromised patients.17 The patient in the case presented was diagnosed with verruca vulgaris. He was treated with cryotherapy and prescribed topical salicylic acid. After several weeks, the patient’s lesions resolved. ■
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2019 39
Dermatologic Look-Alikes Rachel E. Graubard, BSA, and McKenna E. Boyd, BS, are medical students at Baylor School of Medicine. Christopher Rizk, MD, is a dermatologist with Elite Dermatology, in Houston,Texas.
8. Bruggink SC, Koning MND, Gussekloo J, et al. Cutaneous wart-associated HPV types: prevalence and relation with patient characteristics. J Clin Virol. 2012;55(3):250-255. 9. Scott M, Nakagawa M, Moscicki AB. Cell-mediated immune response to
human papillomavirus infection. Clin Vaccine Immunol. 2001;8(2):209-220.
1. Wollina U. Seborrheic keratoses – the most common benign skin tumor
10. Cardoso JC, Calonje E. Cutaneous manifestations of human
of humans. Clinical presentation and an update on pathogenesis and treat-
papillomaviruses, a review. Acta Dermatovenerol Alp Pannonica Adriat.
ment options. Open Access Maced J Med Sci. 2018;6(11):2270-2275.
2. Hafner C, Vogt T. Seborrheic keratosis. J Dtsch Dermatol Ges. 2008;6(8):
11. Cubie HA. Diseases associated with human papillomavirus infection.
3. Braun RP, Ludwig S, Marghoob A. Differential diagnosis of seborrheic
12. Tyring SK. Human papillomavirus infections: epidemiology, pathogenesis,
keratosis: clinical and dermoscopic features. J Drugs Dermatol. 2017;16(9):
and host immune response. J Am Acad Dermatol. 2000;43(1 Pt 2):S18-26.
13. Loo SK, Tang WY. Warts (non-genital). BMJ Clin Evid. 2014;2014:1710.
4. Hafner C, Vogt T, Hartmann A. FGFR3 mutations in benign skin tumors.
14. Stulberg DL, Hutchinson AG. Molluscum contagiosum and warts.
Cell Cycle. 2006;5(23):2723-2728.
Am Fam Physician. 2003;67(6):1233-1240.
5. Hafner C, Hartmann A, Oers JMMV, et al. FGFR3 mutations in seborrheic
15. Miller DJ, Strauch RJ. Management of cutaneous warts of the hand.
keratoses are already present in flat lesions and associated with age and
J Hand Surg Am. 2015;40(11):2274-2276.
localization. Mod Pathol. 2007;20(8):895-903.
16. Young R, Jolley D, Marks R. Comparison of the use of standardized diag-
6. Braun RP, Rabinovitz H, Krischer J, et al. Dermoscopy of pigmented
nostic criteria and intuitive clinical Ddiagnosis in the diagnosis of common
seborrheic keratosis: a morphological study. Arch Dermatol. 2002;138(12):
viral warts (verrucae vulgaris). Arch Dermatol. 1998;134(12):1586-1589.
17. Ferguson SB, Gallo ES. Nonavalent human papillomavirus vaccination
7. Chakradeo K, Narsinghpura K, Ekladious A. Sign of Leser–Trélat. BMJ Case
as a treatment for warts in an immunosuppressed adult. JAAD Case Rep.
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40 THE CLINICAL ADVISOR • OCTOBER 2019 • www.ClinicalAdvisor.com
LEGAL ADVISOR CASE
© SOLIDCOLOURS / GETTY IMAGES
Negligence and Mistaken Identity A PA is concerned about a patient’s injury but does not seek the advice of her supervising physician. BY ANN W. LATNER, JD
This month’s case involves a charge of negligence against a physician assistant whom the patient believed to be a physician. The patient, Mrs G, was hurrying to her job as an assistant manager at a bank when her shoe became caught on a section of uneven pavement, causing her to fall to the ground. As she fell, she extended her hands reflexively and landed on them forcefully. A passerby stopped and helped her to call her husband, who came and took her to the emergency department of the local hospital. After being evaluated by emergency department staff, Mrs G was diagnosed with an intra-articular fracture of the right dorsal radius, as well as a stress fracture of the left wrist. A temporary splint was applied to her right wrist, and she was referred to an orthopedic practice for follow-up treatment. Two days later, Mrs G and her husband were sitting in the waiting room of the orthopedic practice when Ms M, a physician assistant, appeared and introduced herself. She told Mrs G that she would be treating her today and escorted her to an examination room.
After clearly outlining a patient’s options, encourage them to get a second opinion if you believe they are making the wrong decision in their care.
Ms M had been working at the orthopedic practice for 7 years. She liked the work and most of her coworkers but was wary of Dr P, one of the supervising physicians who could be bad-tempered. If he was the physician on call when Ms. M was working, she tried to avoid asking him anything for fear of being snapped at. Fortunately, she didn’t feel the need to ask too many questions at this point in her career. Most of the work she did was repetitive, and after 7 years, she felt competent in diagnosing and treating most injuries. Ms M ushered Mrs G into the examination room and asked her to describe how she became injured. Mrs G recounted the incident in great detail — how she had caught her foot on the pavement, how she had felt as if she were falling in slow motion, and how she had extended her hands as a reflex to block the fall. Ms M 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.
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2019 41
LEGAL ADVISOR examined the patient’s wrists and noticed that the right wrist had undergone extensive damage. She explained to the patient that the stress fracture in the left wrist would heal on its own by limiting mobility. She took radiographs of both wrists and then informed Mrs G of her treatment options. “Your right wrist, unlike your left one, will not heal on its own,” Ms M explained. “You have 2 options — casting or surgery.” The patient responded, “I really don’t want surgery. Will the casting fix it too?” Ms M explained to the patient that the injury would heal with either treatment but that it would take longer with casting.“I would recommend you opt for surgical treatment,” said Ms M. “The healing process will be shorter.” “No, I don’t want surgery. I’m willing to wait longer for the recovery,” said Mrs G.
Always announce your title so that it is clear to patients from which type of provider they are receiving care. Ms M nodded and explained the casting process to Mrs loG. Ms M then performed a closed reduction with anesthetic before re-splinting the patient’s right wrist. Mrs G was instructed to return in a week to have a cast placed. Upon Mrs G’s return 1 week later, Ms M performed a second closed reduction with anesthetic before placing the wrist in a cast. Mrs G was scheduled to return regularly to have the cast checked. At Mrs G’s 4-month follow-up, Ms M became concerned that the wrist wasn’t healing properly. However, she was uncomfortable approaching Dr P, who was the supervising physician scheduled that day and busy with his own patients. When Ms M examined Mrs G in the fifth month of treatment, Ms M knew unequivocally that the wrist wasn’t healing properly. She asked Mrs G to wait while she stepped out of the examining room to speak with one of the physicians, who told her to refer the patient to a hand specialist. “Who were you talking to?” asked the patient. “Oh, one of the physicians,” answered Ms M. “He thinks you should be referred to a hand specialist.” Mrs G responded, “Wait, aren’t you a physician?” “No, I’m a physician assistant,” said Ms M.“I told you that when I introduced myself.” The patient grabbed the referral for the hand surgeon and left in a fury.
A few hours later, the hand surgeon called Ms M and admonished her for not referring Mrs G for consultation with a hand specialist sooner. The patient eventually required major surgery consisting of an osteotomy with placement specifically osteotomy with placement of a plate and 10 screws. Mrs G lost range of motion and grip strength in her wrist and hand, and she was no longer able to operate a computer keyboard at work. She hired a plaintiff ’s attorney and filed a lawsuit against Ms M and the orthopedic practice. Legal Background
Ms M met with the defense attorney provided by her insurance company. The attorney informed her that the patient was claiming that Ms M misrepresented herself as a physician and that she gave Mrs G bad advice and was negligent in her treatment. Ms M explained to the attorney that she had indeed introduced herself as a physician assistant. She further asserted that the letters “PA” were on all of the patient’s paperwork and her prescriptions, as well as on Ms M’s lab coat.“I recommended to the patient that she undergo surgical correction,” said Ms M. “It was her decision to proceed with the alternative option of casting.” Settlement negotiations failed, and the case ultimately went to trial. The plaintiff introduced testimony from orthopedic experts, who faulted Ms M on her treatment of the patient and for failing to notify a specialist sooner, when she first began to suspect that the bone wasn’t healing properly. They also faulted Ms M’s employer for not executing proper oversight. In turn, the defense introduced experts to testify that casting is a valid treatment option for a wrist fracture. After a 9-day trial, which included a day and a half of deliberations, the jury found Ms M and the orthopedic practice liable and awarded more than $500,000 to the plaintiff. Protecting Yourself
Always announce your title so that it is clear to patients from which type of provider they are receiving care. After outlining all of a patient’s options, encourage them to get a second opinion if you believe they are making the wrong decision in their care. Most importantly, never hesitate to ask for advice from supervising staff when you believe when you believe a patient has a problem that you cannot solve. It is well worth risking irritating a supervisor to ensure that a patient is getting the proper treatment. ■ Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, New York.
42 THE CLINICAL ADVISOR • OCTOBER 2019 • www.ClinicalAdvisor.com