A P E E R - R E V I E W E D F O RU M F O R N U R S E P R AC T I T I O N E R S
Highlights From Spring 2021 Virtual Medical Meetings LEGAL ADVISOR
Missed Cues Lead to Abrupt Death
A Case of Sudden-Onset Dysphagia and Vomiting in 24-Year-Old Man
Pruritic Papules That Arise During Pregnancy
M AY / J U N E 2 0 21
Breast Implant-Associated Anaplastic Large Cell Lymphoma: An Update
Director Nikki Kean email@example.com Medical editor Kristin Della Volpe
FROM THE DIRECTOR
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The term is everywhere: burnout. We see it screaming from headlines, we read about it in our medical literature, and we see it when we open our social media accounts. According to Merriam-Webster’s Collegiate Dictionary, the definition of burnout is “exhaustion of physical or emotional strength or motivation usually as a result of prolonged stress or frustration.” Signs of burnout include insomnia, chronic fatigue, difficulty concentrating, apathy, irritability, and anxiety. Although burnout is not recognized as a distinct mental disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), several recent studies have described burnout among nurse practitioners (NPs), physician assistants (PAs), and physicians. The American Academy of PAs 2021 Conference, held May 23 to 26, had 2 posters about burnout among New York State frontline workers and PA leaders. Workplace burnout has been recognized by the World Health Organization in its International Classification of Diseases 11th Revision (ICD-11). However, what I think most of us are experiencing is pandemic burnout. We have been living in a state of fear, anxiety, and loss. Fear of the virus, for our loved ones, for the world. We have lost friends, colleagues, and our freedom to go about our lives as usual. As the pandemic ebbed and then roared back again and again, the collective fear has been replaced by fatigue, malaise, and lethargy. With summer approaching, we all need to recognize the chronic stress we have been working and living under. With the warmer weather, longer days, and more people becoming vaccinated, we are beginning to venture out, take longer walks, plan vacations, and feel the hope of life returning to “normal.” As part of my recovery from burnout, I am focusing on gratitude. I am grateful for my health, my family, my job, and the light at the end of the tunnel. My son, a high school teacher, is excited for inperson classes in the fall and my youngest is excited for a return to a more “normal” college experience. Let us recognize the collective burnout we have experienced and be kind to ourselves, our patients, our families, and our neighbors. Nikki Kean, Director The Clinical Advisor www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY/JUNE 2021 8
© MILJKO / GETTY IMAGES
An Epidemic of Burnout
Assistant editor Jeanelle Jacobs
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CONTENTS M AY / J U N E 2 0 2 1
Conference Roundup Highlights From Spring 2021 Virtual Medical Meetings
FEATURES 20 Aspirin use in COVID-19 patients
1 A Case of Sudden-Onset Dysphagia During Lunch, 2 Unresolved by PPIs The patient is initially misdiagnosed with GERD. 8 Breast Implant-Associated Anaplastic Large Cell 2 Lymphoma: An Update There have been a total of 733 reports of BIA-ALCL. 33 Alcohol Withdrawal: Individualized Care and Pharmacologic Treatment More than 50% of patients with alcohol use disorder will develop withdrawal symptoms within hours of stopping drinking.
33 Management of alcohol withdrawal
37 Hypersensitivity skin reaction
47 Unrecognized medical emergency
From the Director An Epidemic of Burnout
Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com.
Dermatology Clinic ■ Circular Lesions on Hands and Arms ■ Red Lesions on Arms and Flank
Dermatologic Look-Alikes Pruritic Papules During Pregnancy
Legal Advisor Missed Cues Lead to Abrupt Death
Follow us on Twitter @ClinicalAdvisor
MORE WAYS TO FIND US!
Like us on Facebook facebook.com/TheClinicalAdvisor Visit us on the web ClinicalAdvisor.com Download the app ClinicalAdvisor.com/App
CLINICAL CHALLENGE ClinicalAdvisor.com/CaseStudy
Start Colorectal Cancer Screening at Age 45, ACS Recommends
Brady Pregerson, MD Clinical Challenge: Elbow Pain and Numbness in Fingers A man in his 40s presents with worsening pain in his right elbow, numbness in his right pinky and ring fingers, and numbness in the right hand. The symptoms began after he participated in a tug-of-war game 4 days ago. The patient reports that he fractured his right elbow 6 years ago. See the full case at: ClinicalAdvisor.com/CaseMay_June21
The rate of colorectal cancer in people younger than 50 years has doubled since the 1990s, leading the ACS to recommend screening starting at age 45.
New Algorithm Predicts Advanced Liver Disease The CIRRhosis Using Standard tests (CIRRUS) algorithm uses results obtained from routine blood tests to identify patients at high risk for advanced liver disease.
Experiences and Risks Faced by Adolescents With Bipolar Disorder Adolescents with bipolar disorder face challenges in their personal lives such as peer problems, extraversion, family cohesion, and ADHD.
Pregnancy Increases Risk of First-Time Painful Kidney Stones Pregnancy is associated with an increased risk for a first-time symptomatic kidney stone, according to findings from a casecontrolled study.
Hand Dermatitis Rates Have Risen Dramatically in Health Care Workers More than 90% of health care workers have hand dermatitis, according to a new study. The main culprit is an increase in handwashing and use of alcohol-based sanitizers during COVID-19.
THE WAITING ROOM
Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Jim Anderson, MPAS, PA-C, DFAAPA The Importance of Asking About the Small Stuff The author finds that remembering to ask about the small stuff, like medication reconciliation and smoking cessation, improves his ability to keep his patients safe and healthy.
MY PRACTICE ClinicalAdvisor.com/MyPractice Kristin Della Volpe AANP Applauds Updated Opioid Use Disorder Guidance Eligible nurse practitioners and physician assistants can now prescribe buprenorphine for up to 30 patients with opioid use disorder.
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY/JUNE 2021 11
IMAGES: © GETTY IMAGES
EXCLUSIVE TO THE WEB AT
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!
Nonpruritic Rash on Lower Back A 51-year-old woman requests treatment of a rash on her lower back. The site is asymptomatic and does not itch or burn. Her medical history is positive for surgically resected papillary thyroid carcinoma, pulmonary sarcoidosis, and gastroesophageal reflux disease. She is a former smoker. Examination reveals a 5-cm, well-demarcated erythematous patch devoid of scale. CAN YOU DIAGNOSE THIS CASE?
• Tinea corporis • Patch stage of mycosis fungoides
• Cutaneous sarcoidosis • Granuloma annulare
● See the full case at ClinicalAdvisor.com/DermDx_May_June21
In partnership with
Pain in Hips and Buttocks A 74-year-old woman presents for evaluation of bilateral hip and buttock pain with no known precipitating event. She has pain to palpation over the lower back and buttock but no hip pain with bilateral range of motion testing. A pelvic MRI shows extensive edema throughout the entire sacrum and bilateral sacral insufficiency fractures with no step-off of bone. WHAT IS THE BEST TREATMENT OPTION FOR THIS PATIENT?
• • • •
Nonweight-bearing for 4 to 6 weeks Weight-bearing as tolerated with a walker Sacroplasty Open reduction and internal fi xation
● See the full case at ClinicalAdvisor.com/OrthoDx_May_June21
12 THE CLINICAL ADVISOR • MAY/JUNE 2021 • www.ClinicalAdvisor.com
Journal of Orthopedics for Physician Assistants
Conference Roundup Highlights From Spring 2021 Virtual Medical Meetings American Academy of Dermatology, American Association of Neurology, ACC, ENDO 2021, and NAPNAP 2021
The majority (85% to 90%) of adverse drug reactions are predictable based upon the pharmacologic properties of the medicine and the dose given to the patient. Some patients indicate that they can not be given penicillin due to a “family history of penicillin allergy,” but having relatives with a penicillin allergy (without confirmation) is not a valid contraindication, Dr Wendling said. The drug provocation test (DPT) is the gold standard for penicillin allergy testing, although in cases when a clinician is concerned about anaphylaxis, skin testing may be done first. During DPT the patient is given an age-appropriate dose of amoxicillin and observed for 60 minutes.The test is designed to rule out an IgE-mediated immediate reaction, Dr Wendling said. An extended challenge can help identify a T-cell-mediated DHR, she noted. An extended challenge may also help increase confidence in removing penicillin allergy
from the patient’s record so that penicillin can be prescribed for future infections. Since penicillin is the treatment of choice for several common infections, understanding whether or not a patient has a true allergy to the medication is crucial to optimizing patient outcomes. Neither side effects nor family history should be used as a reason to not prescribe penicillin if the patient has an infection that warrants treatment with antibiotics, Dr Wendling said. Diagnostic testing can confirm whether or not the patient has a life-threatening allergy to penicillin. Using second-line antibiotics to avoid prescribing penicillin is associated with increased hospitalization, morbidity, antibiotic resistance, and cost of care. Public health and patient outcomes are dependent on decreasing the number of patients who are not truly allergic to penicillin but receive second-line therapies to avoid the medication, Dr Wendling concluded.
TABLE. Types of Drug Hypersensitivity Reactions Type I
IgG-mediated and complement formation
IgG or IgM and complement activation with immune complex deposition
Serum sickness-like reaction
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PINPOINTING PENICILLIN ALLERGY IN THE PEDIATRIC POPULATION Understanding the characteristics and prevalence of adverse reactions to penicillin in the pediatric population is crucial to optimizing patient outcomes and limiting cost of care, reported Trisha Wendling, DNP, APRN, CPNP-PC, during a presentation at the National Association of Pediatric Nurse Practitioners Annual Meeting (NAPNAP 2021), held March 24 to March 27, 2021. Penicillin allergy is the most commonly reported drug allergy, noted Dr Wendling. Although penicillin allergy is reported in 10% to 20% of hospitalized patients, the true prevalence is estimated to be approximately 4% to 5%. Most children (95%) who develop a rash when given amoxicillin are not truly allergic to the drug when re-exposed. In those cases, noted Dr Wendling, the rash is likely in response to a virus or an interaction between a virus and the antibiotic. Even in cases when the rash is caused by an allergic reaction, 50% of these children will tolerate amoxicillin after 5 years and 80% will tolerate amoxicillin after 10 years. Out of all reported reactions to penicillin, just 5% are anaphylaxis; 38% are rashes, 18% are hives, 9% are angioedema, 6% are gastrointestinal upset, and 5% are itching. Just over one-quarter (26%) of reactions are “unknown.” Approximately 10% to 15% of all adverse drug reactions are drug hypersensitivity reactions (DHRs; Table).
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GUSELKUMAB IMPROVES SYMPTOMS OF PSORIASIS AND PSORIATIC ARTHRITIS Guselkumab treatment was associated with durable, complete skin clearance through 5 years in patients with moderate to severe plaque psoriasis (PsO) and improved disease activity and axial symptoms through 1 year in adults with active psoriatic arthritis (PsA), according to findings presented at the American Academy of Dermatology’s Virtual Meeting Experience (AAD VMX) 2021, held April 23 to April 25, 2021. In theVOYAGE 2 trial, approximately 55.5% of patients who received guselkumab had complete skin clearance, as determined by an Investigator’s Global Assessment (IGA) score of 0, by week 252.Approximately 53% of patients had a Psoriasis Area Severity Index (PASI) 100 skin clearance response (PASI 100) by week 252. Up to 82% of patients achieved a PASI 90 skin clearance response and 85% had an IGA score of 0/1. Efficacy rates were maintained at 5 years. In the DISCOVER-1 and -2 trials, patients with active PsA received either placebo or 100-mg guselkumab every 4 weeks and every 8 weeks. Treatment with guselkumab improved disease activity in the joints as well as across several different domains through 52 weeks. Differences in response rates between the active treatment and placebo groups were observed at 8 weeks of treatment. In the VOYAGE 2 trial, a significantly greater percentage of patients who received guselkumab vs placebo for 16 weeks had an IGA 0/1 response (84% vs 9%, respectively; P <.001). Safety data from the VOYAGE 1 and 2 trials showed that 78.3% of patients who received guselkumab continued treatment through week 252. Low rates of adverse events due to treatment discontinuation were reported.
Ketamine relieved headache pain 70.8% of the time, according to patient report.
INTRANASAL KETAMINE REDUCES PAIN IN REFRACTORY HEADACHE Patients with refractory headache may benefit from treatment with intranasal ketamine spray, according to findings from a single-center retrospective study presented at the American Academy of Neurology 2021Virtual Annual Meeting, held April 17 to April 22, 2021. Patients (N=245) prescribed intranasal ketamine from January 2019 to February 2020 were identified by electronic medical records.A total of 168 of these patients participated in the telephone survey. The patients had a mean age of 44.5 (±13.8) years and the majority (n=134) were women.The most frequently documented diagnosis was chronic migraine (83.9%; n=141) and most of the patients were currently using intranasal ketamine (63.7%; n=107). The average usage of intranasal ketamine was 11.8 (±8.9) days per month. On each usage day, patients administered a mean of 7.9 (±6.9) sprays of ketamine. Average headache intensity was reported to be 7.6 (±1.7) on a 10-point scale prior to taking ketamine and 4.7 (±2.2) after administration (P <.01). Headache relief
after spray occurred after an average of 74.1 minutes. The patients indicated headache relief due to ketamine was successful 70.8% of the time and 71.4% (n=120) reported they used fewer additional acute medications for headache relief while using intranasal ketamine. Adverse effects included fatigue (20.8%), blurred vision or diplopia (20.8%), nausea (15.5%), vivid dreams (10.1%), hallucinations (7.7%), vomiting (3%), tremor (2.4%), extreme fear (1.8%), and myoclonus (1.2%). Study limitations included the singlecenter, retrospective design, and selfreported responses.
SPINAL CORD STIMULATION RELIEVES PAINFUL DIABETIC NEUROPATHY Spinal cord stimulation (SCS) was associated with reduced pain intensity among patients with painful diabetic neuropathy, according to findings from a prospective, multicenter, randomized controlled trial presented at the American Academy of Neurology 2021 Virtual Annual Meeting, held April 17 to April 22, 2021. Researchers recruited patients (N=216) with diabetes who were diagnosed with neuropathy at least 12 months previously, were refractory to medications, had lower limb pain intensity of 5 cm or more on a 0 to 10 cm visual analog scale, little upper limb pain (<3 cm), did not use more than 120-mg morphine equivalents per day, and had controlled hemoglobin A1c (≤10%). Study participants were randomly assigned in a 1:1 ratio to receive 10 kHz SCS with conventional therapy (n=113) or usual therapy alone (n=103). The average pain intensity was 7.6 and 7.0 cm at baseline in the treatment and control cohorts, respectively. At 6 months, pain intensity was 1.7 cm
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY/JUNE 2021 15
Conference Roundup among patients in the treatment group, 85% had at least 50% pain relief, and 2.3% had worsening pain (P <.001); in contrast, the pain intensity was 6.9 cm among patients in the control group, 6.3% had at least 50% pain relief, and 52% had worsening pain symptoms. Improvements in neurologic examination results were found in 65.9% of patients who received SCS and 8.5% of patients in the control group (P <.001). Two patients who had been randomly assigned to the treatment group required device explants due to infection. This study was limited by low sample size and short study duration.
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DUPILUMAB AND TOPICAL CORTICOSTEROIDS IMPROVE ATOPIC DERMATITIS SYMPTOMS A combination of dupilumab and mediumpotency topical corticosteroids significantly improved signs and symptoms of atopic dermatitis (AD) and quality of life in children with severe AD, according to study results presented at the American Academy of Dermatology’s Virtual Meeting Experience (AAD VMX) 2021, held April 23 to April 25, 2021.
Nearly half of patients in the dupilumab arms achieved all 3 clinically meaningful endpoints.
The LIBERTY AD PEDS phase 3 trial enrolled children from 6 to 11 years of age with severe AD. Participants were randomly assigned to receive 300 mg dupilumab every 4 weeks (n=61), 100 mg/200 mg every 2 weeks (baseline weight ≥30 kg: n=59), or placebo (baseline weight <30 kg: n=61; baseline weight ≥30 kg: n=62). Each treatment group also received concomitant mediumpotency topical corticosteroids. Study investigators assessed the percentage of patients who reached the 16-week composite endpoint comprising achievement of 50% or greater improvement in Eczema Area and Severity Index (EASI-50), 3-point or greater improvement in Peak Pruritus Numerical Rating Scale (PP-NRS) score, and 6-point or greater improvement in Children’s Dermatology Life Quality Index (CDLQI). Nearly half of patients in the 300-mg (49.2%) and 200-mg (47.5%) dupilumab arms achieved all 3 clinically meaningful endpoints compared with 8.1% to 9.8% of patients in the placebo groups (P <.0001). The safety profile of dupilumab was consistent with its known safety reported in adult and adolescent patient populations.
CAN VITAMIN D LOWER DIABETES RISK AND REDUCE CA PROGRESSION, MORTALITY? New findings on the impact of vitamin D supplementation on type 2 diabetes risk, cancer mortality, and progressionfree cancer survival were presented at the annual meeting of the Endocrine Society (ENDO 2021), held virtually March 20 to March 23, 2021. Anastassios G. Pittas, MD, from Tufts Medical Center in Boston, Massachusetts, found that vitamin D supplementation decreased the risk for progression to diabetes in people with prediabetes by
16 THE CLINICAL ADVISOR • MAY/JUNE 2021 • www.ClinicalAdvisor.com
approximately 13% in an analysis of 3 large trials. Dr Pittas also found that the protective effect of supplementation may be higher among individuals with prediabetes who have low baseline 25-hydroxyvitamin D levels (<12 ng/mL) and that risk reduction was proportional to serum levels of 25-hydroxyvitamin D achieved. Vitamin D Reduces Cancer Mortality Another study was designed to evaluate whether daily supplementation with vitamin D3 (2000 IU) and marine omega-3 fatty acids (1 g) can be used in the primary prevention of cancer and cardiovascular disease. The study was based on results of the nationwide, randomized, placebo-controlled, 2×2 factorial VITamin D and OmegA-3 TriaL (VITAL).The findings were presented by JoAnn E. Manson, MD, DrPH, of Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts. The total study cohort included 25,871 men and women (men aged ≥50 years, women aged ≥55 years; 5106 Black individuals) over a median treatment period of 5.3 years. Although vitamin D supplementation did not significantly reduce the total incidence of invasive cancer, it was associated with a reduction in total cancer mortality. The association between supplementation and total cancer mortality was more pronounced when the analysis excluded years 1 and 2 to account for latency. This data was not as promising for the other coprimary endpoints of major cardiovascular events (HR, 0.97), other cardiovascular endpoints (no HR available), and all-cause mortality (HR, 0.99). “Additional research is needed to determine which individuals may be most likely to have a net benefit from vitamin D supplementation,” Dr Manson concluded. Continues on page 20
Conference Roundup troponin perturbation over the disease course of COVID-19. The response to increased inflammation associated with severe SARS-CoV-2 infections may contribute to multiorgan dysfunction and lead to long-term sequelae. Additional studies of troponin levels among patients hospitalized with COVID-19 are needed to assess whether reductions in the inflammatory response may decrease troponin levels and subsequent cardiac injury.
EFFECTS OF ASPIRIN THERAPY ON THROMBOTIC COMPLICATIONS IN PATIENTS WITH COVID-19 Antiplatelet therapy with aspirin does not protect patients with COVID-19 from thrombotic events or mortality, according to a study presented during the American College of Cardiology Annual Meeting, held May 15 to May 17, 2021. COVID-19 has been found to be associated with an increased risk for thrombotic events such as stroke, myocardial infarction (MI), and venous thromboembolism (VTE). It is unknown what influence activated platelets may have on COVID19-associated thrombosis and whether antiplatelet therapies may be of benefit in patients with SARS-CoV-2 infection. The Cleveland Clinic team in Ohio evaluated the protein expression of both angiotensin-converting enzyme 2 (ACE2; n=20) and TMPRSS2 (n=20) in healthy human platelets via immunoblotting and confirmed the results via confocal microscopy (ACE2, n=6; TMPRSS2, n=3). For comparison, the authors evaluated the same protein expressions in patients (n=10, each) with coronary artery disease. To determine if antiplatelet therapy protects against MI, VTE, or death, researchers conducted a review of 22,072 patients who were tested for COVID-19 and matched them with 248 COVID-19-positive patients who were not exposed to aspirin or other
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HYPERINFLAMMATION AFFECTS TROPONIN LEVELS IN COVID-19 PATIENTS Troponin levels may be affected by beta natriuretic peptide (BNP), interleukin (IL)-6, and D-dimer concentrations among patients with COVID-19. These findings were presented during the American College of Cardiology Annual Meeting, held May 15 to May 17, 2021. Patients with severe COVID-19 are at risk for having a hyperinflammatory response such as a cytokine storm. Recent data suggest that some patients with COVID-19 experience cardiovascular damage. It remains unclear whether troponin levels during the course of a SARS-CoV-2 infection may be affected by markers of inflammation. To assess the relationship of COVID-19 and troponin, patients (N=586) admitted to Hackensack University Medical Center in New Jersey between February and June of 2020 who underwent at least 2 troponin assessments were retrospectively reviewed for hyperinflammatory responses and clinical outcomes. Mortality was associated with age, hypertension, coronary artery disease, heart failure, previous percutaneous cardiac intervention, use of beta-blockers or statins, hemodialysis, shock, concentrations of C-reactive protein, concentrations of IL-6, and change in troponin levels (all P <.05). Maximum troponin level correlated with BNP (correlation coefficient [r], 0.55; P <.05), D-dimer (r, 0.42; P <.05), and IL-6 (r, 0.30; P <.05) concentrations. Baseline troponin level was also correlated with BNP (r, 0.54; P <.05), D-dimer (r, 0.43; P <.05), and creatinine (r, 0.43; P <.05) concentrations. This study was limited by its retrospective design because there was no predetermined protocol for assessing troponin at set timepoints during patient hospitalization. These findings suggest the hyperinflammatory response may contribute to
Aspirin therapy does not protect against MI, VTE, and stroke in patients with COVID-19.
nonsteroidal anti-inflammatory drugs (NSAIDs) during treatment. Both ACE2 and TMPRSS2 were found to be present on human platelets. No association was shown between the expression of ACE2 (r2=.004; P =.79) or TMPRSS2 (r2=.058; P =.30) and age. A numerically higher expression of ACE2 and TMPRSS2 was seen in patients with coronary artery disease vs patients in the control group. In the propensity-matched analyses of aspirin use, no difference was found in the incidence of MI and VTE. However, aspirin therapy was associated with increased risk for thrombotic stroke (3.6% vs 0.40%; P =.036), as well as the composite endpoint of MI, VTE, and stroke (9.3% vs 2.8%; odds ratio [OR], 3.52; 95% CI, 1.48-8.40; P =.005). NSAID therapy was similarly associated with risk for the composite endpoint (3.8% vs 1.6%; OR, 2.49; 95% CI, 0.58-1.62; P =.046). Neither aspirin therapy (OR, 0.52; 95% CI, 0.51-1.41; P =.52) nor NSAID therapy (OR, 0.97; 95% CI, 0.58-1.62; P =.90) were associated with mortality. The investigators concluded, "Human platelets express the requisite SARSCoV-2 receptors to permit viral access, but antiplatelet therapy consisting of aspirin does not protect from thrombotic events or mortality." ■
FEATURE: KARMEN ELSEN, MPA, PA-C
A Case of Sudden-Onset Dysphagia During Lunch, Unresolved by PPIs A patient presenting with sudden-onset dysphagia and vomiting initially is diagnosed with GERD but does not respond to PPIs. What is your diagnosis?
24-year-old man presents to the emergency department (ED) complaining of suddenonset dysphagia that began 2 hours earlier while he was eating lunch. He states that it feels as though something is “stuck in his throat.” He explains that he tried to drink a glass of water to relieve the feeling but immediately vomited. He is now fearful of eating and drinking.The patient denies any previous episodes of dysphagia and reports no odynophagia, nausea, abdominal pain, heartburn, dyspepsia, weight loss, chest pain, or shortness of breath. He denies a medical history of gastroesophageal reflux disease (GERD) and peptic ulcer disease. He has no known food or drug allergies and is not taking any medications.The patient denies use of alcohol, illicit drugs, and tobacco.
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The prevalence of EoE is estimated at 57 per 100,000 people.
The patient’s vital signs are normal: blood pressure, 118/63 mm Hg; pulse, 95 beats per minute; respiratory rate, 18 breaths per minute; temperature, 97.8 °F; and oxygen saturation, 100%. On physical examination, the patient is alert and oriented x4. He appears uncomfortable but is in no acute distress. Cardiac examination reveals S1 and S2 heart sounds, with regular rate and rhythm without murmurs.The patient’s lungs are clear to auscultation. His neck is symmetrical with no masses. He has a palpable and nontender thyroid. His trachea is midline and palpable in the suprasternal notch. His abdomen is nondistended and nontender, with active bowel sounds. No organomegaly is present. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY/JUNE 2021 21
CASE: SUDDEN-ONSET DYSPHAGIA
Initial Diagnosis and Follow-up
No laboratory or diagnostic tests are ordered. Based on the initial assessment, the ED physician diagnoses the patient with GERD and prescribes a liquid proton pump inhibitor (PPI). The patient is hesitant to take the medication for fear of vomiting, but the doctor reassures him that this is not likely to occur. Twenty minutes after taking the PPI, the patient experiences no improvement of dysphagia. However, because of the patient’s ability to swallow the prescribed medication, the physician determines that no further workup is needed. The patient is sent home and assured that symptoms will resolve soon. Early the next morning, the patient returns to the ED with unresolved dysphagia. He states that he vomited 30 minutes after leaving the ED.The gastroenterology team is consulted and they perform a esophagogastroduodenoscopy (EGD). The EGD reveals a food bolus impaction and esophageal stricture located in the distal third of the esophagus. Mild esophagitis also is noted throughout the esophagus. Given these findings, biopsies are obtained for histology.The results indicate a diagnosis of eosinophilic esophagitis (EoE). Outcome
During the initial EGD, the food impaction is removed and the esophagus is treated with dilation.The patient is discharged home with a prescription for omeprazole 40 mg daily and is referred to an allergist. Allergy testing reveals allergic reactions to dairy, shellfish (shrimp, crab, lobster, clams, mussels, oysters, and scallops), bananas, and sweet potatoes.The allergist suggests diet modification and corticosteroids as treatment options. Given the potential long-term side effects of corticosteroids, the patient decides that an elimination diet and a daily PPI is the best treatment option for him. Two years after being diagnosed with EoE, the patient returns to the gastroenterologist after experiencing another episode of dysphagia. Repeat EGD reveals no stricture but shows diffuse faint corrugated mucosa throughout the esophagus, suggesting worsening disease. Further questioning of the patient reveals that the esophageal findings and recurrent symptoms likely are because of his nonadherence with his diet plan. Discussion
Eosinophilic esophagitis is a chronic immune-mediated disease that is increasingly encountered in clinical practice.1 The disease is characterized by infiltration of eosinophils and other inflammatory cells into the esophageal epithelium.1 This causes tissue remodeling and fibrosis of the esophagus, leading to symptoms of esophageal dysfunction. A strong correlation has been found between the development of EoE in patients with a personal or family history of atopic disease, specifically
asthma, eczema, and food allergies.1 This correlation makes it important to obtain a detailed history to identify possible risk factors for developing EoE. In this case, the patient presented with no medical history of atopic disease, which made this a more challenging diagnosis. A wide variety of symptoms are associated with EoE.Adults can present with dysphagia, heartburn, food impaction, chest pain, odynophagia, and vomiting.1,2 Although these symptoms are common in patients with EoE, they are not exclusive to the disease and can occur with other gastrointestinal disorders. Differentiating EoE and GERD Gastroesophageal reflux disease occurs when the lower esophageal sphincter relaxes, allowing reentry of acid and food into the esophagus, which causes injury and inflammation.3 Patients with GERD can present with symptoms of heartburn, dysphagia, chest pain, reflux, abdominal pain, and nausea.3 The similarity between symptoms of EoE and GERD makes distinguishing these 2 diseases clinically challenging (Table).1-3 The patient in this case presented with dysphagia, a common symptom found in patients with both diseases, and was initially misdiagnosed with GERD. The prevalence of EoE is significantly lower than that of other esophageal diseases, occurring in 57 per 100,000 people.4 The lower prevalence and the nonspecific symptoms associated with EoE may contribute to its frequent misdiagnosis. TABLE. Comparison of EoE vs GERD1-3 Eosinophilic Esophagitis
Age of onset
Infancy, early adulthood
Dysphagia, heartburn, chest pain, odynophagia, vomiting
Heartburn, reflux, dysphagia, chest pain, nausea, abdominal pain
White exudates, longitudinal furrows, fixed rings, edema, strictures
Normal tissue, erythema, erosions, ulcers, strictures
Diet modification, inhaled corticosteroids (swallowed), PPIs
Antacids, diet modification, H2 receptor blockers, lifestyle modifications, PPIs
Strictures, food impactions, “crepe paper esophagus”
Barrett esophagus, esophageal adenocarcinoma
EoE, eosinophilic esophagitis; GERD, gastroesophageal reflux disease; H2, histamine; hpf, high-power field; PPI, proton pump inhibitor
22 THE CLINICAL ADVISOR • MAY/JUNE 2021 • www.ClinicalAdvisor.com
The diagnosis of EoE is based on clinical presentation, histological findings, and the exclusion of other gastrointestinal diseases.3 The diagnosis of EoE should be considered in patients presenting with clinical symptoms of esophageal dysfunction, such as dysphagia, heartburn, chest pain, strictures, and food impactions, and an EGD should be considered to view the mucosa and collect multiple biopsies. In patients with EoE, these biopsies commonly will reveal eosinophilia with 15 or more eosinophils per high-power field (hpf).1,3 Patients with suspected EoE should be given a trial of high-dose PPIs for 8 to 12 weeks followed by repeat EGD. If the patient is still symptomatic and biopsies reveal more than 15 eosinophils per hpf, then a diagnosis of EoE can be established.3 If both symptoms and esophageal eosinophilia improve after the PPI trial, then other disorders such as GERD or PPI-responsive esophageal eosinophilia (PPI-REE) should be considered. Differentiating EoE From PPI-REE
Proton pump inhibitor-responsive esophageal eosinophilia is a relatively new disorder that is genetically and phenotypically indistinguishable from EoE.5,6 Although PPI-REE can be clinically and histologically identical to EoE, patients with PPI-REE can achieve complete remission after high dose-PPI therapy.3 Given the similarities between EoE and PPI-REE, it is important that all patients with suspected EoE be given a PPI trial to rule out PPI-REE. Patients with PPI-REE should continue PPI therapy, tapered down to the lowest possible dose depending on clinical symptoms.5 Follow-up endoscopy should be performed 1 year after diagnosis to ensure continued histological remission.5
and budesonide.6 Although they are not indicated for EoE, corticosteroids are useful in the resolution of EoE symptoms because of their ability to reduce inflammation in the esophagus and suppress eosinophil production.6 Corticosteroids can be prescribed in a liquid or nebulized form. Nebulized corticosteroids are puffed into the mouth and swallowed, not inhaled, to coat the entire esophagus. Educating patients about how to appropriately use these medications is vital to ensure therapeutic efficacy. It also is necessary to inform patients about the possible side effects of swallowed steroid therapy, such as dry mouth, local candida infections, adrenal axis suppression, glaucoma, and bone demineralization.6 Along with diet modification, this patient was prescribed a daily PPI for the management of EoE. Although PPIs are not considered first-line therapy, they may be prescribed for symptomatic treatment. These medications can help reduce acid production, providing relief from heartburn, regurgitation, and dysphagia.6 Although PPIs are helpful in the resolution of these symptoms, they are also effective in treating the underlying inflammatory process and can be used as monotherapy.4 In some cases, patients with EoE can suffer from esophageal strictures and food impactions. Esophageal dilation is used for the immediate relief of symptoms in these patients.1 Understanding when dilation should be performed is an important aspect of managing patients with EoE.8 ■ Karmen Elsen, MPA, PA-C, works in the Digestive Health Center at Augusta University in Augusta, Georgia. References 1. Merves J, Muir A, Chandramouleeswaran PM, Cianferoni A, Wang ML, Spergel
Referral for Allergy Testing in EoE
JM. Eosinophilic esophagitis. Ann Allergy Asthma Immunol. 2014;112(5):397-403.
Once a diagnosis of EoE has been established, patients should be referred to an allergist for testing and determination of food allergens.1 When food triggers are identified and removed from the diet, patients should experience an improvement of symptoms.1 Common diet modifications include the targeted elimination and empiric 6-food elimination diets.1 The targeted elimination diet uses skin patch testing to determine which foods need to be removed from the diet.The empiric 6-food elimination diet focuses on eliminating major food allergens, such as milk, eggs, wheat, soy, peanut and tree nuts, and all seafood, from the diet.7 Although both of these dietary modification strategies are very effective, it is important that providers ensure that patients adhere to the diet.The patient in this case was prescribed a targeted elimination diet but experienced a recurrence of symptoms due to nonadherence. For patients who are nonadherent or whose symptoms are not well controlled with diet alone, providers should consider initiating corticosteroid therapy, such as fluticasone
2. Park H. An overview of eosinophilic esophagitis. Gut Liver. 2014;8(6):590-597. 3. Kia L, Hirano I. Distinguishing GERD from eosinophilic oesophagitis: concepts and controversies. Nat Rev Gastroenterol Hepatol. 2015;12(7):379-386. 4. Dellon ES, Jensen ET, Martin CF, Shaheen NJ, Kappelman MD. Prevalence of eosinophilic esophagitis in the United States. Clin Gastroenterol Hepatol. 2014;12(4):589-596.e1. 5. Molina-Infante J, Rodriguez-Sanchez J, Martinek J, et al. Long-term loss of response in proton pump inhibitor-responsive esophageal eosinophilia is uncommon and influenced by CYP2C19 genotype and rhinoconjunctivitis. Am J Gastroenterol. 2015;110(11):1567-1575. 6. Furuta GT, Katzka DA. Eosinophilic esophagitis. N Engl J Med. 2015;373(17):1640-1648. 7. Greenhawt M, Aceves S. Non-IgE medicated food allergy: eosinophilic esophagitis update on the pathogenesis, clinical features, and management of eosinophilic esophagitis in children. Curr Pediatr Rep. 2014;2(2):127-134. 8. Al-Hussaini A. Savary dilation is safe and effective treatment for esophageal narrowing related to pediatric eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2016;63(5):474-480.
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY/JUNE 2021 23
FEATURE: KRISTEN GRIPPE, MPAS, PA-C; ELISABETH DUER, MPAS, PA-C
Breast Implant-Associated Anaplastic Large Cell Lymphoma: An Update The occurrence rate of BIA-ALCL following breast augmentation with textured implants is variable, ranging from 1 in 355 to 1 in 86,029 patients.
© PDSN / MEDICALIMAGES.COM
Almost 300,000 breast implant surgeries were performed in 2019.
28 THE CLINICAL ADVISOR • MAY/JUNE 2021 • www.ClinicalAdvisor.com
n estimated 1.5 million breast augmentation surgeries are performed worldwide each year, typically for aesthetic or reconstructive purposes.1 In the United States, breast augmentation surgery ranked as the most commonly performed cosmetic procedure in 2019, with 299,715 surgeries reported.2 Because of the cancellation of elective surgeries during the early months of the COVID-19 pandemic, the number of breast augmentations performed in 2020 decreased to 193,073.3 Recent studies have implicated breast implants in the development of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL).4-6 The first documented case was described in 1997; as of January 5, 2020, the US Food and Drug Administration (FDA) had received a total of 733 global and US medical device reports associated with BIA-ALCL, with 36 of those resulting in death.4,5 Of global cases in which a manufacturer was listed, 90.4% involved an Allergan implant, 7.3% involved Mentor implants, 1.5% involved Sientra implants, and 0.9% involved other manufacturers.6 In February 2019, the FDA issued a “Letter to Health Care Providers” to increase awareness of BIA-ALCL, its clinical presentation, and diagnostic recommendations in order to raise awareness of this potentially fatal condition. On July 24, 2019, the FDA asked Allergan to remove Natrelle BIOCELL textured breast implants and tissue expanders from the market.7
Recent studies have shown variability in the occurrence rates of BIA-ALCL with the reported lifetime risk ranging from 1 in 355 to 1 in 86,029 persons depending on the population and type of textured implant studied.6,8 For implants with a textured outer shell, the risk in the US is estimated at 1 in 30,000 persons.6,8 In general, the number of reported cases has dramatically increased in the past decade as more cases are appropriately identified, although epidemiologic statistics may not be accurate due to underreporting.8,9 Among the medical device reports submitted to the FDA as of January 5, 2020, the median age of BIA-ALCL diagnosis is 52 years (range, 37-83 years); 36% of these cases occurred in the United States.5 BIA-ALCL has predominantly been reported in women, but there have been 3 cases reported in transgender maleto-female individuals who received breast implants.9 Some studies have shown that the majority of cases have occurred in Australia and New Zealand, while the lowest number of cases have occurred in Europe, Brazil, and China. Ethnicity may also play a role in conferring risk as there have been very few cases reported in patients of Scandinavian, Asian, African, and Native American descent.8 Pathophysiology
BIA-ALCL has been classified as a rare, peripheral form of non-Hodgkin T-cell lymphoma.Although the formal etiology is unknown, the risk of developing BIA-ALCL is related to the characteristics of the external surface of the implant: cases reported to the FDA have mostly occurred in women whose implants have a textured outer shell vs a smooth outer shell.5 For those cases that have developed in conjunction with a smooth implant, the patient typically reported a history of previously removed textured implants.The inner fill material of the implant does not appear to confer an independent risk as BIA-ALCL has developed with both saline and siliconefilled implants.5 It is theorized that insertion of a breast implant may trigger an inflammatory response with chronic T-cell stimulation; subsequent cell differentiation then results in malignant cell formation.10 Friction generated by the natural movement of textured implants within their surrounding fibrous capsules may contribute to this chronic inflammation.11 In addition, Pseudomonas aeruginosa and Ralstonia pickettii have been found on the surface of implants, demonstrating the potential for implants to chronically harbor bacteria that may cause further recruitment of lymphocytes, particularly CD4+ and CD30+ T cells.9,12,13 In‐vitro bacterial attachment studies show a linear relationship between surface area/roughness and bacterial attachment/growth, supporting the hypothesis that
the uneven surfaces of textured implants are more conducive to bacterial growth.10,13 In an editorial, Santanelli di Pompeo et al have noted the possibility of genetic susceptibility, but chronic inflammation and infection remain the most widely accepted causes of BIA-ALCL.11 Clinical Presentation
BIA-ALCL typically develops approximately 8 to 13 years after the implant is inserted.7,14,15 The most common presentation is a unilateral malignant effusion containing liquefied lymphoma cells and high protein levels. In most cases, the lymphoma cells are contained within the fibrous capsule that forms around the implant (Figure), although approximately 5% of reported cases have shown bilateral effusion.16-18 The effusion frequently causes the affected breast to become edematous with or without associated pain. A solid tumor occurs in about 30% of cases, with or without effusion, and is palpable along the contour of the implant by the patient.16 Skin induration or rashes overlying the effusion may occur but are not common. Other reported signs include axillary or infraclavicular lymphadenopathy, or contractures of the fibrous capsule surrounding the affected implant with associated distortion of the overlying breast shape.12,16 A minimal number of cases have been diagnosed incidentally during an unrelated breast surgery and were asymptomatic or presented with small effusions.16 Differential Diagnosis
Implant rupture must be ruled out in the presence of a large fluid effusion surrounding the implant. Effusions that develop within 1 year of surgery may indicate a postsurgical hematoma or effusion, but periprosthetic fluid collection that
© LETTER H, ET AL. CUREUS. 2016;8(3):E546.
FIGURE. Axial MRI T2-weighted image demonstrating a large fluid collection (red arrows) surrounding an intact right breast implant capsule (blue arrow).
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY/JUNE 2021 29
WOMEN’S HEALTH: BREAST IMPLANT-RELATED COMPLICATIONS
Breast implant-associated anaplastic large cell lymphoma typically develops approximately 8 to 13 years after the implant is inserted. has developed more than 1 year after surgery may indicate BIA-ALCL.16 BIA-ALCL can typically be differentiated from other breast masses based on physical examination and history of breast augmentation surgery. Fibrocystic breast disease may present with multiple bilateral round or rope-like masses that fluctuate in size with hormonal stimulation associated with menstrual cycles. Primary breast malignancies tend to present as a hard irregularly shaped mass, nipple retraction, or bloody nipple discharge. Diagnosis
Initial diagnostic testing could include imaging such as ultrasound or magnetic resonance imaging (MRI) of the affected breast and ipsilateral axilla to assess for effusion and lymphadenopathy.19 Mammography has not been shown to be superior to ultrasound or MRI.16,19 If fluid is found, a fine needle aspiration (>50 mL) should be performed to collect a sample for cytologic pathology.16,19 Likewise, fluid can be collected during a capsulectomy procedure. Cells that have invaded the surface of the capsule, breast parenchyma, or regional lymph nodes can be collected for tissue sampling. On cytology analysis, the cells will appear as large, pleomorphic cells with large nuclei and an increased amount of cytoplasm.9 All ALCL lymphomas, including BIA-ALCL, can usually be distinguished by the presence of “hallmark” cells, which are cells with horseshoe-shaped nuclei.9
POLL POSITION Which of the following is not linked to the etiology of BIA-ALCL? ■ Implant with textured outer shell ■ Bacterial infection within the implant ■ Chronic friction related to implant
12% 34% 41% 13%
■ Silicone-filled implant
A key differentiating factor between BIA-ALCL and other forms of non-Hodgkin lymphoma is that BIA-ALCL is negative for anaplastic lymphoma kinase (ALK), while most other forms of non-Hodgkin lymphoma are ALK-positive.9 The most common marker for BIA-ALCL is an increased CD30 count, often with CD43 and CD4 elevated as well, which can be noted with immunophenotyping.9 Other markers expressed with BIA-ALCL include T-cell intracellular antigen 1 (TIA-1), granzyme B, and epithelial membrane antigen.20 In addition, BIA-ALCL will not have Reed-Sternberg cells, which are pathognomonic for Hodgkin lymphoma.9 Treatment
Once BIA-ALCL is diagnosed, the recommended treatment is to remove the implant with a total capsulectomy and removal of any associated solid tumors.19 In a total capsulectomy, both the implant and the entire surrounding fibrous capsule are removed to help prevent reoccurrence or continued symptomatology. Removal of the contralateral implant should also be strongly considered.21 A study by Clemens et al demonstrated that in the absence of a tumor mass, total capsulectomy resulted in complete remission in 93% of cases at 3 years.21 Cases of reoccurrence or metastasis are most commonly related to an incomplete or partial capsulectomy. In uncomplicated cases, surgery is the only treatment indicated. If the disease has metastasized to regional lymph nodes, chemotherapy treatment is warranted in the form of CHOP, which includes cyclophosphamide, doxorubicin, vincristine, and prednisone.17,22 Radiation therapy may also be considered as adjuvant treatment. Total mastectomy is not required as the lymphoma cells do not invade the surrounding breast tissue.23 The Ann Arbor staging system is utilized to predict lymphoma disease prognosis. As BIA-ALCL typically remains contained to the surrounding fibrous capsule, about 85% of cases are staged as IE.23 About 15% of cases will indicate spread beyond the fibrous capsule into regional lymph nodes and will be staged as IIE.23 It is very rare for the disease to spread outside of the regional lymph nodes. If the disease is confined to the capsule and appropriately excised, the 5-year survival rate is approximately 90%.17 An updated staging system for malignant lymphoma based on Lugano classification also is available.24 Conclusion
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Nurse practitioners and physician assistants working in aesthetic or reconstructive surgical specialties should educate patients Continues on page 32
30 THE CLINICAL ADVISOR • MAY/JUNE 2021 • www.ClinicalAdvisor.com
WOMEN’S HEALTH: BREAST IMPLANT-RELATED COMPLICATIONS
Initial diagnostic testing could include imaging such as ultrasound or MRI of the affected breast and ipsilateral axilla to detect effusions. about BIA-ALCL during presurgical counseling sessions and incorporate this risk into shared decision-making when selecting implant type. The cause of BIA-ALCL appears to be multifactorial; more research should be done to confirm true incidence rates and explore possible pathways of development. It is prudent to continue recommending against textured implants and to investigate any case of breast edema or effusion occurring in relation to implant insertion as the prognosis is most favorable with early and complete surgical intervention. ■
8. Collett D, Rakhorst H, Lennox P, Magnusson M, Cooter R, Deva A. Current risk estimate of breast-implant associated anaplastic large cell lymphoma in textured breast implants. Plast Reconstr Surg. 2019;143(Suppl 3):30S-40S. 9. de Leval L. Breast implant-associated anaplastic large cell lymphoma and other rare T-cell lymphomas. Hematol Oncol. 2019;37(Suppl 1):24-29. 10. Turner S, Inghirami G, Miranda R, Kadin M. Cell of origin and immunologic events in the pathogenesis of breast-implant associated large-cell lymphoma. Am J Pathol. 2020;190(1):2-10. 11. Santanelli di Pompeo F, Sorotos M. EURAPS editorial: BIA-ALCL, a brief overview. J Plast Reconstr Aesthet Surg. 2018;71(6):785-787. 12. Ramos-Gallardo G, Cuenca-Pardo J, Rodríguez-Olivares E, et al. Breast
Kristen Grippe, MPAS, PA-C, is an associate professor in the Physician Assistant Department at Gannon University in Erie and works at Spartansburg Medical Center in Spartansburg, Pennsylvania. Elisabeth Duer, MPAS, PA-C, currently works at Rehabilitation and Fitness Consultants, PLLC, and at AdventHealth Altamonte Springs Hospital in Florida.
implant and anaplastic large cell lymphoma meta-analysis. J Invest Surg. 2017;30(1):56-65. 13. Jones P, Mempin M, Hu H, et al. The functional influence of breast implant outer shell morphology on bacterial attachment and growth. Plast Reconstr Surg. 2018;142(4):837-849. 14. Ghione P, Cordeiro PG, Ni A, et al. Risk of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) in a cohort of 3546 women
prospectively followed after receiving textured breast implants. Hematol
1. Cook JA, Sasor SE, Tholpady SS, Chu MW, Momeni A. Complexity of health
news reporting on breast implant‐associated anaplastic large cell lymphoma.
15. de Boer M, van Leeuwen FE, Hauptmann M, et al. Breast implants and the risk
Breast J. 2019;25(1):163-165.
of anaplastic large-cell lymphoma in the breast. JAMA Oncol. 2018;4(3):335-3341.
2. American Society of Plastic Surgeons. 2019 national plastic surgery statis-
16. Quesada A, Medeiros LJ, Clemens MW, Ferrufino-Schmidt MC, Pino-
tics. Published 2019. Accessed February 25, 2021.https://www.plasticsurgery.
Oviedo S, Miranda RN. Breast implant-associated anaplastic large-cell lym-
phoma: a review. Mod Pathol. 2019;32(2):166-188.
3. American Society of Plastic Surgeons. 2020 national plastic surgery
17. Clemens M, Jacobsen E, Horwitz S. 2019 NCCN consensus guidelines
statistics. Published 2019. Accessed May 3, 2021. https://www.plasticsurgery.
on the diagnosis and treatment of breast implant-associated anaplastic large-
cell lymphoma (BIA-ALCL). Aesthet Surg J. 2019;39(Suppl 1):S3-S13.
4. Swerdlow SH, Campo E, Pileri S, et al. The 2016 revision of the
18. Letter H, Rop B, Edison MN, Turner P. Breast implant-associated anaplastic
World Health Organization classification of lymphoid neoplasms. Blood.
large cell lymphoma: a case report and literature review. Cureus. 2016;8(3):e546.
19. Kricheldorff J, Fallenberg EM, Solbach C, Gerber-Schäfer C, Rancsó C,
5. US Food and Drug Administration. Medical device reports of breast
von Fritschen U. Breast implant-associated lymphoma. Dtsch Arztebl Int.
implant-associated anaplastic large cell lymphoma. Published July 24, 2019.
Accessed February 25, 2021. https://www.fda.gov/medical-devices/breast-
20. Dashevsky BZ, Gallagher KM, Grabenstetter A, et al. breast implant‐
associated anaplastic large-cell lymphoma: clinical and imaging findings at a
large US cancer center. Breast J. 2019;25(1):69-74.
6. Clemens M. BIA-ALCL resources: by the numbers, and what they mean.
21. Clemens MW, Medeiros LJ, Butler CE, et al. Complete surgical excision
American Society of Plastic Surgeons. Published February 24, 2020. Accessed
is essential for the management of patients with breast implant-associated
February 25, 2021. https://www.plasticsurgery.org/for-medical-professionals/
anaplastic large-cell lymphoma. J Clin Oncol. 2016;34(2):160-168.
22. Hallquist Viale P. Breast implants and lymphoma: what is the risk for your
7. US Food and Drug Administration. The FDA requests Allergan voluntarily
patient? J Adv Pract Oncol. 2017;8(6):565-567.
recall Natrelle BIOCELL textured breast implants and tissue expanders from
23. DePaola NE, Coggins H. Breast implant-associated large-cell lymphoma:
the market to protect patients: FDA safety communication. Published July 24,
what we know. J Adv Pract Oncol. 2019;10(1):54-61.
2019. Updated June 1, 2020. Accessed February 25, 2021. https://www.fda.
24. Munakata W, Terauchi T, Maruyama D, Nagai H. Revised staging system
for malignant lymphoma based on the Lugano classification. J Clin Oncol.
32 THE CLINICAL ADVISOR • MAY/JUNE 2021 • www.ClinicalAdvisor.com
FEATURE: CHRISTIAN LYLE, PA-C
Alcohol Withdrawal: Individualized Care and Pharmacologic Treatment More than 50% of patients with alcohol use disorder develop alcohol withdrawal symptoms within hours of discontinuing alcohol use.
© TOMMASO79 / GETTY IMAGES
Alcohol withdrawal occurs within 12 hours of last drink.
lcohol use disorder (AUD) is a leading risk factor for premature death and disability in the US and worldwide.1,2 In the US, nearly 15 million people aged 12 years and older had AUD in 2019 and excessive alcohol use is responsible for approximately 95,000 deaths per year.1,3 Previously described as separate disorders in the Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV), the DSM-5 combines symptoms of both alcohol dependence and alcohol abuse into 1 disorder — AUD — and classifies the disorder as mild, moderate, or severe.2,4,5 Providing individualized care to patients with AUD who seek treatment is challenging. Patients with a history of heavy drinking for a prolonged period who significantly reduce their alcohol consumption or abruptly stop drinking can develop alcohol withdrawal syndrome. This typically occurs within 4 to 12 hours of the last drink with symptoms lasting for up to 5 days.2 More than 50% of patients with AUD develop alcohol withdrawal symptoms when discontinuing or decreasing alcohol use.6 Symptoms of alcohol withdrawal range from anxiety, agitation, tremor, insomnia, nausea, and hallucinations to potentially life-threatening seizures and delirium tremens (DTs; Table 1, page 34).2,5-8 In patients with unsuspected or untreated DTs, mortality rates are reported to be up to 37%.6 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY/JUNE 2021 33
ALCOHOL USE DISORDER
Cessation of or reduction in prolonged, heavy alcohol use Development of ≥2 of the following symptoms within hours or days of alcohol use cessation or reduction: • Autonomic hyperactivity (sweating or pulse rate >100 bpm) • Increased hand tremor • Insomnia • Nausea or vomiting • Transient visual, tactile, or auditory hallucinations or illusions • Psychomotor agitation • Anxiety • Generalized tonic-clonic seizures Signs or symptoms above cause clinically significant distress or impairment in social, occupation, or other important areas of functioning Signs or symptoms above are not attributed to or better explained by another medical condition or mental disorder such as intoxication or withdrawal from another substance bpm, beats per minute
Pathophysiology of Alcohol Withdrawal Syndrome
The effects of alcohol on the central nervous system are linked to the gamma-aminobutyric acid (GABA)-chloride channel receptor complex.9,10 GABA is the main inhibitory neurotransmitter and glutamate is the primary excitatory neurotransmitter in the brain.10,11 The GABA receptor is a pentameric protein, comprised of 5 subunits – 2 alpha, 2 beta, and 1 gamma (Figure).10 In between the alpha and beta subunits lies the binding site for GABA.9,10 Ethanol readily binds to the receptors on the GABA protein complex because of its high affinity for ethanol.12 As a positive allosteric modulator, alcohol acts as a central nervous system depressant because of its inhibitory effect on N-methyl-D-aspartate (NMDA) receptors leading to sedative and anxiolytic effects.9,11 Alcohol withdrawal causes a significant decrease in GABA levels, which subsequently causes a hyperactive response in the nervous system.11 Withdrawal also causes activation of glutamate, which enhances the function of the NMDA receptors.11,13,14 Detecting Alcohol Withdrawal Syndrome
The American Society of Addiction Medicine (ASAM) recommends universal screening for unhealthy alcohol use in medical settings using validated scales to help identify patients with or at risk for AUD and alcohol withdrawal.8
Some of the screening questionnaires for AUD that can be used in both the inpatient and outpatient setting include the following11,15: • Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) • Cut-Down, Annoyed, Guilty, and Eye-Opener (CAGE) • Munich Alcoholism Test (MALT) Alcohol dependence should be considered in women who report more than 1 drink daily or more than 7 drinks per week, and in men who average more than 2 drinks daily or more than 14 drinks per week.16,17 Patients’ average daily and/or weekly alcohol intake, history of previous cessation attempts, history of previous alcohol withdrawals, presence of concurrent medical or psychiatric conditions, and concurrent drug abuse should be taken into consideration as clinicians assess for the presence of withdrawal symptoms.17 The Clinical Institute Withdrawal Assessment for Alcoholrevised (CIWA-Ar) is a 10-item assessment tool that can evaluate the presence of withdrawal symptoms, quantify the severity of symptoms, and individualize treatment selection (Table 2).11,18 Each item is evaluated independently, with all components then aggregated to yield a score correlating with the severity of alcohol withdrawal.11 Each component is scored on a scale from 0 to 7, except for orientation and sensorium, which is scored from 0 to 4. In patients who score less than 8, the presence of alcohol withdrawal symptoms is suggested to be absent or minimal. Patients scoring 8 to 20 are noted to be in mild to moderate withdrawal, and those scoring greater than 20 are considered to be experiencing severe withdrawal symptoms. Patients with scores of 10 or less typically do not need pharmacologic treatment.18
alpha subunit beta subunit gamma subunit
Benzodiazepine binding site extracellular domain
GABA binding site
GABA binding site
FIGURE. Subunits of the GABA receptor.10
34 THE CLINICAL ADVISOR • MAY/JUNE 2021 • www.ClinicalAdvisor.com
© 2019 KERI LEIGH JONES
TABLE 1. DSM-5 Criteria for Alcohol Withdrawal Syndrome5,8
TABLE 2. Components of the CIWA-Ar11,18
because of their effectiveness in reducing the signs and symptoms of withdrawal, such as the incidence of seizure and delirium.8
Nausea and vomiting (0-7)
Tactile disturbances (0-7)
Auditory disturbances (0-7)
Paroxysmal sweats (0-7)
Visual disturbances (0-7)
Orientation and clouding of sensorium (0-4)
Scorea: <8: Very mild withdrawal; 8-14: Mild withdrawal; 15-20: Modest withdrawal; ≥20 Severe withdrawal a
Mild Symptoms For patients experiencing mild withdrawal symptoms (eg, CIWA-Ar score <8) who are at minimal risk of developing severe symptoms or complications of alcohol withdrawal, the ASAM recommends treatment with pharmacotherapy or supportive care alone. Carbamazepine or gabapentin are appropriate pharmacologic treatments for mild symptoms. For patients with mild symptoms who are at risk of developing new or worsening withdrawal while away from the treatment setting, the ASAM recommends use of benzodiazepines, carbamazepine, or gabapentin.8
Interpretation of cutoff scores for mild, modest, and severe vary by source.
Other scales that can be used to assess for the risk for severe alcohol withdrawal include8: • Luebeck Alcohol-Withdrawal Risk Scale (LARS) • Prediction of Alcohol Withdrawal Severity Scale (PAWSS) Although data collected from these assessments are extremely helpful in detection of alcohol withdrawal symptoms, the screening tools should be used as supportive measures in combination with the clinical picture as provided by a detailed history and thorough physical examination. Additionally, laboratory investigations such as urine drug screening, liver functions tests, blood alcohol levels, electrolyte levels, and a complete blood count are mainstays for establishing a diagnosis.17 Treatment Setting
The treatment setting is primarily determined by the severity of the withdrawal symptoms present.11 In patients presenting with mild to moderate withdrawal, outpatient detoxification is considered safe and effective.11,17 Although outpatient followup recommendations include seeing the patient daily until symptoms subside, treatment in this environment is cost effective, less burdensome on acute care hospitals, and minimizes interruptions on the patient’s personal life.11,17 An inpatient setting is warranted for patients who experience seizures or DTs or have severe withdrawal symptoms, abnormal laboratory results, or chronic medical or psychiatric conditions.8,17 Management of Alcohol Withdrawal Syndrome
Patients at risk of developing alcohol withdrawal syndrome (AWS) may be provided with preventative pharmacotherapy with benzodiazepines when attempting to reduce or stop alcohol intake, according to the 2020 ASAM guidelines on AWS. Benzodiazepines are first-line treatment for AWS prophylaxis
Moderate Symptoms Patients with moderate symptoms (eg, CIWA-Ar scores 8-20) should be treated with pharmacotherapy with benzodiazepines being the first-line treatment; carbamazepine or gabapentin are appropriate alternative therapies. Benzodiazepine may be used in combination with carbamazepine, gabapentin, or valproic acid (in patients without liver disease or childbearing potential).8 Severe Symptoms Patients with severe, but not complicated, withdrawal symptoms (eg, CIWA-Ar ≥20) should be treated with benzodiazepines or, as an alternative, phenobarbital (only use if the clinician is experienced with its use). Other options for patients with contraindications to benzodiazepine use include carbamazepine or gabapentin. Adjunctive agents may be used (eg, carbamazepine, gabapentin, and valproic acid).8 Risk for prolonged benzodiazepine use and misuse include memory impairment, psychomotor retardation, depression, and emotional anesthesia in addition to physiologic dependence.17 Because of the high addiction risk, alternative agents such as carbamazepine and gabapentin have less abuse potential, less toxicity, less sedation, and have demonstrated efficacy in the treatment of alcohol withdrawal syndrome.8 For ongoing management of AUD, the Department of Veterans Affairs and the Department of Defense recommends use of acamprosate, disulfiram, naltrexone (extended release), and/or topiramate (off-label) for the initial management of AUD.19 The American Psychiatric Association recommends first-line treatment of AUD with acamprosate and naltrexone, and use of disulfiram, gabapentin (off-label), and topiramate as second-line options.20 Gabapentin is beneficial for treating withdrawal symptoms in patients who will benefit from ongoing gabapentin use for treatment of AUD, according to the ASAM. Gabapentin (an
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ALCOHOL USE DISORDER
analog of GABA) is not thought to modulate GABA receptors. Rather it is believed to enhance GABA activity or convert to GABA itself. 21 Gabapentin is believed to normalize stressinduced GABA activation in the brain that is associated with alcohol dependence.22 Adjunctive therapies with supplemental thiamine, folate, and IV fluids are useful in correcting nutritional and electrolyte abnormalities associated with alcohol withdrawal syndrome symptoms. Folic acid 1 mg daily is recommended and thiamine 100 mg daily is shown to lower the risk of Wernicke encephalopathy.
Between DSM-IV and DSM-5 (NIH Publication No. 13-7999). Retrieved from https://www.niaaa.nih.gov/sites/default/files/publications/DSMfact.pdf 5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013. 6. Rahman A, Paul M. Delirium tremens (DT). In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Updated November 18, 2018. Accessed April 29, 2021. https://www.ncbi.nlm.nih.gov/books/NBK482134/ 7. Martin CS, Vergés A, Langenbucher JW, et al. Algorithm analysis of the DSM-5 alcohol withdrawal symptom. Alcohol Clin Exp Res. 2018;42(6):1073-1083. 8. American Society of Addiction Medicine. Clinical practice guideline on
alcohol withdrawal management. January 23, 2020. https://www.asam.org/
The approach to monitoring during treatment should be individualized to each patient and influenced by symptom severity. Most patients are evaluated daily until symptoms begin to decrease and medication dose is reduced.11 The method or tool used to initially evaluate symptoms and their severity should be consistently used throughout follow-up. Although each patient’s road to recovery is different, symptoms should begin to resolve within a week. Upon completion of treatment, a patient may need to be referred to a long-term outpatient facility, addiction specialist, or inpatient treatment facility for AUD.
docs/default-source/quality-science/the_asam_clinical_practice_guideline_on_ alcohol-1.pdf?sfvrsn=ba255c2_2 9. Zorumski CF, Isenberg KE. Insights into the structure and function of GABA-benzodiazepine receptors: ion channels and psychiatry. Am J Psychiatry. 1991;148(2):162-173. 10. Sigel E, Steinmann ME. Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012;287(48):40224-40231. 11. DeSimone E, Tilleman J, Powell T. Treatment of alcohol withdrawal syndrome. US Pharm. 2014;39(11):38-41. 12. Mihic SJ, Ye Q, Wick MJ, et al. Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors. Nature. 1997;389(6649):385-389.
The ASAM recommends use of pharmacologic agents for patients at risk of developing severe or complicated withdrawal symptoms as well as those with at least moderate alcohol withdrawal. Patient education on the benefits and risks of each therapy is essential to providing informed consent and shared decision-making. ■
13. Hoffman P, Grant K, Snell L, et. al. NMDA receptors: role in ethanol withdrawal seizures. Ann N Y Acad Sci. 1992;654:52-60. 14. Tsai G, Gastfriend DR, Coyle JT. The glutamatergic basis of human alcoholism. Am J Psychiatry. 1995;152(3):332-340. 15. Feuerlein W, Ringer C, Küfner H, Antons K. Diagnosis of alcoholism: the Munich Alcoholism Test (MALT). Curr Alcohol. 1979;7:137-147. 16. US Department of Agriculture and US Department of Health and Human Services. Dietary Guidelines for Americans, 2020-2025. 9th ed.
Christian Lyle, PA-C, graduated from August University physician assistant program in 2020 and is working in gastroenterology in her hometown of Savannah, Georgia.
December 2020. 17. Muncie HL Jr, Yasinian Y, Oge’ L. Outpatient management of alcohol withdrawal syndrome. Am Fam Physician. 2013;88(9):589-595. 18. Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment
of alcohol withdrawal: the revised clinical institute withdrawal assessment for
1. Excessive alcohol use. Centers for Disease Control and Prevention.
alcohol scale (CIWA-Ar). Br J Addict. 1989;84(11):1353-1357.
Updated September 21, 2020. Accessed April 27, 2021.
19. Department of Veteran Affairs. Va/DoD Clinical Practice Guideline for the
Management of Substance Use Disorders. Department of Veteran Affairs;
December 2015. Accessed April 29, 2021. https://www.healthquality.va.gov/
2. Mason BJ, Quello S, Shadan F. Gabapentin for the treatment of alcohol use
disorder. Expert Opin Investig Drugs. 2018;27(1):113-124.
20. American Psychiatric Association. American Psychiatric Association Practice
3. SAMHSA, Center for Behavioral Health Statistics and Quality. 2019
Guideline for the Pharmacological Treatment of Patients With Alcohol Use
National Survey on Drug Use and Health. Table 5.4B – alcohol use
Disorder. American Psychiatric Association; 2018. Accessed April 29, 2021.
disorder in past year among persons aged 12 or older, by age group and
demographic characteristics: percentages, 2018 and 2019. Accessed April
21. Rey, JA. Anxiolytic and hypnotic drugs. In: Lippincotts illustrated reviews:
27, 2021. https://www.samhsa.gov/data/sites/default/files/reports/rpt29394/
Pharmacology, 6th ed. Wolters Kluwer; 2015:121-123.
22. Mason BJ, Quello S, Goodell V, Shadan F, Kyle M, Begovic A. Gabapentin
4. US Department of Health and Human Services, National Institute on
treatment for alcohol dependence: a randomized clinical trial. JAMA Intern
Alcohol Abuse and Alcoholism. (2016). Alcohol Use Disorder: Comparison
36 THE CLINICAL ADVISOR • MAY/JUNE 2021 • www.ClinicalAdvisor.com
Dermatology Clinic CASE #1
Circular Lesions on Hands and Arms TEJAS JOSHI, BS;TARA L. BRAUN, MD; CHRISTOPHER RIZK, MD
A 61-year-old man presents with a 7-month history of lesions on his hands and arms. His medical history includes depression, hypertension, and hyperlipidemia. He has no personal or family history of skin problems. His skin lesions are not painful or itchy, and he is not bothered by their appearance. He has not tried any treatments for the lesions. Physical examination reveals a number of pink, annular plaques with smooth raised borders on the patient’s dorsal forearms and hands. On close inspection, small discrete papules are seen within the plaques. What is your diagnosis? Turn to page 38
Red Lesions on Arms and Flank TIFFANEY TRAN, BS;TARA BRAUN, MD; MUNEEZA MUHAMMAD, MD; CHRISTOPHER RIZK, MD
A 33-year-old Black man presents to a dermatology clinic with a 5-month history of asymptomatic lesions on his arms and trunk. He is otherwise healthy with no personal or family history of skin disease. He has no history of fevers, cough, shortness of breath, or joint pain.The patient has not tried any treatments for these lesions. On examination, there are several smooth, well-demarcated hypopigmented plaques on his upper arms and left flank. He has no similar lesions elsewhere on his body. What is your diagnosis? Turn to page 39 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY/JUNE 2021 37
Dermatology Clinic CASE #1
Localized Granuloma Annulare
Localized granuloma annulare (GA) is a common granulomatous skin condition that presents as skin-colored to erythematous papules and plaques. 1 The first case of GA was described in 1895 by English dermatologist Thomas Calcott Fox as a ringed eruption, and the term granuloma annulare was coined in 1902 by Henry Radcliffe Crocker.2 GA is twice as common in women as in men, occurs most commonly in patients younger than 30 years, and displays no racial predilection.1,3 Localized GA is the most common form of GA, accounting for approximately 75% of cases.1 Generalized GA, defined by the presence of 10 or more lesions or widespread plaques, accounts for 8% to 15% of cases.1 Macular/ patch, subcutaneous, and perforating variants of GA also have been described in the literature.1 Although the etiology of GA is unknown, the inciting event is thought to be a type IV delayed hypersensitivity response to an unknown antigen.The granulomatous response is caused by type 1 helper (TH1) cells, which mediate an inflammatory reaction leading to increased levels of tumor necrosis factor-α, interferon-γ, interleukin (IL)-2, and IL-12.4 In addition, increased macrophage activity releases lysozymes that cause matrix degradation.3,4 Generalized GA may be associated with human leukocyte antigen-BW35, although no genetic etiology of localized GA has been reported.3,5 Although the majority of patients with GA are healthy,1 the condition has been linked to several systemic diseases, including thyroid disease, dyslipidemia, and hematologic and solid malignancies.1,3,4,6 Infectious agents (hepatitis B and C viruses, HIV), trauma, insect bites, and vaccinations also have been implicated as inciting factors for GA.1,3 Classically, the lesions of localized GA are arranged in an annular configuration on the dorsal hands or feet.7 Lesions are limited to the arms and dorsal hands in 60% of GA cases and to the legs and dorsal feet in 20% of cases. Involvement of both the upper and lower extremities, trunk, and other body areas is less common.3 The lesions present as papules or plaques with smooth, raised borders up to 5 cm in diameter.7 Upon closer inspection, these lesions are made up of individual small papules several millimeters in diameter.3 GA generally is asymptomatic, but mild pruritus is present in some cases.7 Histologically, GA is characterized by palisading granulomas around a focal region of collagen degradation as well as
perivascular and interstitial lymphocytes and histiocytes.The presence of mucin is an important hallmark of GA.3,8 GA is diagnosed clinically and histologically; no laboratory test aids in diagnosis.3 Dermoscopic findings of GA are variable but commonly there are whitish regions, which reflect the collagen degradation and mucin deposition seen in GA, as well as yellowish-orange regions and unfocused vascular structures.9 The differential diagnosis for GA includes sarcoidosis, necrobiosis lipoidica, tinea corporis, leprosy, mycosis fungoides, and annular elastolytic giant cell granuloma (AEGCG).3,7 The presence of mucin on histologic examination will rule out sarcoidosis and necrobiosis lipoidica because mucin is absent in
GA is twice as common in women as in men, occurring most commonly in patients younger than 30 years of age. these pathologies.1 Biopsy is also required to definitively rule out mycosis fungoides.3 GA lesions do not display scaling and are not accompanied by vesicles or pustules, which helps distinguish GA from tinea corporis.7 In addition, hyphae will be visualized in a potassium hydroxide preparation of a suspected tinea corporis lesion and not in a GA lesion. Leprosy can be differentiated from GA by the presence of scaling and anesthesia, which are not characteristic of GA.7 If lesions have central hypopigmentation and/or atrophy, the diagnosis of AEGCG is favored.3 Localized GA is a benign, self-limited disease with approximately 50% of cases resolving within 2 years.1 However, up to 40% of cases recur. Reassuring patients about the benign nature of the disease and monitoring them is an appropriate management strategy for many mild cases of localized GA. Patients may seek treatment if lesions are symptomatic or for cosmetic reasons.2,3 Most of the data on treatment of GA is limited to case reports, retrospective studies, and small case series.A lack of conclusive data may be due, in part, to the selflimited nature of the disease, which may make some treatments appear more efficacious than they truly are.6 High-potency topical steroids with or without occlusion are considered first-line therapy for localized disease. Lesions that do not respond to topical steroids can be treated with intralesional corticosteroids.4 Additional local treatment options include cryotherapy and topical tacrolimus.1,3 More extensive disease may be treated with phototherapy or systemic medications (eg, antimalarials, retinoids, biologics, niacinamide).1,3 Our patient was prescribed topical clobetasol, which helped the lesions fade, but he returned a year later with a recurrence.
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He declined treatment for the recurrence because the lesions did not bother him. References 1. Thornsberry LA, English JC. Etiology, diagnosis, and therapeutic management of granuloma annulare: an update. Am J Clin Dermatol. 2013;14(4):279-290. 2. Wang J, Khachemoune A. Granuloma annulare: a focused review of therapeutic options. Am J Clin Dermatol. 2018;19(3):333-344. 3. Rosenbach MA, Wanat KA, Reisenauer A, White KP, Korcheva V, White CR. Non-infectious granulomas. In: Bolognia JL, Schaffer JV, Cerroni L, eds. Dermatology. 4th ed. Elsevier; 2018:1644-1663. 4. Keimig EL. Granuloma annulare. Dermatol Clin. 2015;33(3):315-329. 5. Piette EW, Rosenbach M. Granuloma annulare: clinical and histologic variants, epidemiology, and genetics. J Am Acad Dermatol. 2016;75(3):457-465. 6. Wu W, Robinson-Bostom L, Kokkotou E, Jung HY, Kroumpouzos G. Dyslipidemia in granuloma annulare. Arch Dermatol. 2012;148(10):1131-1136. 7. Hsu S, Le EH, Khoshevis MR. Differential diagnosis of annular lesions. Am Fam Physician. 2001;64(2):289-296. 8. Umbert P, Winkelmann RK. Histologic, ultrastructural and histochemical studies of granuloma annulare. Arch Dermatol. 1977;113(12):1681-1686. 9. Errichetti E, Lallas A, Apalla Z, Di Stefani A, Stinco G. Dermoscopy of granuloma annulare: a clinical and histological correlation study. Dermatology. 2017;233(1):74-79.
Cutaneous sarcoidosis refers to the skin manifestations of sarcoidosis, a chronic granulomatous disorder known to affect the lungs, lymph nodes, and other organs.1 Cutaneous involvement occurs in about one-quarter of patients with sarcoidosis, often as the initial presentation of systemic disease.1 The earliest observation of sarcoidosis is credited to British dermatologist Jonathan Hutchinson, who described painless purple lesions on the skin of a coal wharf worker in 1869.2 A quarter of a century later, Hutchison reported erythematous skin lesions on the face and forearms of a woman with the surname Mortimer and dubbed the skin findings Mortimer’s malady. He noted the absence of ulcerating or crusting in these lesions, which differentiated them from those of tuberculosis or lupus.2 Shortly afterward, in 1897, Norwegian dermatologist Caesar Boeck presented the pathology of nodular lesions resembling Mortimer’s skin findings. Referencing the condition’s sarcoma-like presentation, Boeck referred to the disease
as multiple benign sarkoid of the skin and, therefore, the term sarcoidosis was born.2 The epidemiology of sarcoidosis varies by race, gender, and geographic location with the incidence ranging from 1.4 per 100,000 people in Spain and Japan to 64 per 100,000 in Scandinavia.3,4 In the US, Black individuals are at greater risk for sarcoidosis than White individuals; reported incidences are 35.5 per 100,000 and 10.9 per 100,000 in Black and White individuals, respectively.4 Black patients are also prone to have a more severe disease course marked by rapid progression and higher frequency of relapse.4 Compared with men, women tend to have a slightly greater risk for sarcoidosis across different races and age groups.3,4 The disorder also exhibits a bimodal age distribution, with separate peaks among patients in their 30s and 60s.4 Although extensive research has been conducted on sarcoidosis, its etiology remains elusive. A broad characterization of the disease process is that host factors and infectious and noninfectious environmental factors trigger systemic granulomatous inflammation in genetically susceptible individuals that presents as a heterogeneous group of disorders.5 Potential triggers include infectious agents, such as mycobacteria and Propionibacterium acnes. The role of exposure to various chemicals and metals in the etiology of sarcoidosis also has been debated.5 Sarcoid antigens are presented to CD4+ T cells via major histocompatibility complex class II molecules, leading to a type 1 helper (TH1) cell–predominant immune cascade and granulomatous inflammation in target organs.5 The exact cause of sarcoidosis has yet to be determined, but given the racial predilection and familial clustering of disease, risk factors for sarcoidosis include race, family history, and genetics.5.6 Genome-wide association studies have identified human leukocyte antigen (HLA) alleles associated with higher risk of developing sarcoidosis as well as HLA types linked with sarcoidosis disease course, severity, and organ involvement. For example, HLA DRB1*1501 and HLA DRB3*0101 both have been linked with increased risk for sarcoidosis in White and Black cohorts in the US.6 These genetic findings support the role of aberrant antigen processing and presentation in the pathophysiology of sarcoidosis.6 Specific and nonspecific skin manifestations of sarcoidosis demonstrate significant heterogeneity and may mimic other dermatologic diseases, earning cutaneous sarcoidosis its title as a great imitator.3 Common skin manifestations include papular sarcoidosis, characterized by multiple small macules and papules on the face or neck; plaque sarcoidosis, characterized by erythematous to violaceous plaques on the face, back, buttocks, or extremities; lupus pernio, characterized by indurated red to violaceous plaques on the nose, cheeks, or ears; and scar and tattoo-associated sarcoidosis, in which erythematous papules or nodules appear on scars or tattoos.1,7,8
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Dermatology Clinic Less common manifestations include psoriasiform sarcoidosis, which is characterized by erythematous scaly plaques; hypopigmented sarcoidosis, which is identified by well-demarcated light-colored macules or papules; and Darier-Roussy sarcoidosis, which is characterized by nontender subcutaneous nodules.1,7 Additional rare morphologies may involve ulcerative, erythrodermic, or ichthyosiform lesions.7 Patients also may present with nonspecific lesions such as erythema nodosum (EN), calcinosis cutis, or prurigo.1 Of these, the most common is EN, which is seen more frequently in White patients compared with Black individuals or people of Asian descent.7 EN also may occur as a component of Löfgren syndrome, which is a type of acute sarcoidosis characterized by fever, bilateral hilar lymphadenopathy, arthralgias, and EN.6,7 EN is associated with a favorable prognosis with fewer respiratory symptoms, whereas other skin lesions are associated with more extensive disease.7 The differential diagnosis for cutaneous sarcoidosis includes leprosy, fungal infection, cutaneous lupus, rosacea, psoriasis, and cutaneous malignancy.1 However, because of its highly variable presentation, the diagnosis primarily is formulated according to morphology. For instance, for maculopapular lesions, the physician may additionally consider acne, lichen planus, and benign tumors, and for papulonodular lesions on scars or tattoos, the differential diagnosis also would include hypertrophic and keloid scars.1 The diagnosis of cutaneous sarcoidosis is usually one of exclusion. Serum tests may be useful because elevated antinuclear antibody titers occur in approximately 30% of patients
be performed on specimens to assess for foreign material, but the presence of foreign material does not rule out sarcoidosis.1,9 First-line therapy for cutaneous sarcoidosis consists of topical or intralesional corticosteroids for more limited disease and systemic corticosteroids for more extensive disease or disfiguring lesions.10 Additional nonsteroidal medications used in widespread disease include methotrexate, azathioprine, mycophenolate mofetil, hydroxychloroquine, minocycline, and thalidomide.1,9,10 The tumor necrosis factor inhibitors adalimumab and infliximab also have been used to treat both systemic and cutaneous sarcoidosis.9 Given that cutaneous sarcoidosis may signify systemic disease, chest radiography, pulmonary function tests, ophthalmologic examinations, electrocardiogram, and liver function tests may be warranted to assess for multiorgan involvement.3 In this case, the lesions were biopsied to confirm a diagnosis of hypopigmented cutaneous sarcoidosis. Additional workup for involvement of other organs was negative. He was treated with clobetasol ointment to affected areas twice daily. ■ Tejas Joshi, BS, and Tiffaney Tran, BS, are medical students at Baylor College of Medicine;Tara L. Braun, MD, and Muneeza Muhammad, MD, are residents in the Department of Dermatology at Baylor College of Medicine; and Christopher Rizk, MD, is a dermatologist affiliated with Baylor College of Medicine in Houston,Texas. References 1. Wanat KA, Rosenbach M. Cutaneous sarcoidosis. Clin Chest Med. 2015;36(4):685-702.
Risk factors for sarcoidosis include race, family history, and genetics. Women have a slightly greater risk compared with men.
2. Sharma OP. Sarcoidosis: a historical perspective. Clin Dermatol. 2007;25(3):232-241. 3. Karadag AS, Parish LC. Sarcoidosis: a great imitator. Clin Dermatol. 2019;37(3):240-254. 4. Rybicki BA, Major M, Popovich J, Maliank MJ, Iannuzzi MC. Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization. Am J Epidemiol. 1997;145(3):234-241. 5. Ruocco E, Gambardella A, Langella GG, Lo Schiavo A, Ruocco V. Cutaneous sar
and serum angiotensin-converting enzyme levels are elevated in approximately 60% of patients.9 Diascopy also can be performed on lesions. Applying pressure to the lesion causes blanching and a characteristic yellow-brown “apple jelly” color, although this is easier to appreciate in lighter pigmented skin.9 Skin biopsy can aid in diagnosis, especially in discerning lesions from those of leprosy or lupus.1 The hallmark of cutaneous sarcoidosis is the presence of noncaseating epithelioid granulomas with scant lymphocytes on histologic evaluation. Schaumann bodies or asteroid bodies may be seen.1 When appropriate, stains for acid-fast and fungal organisms should be obtained and tissue culture performed because the histologic differential diagnosis includes multiple infections. Polarization also should
coidos is: an intriguing model of immune dysregulation. Int J Dermatol. 2015;54(1):1-12. 6. Fingerlin TE, Hamzeh N, Maier LA. Genetics of sarcoidosis. Clin Chest Med. 2015;36(4):569-584. 7. Heath CR, David J, Taylor SC. Sarcoidosis: are there differences in your skin of color patients? J Am Acad Dermatol. 2012;66(1):121.e1-121.e14. 8. Sepehri M, Carlsen KH, Serup J. Papular-nodular reactions in black tattoos as markers of sarcoidosis: study of 92 tattoo reactions from a hospital material. Dermatology. 2016;232(6):679-686. 9. Rosenbach MA, Wanat KA, Reisenauer A, White KP, Korcheva V, White CR. Non-infectious granulomas. In: Bolognia JL, Schaffer JV, Cerroni L, eds. Dermatology. 4th ed. Elsevier; 2018:1644-1663. 10. Wijsenbeek MS, Culver DA. Treatment of sarcoidosis. Clin Chest Med. 2015;36(4):751-767.
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Dermatologic Look-Alikes Pruritic Papules During Pregnancy DINA ZAMIL, BS;TARA L. BRAUN, MD; CARLY DUNN, MD; AND CHRISTOPHER RIZK, MD
A 28-year-old woman presents with a 2-day history of a rash on her abdomen. She is 33 weeks pregnant with her first child. The patient has no other medical conditions, has had no recent illnesses, and her pregnancy has been uncomplicated thus far. The rash is very itchy and has been worsening. The patient has not yet tried any treatments for the rash. She denies any recent changes in body washes, lotions, detergents, and other body products. On examination, there are erythematous papules within the abdominal striae, with sparing of the umbilicus.
A 23-year-old Hispanic woman 28 weeks into her second pregnancy presents with a 1-day history of rash.The rash started on her abdomen and is progressing rapidly. She reports having had a blistering rash on her abdomen during her prior pregnancy; the rash was never biopsied. The lesions are extremely itchy. On examination, there are numerous erythematous plaques with small vesicles and erosions within the plaques. Lesions are located on the abdomen, including the periumbilical region, and on the chest, back, and proximal upper and lower extremities.
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Dermatologic Look-Alikes CASE #1
Polymorphic Eruption of Pregnancy
Polymorphic eruption of pregnancy (PEP) is a benign, pruritic self-limiting inflammatory skin condition.1-3 Although the disease was described in 1962 as toxemic rash of pregnancy,4 the first report of PEP often is credited to Thomas J. Lawley, MD, who named the condition pruritic urticarial papules and plaques of pregnancy (PUPPP) in 1979.1,3,5,6 PEP also has been referred to as toxic erythema of pregnancy and late-onset prurigo of pregnancy.3 When a simplified nomenclature system for gestational dermatoses was proposed in 1982, PUPPP became known commonly as PEP.6,7 Estimates for the incidence of PEP range from 1 in 120 to 1 in 200 pregnancies.2,6 Although prevalence estimates range from 0.05% to 0.5% overall, prevalence can be as high as 16% in twin pregnancies and 17% in triplet pregnancies.1,3,6 PEP is more common in White women than in non-White women. It also occurs most commonly in primigravid women in the third trimester, although it can occur after delivery. PEP tends not to recur in subsequent pregnancies.1,3,6 One risk factor linked to PEP is larger belly size, which may explain its association with multiple-gestation pregnancies, increased maternal weight gain, increased newborn birth weight, and male sex of the fetus.1,3,6 One study showed an association between PEP and Rh-positive maternal blood.8 More recently, a case of a pregnant woman with COVID-19 with a clinical presentation consistent with PEP was reported.9 The etiology of PEP is uncertain. It has been suggested that stretching of the abdomen late in pregnancy leads to connective tissue damage; exposure to antigens within collagen could induce an allergic-type reaction that starts within the abdominal striae.1-3 Maternal immune hyperactivity could, thus, predispose some women to PEP.3 Deposition of fetal DNA in skin that causes a graft-vs-host disease state in which fetal lymphocytes attack maternal tissues also is theorized to play a role.1,6 The reaction potentially becomes generalized via cross-reactivity to collagen in normal skin.1 An immune tolerance may prevent PEP from recurring in subsequent gestations.1 Placental factors, human chorionic gonadotropin, sex hormones, high progesterone levels, and increased progesterone receptor immunoreactivity also have been implicated in PEP.1,3 There is no evidence supporting an autoimmune etiology.3 PEP presents predominately on the abdomen, initially within the striae, and characteristically spares the periumbilical region.1
The rash erupts with extremely pruritic erythematous and edematous papules that may coalesce into plaques on the abdomen.The eruption can spread to the extremities, trunk, buttocks, thighs, and back. The majority of patients develop polymorphic features, including annular wheals, target lesions, small vesicles, widespread erythema, and eczematous plaques as PEP progresses.1,3,6 In the early stage of PEP, skin biopsy specimens show edema in the epidermis and upper dermis and a deeper dermal perivascular infiltrate of T-helper lymphocytes, mast cells, neutrophils, and sometimes eosinophils.1,3 Mild focal spongiosis also can be found.1 Biopsies taken from resolving lesions show acanthosis with parakeratosis and hyperkeratosis.1,3 Along blood vessels and the dermal-epidermal junction, histologic studies have found minimal granular deposition of immunoglobulin (Ig)A, complement C3, and IgM.1 However, in most cases, deposits of C3 are not found along the basement membrane of the epidermis, and this can be used to differentiate PEP from pemphigoid gestationis.3
A risk factor for PEP is larger belly size, associated with multiple-gestation pregnancies and increased maternal weight. PEP cannot be diagnosed definitively based on laboratory test results because such findings usually are within normal limits.1,2 Thus, diagnosis is made according to clinical features as well as biopsy, which can be used to exclude similar diseases, especially conditions that may affect the fetus.2,6 Pemphigoid gestationis is the most important diagnosis to rule out because it is associated with premature births and lower birth weights.1,3 Pemphigoid gestationis tends to appear earlier in pregnancy, does not involve striae, involves the umbilicus, and results in positive immunofluorescence of perilesional skin.1,3 Other conditions to rule out include drug-related skin eruptions, urticaria, viral exanthems, and eczematous dermatitis.1,3 Treatment of PEP typically involves topical corticosteroids and oral antihistamines to address symptoms.1-3 In more severe cases with uncontrollable pruritus that may disturb sleep, short courses of systemic corticosteroids can be used. Nonpharmaceutical options for symptomatic relief include cool baths, light cotton clothing, and emollients.1,3 More recently, intramuscular injections of autologous whole blood have shown success in treating postpartum PEP, although limited data support this treatment.1,3 Rarely, cases with especially severe pruritus warrant induction
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Dermatologic Look-Alikes of labor for early delivery.1,3 PEP does not pose a risk to the fetus and usually resolves within 4 weeks after delivery, generally with no scarring or postinflammatory hyperpigmentation.1,2 Our patient was diagnosed clinically with PEP, and her pruritus was well controlled with oral antihistamines and topical steroids.The lesions faded over 3 to 4 weeks, and she had no sequelae from the rash.
Pemphigoid gestationis (PG) is a blistering autoimmune disease of pregnancy resulting from autoantibodies against BP180, a hemidesmosomal dermoepidermal junction protein also known as BPAG 2 or collagen XVII.10-12 In 1872, John Laws Milton, MD, first described the condition, calling it herpes gestationis, a misnomer because the disease is not associated with a herpesvirus.10,13-15 The name was changed later to pemphigoid gestationis to reflect its autoimmune origin.11,14 Incidence estimates for PG vary between 1 in 20,000 to 1 in 60,000 pregnancies.11,16-18 PG occurs throughout the world and although some sources report no racial predilection,16 others describe increased frequency in individuals with lighter skin.18 The median age of onset of affected women is 26 to 32 years.16 Although PG usually occurs in the second or third trimester, it can occur at any point during the pregnancy or postpartum period.10,16,17 Some reports indicate that nearly half of PG cases occur in primigravids,10,17 whereas others describe a greater susceptibility in multiparous women.16,18 Although PG occurs most commonly in pregnant women, it has been diagnosed in women with trophoblastic tumors, such as choriocarcinoma and hydatidiform mole.10,11,17,18 Compared with the general population, patients with PG have increased rates of human leukocyte antigen (HLA)-B8, HLA-DR3, and HLA-DR4 alleles and are more likely to have other autoimmune diseases, such as Hashimoto thyroiditis, Graves disease, systemic lupus erythematosus, vitiligo, ulcerative colitis, alopecia areata, and pernicious anemia.17 In up to 50% of patients, PG recurs in subsequent pregnancies, often more severely.16 There are reports of subsequent pregnancies without PG followed by affected pregnancies; the reason for this variability is unknown.16 It has been proposed that PG arises from abnormal placental expression of major histocompatibility complex (MHC) class II
antigens, resulting in the presentation of BP180 to the maternal immune system.16 BP180 proteins in the placenta are then treated as foreign, leading to production of autoantibodies IgG and C3 against the extracellular noncollagenous 16A region of placental BP180, which is then believed to cross-react with BP180 in the skin.10,12,16 An autoimmune response is mounted with the activation of complement, immune complex deposition, chemoattraction of eosinophils, and subsequent degranulation, all of which leads to blister formation.16 Sex hormone fluctuation also has been hypothesized to play a role in the etiology of PG.16 Patients with PG initially present with intense pruritus,10,16 which can have a significant emotional impact.18 Pruritic erythema generally progresses to erythematous papules and plaques, which then progress into clustered papulovesicles or tense bullae.10,17,18 These lesions generally start on the abdomen, often including the umbilicus and periumbilical region and, in most cases, spread to the entire abdomen.The eruption may generalize to other parts of the body, most commonly the trunk and upper and lower extremities. Facial and mucous membrane involvement is rare.10,16,17 Patients commonly experience spontaneous remission in the later stages of pregnancy, although flares can occur after delivery.These flares can be severe but generally resolve within 4 weeks.11,16 Approximately 10% of newborns born to mothers with PG may have neonatal PG due to transfer of antibodies from mother to fetus.12 The eruption in newborns resolves spontaneously.12
These lesions generally start on the abdomen, often including the umbilicus and periumbilical region. Diagnosis of PG is based on a combination of clinical features, histology, and direct immunofluorescence (DIF).10 When needed, indirect immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and immunoblotting may be used.10 HLA profiling also can be performed to look for HLA-DR3, HLA-DR4, or both.10,16 Histology of PG in the early stages, before development of bullae, shows dermal edema and a perivascular infiltrate of eosinophils, histiocytes, and lymphocytes.16,17 When bullae appear, histology shows subepidermal blisters with spongiosis and eosinophilic infiltrate.17 However, such findings also can be present in PEP, and further testing may be needed to differentiate the 2 conditions.16 DIF shows C3 deposition along the dermal-epidermal junction in 100% of PG cases;
44 THE CLINICAL ADVISOR • MAY/JUNE 2021 • www.ClinicalAdvisor.com
TABLE. Polymorphic Eruption of Pregnancy vs Pemphigoid Gestationis Polymorphic Eruption of Pregnancy1-9
• Pruritic papules • Urticarial plaques • Progresses to polymorphic features
• Intense pruritus • Erythematous papules and plaques • Progresses to clustered papulovesicles, tense bullae
• More prevalent in twin and triplet pregnancies and among primigravid women • More common among White women
• Median age of onset: 26-32 years
Potential risk factors
• Larger belly sizes • Increased maternal weight gain and newborn birth weight • Male sex of fetus • Rh-positive maternal blood
• Choriocarcinoma, hydatidiform mole, and trophoblastic tumors • Alleles to HLA-B8, HLA-DR3, and HLA-DR4 • Prior history of pemphigoid gestationis
• Uncertain • May be related to abdominal stretching and allergic-like reaction to collagen • Fetal DNA deposition in skin may create a graft-vs-host disease
• Abnormal placental expression of MHC II • IgG antibodies and C3 proteins directed against BP180 or collagen XVII
• Abdomen, within the striae • Spares the periumbilical region
• Umbilical region of the abdomen • Can spread to trunk and extremities
• Epidermal and dermal edema • Dermal perivascular infiltrate • Mild focal spongiosis • Most cases have no C3 deposits along basement membrane
• Early stage: dermal edema, perivascular infiltrate • Late stage: subepidermal blisters, spongiosis, eosinophilic infiltrate • C3 deposits along dermal-epidermal junction
• Clinical, based on symptoms and appearance of lesions • Biopsy with DIF
• Clinical, based on symptoms and appearance of lesions • Biopsy with DIF • Indirect immunofluorescence • Immunoblotting • ELISA
• Symptomatic • Topical and systemic corticosteroids • First-generation antihistamines • Cool baths, light cotton clothing, emollients
• Symptomatic • Topical and systemic corticosteroids • Oral antihistamines
DIF, direct immunofluorescence; ELISA, enzyme-linked immunosorbent assay; HLA, human leukocyte antigen; Ig, immunoglobulin; MHC II, major histocompatibility complex class II antigens
this is much less common in PEP.3,16 One study found that immunohistochemistry staining shows C4 deposition along the basement membrane in PG that is not present in PEP.19 Thus, this method can help differentiate PG from other gestational dermatoses.16,19 Indirect immunofluorescence shows IgG autoantibodies against the basement membrane zone in 30% to 100% of patients with PG.18 Immunoblotting and ELISA generally reveal autoantibodies against BP180 and, less commonly, BP230.17 Although peripheral eosinophilia can be found and may correlate with PG severity, routine laboratory results in
patients with PG generally are within normal limits.Antithyroid antibodies, immunoglobin levels, and erythrocyte sedimentation rates may be elevated.14 The most relevant conditions in the differential diagnosis for PG include the dermatoses of pregnancy including PEP, atopic eruption of pregnancy (AEP), and intrahepatic cholestasis of pregnancy (ICP). AEP is common and can be differentiated from PG because it occurs earlier, within the first and second trimesters of pregnancy. PG can be differentiated from PEP, which is clinically the most similar condition, through biopsy and DIF; PEP also characteristically spares
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Dermatologic Look-Alikes the umbilicus. Patients with ICP present with pruritus and develop secondary skin lesions from scratching. Jaundice and elevated bile acid levels in serum also can occur in patients with ICP, distinguishing this condition from PG.16 Other conditions to rule out include erythema multiforme, dermatitis herpetiformis, allergic contact dermatitis, bullous pemphigoid, cicatricial pemphigoid, drug-induced bullous disorders, linear IgA dermatosis, and acute urticaria.14,18 Treatment of PG is designed to treat itching and prevent new blisters. Management depends on the severity of the case. Mild, localized cases can be treated with topical corticosteroids and oral antihistamines. Severe cases may warrant systemic oral corticosteroid taper (prednisone or prednisolone at a dose ranging from 0.3 mg/kg to 0.5 mg/kg, tapered down over time).16,18 This patient’s clinical presentation and biopsy were consistent with PG. She was initially treated with topical steroids, which did not control her symptoms, and her rash continued to progress. She was started on oral prednisone, which controlled her symptoms and improved her rash. Her rash did not flare after delivery or during prednisone taper. ■
8. Ghazeeri G, Kibbi AG, Abbas O. Pruritic urticarial papules and plaques of pregnancy: epidemiological, clinical, and histopathological study of 18 cases from Lebanon. Int J Dermatol. 2012;51(9):1047-1053. 9. Proietti I, Bernardini N, Tolino E, et al. Polymorphic eruption of pregnancy as a possible COVID-19 manifestation. Dermatol Ther. 2020;33(6):e14117. 10. Intong LR, Murrell DF. Pemphigoid gestationis: pathogenesis and clinical features. Dermatol Clin. 2011;29(3):447-452, ix. 11. Sadik CD, Lima AL, Zillikens D. Pemphigoid gestationis: toward a better understanding of the etiopathogenesis. Clin Dermatol. 2016;34(3): 378-382. 12. Cohen S, Strowd LC, Pichardo RO. Pemphigoid gestationis: a case series and review of the literature. J Dermatolog Treat. 2018;29(8):815-818. 13. Milton J. The Pathology and Treatment of Diseases of the Skin. Hardwicke; 1872. 14. Lipozenčić J, Ljubojevic S, Bukvić-Mokos Z. Pemphigoid gestationis. Clin Dermatol. 2012;30(1):51-55. 15. Black MM. The Neil Smith Memorial Lecture: John Laws Milton. The founder of St John’s Hospital for Diseases of the Skin. Clin Exp Dermatol. 2003;28(1):89-91. 16. Sävervall C, Sand FL, Thomsen SF. Pemphigoid gestationis: current perspectives. Clin Cosmet Investig Dermatol. 2017;10:441-449. 17. Daniel BS, Murrell DF. Review of autoimmune blistering diseases: the
Dina Zamil, BS, is a medical student at Baylor College of Medicine,Tara L. Braun, MD, is a resident in the Department of Dermatology at Baylor College of Medicine, Carly Dunn, MD, is resident in the Department of Dermatology at Baylor College of Medicine, and Christopher Rizk, MD, is a dermatologist affiliated with Baylor College of Medicine in Houston,Texas.
pemphigoid diseases. J Eur Acad Dermatol Venereol. 2019;33(9):1685-1694. 18. Fong M, Gandhi GR, Gharbi A, Hafsi W. Pemphigoid gestationis. In: StatPearls. StatPearls Publishing; 2021. Updated March 21, 2021. Accessed April 16, 2021. http://www.ncbi.nlm.nih.gov/books/NBK470287/ 19. Kwon EJ, Ntiamoah P, Shulman KJ. The utility of C4d immunohistochemistry on formalin-fixed paraffin-embedded tissue in the distinction of polymorphic eruption of pregnancy from pemphigoid gestationis. Am J
1. Chouk C, Litaiem N. Pruritic urticarial papules and plaques of pregnancy. In: StatPearls. StatPearls Publishing; 2020. Updated August 14, 2020. Accessed April 17, 2021. http://www.ncbi.nlm.nih.gov/books/NBK539700/ 2. Sävervall C, Sand FL, Thomsen SF. Dermatological diseases associated with pregnancy: pemphigoid gestationis, polymorphic eruption of pregnancy, intrahepatic cholestasis of pregnancy, and atopic eruption of pregnancy. Dermatol Res Pract. 2015;2015:979635. 3. Brandão P, Sousa-Faria B, Marinho C, Vieira-Enes P, Melo A, Mota L. Polymorphic eruption of pregnancy: review of literature. J Obstet Gynaecol. 2017;37(2):137-140. 4. Bourne G. Toxaemic rash of pregnancy. Proc R Soc Med. 1962;55(6):
Case Study Library
462-464. 5. Lawley TJ, Hertz KC, Wade TR, Ackerman AB, Katz SI. Pruritic urticarial papules and plaques of pregnancy. JAMA. 1979;241(16):1696-1699. 6. Taylor D, Pappo E, Aronson IK. Polymorphic eruption of pregnancy. Clin Dermatol. 2016;34(3):383-391. 7. Holmes RC, Black MM. The specific dermatoses of pregnancy: a reappraisal with special emphasis on a proposed simplified clinical classification. Clin Exp
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LEGAL ADVISOR CASE
© THITIPHAT KHUANKAEW / EYEEM / GETTY IMAGES
Missed Cues Lead to Abrupt Death
Physician assistant fails to recognize patient’s risk for sudden cardiac arrest. ANN W. LATNER, JD
Mr A was a 45-year-old physician assistant (PA) who had been working in a midsized practice with several physicians, PAs, and nurse practitioners for the past 6 years. He liked working with Dr S, his supervising physician, and appreciated having the autonomy to see his own patients. One of Mr A’s patients was Mr P, a married security guard with 2 daughters in their 20s.The patient’s medical history included hypertension, dyslipidemia, situational anxiety, and seasonal allergies. One day, Mr P called the office to make an appointment, complaining of shortness of breath. Four days later, Mr P came in for his appointment with Mr A. Mr P noted that for the past 3 months he has been getting winded very easily. “It’s worse if I try to exercise — then I huff and puff and can’t catch my breath,” noted Mr P. He also said he has heartburn and that when he exercises, his jaw hurts. When questioned about the frequency of his symptoms, Mr P described the issues as intermittent but said he felt heartburn or “pressure” during light exercise. “I know I could stand to
One of the most challenging jobs of a clinician is recognizing when something should be treated as an emergency.
lose some weight or get in better shape,“ noted Mr P, “but when I try to push myself, I [get] out of breath and [feel] pressure in my ribs, so I stop.” Mr P’s complaints of dyspnea on exertion, jaw pain, and epigastric pain are noted in his medical record. Mr A also recorded the patient’s vital signs: height, 5’6”; weight, 189 lb; BMI, 28.84. His sitting blood pressure was measured twice (150/88 mm Hg and 138/90 mm Hg). Oxygen saturation rate was 96% on room air. Mr A noted in the record a normal physical examination and regular heart rate and rhythm, with normal S1 and S2 without murmurs, rubs, gallops, or clicks. An electrocardiogram was performed and showed a normal sinus rhythm. Given the new onset of dyspnea on exertion associated with jaw and epigastric discomfort, Mr A planned to order stress echocardiography and have Mr P return in 2 to 4 weeks for a 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 • MAY/JUNE 2021 47
LEGAL ADVISOR follow-up consultation. The plan was electronically signed by both Mr A and his supervising physician, Dr S. Mr A told the patient that he had scheduled the cardiopulmonary stress test (in 3 weeks), after which they would meet again for a follow-up visit. The day before the stress test was scheduled, Mr P suffered a cardiac arrest and died in his home. Mr P’s widow sought the advice of a plaintiff ’s attorney. After reviewing Mr P’s medical records with medical experts, the attorney called Mrs P back and said she had a case. The lawsuit was filed against the medical practice.
referring Mr P to a cardiologist and/or the emergency department for further monitoring, evaluation, and treatment.They noted that the patient should have had immediate stress echocardiography, serial cardiac enzyme tests, and serial electrocardiograms, considering his presenting symptoms. Mr A admitted that he was concerned it was a cardiac issue, which is why he ordered a stress test and a follow-up visit, but that he didn’t appreciate the urgent nature of the complaint. After numerous discussions, the parties settled the case before trial for $3.5 million. Protecting Yourself
The medical practice, including Mr A and Dr S, received notice of the lawsuit and consulted their defense attorney.The defense attorney, like the plaintiff ’s attorney, sent the medical records out to be reviewed by experts.
Mr P’s medical history included hypertension, dyslipidemia, situational anxiety, and seasonal allergies. The plaintiff ’s experts alleged that Mr A, his supervising physician, and the practice had failed to meet the standard of care required in this case by failing to recognize and appreciate Mr P’s risk for sudden cardiac arrest. They noted that the PA had failed to recognize or understand that a single electrocardiogram is not reassuring for the lack of significant cardiac disease and risk for heart attack. The defense experts also were critical after reviewing the medical records.They criticized the PA (and by extension his supervising physician and the practice) for not immediately
One of the most challenging jobs of a clinician is recognizing when something should be treated as an emergency. Sometimes it is obvious — trauma, loss of consciousness, broken bones, or a heart attack in progress. Sometimes, however, it is less obvious. When it comes to cardiac issues, it is better to err on the side of caution. In the case of an overweight, middleaged man with a history of hypertension and dyslipidemia who is complaining of shortness of breath, epigastric pain, and jaw pain, it would have been appropriate to refer the patient to a cardiologist or hospital for further testing and monitoring; however, Mr A relied solely on a single office electrocardiogram and auscultation. Had Mr A referred his patient immediately to a cardiologist or to the emergency department for further screening, the patient may have experienced a different outcome. It is far better to be overly cautious in the case of possible cardiac issues and order further testing immediately than to take a wait-and-see attitude and risk something happening before the next appointment. ■ Ann W. Latner, JD, a former criminal defense attorney, is a freelance medical writer in Port Washington, New York.
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