October 2020 Clinical Advisor by The Clinical Advisor

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■■ Aspirin Fails CVD Test ■■Seasonal Coronaviruses ■■ DNP/MPH Program ■■ Obesity and COVID-19 ■■ CVD Triglyceride Data ■■ Vitamin D Can't Prevent Depression LEGAL ADVISOR

Child’s Respiratory Distress Leads to ED Visit

CASE

Aspiration Pneumonia Mistaken for CommunityAcquired Pneumonia

DERMATOLOGIC LOOK-ALIKES

Hyperpigmented Cutaneous Rash on Lower Leg

OCTOBER 2020

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ANTIDEPRESSANT MANAGEMENT

Pharmacogenetic Testing: Does It Improve Therapy in Patients With MDD? Major depression affects 7.1% of the population.

Director Nikki Kean nikki.kean@haymarketmedia.com Associate editor Madeline Morr

FROM THE DIRECTOR

Production editor Kim Daigneau Group creative director Jennifer Dvoretz Senior production manager Krassi Varbanov Director of audience insights Paul Silver National sales manager Alison McCauley, 973.224.6414 alison.mccauley @ haymarketmedical.com Associate account manager Michael Deverin, 732.343.4921 michael.deverin@haymarketmedia.com Publisher Kathleen Hiltz, 201.774.1078 kathleen.hiltz@haymarketmedia.com Vice president, content, medical communications Kathleen Walsh Tulley General manager, medical communications Jim Burke, RPh President, medical communications Michael Graziani CEO, Haymarket Media, Inc. Lee Maniscalco All correspondence to: The Clinical Advisor 275 7th Avenue, 10th Floor, New York, NY 10001 For advertising sales, call 646.638.6085. For reprints/licensing requests, contact Customer Service at custserv@haymarketmedia.com. Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Features” are not the actual individuals mentioned in the articles. They appear for illustrative purposes only. The Clinical Advisor® (USPS 017-546, ISSN 1524-7317), Volume 23, Number 8. Published 10 times a year, by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. For Advertising Sales & Editorial, call 646.638.6000 (M–F, 9am–5pm, ET). The Clinical Advisor is available on a paid subscription basis at the following annual rates: $75 USA, $85 Canada, $110 for all other foreign, in U.S. dollars, Single copy price: USA $20, Foreign $30. To order or update a paid subscription visit our website at www.ClinicalAdvisor.com or call 800.436.9269. Periodicals postage rate paid at NewYork, NY, and additional mailing offices. Postmaster: Send changes of address to The Clinical Advisor, c/o Direct Medical Data, 10255 W. Higgins Rd., Suite 280, Rosemont, IL 60018. All rights reserved. Reproduction in whole or in part without permission is prohibited. Copyright © 2020

Millions of Americans are living with a mental health condition. In normal years, anxiety and depression are reported to affect about onethird of Americans, according to the US Census Bureau. However, these are not normal times. Living through a global pandemic, multiple natural disasters, and an economic recession have led to a spike in the number of people experiencing mental health issues. In a Kaiser Family Foundation poll conducted in mid-July 2020, “53% of adults in the United States reported that their mental health has been negatively impacted due to worry and stress over the coronavirus.” Mental illness often affects the whole family unit, from the person experiencing symptoms to those who support and care for that person: parents, spouses, siblings, and children. Despite mental illnesses’ reach and prevalence, stigma and misunderstanding remain widespread. Thirty years ago, the US Congress declared the first week of October as Mental Illness Awareness Week to educate the public, fight stigma, and provide support for people with mental illness. The theme this year is “What People With Mental Illness Want You to Know.” This issue features an article on Pharmacogenetic Testing: Does It Improve Therapy in Patients With MDD? The article highlights the research around whether genomic testing can help pick the best antidepressant for a patient. Based on their research, the authors note that testing, which can be expensive, largely benefits patients with treatment-resistant forms of depression. This month we’ve also published a blog by Jim Anderson, MPAS, PA-C, DFAAPA, on Managing Provider Depression in the Era of COVID-19, which can be found on ClinicalAdvisor.com/WaitingRoom. He writes, clinicians need to check in with their emotions now more than ever. “The genesis of depression is often multifactorial. For me, my depression originated from the adjustment to the bizarre and often lonely new COVID world.” The COVID-19 pandemic can cause depressive symptoms to flourish, making it vital for clinicians to check the mental health of their patients and themselves. I hope you enjoy your issue, and stay safe! Nikki Kean, Director The Clinical Advisor www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2020 1

Mental Illness Rises During COVID

Assistant editor Michelle Lampariello

CONTENTS OCTOBER 2020

NEWS 6

Newsline ■■Assessing Aspirin Safety in High-Risk CVD Patients ■■Seasonal Coronaviruses Provide Insight for Future COVID-19 ■■Johns Hopkins Announces New DNP/MPH Dual Degree ■■Higher BMI Linked to Poorer Outcomes From COVID-19

11 High triglycerides not good for heart

FEATURES 2 Pharmacogenetic Testing: Does It Improve Therapy 1 in Patients With MDD Testing for genetic variants may allow clinicians to predict how patients with major depressive disorder metabolize medications. 7 The Art of Managing Long-Acting Reversible 1 Contraception in Teens Hormonal and nonhormonal intrauterine devices and hormonal implants have been proven safe and effective for adolescents.

17 Discussing contraception with teens

9 Aspiration Pneumonia Mistaken for Community2 Acquired Pneumonia Aspiration pneumonia should be part of the differential diagnosis in any case of rapid-onset pneumonia and hypoxic respiratory failure.

DEPARTMENTS

33 Rash appears on the upper back

37 Respiratory distress in young girl

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

Dermatologic Look-Alikes Hyperpigmented Cutaneous Rash

Legal Advisor Child’s Respiratory Distress Leads to ED Visit

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ClinicalAdvisor.com

NEWS ClinicalAdvisor.com/News

CLINICAL CHALLENGE ClinicalAdvisor.com/CaseStudy

Impact of Low-Dose Aspirin on Colorectal and Lower GI Cancer Risk Examined

Brady Pregerson, MD Epigastric Abdominal Pain and Vomiting A patient in his 70s presents with a 1-day history of intermittent epigastric abdominal pain that radiates into his back. The pain has been increasing in severity over the past few hours. The patient vomited after lunch, which led him to seek medical help. The patient has a history of hypertension that is being controlled with metoprolol. He has not experienced fever, diarrhea, or other symptoms associated with his abdominal pain. See the full case at: ClinicalAdvisor.com/CaseOct20

Long-term continuous use of low-dose aspirin has been found to be associated with a decreased risk of CRC; however, the underlying mechanisms for this are conflicting.

Assessment Tool Shows Promise for Monitoring SUD Treatment Success A recently developed 10-item progress assessment tool that monitors substance use disorder (SUD) factors shows promise as a helpful tool in treatment for SUD.

Prasugrel Found Effective for Acute Coronary Syndrome In patients aged <75 years with a body weight of ≥60 kg, prasugrel 10 mg was associated with significantly lower risk for ischemic complications at 1 year compared with ticagrelor.

AHA/AMA Endorse Home Blood Pressure Monitoring to Improve Hypertension Rx Self-measured blood pressure monitoring can prevent misclassification of hypertension in patients with elevated in-office blood pressure (white-coat hypertension).

Maternal Hypertension Increases Risk for Morbidity and Obesity in Children

THE WAITING ROOM

Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Jim Anderson, MPAS, PA-C, DFAAPA Managing Provider Depression in the Era of COVID-19 Now more than ever, clinicians need to check in with their emotions as the COVID-19 pandemic can cause feelings of sadness, loneliness, and depression.

FEATURE ClinicalAdvisor.com/Features

Mothers with hypertension had higher maternal age, higher likelihood of >5 deliveries, greater prevalence of gestational diabetes, and increased likelihood of preterm delivery.

4 THE CLINICAL ADVISOR • OCTOBER 2020 • www.ClinicalAdvisor.com

Screening, Diagnosis of Abdominal Aortic Aneurysms Abdominal aortic aneurysms are likely to be encountered in the primary care setting, making appropriate diagnosis and management indispensable.

IMAGES: MIDDLE, BOTTOM: © GETTY IMAGES

EXCLUSIVE TO THE WEB AT

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

DERM DX

Growth on the Lower Leg An 84-year-old woman is referred for evaluation of 2 skin lesions — a nodular growth on her back and a 0.8-cm deeply pigmented papule on her right shin that was first noted 4 months ago. Her medical history indicates hypertension, coronary artery disease, and stasis dermatitis. CAN YOU DIAGNOSE THIS CONDITION?

• Pyogenic granuloma • Kaposi sarcoma • Pigmented basal cell carcinoma • Hemosiderotic dermatofibroma ● See the full case at ClinicalAdvisor.com/DermDx_Oct20

In partnership with

ORTHO DX

TheJopa.org

Journal of Orthopedics for Physician Assistants

Black Necrosis of the Left Foot A 61-year-old man presents with a 2-month history of an infection in his left foot. The patient has poorly controlled insulin-dependent diabetes and underwent a below-the-knee amputation 2 years ago. His infection started as cellulitis but has progressed to full necrosis of the lateral aspect of the left foot over the course of 2 months. WHICH INTERVENTION WOULD BEST ALLOW FOR A SUCCESSFUL LIMITED AMPUTATION?

• Lower extremity arterial angioplasty • Intravenous antibiotics • Surgical debridement • Diabetic education consultation ● See the full case at ClinicalAdvisor.com/OrthoDx_Oct20

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2020 5

Newsline THE USE OF ASPIRIN as a primary prevention for atherosclerotic cardiovascular disease (ASCVD) in high-risk patients has been controversial.Aspirin is known to lower the risk of heart attack and stroke, but it also may increase the risk of major bleeding episodes. In a new study, researchers have found no evidence that the use of aspirin for higher-risk primary prevention is beneficial. The findings were published in The American Journal of Medicine. The study authors used a database to examine all prospective randomized clinical trials (RCTs) that tested aspirin as a primary prevention method for ASCVD. A total of 12 RCTs that compared aspirin with nonaspirin (either placebo or control) for primary ASCVD prevention were identified (n=145,435).

Patients treated with aspirin had a statistically significant reduction in ASCVD events compared with no aspirin (4.7 vs 5.3 events per 1000 patient-years). Despite the beneficial effects, the authors found a statistically significant increase in major bleeding events for patients treated with aspirin compared with control patients (2.5 vs 1.8 events per 1000 patient-years). “These results trended toward an increased benefit for aspirin in higher-risk patients, but this finding did not meet statistical significance,” the researchers reported. In studies published prior to 2010 (n=7) and during or after 2018 (n=5), aspirin use resulted in a statistically significant reduction of ASCVD events. Researchers found that aspirin had a greater treatment effect in older trials

Assessing Safety of Aspirin in High-Risk Patients With Atherosclerotic CV Disease

A significant increase in major bleeding events was seen with aspirin therapy.

compared with newer trials. The study authors found no heterogeneity of treatment effect between higher vs lower doses of aspirin and major bleeding events. “Despite the thought that aspirin for primary prevention may still be useful for those at high risk for ASCVD, insufficient randomized data currently exist to recommend aspirin in this group,” concluded the authors.

Antibiotic Use May Reduce Efficacy of Hormonal Oral Contraceptives THE EFFICACY OF hormonal contraceptives may be reduced with use of antibiotics, according to a study published online in BMJ Evidence-Based Medicine. Jeffrey K. Aronson, MBChB, DPhil, from Oxford University and Robin E. Ferner, MD, from the University of Birmingham, both in the United Kingdom, examined whether antibiotics impair the effectiveness of oral contraceptives in a database review of Yellow Card reports to the UK Medicines and Healthcare products Regulatory Agency. Data were included from spontaneous reports of suspected adverse drug reactions in people taking antibacterial drugs (74,623), enzyme-inducing medicines (32,872), or control medicines (65,578).

The researchers found that unintended pregnancies were 7 and 13 times more commonly reported with antibiotics and enzyme inducers (positive controls), respectively, compared with control medicines. Congenital abnormalities were not more common with antibiotics, but were reported 7 times more often with enzyme inducers. Diarrhea was not identified as a confounding factor. “This evidence suggests that there is an interaction of antibacterial drugs with hormonal contraceptives, which can potentially impair the effectiveness of the contraceptives,” the authors write. “The precautionary principle dictates that women taking hormonal contraceptives should be advised to take extra contraceptive precautions when a short course of an antibacterial drug is added.”

6 THE CLINICAL ADVISOR • OCTOBER 2020 • www.ClinicalAdvisor.com

Newsline

Seasonality of Coronaviruses May Provide Insight for Future SARS-CoV-2

Coronaviruses, flu, and RSV are more common during winter.

SEASONAL coronaviruses are more prevalent during the winter months, coinciding with influenza and respiratory syncytial virus (RSV) seasons in temperate climate regions, according to a review published in The Journal of Infectious Diseases. After the initial pandemic wave of novel SARS-CoV-2 (COVID-19), it remains unclear what trajectory COVID19 transmission will take. Similar to influenza and RSV, SARS-CoV-2 could recur as a circulating pattern of seasonal outbreaks, which has been observed among other preexisting human seasonal coronaviruses. Currently, there are 4 known seasonal coronaviruses that circulate in human populations, including NL63, 229E, OC43, and HKU1.The systemic review compared the seasonality of seasonal coronaviruses with the influenza virus and RSV and modeled monthly activity of seasonal coronaviruses using sitespecific weather data. In total, seasonality data from 40 sites in 21 countries were included.The number of positive seasonal coronavirus cases by month across years for each site was

aggregated, and the annual average percentage was calculated for strength of virus activity. Heat maps were created to display the activity of seasonal coronaviruses, influenza virus, and RSV for each site to evaluate peak activity for each. Furthermore, meteorological data from each site was extracted to the site to model monthly seasonal coronavirus activity. Results suggested that human seasonal coronaviruses are prevalent in winter months, coinciding with influenza and RSV season in most temperate sites. High activity of seasonal coronaviruses was observed in winter months in most temperate sites, with the exception of China where seasonal coronavirus activity was noted year-round. More variations in seasonal coronaviruses activity were observed in tropical sites. When China was excluded, 53.1% of the annual seasonal coronavirus cases that occurred in temperate sites occurred during influenza seasons, while 49.6% of seasonal coronavirus cases occurred during RSV season (interquartile range, 34.6-61.9 and 30.2-60.2, respectively).At tropical sites and sites in temperate China, there was less overlap observed between seasonal coronavirus activity and influenza activity (20% of seasonal coronavirus cases during the season) and RSV activity (29% of seasonal coronavirus cases during the season). Sites with low temperature and high relative humidity were found to be associated with a higher expected proportion of seasonal coronavirus cases, and dew points had a similar relationship with seasonal coronavirus activity. “Our findings offer clues to the possible post-pandemic circulating season of SARS-CoV-2 and add to the knowledge pool necessary for post-pandemic preparedness for SARS-CoV-2,” the researchers concluded.

8 THE CLINICAL ADVISOR • OCTOBER 2020 • www.ClinicalAdvisor.com

Feeling Dizzy Upon Standing May Point to Later Dementia SYSTOLIC ORTHOSTATIC hypotension (OHYPO) and variability in visitto-visit seated systolic blood pressure (BP) postural change are associated with greater dementia risk, according to a study published online in Neurology. Laure Rouch, PharmD, PhD, from University of California in San Francisco, and colleagues used data from 2131 older adults (mean age, 73 years) participating in the Health, Aging, Body Composition study to evaluate whether OHYPO and visitto-visit BP postural changes variability are associated with incident dementia. OHYPO was measured repeatedly during a 5-year baseline period and was defined as a fall of ≥15 mm Hg in systolic BP or ≥7 mm Hg in diastolic BP after standing from a sitting position for at least one-third of visits. The researchers found that overall, 9% of participants had systolic OHYPO, 6.2% had diastolic OHYPO, and 21.7% developed dementia. Systolic OHYPO was associated with greater dementia risk (adjusted hazard ratio [HR], 1.37) when adjusting for demographics, seated systolic BP, antihypertensive drugs, cerebrovascular disease, diabetes, depressive symptoms, smoking, alcohol, body mass index, and the presence of APOE ε4 alleles. However, there was no association seen for diastolic OHYPO.Variability in seated systolic BP postural changes was also associated with higher dementia risk (highest tertile of variability: adjusted HR, 1.35). “Our findings raise the question of potential preventive interventions to control orthostatic systolic BP and its fluctuations,” the authors write.

Newsline New DNP/MPH Dual Degree Program at Johns Hopkins JOHNS HOPKINS UNIVERSITY announced that students can earn a Doctor of Nursing Practice/Executive Master of Public Health (DNP/MPH) in as few as 3 years through a dual degree program that the university will launch in the summer of 2021. The program aims to provide students with blended knowledge and skills in nursing practice and population health to prepare graduates to work in local and global health agencies, advocacy groups, and academic institutions where leadership is needed to improve health outcomes, promote health equity, and influence policy. “When nursing and public health bring the best of their skills together, there is so much to be accomplished within advancing health equity and developing solutions to our changing national and global health needs,”

Students will complete an integrated DNP project as part of their coursework.

Bloomberg School of Public Health Dean Ellen J. MacKenzie, PhD, ScM said in a press release. Students enrolled in the dual degree program will take courses from the Johns

Hopkins School of Nursing and the Johns Hopkins Bloomberg School of Public Health in both online and inperson formats, noted a press release. Program applicants must have a master’s degree in nursing from an accredited college or university, RN licensure, and 2 years of health care experience. “COVID-19 has amplified the critical importance of nurse leaders who develop interventions that are based in both nursing and public health,” said Dean of the Johns Hopkins School of Nursing Patricia Davidson, PhD, MEd, RN, FAAN, according to the press release.“We are excited to be able to launch the program during this time in history when the perspective of nursing is well recognized and ever essential to creating the path forward to a healthier and more population-focused future.”

SEVERE OBESITY, specifically in men and younger patients, is a risk factor for adverse outcomes from COVID-19, particularly mortality, according to a study published in Annals of Internal Medicine. A retrospective study of members of Kaiser Permanente Southern California who were diagnosed with COVID-19

206 (3%) patients died within 21 days of their COVID-19 diagnosis, with 67% hospitalized and 43% intubated between the index date and date of death. Of the patients that survived, 15% were hospitalized and 3% were intubated. Researchers found a J-shaped association between BMI and risk for death,

Researchers found a J-shaped association between higher body mass index and risk for death from COVID-19, even after adjusting for obesity-related comorbidities. from February 13 to May 2, 2020 was conducted. The researchers focused on the effect body mass index (BMI) had on mortality within 21 days of COVID-19 diagnosis (index date). A total of 6916 patients with COVID-19 were identified;

even after adjusting for obesity-related comorbidities. Compared with normal weight patients, those with class III obesity had 2.68 relative risk of morbidity (95% CI, 1.43-5.04). Patients with a BMI >45 kg/m2 were 4 times at risk

10 THE CLINICAL ADVISOR • OCTOBER 2020 • www.ClinicalAdvisor.com

of dying compared to normal weight patients (95% CI, 2.12 to 8.26). Among patients aged ≤60 years, an increased risk for death with high BMI was found compared with the overall model. For those aged ≥61 years, BMI was associated with death to a much lesser degree and only for the highest measures. Men had a higher risk of death compared with women; women had no increased risk for death associated with BMI. Severe obesity, particularly among younger patients,“eclipses the m ortality risk posed by other obesity-related conditions, such as history of myocardial infarction, diabetes, hypertension, or hyperlipidemia, which suggests a significant pathophysiologic link between excess adiposity and severe COVID-19 illness,” concluded the authors.

Higher BMI Linked to Poor Outcomes From COVID-19

Higher Triglyceride Levels Linked to Adverse Cardiovascular Outcomes

IN PATIENTS WITH type 2 diabetes (T2D) and/or cardiovascular disease (CVD), elevated triglyceride levels were found to be an independent risk factor associated with adverse cardiovascular outcomes, according to a study published in the American Journal of Cardiology. The study, which used data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, sought to determine the prevalence and distribution of hypertriglyceridemia and examine the associations between baseline triglyceride levels and cardiovascular events overall. Participants in the original BARI 2D trial were randomized by whether they were receiving cardiovascular treatment or type 2 diabetes treatment.The protocol included guideline-mandated treatment for hypertension, dyslipidemia, and obesity, in addition to a goal HbA1c of <7.0% regardless of randomization assignment. Lipid measures were obtained from fasting blood acquired prior to randomization. The primary endpoint of the current analysis was time to death due to cardiovascular outcomes, myocardial infarction, or stroke. Secondary outcomes were the individual components of the primary

Every 50 mg/dL rise in triglyceride level was linked to a 3.2% increase in death.

endpoint in addition to time to coronary revascularization and all-cause death. Participants were grouped by baseline triglyceride levels; those with elevated triglyceride levels were further stratified into 3 groups: ≥150 to 199 mg/dL; 200 to 499 mg/dL; ≥500 mg/dL. The study population consisted of 2307 patients (97% of the BARI 2D study; median age, 62 years). Most patients were obese, had a history of T2D just under 10 years, and were prescribed a statin. Overall, 51% of patients had triglyceride levels <150 mg/dL; 18%, 150-199 mg/dL; 28%, 200-499 mg/dL; and 3%, 500-1000 mg/ dL. Patients in the highest triglyceride level group were more likely to be younger, current smokers, have lower HDL-C cholesterol, and higher insulin levels. Elevated baseline triglyceride levels were associated with the primary composite outcome of cardiovascular death, myocardial infarction, and stroke. In adjusted analysis, every 50 mg/dL increase in triglyceride level was associated with a 3.2% increase in cardiovascular death, myocardial infarction, or stroke and a 5.8% increase in cardiovascular death alone. In the fully adjusted analysis, every 50 mg/dL increase in triglyceride level was associated with a 3.8% increase in the primary composite outcome and a 6.4% increase in the secondary outcome. Inclusion of age, sex, region, race, ethnicity, systolic blood pressure, and smoking status covariates modestly increased the impact of triglyceride levels on risk for adverse cardiovascular outcomes. In contrast, the addition of body mass index, T2D duration, HbA1c level, LDL-C, and statin use all modestly attenuated the impact of triglyceride levels on risk for both outcomes. “Whether lowering [triglyceride] levels leads to improved cardiovascular outcomes remains to be seen,” said the authors.

Taking Vitamin D3 Does Not Prevent Depression in Adults LONG-TERM supplementation with 25-hydroxyvitamin D (vitamin D3) did not significantly alter symptoms of late-life depression among the general population, according to study results published in JAMA. A total of 18,353 adults aged >50 years were enrolled in the Vitamin D and Omega-3 Trial-Depression Endpoint Prevention (VITAL-DEP) clinical trial between 2011 and 2014. Participants were randomly assigned to receive either 2000 IU/d cholecalciferol (vitamin D3) and fish oil (n=9181) or a placebo (n=9172). Patients were followed through 2017 and assessed for depression using the 8-item Patient Health Questionnaire depression scale (PHQ-8). A change in PHQ-8 score of 0.5 was considered the minimally important clinical change. The 2 treatment groups were varied demographically; mean participant age was 67.5±7.1 years, 49.2% of participants were women, 27% were minorities, and the mean baseline vitamin D3 level was 31.1 ng/mL.The majority of study participants (n=16,657) had no history of depression and the remaining participants had no treatment for depression during the previous 2 years. Reported incidence of depression or clinically relevant depressive symptoms were similar between the treatment and placebo cohorts (609 vs 625). Reports of depression were similar between treatment and placebo cohorts (459 vs 461, respectively); reports of recurrent depression were also similar (150 vs 164, respectively), and overall risk for incident depression did not differ between cohorts. ■

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2020 11

FEATURE: LAUREN NOLAN, MMSc, PA-C; TIA M. SOLH, MT (ASCP), MSPAS, PA-C

Pharmacogenetic Testing: Does It Improve Therapy in Patients With MDD? Testing for genetic variants may allow clinicians to predict how patients with major depressive disorder metabolize antidepressants.

Most antidepressants are metabolized through the CYP450 pathway.

ajor depressive disorder (MDD) is a common mental disorder that affects more than 264 million people worldwide and is a leading cause of disability, including death by suicide.1 MDD is a complicated disorder that involves the interaction of social, psychological, and biological factors.1 MDD can prevent patients from living healthy, productive lives and can complicate treatment of other comorbid conditions.1 Although MDD commonly is encountered in primary care settings, its treatment has become integrated into all fields of medicine due to its high prevalence. Cognitive behavioral therapy, interpersonal psychotherapy, and antidepressants, such as selective serotonin reuptake inhibitors and tricyclic antidepressants, are the mainstays of MDD treatment.1 Prescribing an antidepressant may be simple, but that does not make it easy. Efficacy and tolerability of antidepressants vary among patients, which can make it challenging to relieve patients’ symptoms.2 Although no genes have been associated with depression,3 several genetic variants may help clinicians predict how patients with MDD will metabolize antidepressants.4 Performing genetic testing of patients with MDD and matching patients with an antidepressant class based on identification of genetic variants that convey sensitivity to particular antidepressants could improve response to drug therapy in patients with MDD.5 Continues on page 14

12 THE CLINICAL ADVISOR • OCTOBER 2020 • www.ClinicalAdvisor.com

PHARMACOGENETICS AND ANTIDEPRESSANT MANAGEMENT

Current Antidepressant Management

The process of selecting an antidepressant should take into account cost, tolerability, adverse effect profiles, and patient preferences.2 When evaluating treatment options for patients with MDD, the current standard of care is to initiate an antidepressant at a starting dose and reassess effectiveness within 2 to 4 weeks, with adjustments to monitoring frequency dependent on the patient’s suicide and self-harm risk, comorbid conditions, age, and concomitant medication use.2 Several metrics are used to determine whether a selected antidepressant is working: • Does the patient feel better? • If not, the clinician should increase dosage to see if the desired effect can be produced. • If dose titration does not reduce symptoms, the clinician should select another antidepressant. • If the patient does feel better, is he or she experiencing adverse effects; if so, how tolerable are they? Clinicians can mitigate adverse effects by decreasing the dosage or switching to a different class of antidepressant. However, several weeks are needed after each change in drug or dose alteration to truly assess response. Finding and settling on a drug that produces a response with minimal adverse effects can take months. During the trial period, patients may become frustrated with the process and stop therapy and/or may be at increased risk for suicide or self-harm. Pharmacogenetic Testing

The study of drug metabolism in patients with MDD is a growing area of interest.3-5 A management approach incorporating pharmacogenetic testing in combination with clinical

POLL POSITION If a person is an extensive metabolizer, they: 6.90% 2.06%

■ Process medications significantly slower ■ Process medications significantly faster ■ Process medications as predicted

6.90% 84.14%

■ Are unable to process medications

For more polls, visit ClinicalAdvisor.com/Polls.

judgment may be superior to the standard trial and error method for finding an effective antidepressant regimen and could improve patient outcomes.5 Genome-wide association studies are used to identify single-nucleotide variations (SNVs, formerly SNPs) in genes related to a particular disease or drug metabolism.6 Several laboratory testing companies offer pharmacogenetic panels to evaluate metabolism of drugs used to treat MDD.3 The FDA also has approved direct-to-consumer genetic testing panels (eg, 23andMe), which are widely available to the public without a health care provider’s prescription.7 A concern with these latter tests is that the results are reported directly from the company to the patient; thus, the patient decides whether or not to present the information to his or her health care provider. Many pharmacogenetic testing panels also include genes that have shown correlations with the pathogenesis of MDD, despite the lack of clinical research replicating the role of these genes in the disorder.3 Drug Metabolism

Most antidepressants are metabolized through the cytochrome P (CYP) 450 pathway; therefore, most drug metabolism genes on pharmacogenetic testing panels are related to CYP450 oxidase enzyme subunits.When pharmaceutical companies develop a drug, they provide primary and proposed secondary enzymes through which a medication is metabolized. Some antidepressants are metabolized through multiple enzymes in the CYP450 pathway. The extent to which a drug is metabolized through primary or secondary enzymes varies among individuals, further complicating understanding of drug metabolism.4 In some patients, the secondary enzymes involved in drug metabolism can compensate for underperforming primary enzymes. Based on their genetic profile, individuals are categorized into 4 main classes: ultra-rapid, extensive, intermediate, or poor metabolizers of drugs metabolized via various CYP450 enzyme subunits.5 • Ultra-rapid metabolizers process medications quickly, decreasing the amount of active metabolite. With ultrarapid drug metabolism, patients may never experience a clinical response to medication. Thus, these patients may require higher doses to achieve the same therapeutic effect as patients who metabolize the medication as predicted. • Extensive metabolizers process the medication as predicted. Pharmaceutical companies provide dosing guidelines based on extensive metabolizers, so clinicians can assume that no dosing adjustments are needed. • Intermediate metabolizers process medications more slowly than extensive metabolizers.6 Because of this, these patients may exhibit variable responses or experience greater adverse effects and may need lower starting doses of drugs

14 THE CLINICAL ADVISOR • OCTOBER 2020 • www.ClinicalAdvisor.com

metabolized via a given CYP450 enzyme subunit than patients who metabolize the drug as predicted. Laboratories often advise clinicians to proceed with caution when prescribing an antidepressant in a patient who is known to be an intermediate metabolizer. • Poor metabolizers process medications significantly more slowly, leaving the patient with higher plasma drug levels than patients who metabolize the medication as predicted.Thus, patients who are poor metabolizers are more susceptible to adverse effects or potential toxicity. Such patients are also at greater risk for adverse effects if practitioners increase dosages of a drug.Therefore, greater caution should be used during dosage changes in these patients, and closer followup should be considered. Clinicians may want to consider avoiding drugs metabolized via the given CYP450 enzyme subunit as first-line therapy and select a medication that uses an alternate enzymatic pathway instead. Most of the laboratory testing companies create a report that categorizes antidepressants based on the prevalence of certain SNVs. For example, because sertraline is metabolized via the 2C19 subunit of CYP450, a patient with a SNV in CYP2C19 (poor metabolizer) would have sertraline listed as a drug that clinicians should use with caution at a lower starting dose.5 Current Research

To date, 7 studies have investigated the use of pharmacogenetic testing in a clinical setting: 2 open-label studies and 5 randomized controlled trials.8-15 All of the studies evaluated the effect of treatment based on pharmacogenetic testing results compared with treatment using the standard trial and error approach.The majority of the studies used different pharmacogenetic testing panels, with each laboratory testing company using proprietary methods to analyze and statistically weight SNVs in their panels. When pharmacogenetic testing was used in these studies, most studies still relied on clinicians to make treatment decisions based on each antidepressant falling into a “use as directed” category or a “use with caution” category that recommended changing the starting dose or switching to an antidepressant metabolized through a different enzyme subunit. Outcomes varied in these studies. Across all the studies, treatment groups that used pharmacogenetic testing to guide medication selection showed higher rates of remission,11,13 response14 (≥50% reduction in Hamilton Rating Scale for Depression-D17 scores), or both, particularly among patients with severe depression.8-12,15 In the GUIDED trial, treatment based on pharmacogenomic testing did not significantly improve mean symptoms but did significantly improve response and remission rates for patients with difficult-to-treat depression compared with the standard treatment approach.15 Patients who were taking drugs found to

be incongruent with their genetic profile (incongruent) before baseline and switched to congruent medications experienced greater symptom improvement (33.5% vs 21.1%), response (28.5% vs 16.7%), and remission (21.5% vs 8.5%) compared with those remaining incongruent.15 Many of the studies, however, included a majority of White subjects, calling into question the external validity of these study results to other races and ethnicities. A meta-analysis by Rosenblat et al showed that pooled results of 6 of the 7 studies resulted in risk ratios for remission and response that favored the use of pharmacogenetic testing over a standard approach, although the authors caution that there are limitations to combining data from studies using different methodologies.16 Despite the study limitations and the fact that many of the pharmacogenetic testing panels included SNVs unrelated to drug metabolism that lack clinically significant correlation to MDD, overall the pharmacogenetic testing groups fared better than the control groups.16 Clinical evidence supporting the use of pharmacogenetic testing to determine adverse effects of antidepressants is still lacking.16 No study to date has been able to predict or avoid adverse effects altogether by using the results of pharmacogenetic testing to select antidepressant therapy. However, although study participants still experienced adverse effects when clinicians used pharmacogenetic testing to guide prescribing practices, many patients had improved outcomes.16 Recommendations for Clinical Practice

When considering pharmacogenetic testing, clinicians should discuss the cost of testing with patients.The cost varies depending on the supplier, but out-of-pocket costs for patients can range from a few hundred dollars to a few thousand dollars. Some insurance companies may cover the testing or a portion of it, and some of the test manufacturers provide discounts for patients who struggle to pay.17,18 Multigene testing is preferred over single-gene testing, given the complexities of MDD and drug metabolism genetics, and it is more cost-effective. In patients with severe depression, higher remission and response rates may make the cost of pharmacogenetic testing seem worthwhile.19 Higher remission rates may result in lower costs of care, greater productivity, and less burden on the patient.19 At this time, because of the limited clinical evidence available, the FDA warns against claims that genetic laboratory tests can predict patient response to specific drugs.20 In addition, the American Psychiatric Association has not incorporated pharmacogenetic testing into its clinical guidelines for treatment of MDD.2 Clinicians should also consider that pharmacogenetic testing has its limitations. It cannot account for food or drug interactions

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2020 15

PHARMACOGENETICS AND ANTIDEPRESSANT MANAGEMENT

Cognitive behavioral therapy, interpersonal psychotherapy, and antidepressants are the mainstays of major depression treatment. that also can affect how a patient metabolizes a drug. In addition, environmental factors play a significant role in the development of MDD, and these are unaccounted for if a clinician relies solely on pharmacogenetic testing to determine treatment.

genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther. 2015;98(2):127-134. 6. National Library of Medicine. Genetics Home Reference. What are genome-side association studies? NIH website. https://ghr.nlm.nih.gov/primer/ genomicresearch/gwastudies. Accessed August 26, 2020.

Conclusion

7. Food and Drug Association. Direct-to-consumer tests. FDA website. https://

Current research suggests that pharmacogenetic testing may improve response and remission rates among individuals with MDD, with several caveats.The cost of testing may not be worth it for patients with mild depression. Patients still may experience adverse effects despite using a drug selected using pharmacogenetic testing. The extent of the response across populations is unknown, particularly if a patient is an intermediate metabolizer. More studies are needed with higher numbers of patients, which will allow analysis of large amounts of genetic data to increase the odds of uncovering additional SNVs. Health care practitioners still should rely on clinical judgment because even when using pharmacogenetic testing, they will need to interpret the patient’s genotype report to select an appropriate medication. In addition, providers who use pharmacogenetic testing to help inform antidepressant choice will need to manage patient expectations. Pharmacogenetic testing offers more information, but there are no guarantees that a patient will improve with the selected antidepressant. Providers should discuss options with patients and apply testing on a case-by-case basis. ■

www.fda.gov/medical-devices/vitro-diagnostics/direct-consumer-tests#list. Accessed August 26, 2020. 8. Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther. 2008;83(2):234-242. 9. Bradley P, Shiekh M, Mehra V, et al. Improved efficacy with targeted pharmacogenetics-guided treatment of patients with depression and anxiety: a randomized clinical trial demonstrating clinical utility. J Psychiatr Res. 2018;96:100-107. 10. Hall-Flavin DK, Winner JG, Allen JD, et al. Utility of integrated pharmacogenomic testing to support the treatment of major depressive disorder in a psychiatric outpatient setting. Pharmacogenet Genomics. 2013;23(10):535-548. 11. Singh AB. Improved antidepressant remission in major depression via a pharmacokinetic pathway polygene pharmacogenetic report. Clin Psychopharmacol Neurosci. 2015;13(2):150-156. 12. Perez V, Salvert A, Espadaler J, et al. Efficacy of prospective pharmacogenetic testing in the treatment of major depressive disorder: results of a randomized, double-blind clinical trial. BMC Psychiatry. 2017;17(1):250. 13. Winner JG, Carhart JM, Altar CA, Allen JD, Dechairo BM. A prospective, randomized, double-blind study assessing the clinical impact of integrated pharmacogenomic testing for major depressive disorder. Discov Med. 2013;16(89):219-227. 14. Hall-Flavin DK, Winner JG, Allen JD, et al. Using a pharmacogenomic algo-

Lauren Nolan, MMSc, PA-C, is a clinician at The Hope Clinic at Emory University,Atlanta, Georgia, and Tia M. Solh, MT(ASCP), MSPAS, PA-C, is associate program director, South College Physician Assistant Program, and a psychiatry physician assistant in Atlanta.

rithm to guide the treatment of depression. Transl Psychiatry. 2012;2(10):e172. 15. Greden JF, Parikh SV, Rothschild AJ, et al. Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: a large, patientand rater-blinded, randomized, controlled study. J Psychiatr Res. 2019;111:59-67. 16. Rosenblat JD, Lee Y, McIntyre RS. The effect of pharmacogenomic testing

References

on response and remission rates in the acute treatment of major depressive

1. World Health Organization. Depression. WHO website. https://www.who.

disorder: a meta-analysis. J Affect Disord. 2018;241:484-491.

int/news-room/fact-sheets/detail/depression. January 30, 2020. Accessed

17. Bousman, CA, Hopwood M. Commercial pharmacogenetic-based

August 26, 2020.

decision-support tools in psychiatry. Lancet Psychiatry. 2016;3(6):585-590.

2. Gelenberg AJ, Freeman MP, Markowitz JC, et al. Practice Guideline for the

18. Bousman CA, Forbes M, Jayaram M, et al. Antidepressant prescribing in

Treatment of Patients With Major Depressive Disorder. 3rd ed. American

the precision medicine era: a prescriber’s primer on pharmacogenetic tools.

Psychiatric Association; 2010.

BMC Psychiatry. 2017;17(1):60.

3. Border R, Johnson EC, Evans LM, et al. No support for historical candidate

19. Groessl EJ, Tally SR, Hillery N, Maciel A, Garces JA. Cost-effectiveness of a

gene or candidate gene-by-interaction hypotheses for major depression

pharmacogenetic test to guide treatment for major depressive disorder.

across multiple large samples. Am J Psychiatry. 2019;176(5):376-387.

J Manag Care Spec Pharm. 2018;24(8):726-734.

4. Guengerich FP. Cytochrome P450 and chemical toxicology. Chem Res

20. Food and Drug Administration. Recommendations for genetic test manu-

Toxicol. 2008;21(1):70-83.

facturers and developers. FDA website. https://www.fda.gov/medical-devices/

5. Hicks JK, Bishop JR, Sangkuhl K, et al. Clinical Pharmacogenetics

safety-communications/fda-warns-against-use-many-genetic-tests-unapproved-

Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19

claims-predict-patient-response-specific#actions. Accessed August 20, 2020.

16 THE CLINICAL ADVISOR • OCTOBER 2020 • www.ClinicalAdvisor.com

FEATURE: TIFFANY LAMBRIGHT, MPH, MS, RN, CPNP-PC; NAOMI SCHAPIRO, PhD, RN, CPNP-PC

The Art of Managing Long-Acting Reversible Contraception for Teens Hormonal and nonhormonal intrauterine devices and hormonal implants have been proven safe and effective for adolescent patients.

dolescent pregnancy rates have been declining steadily since their peak in 1957, largely due to increased access to and use of effective forms of birth control.1,2 Long-acting reversible contraception (LARC) methods, such as hormonal and nonhormonal intrauterine devices (IUDs) and hormonal implants, have been proven safe and effective forms of birth control for adolescent patients and should be included among the full range of contraceptive options they are offered.3,4 LARC provides protection from pregnancy for 3 to 10 years depending on the method, offers noncontraceptive benefits, and may be preferred for adolescents with chronic conditions or with relative cautions or contraindications to estrogencontaining birth control options.5,6 Despite the wide acceptance of LARC methods, a number of barriers can impact their use: medical eligibility, adverse effects, access to methods, and the reluctance of some adolescents and families to consider these methods due to historical coercive uses of birth control among poor women and women of color.5-7 Effective counseling about contraception must take into account individual, sociocultural, and ethical-legal complexities, addressing the developmental needs and personal context of each adolescent patient. LARC provides protection from pregnancy for 3 to 10 years.

LARC METHODS

Both the American Academy of Pediatrics and the American College of Obstetricians and Continues on page 20

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LONG-ACTING REVERSIBLE CONTRACEPTION FOR ADOLESCENTS

Gynecologists recommend LARC methods as first-line options for adolescent patients.4,8 These recommendations are based on the proven safety record of LARC in young and nulliparous patients as well as its increased efficacy and greater continuation and satisfaction rates among adolescents compared with short-acting methods.3,9 Several LARC methods are available in the United States, including 1 progestin-containing subdermal implant (etonogestrel [ENG]), 4 progestin-containing (levonorgestrel [LNG]) IUDs, and 1 nonhormonal copper IUD (Table 1).10-15 Rosenstock et al evaluated 7472 participants enrolled in the Contraceptive CHOICE Project, a prospective cohort study of women offered no-cost contraception.16 The study’s primary objective was to compare 12-month continuation rates among women of various ages. Among adolescents aged 14 to 19 years, method satisfaction rates 1 year after initiation were 54%, 56%, and 65.7% for the ENG implant, copper IUD, and LNG IUD, respectively, versus 33.1% for oral contraceptive pills.16 However, uptake and use of LARC is relatively lower than uptake and use of shorter-acting methods among adolescents.3,9 For many teens, the decision to start a LARC method may be made over several appointments and conversations with

providers, possibly after trials of other methods. Clinicians need to be open to this process and assure that scheduling practices can accommodate their patients’ needs. It is important to respect the adolescent’s choice as well as the process and time it may take to make that choice. Although a LARC method is not going to be the best fit for every adolescent, all patients should be informed about LARC options during comprehensive birth control counseling. This counseling should be patient-centered and not directive or coercive; the focus should be on the patient’s priorities and goals (Table 2).5 Contraindications Outside of confirmed or suspected pregnancy and unexplained genital bleeding, there are few absolute contraindications to LARC for the majority of adolescents. In the case of LNG IUDs and the ENG implant, sensitivity to progestin is a contraindication, as is a history of breast cancer, hepatic tumors, or active liver disease.10-14 Contraindications for both LNG and copper IUDs include distortion of the uterine cavity, pelvic tuberculosis, systemic lupus erythematosus with positive or unknown antiphospholipid

TABLE 1. LARC Medications, Dosage, Duration, Mechanisms of Action, and Adverse Effects

Dose

Etonogestrel (ENG) Subdermal Implant10

Levonorgestrel (LNG) IUD11-14

Copper (CuT380A) IUD15

68 mg (Nexplanon™)

• 52 mg (Liletta™, Mirena™)

Paragard™

• 19.5 mg (Kyleena™) • 13.5 mg (Skyla™) Duration of efficacy

FDA approved for 3 y; research suggests 4-5 y

FDA approved for 3-5 y, depending on product

FDA approved for 10 y

Effects on ovulation, May inhibit ovulation (first year); changes in fertilization, cervical mucus and tubal motility inhibit sperm and implantation migration and fertilization

Inhibition of ovulation not a major mechanism of action; thickens cervical mucus; sterile inflammatory action of foreign body in uterus causes release of glycodelin-A, inhibits fertilization; endometrial sloughing and glandular activity prevents implantation

Does not inhibit ovulation; sterile inflammatory action of foreign body in the uterus causes cytotoxic reaction to both sperm and ovum impairing fertilization; cytotoxic reaction impairs implantation

Onset of effectiveness

Back-up method for 7 days

May be used as emergency contraception; back-up method not needed

Adverse effects

• Irregular spotting/bleeding; may decrease by 6 months

• Spotting, irregular bleeding, usually markedly decreased by 6 months

• Heavier, longer periods, no change in timing of menstrual cycle

• Insertion site briefly sore, bruised

• Lighter to no periods

• Menstrual cramps, mood changes, weight gain, headaches, acne (less common)

• Post-insertion cramping; usually subsides by 6 months

• Post-insertion cramping for several months, stronger cramps during periods

• Skin changes to the upper arm (rare)

• Bloating, nausea, headaches, breast pain, acne (less common)

LARC, long-acting reversible contraception; IUD, intrauterine device; y, years

20 THE CLINICAL ADVISOR • OCTOBER 2020 • www.ClinicalAdvisor.com

• Anemia (less common) • Allergic urticaria (rare)

antibodies, cervical or endometrial cancer, and a history of complicated solid organ transplant with failure or rejection.17 Severe thrombocytopenia, Wilson disease, and an allergy to copper are additional contraindications for the copper IUD.17 In the setting of current pelvic inflammatory disease (PID), purulent cervicitis, or known gonorrheal or chlamydial infection, IUD insertion should be deferred until after successful treatment.18 Unknown gonorrhea or chlamydia status is not a reason to delay insertion, but adolescents should be screened at the time of insertion and treated appropriately if one of these infections is detected (a positive result does not require removal of the IUD).19 Drug Interactions Both ENG and LNG are progestins, synthetic steroid hormones that activate the progesterone receptor. Progestins are metabolized via the cytochrome P450 (CYP) 3A4 pathway.10-14 Other medications, including many anti-inflammatory and anti-seizure medications, are CYP3A4 enzyme-inducing and can increase the metabolism of progestins; there have been documented contraceptive failures in patients taking CYP3A4 enzyme-inducing anti-seizure medications while using the

ENG implant and other low-dose progestins. However, LNG’s primary action in IUDs is local and contributes to only part of the IUD’s efficacy, making it an available option for patients on these anti-seizure medications.19 The copper IUD has no drug interactions,15 which can be especially beneficial for individuals taking multiple medications. Noncontraceptive Benefits In addition to being effective, reversible contraception, LARC methods offer several potential noncontraceptive benefits, which may be the reason some adolescents are interested in a particular method. One noncontraceptive use for LNG IUDs is treatment of heavy uterine bleeding and/or dysmenorrhea.20 This can be relevant for individuals with anemia and/or bleeding disorders (eg, von Willebrand disease), for whom hormonal therapy often is required as part of a regimen to limit heavy menstrual bleeding.4,5 The LNG IUD is also the most effective method of achieving amenorrhea in individuals who have difficulty managing menstrual flow or for whom menstrual flow is distressing (eg, adolescents with developmental delays and transgender or nonbinary youth).20,21 The hormonal implant also can be beneficial for this indication but

TABLE 2.Tips for Counseling Adolescent Patients About Contraception5 • Ask about long-term reproductive plans: if, when, and under what conditions a patient would like to have children. • Ask what is most important in a method; do not assume that efficacy is the only or the most important characteristic. • Encourage adolescents to think about birth control not only in the context of any current relationships but also in relation to how it can support their life, educational, and career goals. • Be inclusive: talk to all adolescents with a uterus about contraceptive options, including those who may identify as male, transgender, or nonbinary, and those who may have an interest in either contraceptive or noncontraceptive benefits of long-acting reversible contraception (LARC). • Be aware of the potential impact of racism and class prejudice on a patient’s beliefs and experiences as well as your own implicit biases.5 • Practice within a reproductive justice framework: respect the patient’s autonomy over their body and choices.5 • Go over expected adverse effects as well as pros and cons of each method, encouraging the patient to ask questions. • Listen to each patient’s concerns, dispel myths, and provide accurate information to help them make their decision. • Always start the conversation about contraception with a teen alone to elicit their confidentiality needs and preferences and to discern whether or not they are being coerced by others. Use this time to screen for sexual abuse or exploitation. • For teens who wish to involve a parent or caregiver in their contraceptive decisions, include that person in the discussion, in the office or by phone. • Make sure you are familiar with the minor consent and confidentiality laws in your statea and how your practice bills for confidential services. For adolescents who cannot involve family members, make sure there is a system set up to protect their confidentiality. • For many teens, the decision to start a LARC method may be made over several appointments and may involve trials of other methods; be open to this and assure that scheduling practices can accommodate these needs. • When a patient decides on a LARC method, include a written consent form that outlines the details of insertion, removal, and potential adverse effects, and give the patient a copy to keep. a Guttmacher Institute. An overview of minors’ consent law. Guttmacher Institute. State policies in brief Web site. https://www.guttmacher.org/state-policy/explore/overview-minors-consent-law. Published 2020. Updated May 1, 2020. Accessed August 3, 2020. b Reproductive Health Access Project. www.reproductiveaccess.org. Accessed August 14, 2020.

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LONG-ACTING REVERSIBLE CONTRACEPTION FOR ADOLESCENTS

In addition to being effective, reversible contraceptive methods, LARC offers several other potential noncontraceptive benefits. does not always lead to amenorrhea. For most teens, the implant is acne-neutral, or even beneficial in helping to clear acne.10 Both the implant and the LNG IUDs can be used in the treatment of endometrial hyperplasia, which is common in patients with polycystic ovarian syndrome.22 Managing Adverse Effects

Managing adverse effects of LARC methods begins with managing patient expectations through comprehensive preinsertion counseling that includes anticipatory guidance about likely and possible adverse effects.6,10-15,23,24 Almost all patients using a LARC method will experience some change to their menstrual cycle.These changes can range from heavier bleeding and cramping, often experienced with the copper IUD, to unscheduled or even continuous irregular bleeding, associated with ENG implants and LNG IUDs, to amenorrhea, often associated with the higher-dose LNG IUDs.6,24 During pre-insertion counseling, providers should ensure that patients understand they will not have a regular menstrual cycle while using progestin-only LARC methods. Explore beliefs and myths about the menstrual cycle and not having a monthly period and reinforce the proven quick return of fertility after removal of LARC.25 In addition, patients often need to be reassured that irregular or unscheduled bleeding does not decrease the efficacy of the method.24 Bleeding changes are cited commonly as a reason for LARC discontinuation26; patients should be counseled to return to the

provider to explore management options if bleeding changes are bothersome. When the patient is motivated to continue the method, managing heavy and/or unscheduled bleeding can improve satisfaction and continuation. Table 3 lists various regimens to manage menstrual bleeding changes commonly associated with LARC.19,23,24 The table is based on studies of specific regimens, and what is used in practice may vary. For example, ibuprofen is not listed as a treatment for LNG IUD-related irregular bleeding but is a common first-line nonsteroidal anti-inflammatory drug (NSAID) used in practice, following the same regimen listed for copper IUD-related heavy bleeding. It is important to note that secondary amenorrhea caused by a contraceptive method does not require medical intervention.19 Discomfort During and Immediately After IUD Insertion Pain during and in the days immediately after IUD insertion generally can be managed with NSAIDs. A prophylactic dose of an NSAID is helpful before insertion. Also consider providing a heating pad for the patient to hold over their abdomen during insertion. A cervical block can be used during the insertion process, but research is mixed as to its effectiveness.27 Another consideration to ease a patient’s anxiety and potential discomfort is to allow the patient to have a chosen support person in the room during insertion. It is standard procedure at some adolescent practices to have a trained staff member Continues on page 24

TABLE 3.Treatment Options for Managing Bleeding Changes LARC Method and Effect on Bleeding

Management Options20,23,24

Heavy bleeding caused by copper IUD

• Ibuprofen, 400 mg 4 times daily for 7 d • Indomethacin, 25 mg 2 times daily for 7 d OR 4 times daily for 3 d • Mefenamic acid, 100 mg 3 times daily for 3 d OR 500 mg 3 times daily for 5 d • Diclofenac, 50 mg 3 times daily for 1 d THEN 25 mg 3 times daily for 4 d • Tranexamic acid, 1500 mg 3 times daily for 5 d • Desmopressin, 300 mcg (intranasal) once daily for 5 d

Heavy and/or irregular bleeding caused by LNG IUD

• Naproxen, 500 mg 2 times daily for 5 d • Tranexamic acid, 500 mg 3 times daily until bleeding stops • Mifepristone, 100 mg once monthly on an ongoing basis

Irregular bleeding caused by ENG implant

• Mefenamic acid, 500 mg 3 times daily for 5 d • Doxycycline, 100 mg once daily for 5 d • Combined estrogen-progestin pill, low dose once daily for 10-20 d (up to 3 mo if needed)

d, days; ENG, etonogestrel; IUD, intrauterine device; LARC, long-acting reversible contraception; LNG, levonorgestrel; mo, months

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LONG-ACTING REVERSIBLE CONTRACEPTION FOR ADOLESCENTS

LEGAL RULINGS ON MINOR CONSENT

Current Threats to Adolescent Confidentiality and Contraceptive Access The legal underpinnings of minor consent in the United States emerged during the 1970s and 1980s, with Supreme Court rulings affirming the rights of mature minors to make some medical decisions and the right to privacy in consenting to contraception and abortion.1,2 Minors’ ability to consent to contraception varies from state to state, with 22 states and the District of Columbia having no restrictions.3 However, the right to consent does not necessarily mean access to contraception.Twenty-one states have allowed insurance companies to opt out of the contraceptive mandate in the Affordable Care Act,4 and a recent Supreme Court decision allows religious institutions in every state to opt out of providing this service.5 Coinciding with these opt-outs, the percentage of hospitals and health systems run by religious organizations that do not provide contraception has increased, particularly in the South and Midwest.6 Recent federal executive decisions raise concerns about whether teens from low-income households can continue to rely on confidential and affordable access to contraception through clinics funded by Title X,7 which has provided

available to provide patients with a hand to hold, a helpful distraction, and guidance on coping techniques. While heavy cramping may decrease over time for some patients, in others it may persist.28 Patients should be counseled on how to appropriately treat painful or debilitating cramps, with NSAIDs being first-line treatment after assuring correct placement of the device and no other underlying problem.19 Acne Acne caused or worsened by a progestin-containing LARC should be treated the same as acne due to other causes. Treatment of moderate to severe acne should include combination therapy with a topical retinoid and a topical antimicrobial that contains benzoyl peroxide. Consider adding a daily oral antibiotic for the shortest duration necessary (no more than 3-4 months). Alternative adjunctive therapies include spironolactone and/or combined hormonal oral contraceptives.29 Uncommon Adverse Effects Less common adverse effects and complications of IUD use in adolescents include expulsion, perforation, infection, and ectopic pregnancy, but occurrence rates for each of these are

longstanding family planning funding for low-income individuals8 whether or not their state allowed contraceptive consent and/or funding for minors. The impact of these changes on contraceptive access is unknown, but past research shows that access to effective contraception, including LARC, is a primary factor contributing to the decline of teen pregnancy.9 References 1. Schlam L, Wood JP. Informed consent to the medical treatment of minors: law and practice. Health Matrix Clevel. 2000;10(2):141-174. 2. Schapiro NA, Mejia J. Adolescent confidentiality and women’s health: history, rationale, and current threats. Nurs Clin North Am. 2018;53(2):145-156. 3. Guttmacher Institute. State legislation tracker. Major developments in sexual and reproductive health. https://www.guttmacher.org/state-policy/explore/insurance-coverage-contraceptives. Accessed August 29, 2020. 4. American College of Obstetricians & Gynecologists. ACOG Committee Opinion No. 803: confidentiality in adolescent health care. Obstet Gynecol. 2020;135(4):e171-e177. 5. Keith K. Supreme court upholds broad exemptions to contraceptive mandate — for now. Health Affairs Blog. July 9, 2020. 6. Takahashi J, Cher A, Sheeder J, Teal S, Guiahi M. Disclosure of religious identity and health care practices on Catholic hospital websites. JAMA. 2019;321(11):1103-1104. 7. Schapiro NA. Title X regulatory changes and their impact on adolescent health. J Pediatr Health Care. 2020;34(2):171-176. 8. Napili A. Title X (Public Health Service Act) Family Planning Program. Washington DC: Congressional Research Service; August 31, 2017. RL33644. 9. Lindberg L, Santelli J, Desai S. Understanding the decline in adolescent fertility in the United States, 2007-2012. J Adolesc Health. 2016;59(5):577-583.

low. Although IUD expulsion is more common in younger and nulliparous patients, rates are still relatively low: approximately 6% in patients aged 13 to 19 years.30 The risk for PID secondary to IUD insertion also is quite low: 0% to 2% in the absence of cervical infection and 0% to 5% with an unknown cervical infection.31 Evidence does not definitively indicate a higher risk for PID in adolescents compared with older patients.32 Similarly, perforation, seen in about 0.1% of all insertions, does not seem to be more common in adolescents compared with older patients.32 The ability to calculate the risk for ectopic pregnancy in IUD users is limited by low pregnancy rates among IUD users. It is important to note that IUDs do not cause ectopic pregnancy. Even though the percentage of pregnancies that are ectopic is higher in IUD users compared with the percentage among all pregnancies, because IUD failure is so rare, the absolute risk for ectopic pregnancy is significantly lower in patients with an IUD than in the general population.33 In general, clinicians should help teens manage adverse effects of LARC methods, determining what is reasonable for them, and always remove a device at the patient’s request, regardless of how long they have had it.

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Continues on page 28

LONG-ACTING REVERSIBLE CONTRACEPTION FOR ADOLESCENTS

Conclusion

14. Skyla [package insert]. Whippany, NJ: Bayer HealthCare; 2018.

The COVID-19 pandemic has magnified preexisting health inequities in access to health care.34 Clinics serving adolescents have closed and others are conducting most visits via telehealth. Challenges for teens seeking contraception include lack of access to smartphones or laptops, lack of consistent Wi-Fi or cell phone access, and crowded living conditions.The use of headphones, asking yes-or-no questions, and using the chat function can help protect patient confidentiality.35 Maintaining and increasing access to LARC and other contraceptive methods during these challenging times will require creativity on the part of clinics, providers, and patients to ensure that adolescents can make autonomous decisions about their sexual health. ■

15. Paragard [package insert]. Trumbull, CT: CooperSurgical, Inc; 2020. 16. Rosenstock JR, Peipert JF, Madden T, Zhao Q, Secura GM. Continuation of reversible contraception in teenagers and young women. Obstet Gynecol. 2012;120(6):1298-1305. 17. Nelson AL. Contraindications to IUD and IUS use. Contraception. 2007;75(6 suppl):s76-s81. 18. Hardeman J, Weiss BD. Intrauterine devices: an update. Am Fam Physician. 2014;89(6):445-450. 19. Curtis KM, Jatlaoui TC, Tepper NK, et al. US selected practice recommendations for contraceptive use, 2016. MMWR Recomm Rep. 2016;65(4):1-66. 20. Bayer LL, Hillard PJA. Use of levonorgestrel intrauterine system for medical indications in adolescents. J Adolesc Health. 2013;52(4 suppl):s54-s58. 21. Guss CE. Intrauterine devices in gender minority youth: an option to decrease dysphoria and unintended pregnancies. J Adolesc Health. 2019;65(1):3-4.

Tiffany Lambright, MPH, MS, RN, CPNP-PC, is a pediatric nurse practitioner and assistant clinical professor at the University of California, San Francisco, with expertise in the intersection of adolescent development and sexual/reproductive health. Naomi Schapiro, PhD, RN, CPNP-PC, is a professor emeritus of family health care nursing at the University of California, San Francisco, and a pediatric nurse practitioner at La Clinica de la Raza.

22. Fitzgerald S, DiVasta A, Gooding H. An update on PCOS in adolescents. Curr Opin Pediatr. 2018;30(4):459-465. 23.Villavicencio J, Allen RH. Unscheduled bleeding and contraceptive choice: increasing satisfaction and continuation rates. Open Access J Contracept. 2016;7:43-52. 24. Friedlander E, Kaneshiro B. Therapeutic options for unscheduled bleeding associated with long-acting reversible contraception. Obstet Gynecol Clin North Am. 2015;42(4):593-603. 25. Sangraula M, Garbers S, Garth J, Shakibnia EB, Timmons S, Gold MA.

References

Integrating long-acting reversible contraception services into New York City

1. Ventura SJ, Hamilton BE, Matthews TJ. National and state patterns of teen

school-based health centers: quality improvement to ensure provision of

births in the United States, 1940-2013. Natl Vital Stat Rep. 2014;63(4):1-34.

youth-friendly services. J Pediatr Adolesc Gynecol. 2017;30(3):376-382.

2. Lindberg L, Santelli J, Desai S. Understanding the decline in adolescent

26. Moreau C, Cleland K,Trussell J. Contraceptive discontinuation attributed to

fertility in the United States, 2007-2012. J Adoles Health. 2016;59(5):577-583.

method dissatisfaction in the United States. Contraception. 2007;76(4):267-272.

3. Sherin M, Waters J. Long-acting reversible contraceptives for adolescent

27. Hillard PJA. Practical tips for intrauterine device counseling, insertion, and pain

females: a review of current best practices. Curr Opin Pediatr. 2019;31(5):675-682.

relief in adolescents: an update. J Pediatr Adolesc Gynecol. 2019;32(5s):s14-s22.

4. American College of Obstetrics & Gynecology. ACOG Committee

28. Diedrich JT, Desai S, Zhao Q, Secura G, Madden T, Peipert JF. Association

Opinion No. 735: adolescents and long-acting reversible contraception:

of short-term bleeding and cramping patterns with long-acting reversible

implants and intrauterine devices. Obstet Gynecol. 2018;131(5):e130-e139.

contraceptive method satisfaction. Am J Obstet Gynecol. 2015;212(1):50.e1-8.

5. Menon S, Committee on Adolescence. Long-acting reversible contracep-

29. Zaenglein AL. Acne vulgaris. N Engl J Med. 2018;379(14):1343-1352.

tion: specific issues for adolescents. Pediatrics. 2020;146(2):e2020007252.

30. Aoun J, Dines VA, Stovall DW, Mete M, Nelson CB, Gomez-Lobo V.

6. Itriyeva K. Use of long-acting reversible contraception (LARC) and the

Effects of age, parity, and device type on complications and discontinuation

Depo-Provera shot in adolescents. Curr Probl Pediatr Adolesc Health Care.

of intrauterine devices. Obstet Gynecol. 2014;123(3):585-592.

2018;48(12):321-332.

31. Mohllajee AP, Curtis KM, Peterson HB. Does insertion and use of

7. Dehlendorf C, Ruskin R, Grumbach K, et al. Recommendations for intra-

an intrauterine device increase the risk of pelvic inflammatory disease

uterine contraception: a randomized trial of the effects of patients’ race/

among women with sexually transmitted infection? A systematic review.

ethnicity and socioeconomic status. Am J Obstet Gynecol. 2010;203(4):319.e1-8.

Contraception. 2006;73(2):145-153.

8. Committee on Adolescence. Contraception for adolescents. Pediatrics.

32. Jatlaoui TC, Riley HEM, Curtis KM. The safety of intrauterine devices

2014;134(4):e1244-1256.

among young women: a systematic review. Contraception. 2017;95(1):17-39.

9. Society for Adolescent Health and Medicine. Improving knowledge about,

33. Russo JA, Miller E, Gold MA. Myths and misconceptions about long-acting

access to, and utilization of long-acting reversible contraception among

reversible contraception (LARC). J Adoles Health. 2013; 52(4 Suppl):S14-S21.

adolescents and young adults. J Adolesc Health. 2017;60(4):472-474.

34. Yancy CW. COVID-19 and African Americans. JAMA. 2020; April 15. doi:

10. Nexplanon [package insert]. Whitehouse Station, NJ: Merck & Co., Inc; 2019.

10.1001/jama.2020.6548.

11. Mirena [package insert]. Whippany, NJ: Bayer HealthCare; 2020.

35. Barney A, Buckelew S, Mesheriakova V, Raymond-Flesch M. The COVID-19

12. Lilletta [package insert]. Irvine, CA: Allergan USA; 2019.

pandemic and rapid implementation of adolescent and young adult telemedicine:

13. Kyleena [package insert]. Whippany, NJ: Bayer HealthCare; 2018.

challenges and opportunities for innovation. J Adolesc Health. 2020;67(2):164-171.

28 THE CLINICAL ADVISOR • OCTOBER 2020 • www.ClinicalAdvisor.com

FEATURE: PAULA M. BARRENECHEA, MPAS, PA-C; STEVIE M. REDMOND, MPA, PA-C

Aspiration Pneumonia Mistaken for CommunityAcquired Pneumonia A patient with a history of achalasia presents to the emergency department with pneumonia that quickly leads to hypoxic respiratory failure.

It can be difficult to differentiate aspiration pneumonia from other causes.

53-year-old woman presents with a 3-day history of generalized body fatigue, fever, weakness, and shortness of breath. The patient’s medical history is significant for achalasia but otherwise is noncontributory. At triage, the patient’s vital signs are taken. An electrocardiogram (ECG) shows atrial flutter. A chest radiograph reveals bibasilar infiltrates and bilateral pleural effusions, indicative of pneumonia. Complete blood cell count and complete metabolic panel results are within normal limits. Because radiography shows infiltrates and the patient is having trouble breathing and is experiencing progressively worsening fever, chills, sweats, and rigors, she is admitted, treated with intravenous (IV) antibiotics, and monitored. The patient converts to a normal sinus rhythm after admission but shortly thereafter goes into shock (Table 1, page 30). Her heart rate increases to 109 beats per minute, her blood pressure decreases, and her O2 saturation level drops to 92%, despite delivery of 4 liters of O2 per minute via nasal cannula. Collectively, these changes indicate systemic inflammatory response syndrome and hypoxic respiratory failure. A second chest radiograph shows increasing interstitial and alveolar radiodensities in the lower lungs.The patient’s antibiotic regimen is changed to levofloxacin, piperacillin/tazobactam, and vancomycin. The patient is transferred to the intensive care unit (ICU) and placed on a ventilator. A pulmonologist is called to consult on the

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2020 29

A CASE OF ACHALASIA AND ASPIRATION PNEUMONIA

TABLE 1. Summary of Patient’s Vital Signs Vital Signs

At Triage

After Admission

Blood pressure, mm Hg

127/77

93/44

Heart rate, beats/min

109

Respiratory rate, breaths/min

O2 saturation rate, %

94 (on room air)

92 (on nasal cannula)

case. Cultures for Legionella antigens, influenza A and B, and methicillin-resistant Staphylococcus aureus are negative. A CT scan of the chest, which is more sensitive and specific for aspiration pneumonia, empyema, and abscess than radiographs, shows diffuse alveolar and ground glass opacities, a common finding in early interstitial lung disease.1,2 Although cultures did not reveal any significant abnormal findings, a bronchoscopy recovers slightly sanguineous, cloudy fluid. After the patient is on a ventilator for 10 days, sputum cultures are positive for Candida albicans infection, a common cause of nosocomial sinusitis and a common sequela of endotracheal intubation due to impairment of sinus drainage.3 A therapeutic thoracentesis is considered, but because the effusions remain stable, it is deemed unnecessary. During the next 4 days of hospitalization, the patient continues to be febrile, with her temperature ranging from 37.5°C to 38°C, and her respiratory rate is 20 to 30 breaths per minute. However, chest radiographs show progressively decreasing bibasilar infiltrates. After another 5 days of intubation, the respiratory therapy team attempts ventilator weaning, which initially fails. Her laboratory values show hypocalcemia, hypokalemia, and anemia. The following day, the patient appears more comfortable, more easily aroused, and a chest radiograph reveals considerably less bibasilar infiltrates. Due to these improvements, the respiratory team decides to reattempt ventilator weaning. Pulmonology provides continuous positive airway pressure ventilation, with gradual weaning from the pressure support to increase the likelihood of spontaneous breathing. Weaning from the ventilator is successful. For the next 4 days, the patient continues IV antibiotics and daily chest radiographs to monitor her bibasilar infiltrates. At discharge, the patient is instructed to take oral antibiotics and practice breathing with a spirometer to increase her forced expiratory volume capacity. She follows up with the pulmonologist every 2 weeks for the next 2 months to monitor for the complete resolution of the bibasilar infiltrates and effusions on chest radiograph.

Misdiagnosis of Community-Acquired Pneumonia

On a follow-up visit to the pulmonologist, she is told that she had a severe case of community-acquired pneumonia (CAP), likely caused by her close work with children. However, the lack of positive cultures for Streptococcus pneumoniae, Haemophilus influenzae, and Legionella pneumophila, common causes of CAP, call this diagnosis into question. Six months after the resolution of her pneumonia, the patient experiences worsening achalasia symptoms consisting of increased frequency of heartburn and difficulty swallowing, which prompts her to make an appointment with her gastroenterologist. The physician orders a barium swallow to test her esophageal motility. The results reveal decreased peristaltic functioning of her distal esophagus. In addition, they show increased pressure and tightening of her lower esophageal stricture, as seen by a “bird’s beak” appearance on radiography.4 The gastroenterologist refers the patient to a general surgeon to discuss the possibility of performing a laparoscopic Heller myotomy (LHM) to release the tightened lower esophageal sphincter (LES). Initially, the surgeon is hesitant to consider the procedure because this treatment option usually is reserved for patients with severe achalasia who are at least 60 years of age. Because the LHM procedure loosens the LES, gastroesophageal reflux symptoms can occur. Other complications of the surgery include esophageal perforation and recurrent dysphagia due to incomplete myotomy.5 Without the surgery, however, the patient likely will continue to live with untreated achalasia, placing her at risk for further episodes of aspiration pneumonia as well as the development of esophageal squamous cell cancer. Although the risk is not absolute, there is a heightened risk for esophageal cancer in patients with achalasia.4 Bacterial overgrowth from trapped food in the esophagus may be a key contributor to chronic esophageal inflammation, worsening achalasia symptoms, and the development of a neoplastic process in the esophagus.6 The patient’s recent history of abrupt-onset dyspnea with rapid progression to hypoxic respiratory failure leads the surgeon to believe that her suspected CAP actually had been a case of aspiration pneumonia. He believes that her worsening achalasia symptoms contributed to her pneumonia. After considering the patient’s entire clinical picture, he decides to carry out the LHM procedure. The patient responds well to the procedure, and does not have any complications apart from some gastroesophageal reflux symptoms, which are controlled by proton-pump inhibitors. She has had no achalasia-related symptoms of heartburn and dysphagia. Five years later, she has not had any recurrences of aspiration pneumonia.

30 THE CLINICAL ADVISOR • OCTOBER 2020 • www.ClinicalAdvisor.com

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A CASE OF ACHALASIA AND ASPIRATION PNEUMONIA

Aspiration pneumonia should remain a differential diagnosis in any case of rapid-onset pneumonia and hypoxic respiratory failure. Aspiration Pneumonia

Aspiration that leads to pneumonia is more commonly thought to result from aspirating a large amount of food, saliva, or fluid. However, clinical research shows that microaspirations have a high chance of resulting in aspiration pneumonia.7 The identified risk factors for aspiration include a history of dysphagia, reduced consciousness, gastric reflux, suppressed cough reflex, a recent surgical procedure in the oropharyngeal region, and intubation. Increased age also is a known risk factor for aspiration because the esophageal muscles and epiglottis weaken with age.8 Patients with known, preexisting conditions that may increase their risk for aspiration need to be made aware of this heightened risk (Table 2).9 To minimize the risk for aspiration, they should be encouraged to eat and drink slowly, chew for at least 30 seconds before swallowing, and tuck the chin to provide support to the esophageal muscles during swallowing. Additional strategies to prevent aspiration include sitting up for at least 3 hours after eating, elevating the head of the bed or sleeping with more pillows, and working with a speech pathologist to improve swallowing techniques.10 In the case presented, the patient had a history of achalasia and mild dysphagia and had been practicing preventive

measures such as eating and drinking slowly. Thus, even with precautions, aspiration can occur. Patients at risk should be educated on how rapidly aspiration pneumonia symptoms, such as dyspnea and respiratory failure, can develop, so they know to seek prompt medical intervention. Hospital precautions always should be taken with patients who have been extubated recently or who have a history that puts them at increased risk for aspiration. Aspiration pneumonia should be considered with any case of rapid-onset pneumonia and rapid progression to hypoxic respiratory failure.This awareness will better direct treatment for patients who need rapid and critical attention. ■ Paula M. Barrenechea, MPAS, PA-C, is a physician assistant fellow at MD Anderson Cancer Center, in Houston. Stevie M. Redmond, MPA, PA-C, is an associate professor in the Department of Physician Assistant, at Augusta University, in Augusta, Georgia. References 1. Collins J, Stern EJ. Ground glass opacity at CT: the ABCs. AJR Am J Roentgenol. 1997;169(2):355-367. 2. Khan AN, Sabih A. Aspiration pneumonia imaging. Medscape.website. https://emedicine.medscape.com/article/353329-overview#a. January 23,

TABLE 2. Diseases and Conditions With Risk Factors for Aspiration Pneumonia9 Risk Factor

Disease/Condition

Altered consciousness

Alcoholism, drug overdose, seizures, head trauma, general anesthesia

Dysphagia

Gastroesophageal reflux disease, achalasia, esophageal stricture, neoplasm, diverticula, tracheoesophageal fistula, incompetent cardiac sphincter, oropharyngeal obstruction, xerostomia

2016. Accessed August 31, 2020. 3. Le Moal G, Lemerre D, Grollier G, Desmont C, Klossek JM, Robert R. Nosocomial sinusitis with isolation of anaerobic bacteria in ICU patients. Intensive Care Med. 1999;25(10):1066-1071. 4. Howard PJ, Maher L, Pryde A, Cameron EW, Heading RC. Five year prospective study of the incidence, clinical features, and diagnosis of achalasia in Edinburgh. Gut. 1992;33(8):1011-1015. 5. Zaninotto G, Costantini M, Portale G, et al. Etiology, diagnosis, and treatment of failures after laparoscopic Heller myotomy for achalasia. Ann Surg. 2002;235(2):186-192. 6. Nesteruk K, Spaander MCW, Leeuwenburgh I, Peppelenbosch MP, Fuhler GM. Achalasia and associated esophageal cancer risk: what lessons can we

Neurologic disorders

Mechanical obstruction

Multiple sclerosis, myasthenia gravis, Parkinson disease, dementia, pseudobulbar palsy, amyotrophic lateral sclerosis, stroke Nasogastric tube, percutaneous endoscopic gastrostomy tube, endotracheal intubation, tracheostomy, upper endoscopy, bronchoscopy

learn from the molecular analysis of Barrett’s-associated adenocarcinoma? Biochim Biophys Acta Rev Cancer. 2019;1872(2):188291. 7. Bassis CM, Erb-Downward JR, Dickson RP, et al. Analysis of the upper respiratory tract microbiotas as the source of the lung and gastric micro biotas in healthy individuals. mBio. 2015;6(2):e00037. 8. Muder RR. Pneumonia in residents of long-term care facilities: epidemiology, etiology, management, and prevention. Am J Med. 1998;105(4):319-330.

Other

Protracted vomiting, poor dental hygiene, drowning, supine position, large-volume tube feedings, general debility, ascites, gastroparesis, ileus, glottic insufficiency

9. Lo WL, Leu HB, Yang MC, Wang DH, Hsu ML. Dysphagia and risk of aspiration pneumonia: a nonrandomized, pair-matched cohort study. J Dent Sci. 2019;14(3):241-247. 10. Fink TA, Ross JB. Are we testing a true thin liquid? Dysphagia. 2009;24(3):285-289.

32 THE CLINICAL ADVISOR • OCTOBER 2020 • www.ClinicalAdvisor.com

Dermatologic Look-Alikes Hyperpigmented Cutaneous Rash SAMI YOUNES, BS; JOANNE JACOB, BS; EMILY BURNS, BA; CHRISTOPHER RIZK, MD

CASE #1

CASE #2

A 40-year-old woman presents to the dermatology clinic for evaluation of a dark rash on her shin. She reports that she has had the rash for 3 years and describes it as extremely itchy and spreading. Physical examination shows hyperpigmented papules that are approximately 1 to 3 mm in diameter on the pretibial region of the patient’s leg. She reports no other medical problems, no relevant family history, and no systemic symptoms, and she takes no medications. Histologic examination with Congo red staining reveals eosinophilic infiltrate in the papillary dermis, with apple green birefringence.

A 30-year-old woman presents to the dermatology clinic for evaluation of dark rippled lesions in the interscapular area and upper back. The lesions are pruritic and have persisted for the past 3 years. Physical examination reveals a circular area of slightly hyperpigmented papules on her upper back that is approximately 1 to 3 mm in diameter. She reports no pain, no other medical problems, no family history, and she does not take any medications. Histologic examination with Congo red staining reveals eosinophilic infiltrate in the papillary dermis with apple green birefringence.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2020 33

Dermatologic Look-Alikes CASE #1

Lichen Amyloidosis

Amyloidosis is the deposition of extracellular amyloid protein throughout the body with impaired functioning of the affected organs.When isolated to the skin, it is termed primary cutaneous amyloidosis (PCA), with numerous subtypes such as nodular, macular, and lichen (papular).1 Lichen amyloidosis (LA) primarily affects individuals of Southeast Asian and Central and South American descent.The condition is less common in European or North American populations.1,2 Although studies disagree on the sex prevalence of PCA as a whole, LA seems to occur more frequently in men than women.3 The etiology of LA is not well understood, but it is strongly associated with chronic skin irritation and friction.3 Focal epidermal damage can cause necrosis of keratinocytes and transformation into amyloid within the upper dermis.4 Patients who present with LA often have a history of using scrub products or mechanical exfoliation during bathing. An additional risk factor may be dry skin; cases of LA frequently increase during the winter months.3 LA often presents on areas of the body that are easily scratched, and scratching worsens the pigmentation and accelerates amyloid formation.5 LA can be an autosomal-dominant disorder, with many patients presenting with a family history of LA.6 There is a less common link between LA and multiple endocrine neoplasia type 2A, which should be considered in risk calculations.7 LA often presents clinically as pruritic, painless, dome-shaped yellow-brown papules. The pigmentation in these lesions is not uniform and presents as hyperpigmented dots surrounding a depigmented center.3 The papules often are 1 to 3 mm in size and very closely interspersed.2 The lesions tend to appear on extensor surfaces, such as the pretibial region of the lower limbs, but also can present on the face, neck, and axilla. Spontaneous resolution of LA occurs over 6 to 20 months, but hypertrophic lesions can last longer.3 An uncommon variant of LA can present with bullae in either intraepidermal or subepidermal layers.8 On dermoscopy, LA lesions display white central hubs or a whitish scar-like center, with surrounding brown dots.4 When biopsied and examined histologically, the center scarring corresponds to orthohyperkeratosis and acanthosis.4 This central scarring can be structureless and disorganized or well defined by radial streaking and a rim.4,5 An eosinophilic infiltrate

can be noted in the papillary dermis as well.2 Amorphous amyloid deposits can be noted in this layer and often are associated closely with melanin granules. Diagnosis often is supplemented by a Congo red stain and observation of the classic apple green birefringence of amyloid deposits under polarized light.3 The differential diagnosis of LA can include prurigo nodularis, colloid milium, and post-inflammatory hyperpigmentation.2,4 The bullous presentation of LA can present similarly to bullous pemphigoid.8 Clinical guidelines suggest that a Congo red stain of a punch biopsy should be used to rule out all nonamyloidosis diagnoses because different types of lesions appear similar on physical examination.1 LA will display a unique immunofluorescence to immunoglobulin (Ig) M, C3, and IgA throughout lesions in either the basement membrane or the papillary dermis. This can aid in diagnosis and help differentiate LA from other conditions.1,3 Chuang et al recommend dermoscopy before invasive skin biopsy because the latter often is not necessary to determine therapeutic management once a diagnosis of LA is made.Thus, they suggest using the unique central scarring and surrounding pigmentation pattern to differentiate LA from other types of lesions to minimize the risk for post-biopsy scarring.4 Both macular amyloidosis (MA) and LA will display apple green birefringence with a Congo red stain and can be difficult to differentiate clinically. LA generally presents with more pruritus and will display central scarring and corresponding orthohyperkeratosis not seen in MA.4 Although the central hub of LA is predominantly white, the central hub of MA can be either white, brown, or a combination of those, and papules usually are organized in a rippled pattern.1,4 Patients may present with overlapping features of LA and MA, called biphasic amyloidosis. LA is limited to the skin, so the goals of treatment are to decrease pruritus and improve the appearance of the lesion. Treatment recommendations are based on clinical experience and case reports; high-quality data from randomized clinical trials are lacking in the literature. Treatment often includes topical steroids, dimethyl sulfoxide, cyclosporine, or tacrolimus, but these treatments have variable and unpredictable results.3 Other methods of treatment include surgery and laser procedures, but determining if a lesion will respond to such treatment often requires individual case consideration.4 Grimmer et al demonstrated improved resolution of LA pruritus and pigmentation with oral acitretin and bath-water psoralen ultraviolet A therapy (PUVA), a combination often used in the treatment of psoriasis.9 This combination therapy also was associated with reduced recurrence of LA.9 Topical tocoretinate, an ester-bound formulation of retinoic acid and tocopherol, has been shown to have results that are similar to those of oral retinoic acid and can help with symptoms of pruritis.10

34 THE CLINICAL ADVISOR â&#x20AC;˘ OCTOBER 2020 â&#x20AC;˘ www.ClinicalAdvisor.com

The patient in this case was prescribed a topical corticosteroid to be administered twice daily. In addition, she wrapped her calves in occlusive dressings to prevent scratching at night.The appearance of the lesions substantially improved with this regimen.

CASE #2

Macular Amyloidosis

Macular amyloidosis (MA) commonly occurs in populations of the Middle East, Asia, and Central and South America. Women, especially those aged 20 to 50 years, are more likely than men to present with MA.11 On physical examination, MA usually presents as symmetric pruritic and hyperpigmented patches or thin plaques of gray-brown macules in a rippled pattern.12 Unusual variants of MA can present as periocular hyperpigmentation, nevoid hyperpigmentation along Blaschko lines, and diffuse MA characterized by an incontinentia pigmenti-like pattern.13 MA lesions usually occur in the interscapular area, shins, and forearms. Lesions also have been reported to appear on the chest, face, neck, thighs, and axilla.11

Histologically, a hematoxylin and eosin-stained skin biopsy shows eosinophilic faceted amyloid deposits within the papillary dermis, along with frequent foci of pigmentary incontinence. Other findings include basal vacuolar changes, epidermal apoptotic bodies, and the presence of melanophages in dermal deposits.12 Congo red stain shows apple green birefringence under polarized light, revealing amyloid deposits. Direct immunofluorescence shows IgG, IgM, and C3 in the amyloid deposits.14 Electron microscopy reveals the amyloid deposits as linear, non-branching filaments with hollow cores and diameters of 6 to 10 mm. A histopathologic study of patients with MA revealed that 9% have parakeratosis, 27% have acanthosis, and 64% have basal cell vacuolization in the epidermis. Dermal examination of these patients revealed that 82% have melanin incontinence and 91% have perivascular inflammatory infiltration.15 Patients with MA have a varied clinical presentation, so the condition may be confused with other causes of hyperpigmentation. Ahmed et al reported instances of patients diagnosed with MA presenting with asymptomatic homogenous patches on the legs that gradually grew darker and spread to the arms.16 Skin biopsy and immunohistochemical stains indicated the presence of amyloid deposits consistent with MA.Thus, appearance on initial examination cannot be used as a means of diagnosis in all cases. Prolonged friction seems to be the most common factor inciting MA, with UV radiation, atopy, and genetics also playing a role in its pathogenesis.13,17 The amyloid deposits

TABLE. Characteristics of Lichen Amyloidosis and Macular Amyloidosis Lichen Amyloidosis1-10

Macular Amyloidosis1,11-18

Dermatologic Presentation • Pruritic and painless • White central hubs or a whitish scar-like center surrounded by brown dots

• Sometimes pruritic • Grey-brown macules oriented in hyperpigmented patches with a rippled pattern

Associations

• More prevalent in Asian, Central/South American, and Middle Eastern populations • Scrubbing, chronic itching, or mechanical exfoliation • Usually sporadic but familial cases have been reported • Multiple endocrine neoplasia type 2A

• More prevalent in Asian, Central/South American, and Middle Eastern populations • Usually sporadic, but familial cases have been reported • Autoimmune conditions • Multiple endocrine neoplasia type 2A

Etiology

• Chronic epidermal injury leading to conversion of keratinocytes into amyloid in the dermis

• Unclear etiology; chronic abrasion, sunlight, and genetic factors

Characteristic Location

• Pretibial area of lower extremities • Areas that are easily scratched

• Upper back (interscapular region) • Extensor surfaces

Histology

• Eosinophilic infiltration of amyloid in the papillary dermis • Orthohyperkeratosis and acanthosis in center of lesions

• Eosinophilic infiltration of amyloid in the papillary dermis • Normal-appearing epidermis

Diagnosis

• Physical examination, dermoscopy, histopathologic examination

• Physical examination and histopathologic examination

Treatment

• Topical steroids, topical tocoretinate, oral acitretin, and bath psoralen ultraviolet A therapy

• Sedating antihistamines, topical steroids, topical dimethyl sulfoxide, phototherapy

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2020 35

Dermatologic Look-Alikes in MA are keratinocyte-derived, but the mechanism behind apoptosis of keratinocytes is unclear. Two theories have been proposed to describe generation of the amyloid deposits in MA: fibrillar body and secretory.17 The fibrillar body theory states that necrotic epidermal cells are transformed into amyloid by fibroblasts and macrophages through a process called filamentous degeneration, whereas the secretory theory states that disrupted basal cells secrete amyloid, which then assemble at the dermal-epidermal junction.17 MA is associated with multiple autoimmune diseases including systemic lupus erythematosus, sarcoidosis, IgA nephropathy, ankylosing spondylitis, rheumatoid arthritis, and autoimmune thyroiditis. Genetically linked MA (10% frequency)17 is associated with the autosomal dominant disorder multiple endocrine neoplasia type 2A. Progeny from a family with a history of MA should be tested for the presence of the RET proto-oncogene, and prophylactic thyroidectomy should be considered to prevent malignancy.17 Clinical and histologic analyses are used to diagnose MA.The differential diagnosis includes postinflammatory hyperpigmentation, erythema dischromicum, tinea versicolor, phototoxic dermatitis, notalgia paresthetica, and poikiloderma of Civatte.13 Skin biopsy is effective in differentiating MA from these conditions. MA results in a characteristic rippling of the skin but is more subtle in appearance than LA. MA also tends to present with less pruritus than LA.The quantity of amyloid deposits is not a distinguishing feature between these 2 conditions. Biphasic amyloidosis, which contains both MA and LA lesions, is present in about 18% to 25% of patients with PCA.18 Treatment of MA is aimed at relieving itching, eliminating amyloid deposits, and improving the appearance of the lesions. No uniformly effective treatment is available.11 Some common treatments include sedating antihistamines, topical/ intralesional steroids, dimethyl sulfoxide, and phototherapy. Conservative therapies, such as topical corticosteroids, should be attempted before more invasive therapies are considered. Surgical therapy, including excision, laser vaporization, and dermabrasion of lesions, also may be used. Systemic treatments, such as cyclosporine and cyclophosphamide, have some level of effectiveness in reducing pruritus and clearing lesions, but these agents carry a higher risk of systemic adverse effects.13 There are no high-quality randomized clinical trials of MA; thus, management recommendations and timeline of care are based on an individual’s response to treatment. No systemic abnormalities are associated with MA, so laboratory testing is not needed.11 The patient in this case was encouraged to avoid scratching the affected area. A topical corticosteroid applied twice daily resulted in an improved appearance. ■

Sami Younes, BS, Joanne Jacob, BS, and Emily Burns, BA, are medical students at Baylor College of Medicine, in Houston,Texas, and Christopher Rizk, MD, is a certified dermatologist at Elite Dermatology in Houston. References 1. Mehrotra K, Dewan R, Kumar JV, Dewan A. Primary cutaneous amyloidosis: a clinical, histopathological and immunofluorescence study. J Clin Diagn Res. 2017;11(8):WC01-WC05. 2. Kim Y, Ioffreda MD, Chung CG. Lichen amyloidosis of the scalp and forehead. Dermatol Online J. 2017;23(11):13030/qt8td105j9. 3. Salim T, Shenoi SD, Balachandran C, Mehta VR. Lichen amyloidosus: a study of clinical, histopathologic and immunofluorescence findings in 30 cases. Indian J Dermatol Venereol Leprol. 2005;71(3):166-169. 4. Chuang YY, Lee DD, Lin CS, et al. Characteristic dermoscopic features of primary cutaneous amyloidosis: a study of 35 cases. Br J Dermatol. 2012;167(3):548-554. 5. Shimoda Y, Sato Y, Hayashida Y, et al. Lichen amyloidosus as a sweat gland/ duct-related disorder: resolution associated with restoration of sweating disturbance. Br J Dermatol. 2017;176(5):1308-1315. 6. Arita K, South AP, Hans-Filho G, et al. Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis. Am J Hum Genet. 2008;82(1):73-80. 7. Scapineli JO, Ceolin L, Puñales MK, Dora JM, Maia AL. MEN 2A-related cutaneous lichen amyloidosis: report of three kindred and systematic literature review of clinical, biochemical and molecular characteristics. Fam Cancer. 2016;15(4):625-633. 8. Biswas P, Aggarwal I, Sen D, Sumi A, Ghosh A. Bullous pemphigoid clinically presenting as lichen amyloidosis. Indian J Dermatol Venereol Leprol. 2014;80(6):544-546. 9. Grimmer J, Weiss T, Weber L, Meixner D, Scharffetter-Kochanek K. Successful treatment of lichen amyloidosis with combined bath PUVA photochemotherapy and oral acitretin. Clin Exp Dermatol. 2007;32(1):39-42. 10. Terao M, Nishida K, Murota H, Katayama I. Clinical effect of tocoretinate on lichen and macular amyloidosis. J Dermatol. 2011;38(2):179-184. 11. Bandhlish A, Aggarwal A, Koranne RV. A clinico-epidemiological study of macular amyloidosis from north India. Indian J Dermatol. 2012;57(4):269-274. 12. Molina-Ruiz AM, Cerroni L, Kutzner H, Requena L. Cutaneous deposits. Am J Dermatopathol. 2014;36(1):1-48. 13. Heaton J, Steinhoff N, Wanner B, Krutchik M. A review of primary cutaneous amyloidosis. J Am Osteopath College Dermatol. 2017;38(14):46-49. 14. Melo BLA, Cosa IS, Goes CAM, Tigre CAF, André NF. An unusual presentation of macular amyloidosis. An Bras Dermatol. 2011;86(4 suppl 1):s24-s27. 15. Venugopal SB, Muralidhar A. Primary localized cutaneous amyloidosis — a clinicopathological study. Arch Med Health Sci. 2019;7(1):38-41. 16. Ahmed I, Charles-Holmes R, Black MM. An unusual presentation of macular amyloidosis. Br J Dermatol. 2001;145(5):851-852. 17. Nahidi Y, Meibodi NT, Meshkat Z, Nazeri N. Macular amyloidosis and Epstein-Barr virus. Dermatol Res Pract. 2016;2016:6089102. 18. Vijaya B, Dalal BS, Sunila, Manjunath GV. Primary cutaneous amyloidosis: a clinico-pathological study with emphasis on polarized microscopy. Indian J Pathol Microbiol. 2012;55(2):170-174.

36 THE CLINICAL ADVISOR • OCTOBER 2020 • www.ClinicalAdvisor.com

LEGAL ADVISOR CASE

Respiratory Distress in Young Girl Child goes into cardiac and respiratory arrest hours after discharge from ED

ANN W. LATNER, JD

Anna, a 4-year-old girl with a history of asthma, was taken by her parents to an urgent care clinic where she was diagnosed with an upper respiratory infection and streptococcal pharyngitis for which she was prescribed an antibiotic. Two days later, her parents brought her into the emergency department (ED) after she began having trouble breathing despite using her asthma medications. The child previously had visited the same ED over 30 times and had been admitted several times. The child arrived at the hospital at 2:00 AM and was seen by a team consisting of Dr E and Nurse R.Within 3 minutes of the patient’s arrival, Dr E ordered that the patient be given ipratropium and albuterol by nebulizer. By 2:11 AM, Nurse R had completed her triage assessment. She noted that Anna had labored breathing and was wheezing. Her pulse was 156 beats/min, respiration rate was 36, and pulse oximetry on room air was 91%.Twenty minutes later, Nurse R noted in the chart that Anna had tolerated the ipratropium and albuterol treatment well, with no adverse reactions, and that her respiratory status improved.

The Emergency Medical Treatment & Labor Act was enacted in 1986 to ensure public access to emergency medical services regardless of ability to pay.

At approximately 2:30 AM, Dr E examined the child and determined that she no longer had signs of respiratory distress. She was breathing normally without the use of accessory muscles, and although she was wheezing, the doctor noted in the chart that the symptoms were “mild.” At 2:45 AM the child, with her mother accompanying her, was taken to radiology for a chest radiograph. A half hour later, Nurse R noted that Anna was administered albuterol inhalation. At approximately 3:30 AM, Nurse R took the child’s vitals again. They were recorded in the chart as pulse rate, 145 beats/min; respiration rate, 34 breaths/min, and pulse oximetry level, 99%; however, the chart did not specify whether this rate was measured on room air or with supplemental oxygen.A short while later, Nurse R administered dexamethasone to the patient. Continues on page 39

Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

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LEGAL ADVISOR At 3:50 AM, Dr E reviewed Nurse R’s notes, Anna’s vital signs, the laboratory results, and radiology report. He met with Anna’s parents and spoke to them about her condition. He told them that the test results did not support admitting her to the hospital, but he stressed the need for outpatient followup care. He said that her condition was “back to baseline,” noting that her symptoms had resolved after treatment. The child’s mother was concerned that Anna was still wheezing and breathing faster than normal, but the physician ordered that she be discharged. Nurse R noted that the child had tolerated both the albuterol and dexamethasone treatments with no adverse reaction and that her respiratory status improved. The child was discharged at 4 AM.

During the 2 hours that Anna had been in the ED, she was examined by Dr E once, a half hour after her arrival. The physician did not see her again prior to discharge. Anna’s parents took her to her grandmother’s house after she was discharged because they had to go to work. At approximately 7 AM, the grandmother found Anna unresponsive and called 911. The child was taken by ambulance to the hospital, where she was treated for respiratory and cardiac arrest, leading to brain death. She was taken off life support 6 days later and died.

emergency medical conditions. If a hospital is unable to stabilize a patient, or if the patient requests, an appropriate transfer must be implemented. The hospital’s attorneys moved for summary judgment, asking the court to dismiss the case against it. The hospital claimed that it had provided an appropriate medical screening as required by EMTALA. Thus, the issue at stake was whether the child’s condition had been stabilized before discharge. The hospital argued that the “failure to stabilize” claim should fail because after Dr E recognized that the child had an emergent medical condition, he treated it and believed her to be stable.The hospital argued that Dr E was not required by EMTALA to rescreen the child before discharge because the Act requires only that a hospital provide an initial screening when a patient presents. The plaintiffs introduced expert testimony from a physician who contended that Dr E did not wait long enough after the child’s final breathing treatment to discharge her. The expert contended that the final pulse oximetry reading of 99% was measured so closely to her final breathing treatment that the supplemental oxygen given during the treatment could have artificially increased the reading beyond what the child was able to maintain on her own. The expert witness also opined that Dr E discharged Anna without observing her for long enough to know whether the steroid he administered would be an effective treatment. The court held that the plaintiffs had presented evidence sufficient to create a genuine dispute of facts as to whether the child had received proper care to stabilize her, and the court denied the defendant’s motion to dismiss. This case is on track to proceed to trial (if it does not get settled out of court).

Legal Background

Protecting Yourself

Anna’s parents consulted with a plaintiff ’s attorney, who believed that they had a case against the hospital. The attorney filed suit on behalf of the parents, alleging that Anna had presented to the hospital with an emergent medical condition and that the hospital and staff had failed to stabilize her before discharge, as required by Emergency Medical Treatment & Labor Act, known commonly as EMTALA. The law was enacted in 1986 to ensure public access to emergency medical services regardless of ability to pay. The Act requires hospitals that participate in Medicare and offer emergency services must provide a medical screening examination when requested for an emergency medical condition, including active labor, regardless of whether the patient has insurance and can pay or not. Hospitals are required to provide stabilizing treatment for patients with

EMTALA defines “to stabilize” as “to provide such medical treatment of the condition as may be necessary to assure, within reasonable medical probability, that no material deterioration of the condition is likely to result from or occur during the transfer of the individual from a facility.” (“Transfer” includes discharge under EMTALA.) Assessing and treating an emergency medical condition is not enough under EMTALA — the patient also must be stabilized such that no severe consequence will result from the patient’s transfer or discharge. Taking the extra time to monitor a patient and screen the patient before discharge could save lives and protect against liability. ■

During the 2 hours that the patient had been in the ED, she was examined by Dr E once, a half hour after her arrival.

Ann W. Latner, JD, a former criminal defense attorney, is a freelance medical writer in Port Washington, New York.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2020 39

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