Clinical Advisor January/February 2022 Issue by The Clinical Advisor

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CASE

Atypical Posterior Stroke: Diagnosing Cause of Vertigo in Primary Care LEGAL ADVISOR

NP Sued for Missed Hip Fracture

JANUARY/FEBRUARY 2022

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INFECTIOUS DISEASE

Community-Acquired Clostridioides difficile Cases in Children on the Rise Prior antibiotic exposure is the most significant risk factor for infection.

FEATURE

Diagnosis and Staging of Chronic Obstructive Pulmonary Disease by PCPs

DERMATOLOGY CLINIC

Red Patches Over Face, Chest, and Upper Limbs

FROM THE DIRECTOR

Director Nikki Kean nikki.kean@haymarketmedia.com Medical editor Kristin Della Volpe

Production editor Kim Daigneau Group creative director Jennifer Dvoretz Senior production manager Krassi Varbanov Account executive Michael Delaney, 551.206.5334 michael.delaney@haymarketmedia.com Publisher Kathleen Hiltz, 201.774.1078 kathleen.hiltz@haymarketmedia.com Vice president, content, medical communications Kathleen Walsh Tulley Chief commercial officer Jim Burke, RPh President, medical communications Michael Graziani Chairman & 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 25, Number 1. Published 6 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 © 2022

I am officially a statistic. After my family received our booster shots, we went into the Thanksgiving holiday feeling pretty optimistic. Little did we know that my daughter had been exposed to COVID-19 a few days before returning home from college. Hello, Delta. After recovering from Delta, we approached the Christmas holiday feeling pretty confident. Then came home my other daughter from Portland, Oregon. Welcome, Omicron. My story is not unique. Since it was first reported in late November 2021, the Omicron variant has been steamrolling across the US, causing millions of infections. A record 1.4 million new cases of COVID-19 were reported on Monday, January 10, 2022. Not surprisingly, transmission rates have been reported as high as 99.1% in some counties. Many health care providers have compared this new surge to the beginning of the pandemic when no one had any defenses against the virus. The sheer number of people being infected with the Omicron variant, especially younger unvaccinated children, has overwhelmed our health care system. The Centers for Disease Control and Prevention reported that the rate of COVID-19 hospitalizations among children younger than 5 years has grown substantially with the arrival of Omicron, while the rate for children aged 5 to 17 years has remained relatively stable. This new surge has hit everyone hard. Just when we thought we had this thing under control, the virus had other ideas. Catherine R. Judd, MD, PA-C, recently warned of a mental health pandemic among health care workers: “The mental health fallout from the COVID-19 pandemic demands recognition, intervention, and mitigation strategies.” She compares health care workers to combat veterans and warns of a moral injury, which occurs when people are forced to make decisions that shift their moral compass. We want to know how you are faring, please take the quiz in Ms Judd’s article by searching our website for “moral injury.” We will be reporting on the results of the survey in the next issue of The Clinical Advisor. Nikki Kean, Director The Clinical Advisor

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2022 1

Guess Who’s Coming to Dinner?

Assistant editor Jeanelle Jacobs

CONTENTS JANUARY/FEBRUARY 2022

FEATURES

1 The uninvited dinner guest.

11 Posterior stroke may present as vertigo.

Diagnosis and Staging of Chronic Obstructive Pulmonary Disease by PCPs Using the GOLD standards for COPD staging will identify high-risk patients, improve delivery of care, and reduce health care costs.

Atypical Posterior Stroke: Diagnosing Cause of Vertigo in Primary Care The HINTS examination performed within 48 hours of symptom onset has a sensitivity of 100% and specificity of 96% for diagnosing stroke.

Community-Acquired Clostridioides difficile Cases in Children on the Rise A thorough clinical evaluation of diarrhea must rule out other causes, such as viral enteritis, parasitic infection, bacterial infection, and inflammatory bowel disease.

DEPARTMENTS 1

From the Director Guess Who’s Coming to Dinner?

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

Dermatology Clinic ■ Red Patches Over Face, Chest, and Upper Limbs ■ Itchy Rash After COVID-19

Legal Advisor Nurse Practitioner Sued for Missed Hip Fracture

15 Hypersensitivity reaction after COVID-19.

29 Misdiagnosis does not equal malpractice.

MORE WAYS TO FIND US!

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

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EXCLUSIVE TO THE WEB AT

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NEWS

CLINICAL CHALLENGE

ClinicalAdvisor.com/News

ClinicalAdvisor.com/Clinical-Challenge

National Nurses United Call for Permanent OSHA COVID-19 Standards In light of Omicron, nurses are calling for a permanent OSHA standard built on current emergency temporary standards and updated scientific knowledge of the virus.

Duloxetine Failed to Reduce Pain in Patients With Osteoarthritis The study found no clinically relevant or statistically significant effect of duloxetine on pain scores at 3 or 12 months in patients with chronic hip or knee osteoarthritis.

THE WAITING ROOM

Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom

Black, Hispanic Patients Are Less Likely to Have Bariatric Surgery Patients with obesity in the study who underwent bariatric surgery were more likely to be White, have a higher education level, not receive SNAP, and considered food secure.

Early Trauma Increases Risk for Substance Abuse

MIDDLE, BOTTOM IMAGES: © GETTY IMAGES

Brady Pregerson, MD Generalized Weakness and Dehydration A 63-year-old man with a history of thyroid cancer presents to the emergency department with a 4-day history of generalized weakness and loss of appetite. He has no history of recent falls and he denies any pain, heart palpitations, vomiting and/ or diarrhea, focal weakness, syncope, or other complaints. See the full case at: clinicaladvisor.com/case_january_february22

The authors of the study noted that early trauma could include emotional, physical and sexual abuse, neglect, mental illness, divorce and separation, and substance misuse.

Rates of HCV Treatment Declined From 2015-2020 The COVID-19 pandemic and opioid crisis created new barriers to HCV treatment, leading to the lowest annual treatment rate in 5 years.

Jim Anderson, MPAS, PA-C, DFAAPA Mandatory COVID-19 Vaccines Needed for Health Care Workers Amid the vaccine debate, Jim Anderson wonders how any health care worker — PA, nurse practitioner, physician, or nurse — could square not getting vaccinated after vowing to protect and improve the health of all Americans.

MY PRACTICE ClinicalAdvisor.com/MyPractice April N. Kapu, DNP, APRN, ACNP-BC, FAANP, FCCN, FAAN Creating Healthy Work Environments for NPs During the COVID-19 Pandemic The president of AANP discusses what constitutes a healthy work environment in hospitals and how to create professional and personal barriers to manage burnout.

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Conference Roundup Advances in Inflammatory Bowel Diseases (AIBD) 2021 Annual Meeting December 5 to 7, 2021 Orlando, Florida

IMID ASSOCIATED WITH INCREASED RATES OF PSYCHIATRIC DISORDERS Patients with childhood-onset immunemediated inflammatory diseases (IMID) have an increased prevalence of anxiety and mood disorders compared with control individuals, according to research presented at the AIBD 2021 Annual Meeting. The investigators searched the Pubmed, PsychINFO, and Embase databases for studies regarding pediatric-onset inflammatory bowel disease (pIBD), rheumatic diseases (RD), and autoimmune liver diseases. The studies that reported prevalence rates of diagnosed psychiatric

Patients with IMID have an increased prevalence of anxiety and mood disorders.

disorders and/or suicide were included in the review. Random-effects meta-analysis was used to calculate the pooled prevalence rates of psychiatric disorders reported by 3 or more studies within the same IMID. Psychiatric disorders were grouped according to International Classification of Diseases-10th Revision.The risk for bias was assessed independently by 2 authors with use of the New-Castle Ottawa scale. A total of 23 studies were included in the review — 13 regarding psychiatric disorders in pIBD and 10 in RD. No studies reported on psychiatric disorders in autoimmune liver diseases. Among patients with pIBD, the prevalence rates for anxiety and mood disorders were 6% (95% CI, 4%-9%) and 4% (95% CI, 2%-8%), respectively, in register-based studies, and 33% (95% CI, 25%-41%) and 18% (95% CI, 12%26%), respectively, in studies that used psychiatric assessment. The pooled estimates for RD were 13% (95% CI, 12%-15%) for anxiety disorders and 20% (95% CI, 15%-26%) for mood disorders. Suicide risk was increased in pIBD but not in juvenile idiopathic arthritis, the most common RD, according to analysis of single studies. The study authors noted that only pooled estimates on emotional disorders were possible and that studies on a wider variety of psychiatric disorders are needed.

4 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2022 • www.ClinicalAdvisor.com

PATIENTS WITH IBD SHOULD EAT LESS PROCESSED RED MEAT Increased frequency of processed meat consumption is associated with higher risk for mortality in patients with inflammatory bowel disease (IBD), according to research presented at the AIBD 2021 Annual Meeting. Data from 5763 patients with IBD in the United Kingdom (UK) Biobank who were recruited from 2007 to 2010 and followed until March 13, 2021, were included in this analysis.A simplified food frequency questionnaire was used to collect baseline dietary information and deaths were ascertained from the death registry. Meat consumption of 0.1 to 0.9 times per week was used as a reference. The mean patient age was 57.3 (SD, 7.9) years, 3028 (52.5%) were women, and 1834 and 3929 patients were diagnosed with Crohn disease (CD) and ulcerative colitis (UC), respectively. Follow-up time on average was 11.7 years, during which 590 deaths over 67,095 person-years were documented. Compared with processed meat consumption of less than once per week, consuming processed meat more than 4 times per week was associated with an increased risk for mortality (hazard ratio [HR], 1.53; 95% CI, 1.06-2.23; P =.025). This association was observed among patients with CD (HR, 2.01; 95% CI, 1.12-3.62; P =.020) but not UC (HR, 1.27; 95% CI, 0.77-2.09; P =.346). No association was found between mortality

PARENTS MAY HAVE ANXIETY, DEPRESSION YEARS INTO CHILD’S IBD Parents of children with inflammatory bowel diseases (IBD) were found to have increased symptoms of distress, continuing over the course of their child’s disease, according to research presented at the AIBD 2021 Annual Meeting. Previous research has identified a pattern of elevated symptoms of depression and anxiety among parents of children with IBD. This study aimed to better assess how these symptoms change over the disease course of IBD. Investigators from Children’s Hospital of Pittsburgh in the United States recruited parents (N=155) of children with IBD aged 2 to 17 years for this cross-sectional study. Stratified by diagnosis time (<6 months vs >1 year), parental distress was assessed using the Patient Reported Outcomes Measurement Information System Short Form v1.0Anxiety (PROMIS-ANX), Patient Health Questionnaire-8 (PHQ-8), and Impact of Event Scale Revised (IESR).The parents’ children were recently diagnosed (n=52) or had established IBD (n=103). Clinically elevated PROMIS-ANX scores were observed among 52% of the newly diagnosed cohort. There was no significant change in PROMIS-ANX scores during the transition from newly diagnosed to established disease (mean, 3.77 vs 3.74; P =.220). Depression scores were clinically elevated among 45% of the parents of newly diagnosed children. Similar to anxiety, the transition to established disease did not

affect depression scores (mean, 1.426 vs 1.346; P =.266). For IES-R, parents of children who were recently diagnosed were more distressed compared with the parents of children with established disease (mean, 2.03 vs 1.62; P =.017). Additional stratification of parents with children diagnosed <3 months (n=37) and >5 years (n=41) previously found no difference between cohorts for PROMIS-ANX (P =.371) or PHQ-8 (P =.605) scores but a significant change in IES-R scores (P =.0478). This study found that parents of children with IBD had clinically elevated anxiety and depression scores.There did not appear to be a temporal pattern to their anxiety or depression and scores remain elevated even years after their child’s diagnosis. For distress measured by IES-R scores, there did appear to be a temporal pattern with a reduction in concordance with time since diagnosis. Additional studies are needed to assess potential interventions to mitigate the negative impact on parents.

USTEKINUMAB THERAPY LINKED TO HIGHER RATES OF CD REMISSION Ustekinumab treatment was associated with a high rate of remission among patients with Crohn disease (CD) who had previously failed to respond to antitumor necrosis factor (TNF) therapy, according to data from a real-world study presented at the AIBD 2021 Annual Meeting. Ustekinumab, a monoclonal antibody against the interleukin (IL)-12/23 subunit p40, was approved for the treatment of moderate to severe CD and ulcerative colitis. Researchers from the University of Massachusetts Medical School retrospectively reviewed patient records in a cohort of 34 patients with CD who had failed at least 1 anti-TNF treatment before induction with ustekinumab; 59%

and consumption of fish, unprocessed poultry, or unprocessed red meat. Researchers recommended a modified diet for patients with IBD that limits consumption of processed meat, whether alone or in combination with medication use.

The proportion of patients with fistulizing disease who achieved remission was 70%.

of patients were women and 50% had fistulizing disease. Clinical remission was achieved by 70.5% of patients.Among those in remission, 29% were also taking concomitant steroids or immunomodulators at the time of remission. This relatively high remission rate also was found among the subgroup of patients with fistulizing CD (70%). Among patients with data on C-reactive protein levels (70%), the average level prior to ustekinumab induction was 2.4, which trended downward to 1.98 (95% CI, -0.064 to 1.08; P =.079) after starting therapy.Among the patients with fecal calprotectin data (18%), mean fecal calprotectin levels prior to ustekinumab induction were 386. Like C-reactive protein, fecal calprotectin also trended downward after ustekinumab exposure (mean, 175; 95% CI, -106.25 to 528.46; P =.148). This study found that ustekinumab was associated with a high rate of remission, even for patients with fistulizing CD, among a difficult to treat population who had prior failed anti-TNF therapy. ■

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FEATURE: SHANNON HARRIS, DNP, FNP-BC, CCRN; LORI PREWITT MOORE, DNP, FNP-BC, RN, CHSE

hronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide and follows cancer as the fourth-leading cause of death in the United States (N=156,979 deaths annually).¹ The direct costs for COPD admissions in the United States are approximately $50 billion annually.² The percentage of US adults who have ever been diagnosed with COPD (including emphysema and chronic bronchitis) is 4.6%,1 and the prevalence is 2-fold higher in rural areas of the country than in large metropolitan areas (8.2% vs 4.7%; Figure 1).3,4 In the United States, COPD is mainly diagnosed and managed in the primary care setting; however, misdiagnosis rates range from 10% to 40%.5 The primary goal of COPD management is to effectively manage symptoms and improve quality of life. Understanding and implementing the Global Initiative for Chronic Obstructive Lung Disease (GOLD) standards will guide providers in diagnosing and staging patients with COPD accurately and selecting appropriate prescriptive therapy.6 Using the GOLD standards for COPD will help clinicians more effectively identify high-risk patients, improve delivery of care, and reduce exorbitant spending of health care dollars.

COPD is misdiagnosed in up to 40% of patients.

Pulmonary Function Tests

Diagnosis of COPD should be considered in any patient presenting with dyspnea, chronic cough or sputum production, history of recurrent lower respiratory tract infections or low birth weight,

6 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2022 • www.ClinicalAdvisor.com

and/or a history of exposure to COPD risk factors (eg, genetic factors or congenital/developmental abnormalities; tobacco smoking; exposure to occupational dusts, vapors, fumes, gases, or other chemicals; exposure to smoke from home cooking/heating fuels). After completion of a thorough patient assessment, pulmonary function tests (PFTs) should be ordered for patients with suspected COPD.7 Spirometry is the preferred tool for detecting airflow limitation and diagnosing COPD.6,7 Spirometry performed in a primary care clinic is as reliable as that performed in a pulmonary function laboratory as long as the clinician is skilled with calibration of the machine, administration of the test, and interpretation of the results.6,7 Many hospitals complete outpatient PFTs in the respiratory department, and clinicians must be proficient in interpreting the results. Key components of spirometric assessment are as follows6: • Forced expiratory volume (FEV1): the amount of air exhaled in the first second of expiration • Forced vital capacity (FVC): volume of air forcibly exhaled from the point of maximal inspiration • FEV1/FVC: ratio of these 2 measurements expressed as a fraction A postbronchodilator FEV1/FVC <0.7 confirms airflow limitation and COPD diagnosis in patients with appropriate symptoms and exposures to noxious stimuli. Suggested bronchodilator doses include 400 µg short-acting β2-agonist, 160 µg short-acting anticholinergic, or both agents combined. Timing of FEV1 measurement is based on which agent is used: at 10 to 15 minutes after a short-acting β2-agonist or 30 to 45 minutes after a short-acting anticholinergic or combination of both agents. These measurements should be compared

Model-Based COPD Prevalence by County, United States, 2018

Percent (%): ■ 3.5-7.0 ■ 7.1-8.9 ■ 9.0-10.9 ■ 11.0-13.4 ■ 13.5-19.7 Reprinted from the CDC.4

FIGURE 1. Model-based county-level prevalence estimates of COPD among adults in the United States during 2018. Counties with the highest model-based COPD prevalence estimates were clustered along the Ohio and lower Mississippi Rivers.

Gold Classification

Airflow Limitation Severity

FEV1 Measurement

GOLD 1

Mild

FEV1 ≥80% predicted

with reference volumes based on age, height, sex, and race.6 Additional spirometry tips provided in the GOLD report include recording long enough for a volume plateau to be reached, which may be more than 15 seconds in a patient with severe disease. Practitioners should use the largest of the individual FEV1 and FVC measurements taken from any of 3 technically satisfactory curves, with the curves varying no more than 5% or 150 mL, whichever is the greater value. The FEV1/FVC ratio should be derived from the technically acceptable curve that has the largest sum of FEV1 and FVC.6 The GOLD report provides guidance on assessing the level of airflow limitation, impact of COPD on patient’s health status, and risk for future exacerbations. The FEV1 will guide clinicians in determining GOLD stage of disease severity (Table 1).

GOLD 2

Moderate

50% ≤FEV1 <80% predicted

Symptom Assessment

GOLD 3

Severe

30% ≤FEV1 <50% predicted

GOLD 4

Very severe

FEV1 <30% predicted

TABLE 1. GOLD Classification of Airflow Limitation Severity in COPDa

COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in the first second of expiration. In patients with postbronchodilator FEV1/FVC <0.7.

Adapted from Global Initiative for Chronic Obstructive Lung Disease.6

Previously, a measure of breathlessness such as the Modified British Medical Research Council (mMRC) dyspnea scale was used as the sole assessment of symptom severity.6 The revised GOLD assessment scheme includes use of spirometry to assess severity of airflow limitation; assessment of either dyspnea via the mMRC or symptoms using the COPD Assessment Test (CAT); and history of moderate and severe exacerbations, including prior hospitalizations (Figure 2, page 8).6

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RESPIRATORY DISEASES: COPD

Assessment of Symptoms/ Risks for Exacerbations

Assessment of Airflow Limitation GOLD Grade

FEV1 (% Predicted)

≥80

50-79

30-49

Exacerbation History

<30

≥2 or ≥1 leading to hospitalization

0 or 1 not leading to hospitalization

CAT, COPD Assessment Test; ICS, inhaled corticosteroid; LABA, long-acting β agonist; LAMA, long-acting muscarinic antagonist; mMRC, Modified British Medical Research Council dyspnea scale.

Group C LAMA

Group D LAMA or LAMA + LABA or ICS + LABA

Group A Bronchodilator

Group B LABA or LAMA

mMRC 0-1 CAT <10

mMRC ≥2 CAT ≥10

Adapted from Global Initiative for Chronic Obstructive Lung Disease.6

FIGURE 2. GOLD assessment tool for COPD.

Modified British Medical Research Council Dyspnea Scale

The mMRC dyspnea scale is a concise, patient-centered tool that measures the level of dyspnea when walking or exercising. Patients with scores of 0 to 1 are in group A or C, and patients with scores of 2 to 5 are in group B or D (Table 2).5,8 COPD Assessment Test

The CAT is an easily administered, 8-item health questionnaire that assesses dyspnea and activity limitations to calculate a score that captures symptom burden and impact of COPD on activities of daily living.9 Results range from a score of 0 to 40, and 10 is a cutoff for consideration of regular treatment

for symptoms, including breathlessness.6 This information also can improve communication between the patient and the health care team when assessing the impact of symptoms beyond dyspnea on activities of daily living.6,10 COPD Classification Group Guides Treatment

Initiation of pharmacotherapy for COPD is based on the ABCD assessment scheme in the GOLD report (Figure 2).6 Patients in group A should be prescribed a long- or shortacting bronchodilator. Patients in group B should be prescribed a long-acting muscarinic antagonist (LAMA) or a long-acting β agonist (LABA); there is no evidence to recommend one class over the other, and the choice should

TABLE 2. Modified British Medical Research Council Scale mMRC Grade

Degree of Breathlessness

I only get breathless with strenuous exercise

I get breathless when walking fast on flat ground or walking up a slight hill

I walk slower than people my age on flat ground because of breathlessness or I have to stop to breathe when walking at my own pace on flat ground

I stop for breath after walking approximately 100 yd or after a few minutes walking on flat ground

I am too breathless to leave the house or I am breathless when getting dressed or undressed

Adapted from Fletcher CM.8

8 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2022 • www.ClinicalAdvisor.com

be dependent upon the patient’s perception of symptom relief. If a patient in group B continues to have symptoms, a combination LAMA plus LABA may be used as control therapy. A LAMA is the choice for initial therapy among patients in groups C and D. Group D patients may be more symptomatic and may benefit from combination therapy with a LAMA plus LABA (for persons with CAT ≥20) or a LABA plus inhaled corticosteroid (ICS) (for persons with blood eosinophil counts ≥300 cells/µL). If the patient is experiencing persistent breathlessness or is exercise-intolerant, combination treatment should be used. If there is no improvement with dual therapy, treatment should be changed to triple therapy with LAMA, LABA, and ICS. If patients on triple therapy still have exacerbations, treatment options are to add roflumilast, add a macrolide, or stop ICSs if the patient reports lack of efficacy or adverse effects (eg, pneumonia).

may reduce daily symptoms, reduce hospital admissions, and improve quality of life. ■ Shannon Harris, DNP, FNP-BC, CCRN, is an assistant professor at the University of South Alabama College of Nursing and a nurse practitioner at Diagnostic Medical Clinic, both in Mobile, Alabama. Lori Prewitt Moore, DNP, FNP-BC, RN, CHSE, is an assistant professor at the University of South Alabama College of Nursing. References 1. Centers for Disease Control and Prevention. Chronic obstructive pulmonary disease (COPD) includes: Chronic bronchitis and emphysema. Updated September 13, 2021. Accessed December 9, 2021. 2. Press VG, Konetzka RT, White SR. Insights about the economic impact of chronic obstructive pulmonary disease readmissions post implementation of the hospital readmission reduction program. Curr Opin Pulm Med. 2018;24(2):138-146. 3. Croft JB, Wheaton AG, Liu Y, et al. Urban-rural county and state differences

Nonpharmacologic Management of COPD

in chronic obstructive pulmonary disease - United States, 2015. MMWR Morb

Smoking cessation and physical activity are recommended for all patients with COPD.6 For patients in groups B, C, and D, pulmonary rehabilitation is also recommended. The GOLD report has added COVID-19 vaccination to its list of recommended vaccines, which also includes influenza, pneumococcal, and pertussis vaccinations. Long-term oxygen therapy is recommended for stable patients with: • Partial pressure arterial oxygen (PaO2) ≤55 mm Hg or arterial oxygen saturation (SaO2) ≤88% with or without hypercapnia confirmed twice over 3 weeks; or • PaO2 55 mm Hg to 60 mm Hg or SaO2 88% in patients with pulmonary hypertension, peripheral edema suggesting congestive cardiac failure, or polycythemia.

Mortal Wkly Rep. 2018;67(7):205-211. 4. Centers for Disease Control and Prevention. Data and statistics: COPD death rates in the United States. Updated June 14, 2021. Accessed December 13, 2021. 5. Ragaišienė G, Kibarskytė R, Gauronskaitė R, et al. Diagnosing COPD in primary care: what has real life practice got to do with guidelines? Multidiscip Respir Med. 2019;14:28. 6. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, 2022 Report. Accessed December 10, 2021. 7. Graham BL, Steenbruggen I, Miller MR, et al. Standardization of spirometry 2019 update. An official American Thoracic Society and European Respiratory Society technical statement. Am J Respir Crit Care Med. 2019; 200(8):e70-e88. 8. Fletcher CM. Standardised questionnaire on respiratory symptoms: a statement prepared and approved by the MRC Committee on

COVID-19 and COPD

Aetiology of Chronic Bronchitis (MRC breathlessness score). BMJ.

The GOLD report recommends COVID-19 testing for patients with COPD who present with new or worsening respiratory symptoms, fever, or other COVID-19 symptoms.6 Patients should continue taking ICSs, long-acting bronchodilators, roflumilast, chronic macrolides, systemic steroids, and antibiotics as indicated during the pandemic.6

1960;2:1662. 9. Gil HI, Zo S, Jones PW, et al. Clinical characteristics of COPD patients according to COPD assessment test (CAT) score level: cross-sectional study. Int J Chron Obstruct Pulmon Dis. 2021;16:1509-1517. 10. Munari AB, Gulart AA, Dos Santos K, Venâncio RS, Karloh M, Mayer AF. Modified Medical Research Council dyspnea scale in GOLD classification better reflects physical activities of daily living. Respir Care. 2018;63(1):77-85.

Summary

11. Halpin DMG, Criner GJ, Papi A, et al. Global Initiative for the Diagnosis,

Most patients with COPD have not undergone appropriate PFTs or are receiving inadequate mediations according to their GOLD class.12 The estimated $50 billion spent annually on COPD therapy cost could be decreased by improving diagnosis and staging of this disease and implementing appropriate therapy.2 Using the GOLD standards to classify COPD stage and prescribe the correct pharmaceutical management

Management, and Prevention of Chronic Obstructive Lung Disease. The 2020 GOLD Science Committee report on COVID-19 and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2021;203(1):24-36. 12. Rohde J, Joseph A, Tambedou B, et al. Reducing 30-day all-cause acute exacerbation of chronic obstructive pulmonary disease readmission rate with a multidisciplinary quality improvement project. Cureus. 2021: 13(11): e19917.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2022 9

FEATURE: HANNAH GRACHEK, PA-C; KELLY S. REED, PharmD, MPA, PA-C

Atypical Posterior Stroke: Diagnosing Cause of Vertigo in Primary Care A patient presenting with dizziness undergoes a thorough workup to identify a peripheral or central cause of vertigo.

57-year-old woman presents to her primary care provider with complaints of dizziness, which began 3 hours ago and is continuous. She describes the dizziness as a room-spinning sensation that is not relieved or associated with any particular position. The dizziness is associated with headache, nausea, vomiting, weakness, and loss of balance. She rates the dizziness severity as an 8 out of 10. The patient denies fever, chills, fatigue, night sweats, weight changes, head injury, tinnitus, hearing loss, otorrhea, otalgia, vision changes, recent upper respiratory tract illness, or syncopal episodes. She states she has never experienced anything like this before. The patient’s medical history is significant for morbid obesity (body mass index, 48), type 2 diabetes, hypothyroidism, and hyperlipidemia. She notes that she does not exercise and that her diet consists of fast food most days of the week. She admits to occasional alcohol use once or twice a month and denies tobacco or drug use.

Examination

Example of an MRI in a patient with posterior ischemic stroke.

The patient appears disheveled but alert and oriented to person, place, time, and situation. Vital signs are shown in Table 1, page12. Her head and face are symmetrical with no signs of ptosis or facial droop. Eye examination (pupil, equal, round, reactive to light) is normal, and ophthalmoscopic examination shows initial signs of cataracts bilaterally. No exudates, hemorrhages, www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2022 11

NEUROLOGY

Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo and affects 15% to 20% of adults annually. or angiogenesis are present. Hearing and ear examinations are normal. No pain is reported on palpation of frontal sinuses. Mucous membranes appear moist without edema or erythema. Lips and gingiva are pink. Tonsils present bilaterally with no erythema or edema. Heart rate and rhythm are normal, and normal S1 and S2 sounds are heard with the patient leaning forward with no murmur appreciated. Cranial nerve examination is normal. A neurologic examination finds the patient off balance with an unsteady gait when attempting to walk across the examination room; Romberg test is positive. All other tests are normal with reflexes 2+ bilaterally. Complete blood cell count is within normal limits but the patient’s blood glucose level is elevated (180 mg/dL). An electrocardiogram is performed and shows normal sinus rhythm with no ischemic changes noted. A Head Impulse, Nystagmus, and Test of Skew (HINTS) examination is performed because the patient reports continuous vertigo symptoms. The HINTS examination is used to differentiate between a central or peripheral cause of dizziness. The results from the bedside HINTS assessment on this patient are as follows: • Nystagmus type is bidirectional • Skew deviation is positive for vertical deviation of the left eye • Head impulse test is normal

POLL POSITION What is the best test to differentiate between a central or peripheral cause of dizziness?

■ Dix-Hallpike maneuver ■ HINTS examination

15.15% 35.23%

12.88%

■ Epley maneuver ■ Tilt test

36.74%

For more polls, visit ClinicalAdvisor.com/Polls.

TABLE 1. Vital Signs Weight, kg

127

Height, in

Body mass index

Temperature, °C

36.5

Blood pressure, mm Hg Supine

124/76

Standing

120/72

Heart rate, bpm Supine Standing

80 84

Respiration rate, breaths per min

bpm, beats per minute

Treatment

The results from the HINTS examination are concerning for a central etiology of the patient’s vertigo. A posterior stroke is suspected. An ambulance is called and the patient is transported to a stroke center. The patient undergoes diffuse weighted magnetic resonance imaging (MRI) and is diagnosed with an ischemic posterior stroke located in the medial branch of the posterior inferior cerebellar artery. The diagnosis is within the 4.5-hour window for administration of thrombolytics. She has full resolution of neurologic symptoms after administration of tissue plasminogen activator. Discussion

Dizziness is a common complaint for which patients seek medical care. It has been reported that 5.6 million office visits per year are due to dizziness in the United States.1 Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo and affects 15% to 20% of adults annually.2 In addition to BPPV, causes of peripheral vertigo include Ménière disease, vestibular neuronitis, and vestibular migraine. Taking a detailed patient history and performing the correct physical examination is important for helping to identify the

12 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2022 • www.ClinicalAdvisor.com

The HINTS examination performed within 48 hours of symptom onset has a sensitivity of 100% and specificity of 96% for diagnosing stroke. cause of vertigo and ruling out potentially life-threatening diseases, including posterior circulation stroke. Posterior strokes can be missed in patients who present with dizziness.3 In a study of 1666 patients who presented to the emergency department with dizziness, 35% of those with stroke/transient ischemic attack were misdiagnosed.4 Medical providers need to recognize the subtle signs and symptoms of stroke and know when to perform the HINTS examination. In a comparative study, the sensitivity and specificity of the HINTS examination were found to be greater than those of MRI if performed less than 48 hours from symptom onset.3 When taking a patient history, it is best to determine the timing and triggers of vertigo rather than the characteristics. In one study, patients changed the description of their dizziness half of the time when asked repeated questions within a 10-minute time frame whereas reporting of the timing and triggers of symptoms was more consistent.5 The timing of vertigo is used to differentiate between 2 syndromes: episodic vestibular syndrome or acute vestibular syndrome. Episodic vestibular syndrome is classified by periods of transient vertigo, dizziness, or unsteadiness lasting seconds, hours, or occasionally days. Episodic vestibular syndrome is further classified into triggered or spontaneous subtypes. Triggered episodic vestibular syndrome (t-EVS) is aggravated

by a trigger, the most common being head movement or changes in body position.6 Orthostatic hypotension is the most common cause of t-EVS followed by BPPV. Spontaneous episodic vestibular syndrome (s-EVS) lasts minutes to hours and has no associated trigger. The most common form of s-EVS is vestibular migraine.6 Acute vestibular syndrome (AVS) is continuous vertigo, dizziness, or unsteadiness that lasts days to weeks and includes symptoms of new vestibular system dysfunction, including vomiting, nystagmus, and impaired gait.6 Acute vestibular syndrome is further classified into traumatic/toxic or spontaneous subtypes. Traumatic/toxic AVS is caused by head trauma or drug intoxication. Spontaneous acute vestibular syndrome (s-AVS) has no apparent trigger. The most common cause of s-AVS is vestibular neuritis; however, 10% to 20% of patients with s-AVS present with stroke.6 Once the practitioner has taken a detailed history, a thorough physical examination should be performed and should include taking orthostatic vital signs, performing a cardiac examination, and detailed examination of the head, ears, eyes, and nervous system. In addition, patients with details consistent with AVS should undergo the HINTS examination to differentiate a peripheral cause of vertigo from a potentially devastating central cause. Evidence has shown that this examination alone can accurately help

How to Perform the HINTS Examination To perform the Head Impulse, Nystagmus, and Test of Skew (HINTS) examination, have the patient sit comfortably in a chair. Nystagmus type is first observed. Nystagmus is observed in the patient first during primary gaze, then lateral gaze. If nystagmus is not present, then acute vestibular neuronitis or stroke is unlikely and the rest of the HINTS examination should be stopped as it may show false results.7 If nystagmus is present, the direction of the fast-beating component is noted. Unidirectional nystagmus is reassuring as it indicates a peripheral cause of vertigo. Bidirectional nystagmus is concerning for a central pathology. The next component of the examination is a Test of Skew. This is done by performing the cover-uncover test for each eye and observing if there is any vertical movement of the uncovered eye. A normal response is no vertical correction whereas vertical skew is worrisome for a central pathology.

Finally, the Head Impulse test is performed by holding the patient’s head while the patient looks directly at the provider’s nose.The head is then moved back and forth slowly left to right and then briskly to the center. This tests the vestibulo-ocular reflex. A positive result will show the eyes moving with the head, then snap back in a fast corrective movement to look at the provider’s nose.This is called a corrective saccade.1 The test is negative if the eyes do not remain on target, therefore demonstrating a lack of corrective saccade.7 In this instance, a positive or abnormal head impulse indicates a peripheral cause of vertigo whereas a negative or normal head impulse test is worrisome for posterior stroke (Table 2). A single central finding on any of the 3 components rules in a posterior circulation stroke.7 The acronym INFARCT can be used to remember the worrisome signs for stroke (Impulse Normal, Fast phase Alternating, Refixation on Cover Test).

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NEUROLOGY

TABLE 2. Interpretation of the HINTS Examination7 Positive Finding for Peripheral Cause

Positive Finding for Central Cause

Head Impulse test

Saccade

No saccade

Nystagmus

Unidirectional

Bidirectional

Test of Skew

No skew

Vertical skew

spontaneously resolve with time on its own. Spontaneous recovery occurs in 20% of patients within 1 month, and up to 50% of patients recover within 3 months.1 ■ Hannah Grachek, PA-C, practices in primary care in Buford, Georgia. Kelly S. Reed, PharmD, MPA, PA-C, is an assistant professor in the Physician Assistant Program at Augusta University in Augusta, Georgia. References 1. Bhattacharyya N, Gubbels SP, Schwartz SR, et al. Clinical practice guideline: benign paroxysmal positional vertigo (update). Otolaryngol Head Neck Surg. 2017;156(3_suppl):S1S47. 2. Palmeri R, Kumar A. Benign paroxysmal positional vertigo. In:

identify 10% to 20% of patients with AVS resulting from posterior stroke.5 Primary care providers can learn to perform and interpret the HINTS bedside examination to help minimize misdiagnosis. The HINTS examination when performed within 48 hours of symptom onset has a sensitivity of 100% and specificity of 96% for diagnosing stroke.3 The bedside examination rules out stroke more accurately than early MRI; however, it is underutilized because of lack of training (see How to Perform HINTS Examination and Table 2).3,7 Primary care providers should also be aware that patients presenting with continuous vertigo secondary to posterior stroke are more likely to have associated gait disturbance, focal neurologic complaints, headache, sudden onset of symptoms, positional isolated vertigo, and auditory symptoms. When any of these symptoms are present, the HINTS examination should be utilized in the workup of the patient; however, these typical neurologic symptoms can be absent in some patients who present with mass effect from large cerebellar infarction.3 Sometimes, the only symptom that these patients exhibit is severe truncal ataxia.3 If the HINTS examination does not suggest a central cause or the patient presents with episodic vertiginous symptoms then a peripheral cause of vertigo such as BPPV should be considered. The diagnosis of peripheral causes involves performing the Dix-Hallpike maneuver.When performing the maneuver, the latency, direction, time course, and duration of nystagmus are noted for diagnosis.8 The nystagmus produced by the Dix-Hallpike maneuver for the most common type of BPPV, posterior canal BPPV (pc-BPPV), is upward torsional nystagmus beating toward the lowermost ear.9 The nystagmus develops with a brief latency of several seconds and fatigues with repeated maneuvers.9 The Dix-Hallpike maneuver is the gold standard test for diagnosing pc-BPPV. The treatment of choice is to perform a canalith repositioning maneuver, also known as the Epley maneuver; however, BPPV can

StatPearls. StatPearls Publishing; 2021. 3. Kattah JC, Talkad AV, Wang DZ, Hsieh YH, Newman-Toker DE. HINTS to diagnose stroke in the acute vestibular syndrome: three-step bedside oculomotor examination more sensitive than early MRI diffusion-weighted imaging. Stroke. 2009;40(11):3504-3510. 4. Kerber KA, Brown DL, Lisabeth LD, Smith MA, Morgenstern LB. Stroke among patients with dizziness, vertigo, and imbalance in the emergency department: a population-based study. Stroke. 2006;37(10):2484-2487. 5. Edlow JA, Newman-Toker D. Using the physical examination to diagnose patients with acute dizziness and vertigo. J Emerg Med. 2016; 50(4):617-628. 6. Tehrani ASS, Kattah JC, Kerber KA, et al. Diagnosing stroke in acute dizziness and vertigo: pitfalls and pearls. Stroke. 2018;49(3):788-795. 7. Edlow JA, Gurley KL, Newman-Toker DE. A new diagnostic approach to the adult patient with acute dizziness. J Emerg Med. 2018;54(4):469-483. 8. von Brevern M, Bertholon P, Brandt T, et al. Benign paroxysmal positional vertigo: diagnostic criteria. J Vestib Res. 2015;25(3-4):105-117. 9. Lee SH, Kim JS. Benign paroxysmal positional vertigo. J Clin Neurol. 2010;6(2):51‐63.

Case Study Library Check out all of our case studies in obesity, diabetes, and other important topics in primary care — along with our clinical challenges — by visiting us at: ClinicalAdvisor.com/Case-Study

14 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2022 • www.ClinicalAdvisor.com

Dermatology Clinic CASE #1

Red Patches Over Face, Chest, and Upper Limbs DINA ZAMIL, BS; TARA L. BRAUN, MD

A 42-year-old Hispanic man with no prior medical history presents with a 2-month history of a rash on his face, chest, and arms. He reports that the rash gets worse after sun exposure and he has associated joint pain. He has taken over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) for the joint pain and topical steroids for the rash with no symptomatic relief. Physical examination reveals erythematous patches over the malar cheeks and dorsal nose sparing the nasolabial fold and erythematous macules on the forearms and chest. What is your diagnosis? Turn to page 16

CASE #2

Itchy Rash After COVID-19 CHRISTOPHER NGUYEN, BA; TARA L. BRAUN, MD; CHRISTOPHER RIZK, MD

A 54-year-old woman with a history of depression presents to the clinic with a 1-year history of an intermittent rash. She was hospitalized for COVID-19 approximately 1 year ago and soon after developed a rash all over her body.The lesions persist for several days and have a burning sensation.The patient has no associated joint pain or other systemic symptoms. She tried antihistamines for the rash with no symptomatic relief. On examination, erythematous wheals are evident on her arms and legs as well as her back and abdomen. What is your diagnosis? Turn to page 17 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2022 15

Dermatology Clinic CASE #1

Systemic Lupus Erythematosus

In systemic lupus erythematosus (SLE), the immune system loses tolerance for self-antigens, resulting in multiorgan damage.1,2 The cutaneous manifestations of SLE were first described by Hippocrates in the fifth century.3,4 In the 13th century, Rogerius reported facial lesions that resembled wolf bites (lupus translates to wolf in Latin).5 Descriptions of lupus written by Cazenave, Bateman, and von Hebra focused on dermatologic aspects of the disease.5 Moritz Kaposi reported systemic symptoms of lupus in 1872, and Sir William Osler is credited as the first to recognize the multiorgan damage that is characteristic of SLE.5,6 Prevalence estimates for SLE vary between 20 and 150 cases per 100,000 individuals and have been increasing with improved recognition of the disease.7 Systemic lupus erythematosus has a predilection for adult women in their 30s or 40s; children comprise only 15% to 20% of cases.5 In the United States, SLE is less common among individuals of European ancestry and more common among the Black population and people of Hispanic and Asian descent. These latter groups also experience greater involvement of internal organs.1,5,7 Studies have linked genes for human leukocyte antigen (HLA) and complement components C1, C2, and C3, as well as at least 70 susceptibility loci to SLE.1 Female hormones have been associated with SLE, explaining the higher prevalence in women.7 Antithyroid antibodies, elevated thyroid-stimulating hormone, and altered autonomic nervous system response to the hypothalamic axis also have been reported in SLE patients.5 Immune dysfunction in SLE is precipitated by a combination of factors such as genetics, emotional factors, and environmental influences (eg, infections and exposure to chemicals or UV light). This dysfunction causes autoantibody development, immune complex deposition, inflammation, and complement activation, which in turn result in tissue injury.8 The lack of self-tolerance depends on how efficiently a patient’s immune system presents antigens to T cells.5 Production of abundant immunoglobulin G (IgG) autoantibodies and circulating abnormal inflammatory cells are mechanisms reported to lead to skin damage in SLE.9 Apoptosis of keratinocytes is also a key event in the development of cutaneous lesions.8 In general, dermatologic findings in SLE are divided into 3 groups: acute cutaneous (ACLE), subacute cutaneous (SCLE), and chronic cutaneous (CCLE).5 These categories are not mutually exclusive and may present concomitantly in any given patient.10

Patients with ACLE display transient photodistributed lesions in the classic dermatologic manifestation of SLE, the bilateral malar erythema or butterfly rash.This rash can appear solely in the center of the face, classically sparing the nasolabial fold, or it may be a generalized maculopapular exanthema. The rash usually is accompanied by systemic effects on other organs, and antidouble-stranded DNA (dsDNA) antibodies may be present.8,10 The other subtypes, SCLE and CCLE, are associated with a relatively lower risk for systemic disease. Although SCLE is also a photosensitive eruption, it lasts longer than ACLE and does not cause atrophy or scarring. The CCLE subtype includes discoid lupus, lupus erythematosus tumidus, lupus erythematosus panniculitis, and chilblain lupus. Sun exposure can trigger dermatologic findings in SLE, and patients may mistake this rash for a sunburn. Severe facial swelling may occur, although these cutaneous symptoms tend to resolve without residual pigmentation or scarring.11 Patients with SLE also can have nonspecific cutaneous findings. Raynaud phenomenon, livedo reticularis, and urticarial vasculitis are examples of such findings; these conditions suggest a potential underlying autoimmune disease.10,11

Sun exposure can trigger dermatologic findings in SLE, and patients may mistake this rash for a sunburn. The most common areas affected in SLE are the joints, skin, kidneys, hematologic system, central nervous system, and pleural and pericardial serosal surfaces. Per the 2019 American College of Rheumatology (ACR) guidelines, diagnosis of SLE requires at least 1 positive antinuclear antibody (ANA) test followed by 7 clinical criteria (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal), and 3 immunologic domains (antiphospholipid antibodies, complement proteins, SLE-specific antibodies).12 The Systemic Lupus International Collaborating Clinics require 4 criteria for SLE diagnosis with at least 1 clinical criterion and 1 immunologic criterion or lupus nephritis as the sole clinical criterion in the presence of ANA or anti-dsDNA antibodies.13 In both classification systems, immunologic criteria are required for a definitive SLE diagnosis.5 Mucocutaneous SLE is diagnosed via immunohistology and histopathology. Histologic findings vary depending on the subtype but always include vacuolar degeneration and

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lymphohistiocytic inflammation. The ACLE subtype presents with less pronounced dermal involvement and more vacuolar degeneration of the basal layer with some sparse lymphocytic infiltrate in the upper dermis. Discoid lesions tend to have more follicular plugging, periadnexal inflammation, and scarring.10 Recurrent miscarriages and abnormal complete blood cell count and differential, urinalysis, and/or comprehensive metabolic profile support a diagnosis of SLE.Various antibodies also can be present, including antiphospholipid, anti-RNP, anti-SM, anti-SSA, anti-SSB, anti-dsDNA, and antinuclear antibodies. When indicated, clinicians may wish to obtain supportive imaging such as a chest radiograph, renal imaging, and contrast angiography.5 The differential diagnosis for localized ACLE is contact dermatitis, acne rosacea, seborrheic dermatitis, dermatomyositis, erysipelas, and photodermatitis. These pathologies are differentiated via characteristic clinical features. Generalized ACLE can be confused with erythema multiforme and morbilliform drug reactions, but these conditions do not present with butterfly erythema.The differential diagnosis for SCLE includes polymorphic drug eruption, psoriasis, tinea corporis, and superficial gyrate erythema, which also are distinguished clinically. Several conditions may mimic CCLE depending on the stage and evolution of CCLE lesions. Diseases that mimic the nonscaling pattern of CCLE are polymorphic light eruption, Jessner lymphocytic infiltration of the skin, lymphocytoma cutis, granuloma facile, chilblain, and sarcoidosis.The scaling phase of CCLE may look similar to actinic keratoses, seborrheic dermatitis, tinea faciei, psoriasis, and lichen planus. Both clinical features and histology can help differentiate CCLE from these conditions.11 SLE treatment is complex and usually requires consultations with multiple specialists. Before treatment initiation, disease severity, degree of inflammation, and level of organ dysfunction should be ascertained.5 For skin findings, topical or intralesional corticosteroids and topical calcineurin inhibitors are first-line treatments. Rigorous sun protection also is essential for these patients because the lesions are exacerbated by sunlight.10 Lesions resistant to topical medications may require systemic therapy.10 Systemic medications used to treat SLE include glucocorticoids, antimalarial agents, immunosuppressants, NSAIDs, and biologics that target B cells. Recently, inhibitors of B-lymphocyte stimulators such as belimumab have shown potential for treatment of mild to moderate SLE.1 Biopsy results for the patient in this case were consistent with ACLE and his ANA was positive. He was started on topical steroids and hydroxychloroquine. Rheumatology was consulted to assist with his management.

Dina Zamil, BS, is a medical student and Tara L. Braun, MD, is a resident in the Department of Dermatology at Baylor College of Medicine in Houston,Texas. Please go to ClinicalAdvisor.com/home/dermatology/dermatologyclinics/ for a complete listing of references noted in this article.

CASE #2

Urticarial Vasculitis

Urticarial vasculitis (UV) is a condition characterized by urticarial lesions with histopathologic findings of leukocytoclastic vasculitis (LCV). It was first reported by Wills and Lond in an 1890 case report describing 2 young men who presented with a purpuric rash and wheals accompanied by fever, arthritis, and angioedema.1 Almost 70 years later, in 1956, McCombs et al published a report of 2 patients with wheals and vasculitic characteristics on histology.1 Since first described in the 19th century, the condition also has been called hemorrhagic urticaria and allergic vasculitis.1 The precise prevalence of UV worldwide is unknown, largely because of its rarity; however, in patients presenting with chronic urticarial rash with histology that meets the criteria for LCV, the prevalence is estimated to be about 5%.2 In the United States, the incidence of UV is estimated to be 0.5 per 100,000 personyears with a median age at diagnosis of 51 years and a female predominance (70%-74%).3 The disease rarely affects infants and children, with only 2 reported infantile cases in the literature and diagnosis in only 1% of children with any type of vasculitis.1,2 Urticarial vasculitis is classified as a type III hypersensitivity reaction or an immune complex-mediated complement activation in the lumen of blood vessels. It generally can be divided based on serum complement levels into normocomplementemic and hypocomplementemic subtypes.1 The majority of UV cases are idiopathic in origin, although some have been tied to medications such as cimetidine, diltiazem, fluoxetine, methotrexate, nonsteroidal anti-inflammatory drugs, telmisartan, enalapril, and levetiracetam.2 Associations with underlying diseases such as autoimmune conditions, infection, myelodysplastic disorders, and malignancy also have been reported.1 Up to 20% of patients with systemic lupus erythematosus reportedly have UV (more commonly the hypocomplementemic subtype), and associations with Sjogren

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Dermatology Clinic syndrome and inflammatory bowel disease also have been described.1,2 Infections linked to UV include streptococcal infections, tuberculosis, COVID-19, and hepatitis B and C.2 Urticarial vasculitis most commonly affects women, particularly in the fourth and sixth decades of life.2 The use of specific medications and the presence of certain underlying infectious, autoimmune, or malignant conditions have been linked to UV cases. Some investigators have proposed a genetic component to the disease, citing familial cases of the severe and systemically active form of UV called hypocomplementemic urticarial vasculitis syndrome (HUVS), which has been described in a pair of identical twins and among 3 siblings.2 In HUVS patients, cigarette smoking appears to be a strong risk factor for the development of pulmonary disease, which is a leading cause of death among UV patients.4

Patients with UV typically present with indurated wheals that are not blanchable or are partially blanchable with macules. Patients with UV typically present with indurated wheals that are nonblanchable or are partially blanchable and have a central dark-red or dark-brown macule.When symptomatic, these lesions generally are described as painful or burning but typically are not pruritic.2 Dermoscopy can be a useful tool to identify small areas of vascular necrosis that do not present as frank purpura.5 In addition to cutaneous symptoms, 9% to 56% of patients with UV present with systemic symptoms and signs, such as angioedema, purpura, fever, asthenia, arthralgia, lymphadenopathy, abdominal pain, and/or ocular, pulmonary, or renal manifestations.1 The most common laboratory abnormalities in UV are an elevated erythrocyte sedimentation rate (ESR) and hypocomplementemia.2 Although both abnormalities are fairly nonspecific, the latter can serve as a useful prognostic marker because hypocomplementemic UV is associated with a higher risk for complications and systemic involvement.4 Biopsy of skin lesions may reveal findings of LCV, such as erythrocyte extravasation, vascular and perivascular infiltration of polymorphonuclear leukocytes with nuclear dust, and fibrinoid necrosis of vascular walls.1 Direct immunofluorescence may show deposition of complement in vessel walls.1 Clinicians also should consider complete blood cell count, renal function tests, hepatitis/liver studies, and measurement of antinuclear antibodies to evaluate for possible extracutaneous manifestations and associations listed above.2 It is important to distinguish UV from acute common urticaria and chronic idiopathic urticaria because these and many

other conditions can present with urticarial rash. Schnitzler syndrome is an autoinflammatory urticarial condition that also may be mistaken for UV. Other diagnoses to consider include Wells syndrome, erythema migrans, and urticaria multiforme.2 Diagnosis of UV requires both clinical manifestations of urticaria and histopathologic evidence of LCV. Lesional biopsy (ideally performed within the first 24-48 hours of rash appearance) is considered the gold standard for diagnosis.2,5 The clinical picture often helps exclude other diagnoses. For instance, unlike in UV in which lesions last longer than 24 hours and often for several days, chronic urticaria wheals generally resolve after 2 to 8 hours. In addition, the lesions of UV can leave behind areas of hyperpigmentation not seen in chronic idiopathic urticaria. Finally, true urticarial lesions are pruritic and coalesce into large (>10 cm) lesions, whereas those in UV are asymptomatic or painful/burning and smaller (0.5-5 cm in diameter). Differentiation from Schnitzler syndrome may require biopsy; although histopathology exhibits neutrophilic infiltrate in both conditions, no evidence of vasculitis is found in Schnitzler syndrome.2 It is difficult to treat UV; no clinical algorithms exist to guide therapy and many drugs have shown limited efficacy and/or adverse effects.Antihistamines and montelukast are ineffective in most patients with UV.1 The most effective treatment is corticosteroids, which allowed for improvement or remission of cutaneous and systemic symptoms in over 80% of patients across 144 studies when used alone or in combination with other drugs.1 However, treatment must be weighed against the unfavorable side effects of steroid use. Patients with more resistant cases of UV may respond to immunosuppressive drugs such as dapsone, colchicine, cyclophosphamide, mycophenolate mofetil, cyclosporine, and azathioprine.2 The combination of 1 or more immunomodulatory agents with steroids may allow for steroid tapering and improved efficacy. Biologics such as omalizumab, anakinra, tocilizumab, and rituximab are additional options. In this case, a punch biopsy of the patient’s rash was consistent with UV. Preliminary workup showed elevated ESR, normal antinuclear antibody titer, and normal complement levels. Her liver function tests, renal function test, and complete cell blood count were within normal limits. She was started on oral corticosteroids, which improved her rash. ■ Christopher Nguyen, BA, is a medical student at Baylor College of Medicine in Houston, Texas; Tara L. Braun MD, is a resident physician in the Department of Dermatology at Baylor College of Medicine; and Christopher Rizk MD, is a dermatologist at Elite Dermatology in Houston. Please go to ClinicalAdvisor.com/home/dermatology/dermatologyclinics for a complete listing of references noted in this article.

18 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2022 • www.ClinicalAdvisor.com

Conference Roundup 2021 San Antonio Breast Cancer Symposium (2021 SABCS)

PREMENOPAUSAL ER+ BREAST CA PATIENTS BENEFIT FROM AI RX Premenopausal women undergoing ovarian suppression for estrogen receptorpositive (ER+) early-stage breast cancer had a lower risk for breast cancer recurrence when treated with an aromatase inhibitor (AI) rather than tamoxifen, according to findings presented at the 2021 SABCS. The meta-analysis included patient data from 4 randomized clinical trials including 7030 premenopausal women with ER+ breast cancer. All women had undergone ovarian suppression or ablation and were randomly assigned to either an AI or tamoxifen for 3 years (ABCSG XII trial) or 5 years (SOFT, TEXT, and HOBOE trials).The primary outcomes were time to invasive breast cancer recurrence and breast cancer mortality. The annual rate of recurrence averaged 21% lower for women assigned to an AI compared with tamoxifen (rate ratio [RR], 0.79; 99% CI, 0.69-0.90; P =.0005). At 10 years, a 2.8% absolute gain in any recurrence was found (17.5% for tamoxifen vs 14.7% for AI). The main benefit from an AI was seen in years 0 to 4 of follow-up when the women were actively taking the treatments (RR, 0.68; 95% CI, 0.58-0.80); no further benefit or loss of benefit was found after therapy was completed during years 5 to 9 of follow-up (RR, 0.98; 99% CI, 0.73-1.32). Subgroup analyses

showed that the reduction in recurrence during this period did not vary by age; body mass index; tumor size, grade, histological subtype; or presence and absence of chemotherapy. Although distant recurrence was reduced with an AI (RR, 0.83; 95% CI, 0.71-0.97; P =.02), no difference in breast cancer mortality was found. Longer follow-up is needed to assess this effect, the researchers noted. No increase in rates of nonbreast cancer death or fractures was found in women receiving an AI.

RIBOCICLIB/LETROZOLE COMBO HELD EFFECTIVE ACROSS BC SUBGROUPS The addition of ribociclib to letrozole prolonged overall survival (OS) across multiple subgroups compared with placebo and letrozole among postmenopausal patients with hormone receptor (HR)-positive and HER2-negative advanced breast cancer, according to a prespecified exploratory subgroup analysis of the MONALEESA-2 trial presented at the 2021 SABCS. “Consistent improvement in long-term survival at 5 and 6 years with ribociclib was observed in all subgroups analyzed,” according to lead author Joyce O’Shaughnessy, MD. The phase 3 MONALEESA-2 trial evaluated the first-line treatment of postmenopausal patients with HR-positive, HER2-negative advanced breast cancer with letrozole plus ribociclib or placebo.

The results demonstrated significantly longer OS with ribociclib compared with placebo in the intention-to-treat population (hazard ratio [HR], 0.76; 95% CI, 0.63-0.93; P =.004).The present prespecified analysis is of 668 patients within subgroups of special interest, but was exploratory and not powered for significance testing. The OS benefit with the addition of ribociclib to letrozole was consistent across subgroups, including number of metastases and metastatic sites. Patients with less than 3 metastatic sites demonstrated a median OS of 68.0 and 56.1 months with ribociclib and placebo, respectively, which translated

December 7 to 10, 2021 San Antonio, Texas

Ribociclib combined with letrozole prolonged overall survival across subgroups.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2022 19

Conference Roundup

RACIAL DISPARITIES IN BREAST CANCER-RELATED LYMPHEDEMA RISK Black women experience higher rates of breast cancer-related lymphedema after axillary lymph node dissection compared with White women, according to the results of a study presented at the 2021 SABCS. Black race was the strongest predictor of lymphedema in this study. Axillary lymph node dissection remains the main risk factor for lymphedema, but other risk factors are inconsistent in studies. Epidemiologic studies have reported an increased susceptibility to lymphedema among Black women, but prospective clinical data are lacking. This prospective study included 304 patients with breast cancer who underwent axillary lymph node dissection between November 2016 and March 2020. Of these, 276 had at least 1 longitudinal measurement after baseline.

Sixty percent of patients were White, 20% were Black, 11% were Asian, and 6% were Hispanic. To measure lymphedema, the researchers measured arm volume at baseline, postoperatively, and at 6-month intervals for a total of 2 years. Lymphedema was defined as a relative volume change of 10% or greater. The 24-month lymphedema rate was 39.4% for Black women, 27.7% for Hispanic women, 23.4% for Asian women, and 20.5% for White women. Women who received neoadjuvant chemotherapy were significantly more likely to develop lymphedema compared with those who had surgery upfront (30.9% vs 11.1%; P =.0066). Black women were 3.5 times more likely to develop lymphedema compared with White women. Hispanic women had a 3-fold increased risk for lymphedema compared with White women, but the researchers noted that the population of Hispanic patients was small. Black race was the strongest predictor of lymphedema development in multivariable analysis (odds ratio [OR], 4.41;

Black women experience higher rates of lymphedema compared with White women.

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P <.001). Other independent risk factors for lymphedema development were receipt of neoadjuvant chemotherapy (odds ratio [OR], 2.08), older age (OR, 1.04 per 1-year increase), greater number of lymph nodes removed (OR, 1.05 per 1 additional lymph node), and increasing time from surgery (OR, 1.70 per 6-month increase). Black women were 3.85 times more likely to have a higher relative volume change compared with White women (P =.007); no difference in lymphedema severity was found among Hispanic and Asian women. Further research is needed to understand the biologic mechanisms behind the racial disparities found in this study as well as possible preventive strategies, the authors concluded.

MARKER CLIP PLACEMENT LACKING DURING BIOPSY Half of patients with breast cancer being considered for neoadjuvant chemotherapy do not have a marker clip placed at the time of biopsy, which may delay chemotherapy or result in mastectomy according to findings presented at the 2021 SABCS. The researchers retrospectively evaluated data from 800 patients with breast cancer who were candidates for chemo therapy at a single center between 2018 and 2019. A marker clip was placed at initial biopsy in 49% of patients. Of patients without initial clip placement, 42% had a clip placed before initiation of neoadjuvant chemotherapy. Patients without a clip placed at the time of biopsy experienced a 5.5-day delay in the initiation of neoadjuvant chemotherapy compared with patients with a clip placed at biopsy. This delay was associated with significant anxiety among the patients. Overall, 79% of surveyed radiologists said they were not aware of national guidelines for clip placement. ■

to a 6-year survival rate of 47.7% and 36.1%, respectively (HR, 0.78; 95% CI, 0.61-1.00). Survival was lower overall for patients with 3 or more metastatic sites, but ribociclib significantly prolonged survival compared with placebo with a median of 55.5 or 46.5 months, respectively (HR, 0.71; 95% CI, 0.51-0.98).The 6-year OS was 37.9% with ribociclib and 24.2% with placebo. The OS benefit was similar among patients with or without bone-only metastases as the intention-to-treat (ITT) population. Patients with liver metastases also benefit from the addition of ribociclib, with a 6-year OS of 31.0% compared with 18.9% with placebo. Prior chemotherapy did not affect the benefit of ribociclib. The OS benefit among patients who received prior endocrine therapy was less clear, and Dr O’Shaughnessy noted that the sample size was small for patients who had previously received an AI.

FEATURE: HEATHER ADAMS, MSPAS, PA-C; ELIZABETH NGUYEN, PA-C

Community-Acquired Clostridioides difficile Cases in Children on the Rise Increase in pediatric cases of C difficile is linked to use of broad-spectrum antibiotics, recurrent infections, and a growth in highly virulent strains.

Clostridioides difficile is a normal constituent of the gut microbiota.

lostridioides difficile is a spore-forming, anaerobic, gram-positive, toxin-producing bacillus found in the gastrointestinal (GI) tract of humans and animals.1-3 Although C difficile is a normal constituent of the gut microbiota, the overcolonization of this pathogen can cause a range of colonic conditions.1 A case-controlled retrospective study conducted from January 2012 through December 2016 found the overall incidence of communityacquired Clostridioides difficile infection (CDI) cases to be 13.7 per 100,000 children per year, with a substantial increase in cases from 2012 (9.6/100,000).4 In 2018, the Centers for Disease Control and Prevention Emerging Infections Program reported 15,591 cases of C difficile in 10 states. Among children aged 1 to 17 years, the incidence of illness was 26.7 per 100,000 persons and 9.03 per 100,000 persons for community-acquired and health care-associated CDIs, respectively.5 Many factors have increased the rate of CDI in children, such as the increasing use of broadspectrum antibiotics, greater number of recurrent infections, and an increase in highly virulent strains.6,7 It is essential that health care professionals recognize the growing incidence of pediatric CDI in both the community and in health care facilities. Proper hand hygiene and minimizing overprescribing of antibiotics are essential to prevent this deadly infection in children.8 The establishment of an antibiotic stewardship

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The pathogenic potential of C difficile ranges from asymptomatic colonization to toxic megacolon, septic shock, and pseudomembranous colitis. program in hospitals and private practice can greatly reduce the use of inappropriate antibiotics.8,9 Etiology and Pathogenesis

C difficile spores are acquired person to person through the fecal-oral route or via fomites on environmental surfaces or contaminated hands.2,10 As noted, certain antibiotic usage can disrupt normal GI flora and allow C difficile spores to germinate, overcolonize the colon, and alter the normal GI microbiome.2 After colonization of the colon, C difficile releases 2 pathogenic toxins (A and B); toxin B is 10 times more potent and virulent than toxin A.2,6,11 These toxins bind to receptors on the plasma membrane of the colonocyte, enter the cytoplasm, and trigger apoptosis.3 This cell death results in a progressive compensatory inflammatory reaction at the colonic mucosa that leads to diarrhea or colitis.3,12 A virulent strain of C difficile, referred to as the North American pulse type 1 (NAP1) strain, is more prevalent among hospitalacquired CDI and is associated with more severe illness.11 Signs and Symptoms

The pathogenic potential of C difficile ranges from asymptomatic colonization to toxic megacolon, septic shock, pseudomembranous colitis, and even death.3 The classic presentation of mild to moderate CDI is an acute diarrheal illness described as profuse watery diarrhea accompanied by fever and lower abdominal cramping.2 The World Health Organization defines diarrhea as the presence of 3 or more loose stools within 24 hours.3 Vomiting and bloody stools may also be present but are not common GI manifestations of CDI.2 Children with severe or fulminant disease frequently present with the classic presentation of CDI accompanied with hemodynamic instability, leukocytosis, or lactic acidosis.2 Infants younger than age 12 months frequently have asymptomatic colonization of C difficile.2,7 The exact mechanism of this colonization is unclear, but many theories have been proposed, such as young age, protective factors in mother’s breast milk in the development of the neonatal microbiota, preferential colonization of less pathogenic strains, and lack of intestinal toxin receptors that are required for CDI.2,3,13 Colonization rates of C difficile vary widely from newborns to children younger than age 2 years.1 Genomic analysis of newborn GI tracts have demonstrated varying degrees of C difficile colonization because of maternal and placental microbiome colonization.11

Making the Diagnosis

A thorough clinical evaluation must rule out other causes of diarrhea, such as viral enteritis, parasitic infection, bacterial infection, and inflammatory bowel disease; testing every child with diarrhea for CDI may lead to misdiagnosis and inappropriate treatment.8 Testing for CDI is indicated according to the patient’s history of new-onset diarrhea with no clearly attributable cause, such as an inflammatory bowel disease (IBD) exacerbation, laxative use, or enteral tube feedings.2 Medical providers must keep in mind that diarrheal illnesses in pediatric patients frequently have viral etiologies. Symptoms such as nausea, vomiting, or fever are more commonly associated with viral diarrhea than CDI.2 Abdominal discomfort, cramps, and diarrhea can also be present in other conditions, such as ischemic colitis, adverse effects (AEs) of medications, and postradiation colitis.2,14 Patient Risk Factors Several risk factors are associated with pediatric CDI. Prior antibiotic exposure is the most significant risk factor for both community-acquired and hospital-acquired pediatric CDI.1,2,11 The use of multiple concomitant antibiotic and prolonged antibiotic therapy also increases the risk for pediatric CDI.8 Although any antibiotic may be responsible for CDI, certain antibiotic classes have been more frequently associated with this infection. In a case-control study performed in pediatric patients, the usage of macrolides, fluoroquinolones, clindamycin, tetracyclines, and third-generation cephalosporins were found to be strong risk factors of community-acquired pediatric CDI.15 Although antibiotic exposure is frequently associated with CDI, more than 40% of children with CDI in this study did not report previous antibiotic exposure.15 Other risk factors associated with pediatric CDI include recent exposure to individuals with C difficile infection; increased length of hospitalization; diet; food additives; use of proton pump inhibitors; GI devices, such as gastrostomy (G tube) or jejunostomy tubes (J tubes); and being an organ transplant recipient.8 Pediatric patients at risk for CDI often have underlying comorbidities, such as malignancy, IBD, and being a solid organ transplant recipient (Table 1).16-18 Testing The diagnosis of pediatric CDI is made by stool tests. Major associations recommend enzyme immunoassay (EIA) for glutamate dehydrogenase (GDH) as a screening tool because

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A thorough clinical evaluation must rule out other causes of diarrhea, such as viral enteritis, parasitic infection, bacterial infection, and IBD. of its near 100% sensitivity.8 Glutamate dehydrogenase is an antigen that is present in CDI.1 Positive GDH screenings only indicate presence of C difficile, regardless of toxigenic or nontoxigenic strain.1,8 An initial GDH screening is typically performed in conjunction with a nucleic acid amplification test (NAAT), often through polymerase chain reaction (PCR), to detect the genes responsible for the production of toxins A and B.1,2,7 Although NAAT has been recognized as the most sensitive method for detection of C difficile, a first-line standard testing method has not been established.3 The American Academy of Pediatrics (AAP) states that the testing of children younger than age 1 year is not routinely recommended in children with diarrhea unless the patient has known risk factors, such as gut motility disorders or Hirschsprung disease, or if the patient is in the setting of a C difficile outbreak.3 Children between the ages of 1 and 2 years should not be tested unless other viral etiologies have been investigated and ruled out. Pediatric patients older than age 2 years should be tested in patients with prolonged or worsening diarrhea.3,16 Testing for alternative or concomitant enteropathogens should also be considered, including stool culture of other organisms and ova and parasite testing.1 A multistep approach for screening and confirmatory testing seems to be the best strategy for diagnosis.1,2,4 Biomarkers such as fecal calprotectin TABLE 1. CDI in Special Pediatric Populations16-18 Children with IBD

• 7%-24% incidence rate • 10× the risk of developing CDI than patients without IBD • 34% recurrence rate

Children with cancer

• 27% incidence rate • >15× the risk of developing CDI than patients without cancer • 26% recurrence rate

Recipients with solid organ transplant

• 1.3%-31% incidence rate • 7× to 13× the risk of developing CDI than nontransplant hospitalized patients • 19.7% recurrence rate

CDI, Clostridioides difficile infection; IBD, inflammatory bowel disease.

can also be ordered: an increase of this neutrophil product can be used as a marker for intestinal inflammation and may be useful in deciphering colonization vs true infection. Fecal leukocytes may also be present in stools.8 Abdominal radiographs or noncontrast abdominal computed tomography (CT) scans may be ordered for severe or fulminant disease to rule out colonic dilation,19 wall thickening, or perforation.2,7 Although colonoscopy with biopsy is extremely sensitive, this invasive imaging modality is only considered in atypical presentations.20 Treatment

The initial step in management of pediatric CDI is prompt cessation of the inciting antibiotic therapy.2,7,16 In very mild disease, discontinuation of antibiotics may be sufficient to reverse the disease process without use of medications.2 The continuation of antibiotic therapy puts the patient at increased risk for recurrent infection.7 If antibiotic therapy cannot be terminated because of concomitant infection, switch to an antibiotic with the narrowest spectrum.2 Empiric antibiotic therapy against C difficile should be commenced if the results of testing are delayed for greater than 48 hours or if the patient is showing signs of severe or fulminant infection.2,7 If not, it is recommended that positive laboratory results be obtained before treatment is initiated.2 Symptomatic support with aggressive intravenous (IV) fluid resuscitation is crucial in children with diarrhea.1 Antimotility drugs, such as loperamide, are discouraged because of associated poor outcomes, such as toxic megacolon or ileus, but are considered safe to use once antibiotic treatment against CDI has been initiated.2,11 Antibiotic treatment for pediatric CDI depends on the severity of illness and whether it is the first episode or a recurrence of infection (Table 2, page 24).8,21 In the 2017 updated Infectious Diseases Society of America guidelines, the severity of illness is defined as nonsevere (previously mild/ moderate), severe, and fulminant (previously complicated).8 For children with nonsevere CDI, the recommended antibiotics are metronidazole and vancomycin for 10 days.8,21 In nonsevere cases of CDI, clinical improvement with antibiotic therapy should occur within 1 to 2 days of initiation, but about 31% of pediatric cases need a second course of antibiotics.1,11 For children with severe CDI, the guidelines recommend oral vancomycin over metronidazole whereas for fulminant CDI, the guidelines recommend vancomycin for 10 days (oral or rectal) with or without metronidazole IV for 10 days.8,21

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TABLE 2. Disease Severity and Current Recommended Pediatric Dosing for CDII8,21 Disease Severity

Clinical Manifestations

Treatment

Comments

Discontinue antimicrobial agents and begin rehydration via IV fluid First episode, nonsevere

• Nonbloody diarrhea • Mild abdominal discomfort/tenderness • WBC <15,000/mm3 • Afebrile

Metronidazole: • 7.5 mg/kg/dose 3 or 4×/d × 10 days (maximum 500 mg) OR Vancomycin: • 10 mg/kg/dose 4×/d × 10 days (maximum 125 mg 4×/d)

First episode, severe disease

Must have at least 1: • Severe abdominal pain • Hypoalbuminemia • Lactic acidosis • WBC >15,000/mm3 • Serum albumin ≤3 g/dL • Creatinine level 1.5× greater than baseline

Vancomycin – Oral: • The efficacy of fidaxomicin in severe • 10 mg/kg/dose 4×/d × 10 days or complicated/fulminant disease for (maximum 500 mg) pediatric CDI needs further investigation Vancomycin – Rectal: • Age 1-3 years: 250 mg/50 mL every 6 hours • Age 4-9 years: 375 mg/75 mL every 6 hours • Age ≥10 years: 500 mg/100 mL every 6 hours

First episode, fulminant disease

Clinical manifestations of severe CDI accompanied by at least 1 of the following: • Hypotension • Shock • Mental status changes • Fever >38.5°C • End organ failure • Respiratory distress • Hemodynamic instability • Ileus • Gastrointestinal perforation • Toxic megacolon

Vancomycin – Oral: • Consider early surgical consultation • 10 mg/kg/dose 4×/d × 10 days in all patients with complicated or (maximum 500 mg 4×/d) fulminant disease Vancomycin – Rectal: • Age 1-3 years: 250 mg/50 mL every 6 hours • Age 4-9 years: 375 mg/75 mL every 6 hours; • Age ≥10 years: 500 mg/100 mL every 6 hours AND/OR IV metronidazole: • 10 mg/kg/dose 3×/d × 10 days (maximum 500 mg)

• Metronidazole is considered first-line therapy for mild to moderate diseaseI • Vancomycin and fidaxomicin are markedly more expensive than metronidazole • May consider switching metronidazole to vancomycin if no response in 5-7 days • Fidaxomicin should only be used in patients aged ≥6 years

First recurrence

Metronidazole: • 7.5 mg/kg/dose 3 or 4×/d x 10 days (maximum 500 mg) OR Vancomycin: • 10 mg/kg/dose 3×/d × 10 days or • 10 mg/kg/dose 4×/d for 10 days (maximum 125 mg)

• Repeat same antibiotic regimen as initial episode if possible

Second or greater recurrence

Vancomycin pulsed taper regimen: • 10 mg/kg/dose by mouth or by rectum 4×/d OR Vancomycin • for 10 days followed by Rifaximin • 10 mg/kg 3×/d for 20 days OR Fecal microbiota transplantation

• Fecal microbiota transplantation should be considered after the third recurrence

Discontinuation of antimicrobial agents and rehydration via IV fluid are essential to treatment. CDI, Clostridioides difficile infection; IV, intravenous; WBC, white blood cell count.

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Metronidazole is the preferred initial treatment for nonsevere pediatric CDI because of its affordability and efficacy against vancomycin-resistant enterococcus (VRE).8 Metronidazole is typically administered orally 3 times a day for 10 days. It is secreted across the intestinal mucosa, causing it to achieve high fecal concentrations. This medication is associated with more frequent AEs than vancomycin, such as nausea, vomiting, metallic taste, and abdominal cramps. Serious complications, such as encephalopathy or peripheral neuropathy, are uncommon but are still possible with metronidazole.2,7 Metronidazole is typically avoided for recurrent episodes as repeat exposure may lead to neurotoxicity.2,12 Vancomycin is not absorbed in the GI tract, causing it to achieve high fecal concentrations and, in turn, producing higher rates of recovery.16 Notable AEs of vancomycin include abdominal pain, nausea, and hypokalemia.7 Fidaxomicin is a new macrolide that was approved for use in pediatric CDI patients aged 6 months and older in February 2020.22 Fidaxomicin has minimal systemic absorption, leading to high concentrations in the colon, and may have other benefits compared with vancomycin.The SUNSHINE study was a multicenter, randomized, blinded clinical trial that enrolled pediatric patients from 39 sites to evaluate the efficacy of vancomycin and fidaxomicin in pediatric CDI. Although both treatments are effective for pediatric CDI, study results showed evidence of higher clinical response and cure and lower recurrence with the use of fidaxomicin compared with vancomycin.23 Fidaxomicin has been shown to cause less new-onset colonization of Candida and vancomycin-resistant enterococcus (VRE) species.24 Despite promising results thus far, more studies are necessary to evaluate fidaxomicin and its efficacy in recurrent pediatric CDI. Rifaximin is an oral rifamycin derivative antibiotic that is being evaluated as an alternative initial treatment for CDI because of its favorable side effect profile.25 Rifaximin has been shown to stimulate the growth of Lactobacillus in the gut and does not significantly alter the gut flora.26 In a small, randomized, controlled trial comparing the efficacy of metronidazole with rifaximin in patients aged 12 to 18 years with IBD and nonsevere CDI, there was no statistically significant difference in the results.25 This could indicate that rifaximin could be a viable alternative for pediatric patients with CDI and coexisting IBD. Further studies are needed to provide evidence of rifaximin’s efficacy and ability to decrease recurrence rates and to gain FDA approval for use of this medication for pediatric CDI. Recurrent Clostridioides difficile Infection

Approximately 22% of children with an initial episode of CDI will have a recurrence.27 The guidelines for treatment

for a nonsevere first recurrence is metronidazole for 10 days or vancomycin for 10 days. For a second or subsequent recurrence, vancomycin is given in a tapered and pulsed regimen or for 10 days followed by rifaximin for 20 days or fecal microbiota transplantation (FMT).8 Fecal Microbiota Transplantation

Fecal microbiota transplantation should be considered as a treatment option for pediatric patients with 3 or more recurrences for whom antibiotic therapy is not successful.6,8,28 Fecal microbiota transplantation is the administration of fecal content and gut organisms from a healthy donor’s GI tract into a patient with recurrent CDI via a nasogastric tube, colonoscopy, or enema.2,12 For patient with CDI, FMT through oral capsules is the preferred method of fecal administration.2,7 The goal of FMT is to restore the GI tract into a healthy balanced microbiome to discourage C difficile colonization and generate an immunologic response that promotes eradication of C difficile.2 Limited data exist regarding FMT in pediatric patients, with much of that available information consisting of individual case studies.29 A few studies on FMT in pediatric CDI do show promising results, supporting the consideration of FMT as a treatment strategy for pediatric CDI. In a retrospective study that included 335 pediatric patients with CDI (age range, 11-23 years), 81% had a successful outcome after a single FMT and 86.6% had a successful outcome after a first or repeated FMT.30 Additional data is required to evaluate the efficacy and safety of FMT to support the use of this treatment in recurrent pediatric CDI. The 2019 safety alert for use of FMT in adults cannot be ignored and, as biotherapeutics are explored as a possible alternative to this treatment in adults, the use of FMT in children should also be further assessed for safety and efficacy.31 Complications/Prognosis

Recurrent CDI is the most common complication of pediatric CDI, occurring in approximately 22% of cases.27 Recurrent CDI is defined as an episode of symptom onset and positive assay results at least 60 days after the completion of a primary treatment regimen for CDI.1,2,8 Recurrent episodes can be caused by persistence of dormant spores within intestines, relapse of previous infecting strain, infection with a new strain, or low levels of antitoxin antibody levels.29 Pediatric patients with IBD are also more likely to have recurrent disease.6,25 Infection with the virulent NAP1 strain of C difficile has also been associated with an increased likelihood of recurrence.11 Studies report that approximately 3% to 7% of pediatric CDI patients develop fulminant disease.32,33 Fulminant disease is

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characterized by hemodynamic instability, respiratory failure, a megacolon greater than 7 cm in diameter, hypotension, or shock.8 Aggressive and prompt diagnostic and therapeutic interventions are necessary in fulminant disease.8 Prevention

Children with suspected or confirmed CDI should be isolated with strict contact precautions enforced. C difficile spores can linger on surfaces for up to 5 months.2 Spores are resistant to extreme temperatures and alcohol-based cleaning agents, making prevention of transmission extremely difficult.2,11 When disinfecting surfaces in the child’s room or hospital room, sporicidal agents such as hypochlorite are preferred.2 Bleach, hydrogen peroxide vapor, and ultraviolet light are other methods of disinfecting hospital rooms of patients with CDI.2,11 Hospital environments are the most common source of C difficile acquisition among hospitalized pediatric patients.8 Colonization risk increases with the length of hospital stay.1 Health care personnel must wear gowns and gloves before contact with the patient occurs. Proper hand hygiene should be performed before and after contact with a pediatric patient with CDI, and after removal of gloves.2,11 Use of alcohol-based hand rubs are not adequate to eradicate C difficile spores from hands.8 Soap and water are the preferred agents for handwashing because they are more effective at removing spores from hands.2,11 Probiotics The efficacy of probiotics in the prevention of pediatric CDI has been studied in randomized trials.34,35 In an analysis of 31 studies, which included 8672 patients, probiotics reduced the risk for CDI: 1.5% with probiotics and 4% without (relative risk [RR]=0.4 [95% CI, 0.3-0.52]). Baseline CDI rates from the included studies ranged from 0 to 40%, with only those studies with baseline CDI rates >5% (n=13) showing a significant reduction in CDI risk. The subgroup analysis of 6 pediatric studies with 1141 patients demonstrated a 65% reduction in the risk for CDI (RR=0.35 [95% CI, 0.19-0.63]).34

in hospitalized patients, combatting the progression of the contemporary antibiotic resistance crisis.9 Unfortunately, many primary care providers do not recognize antibiotic resistance and inappropriate prescribing as a problem in their office. In a recent survey, more primary care providers agreed that antibiotic resistance was a problem in the United States (94%) than in their practice (55%) and that inappropriate antibiotic prescribing was a problem in outpatient settings (91%) but not in their practice (37%). Most respondents (91%) believed that antibiotic stewardship was appropriate in office-based practices, but they ranked antibiotic resistance as less important than other public health issues, such as obesity, diabetes, opioids, smoking, and vaccine hesitancy. 36 Conclusion

Pediatric CDI is becoming increasingly common. It is essential that health care professionals recognize the growing incidence of pediatric CDI in both the community and in health care facilities. Newer treatments such as rifaximin, fidaxomicin, and FMT are promising. More studies aiming to elucidate the efficacy of these medications in pediatric populations would further the cause of adequately preventing and treating CBI in children. ■ Heather Adams, MSPAS, PA-C, works at Women’s Wellness and Gynecology in Erie, Pennsylvania, and is an associate professor at Gannon University in the Physician Assistant program. Elizabeth Nguyen, PA-C recently graduated from the Gannon University Physician Assistant Program. She works in psychiatry at Piedmont Access to Health Services (PATHS) in Danville,Virginia. References 1. Borali E, De Giacomo C. Clostridium difficile infection in children: a review. J Pediatr Gastroenterol Nutr. 2016;63(6):e130-e140. 2. Alvarez AM, Rathore MH. Clostridium difficile infection in children. Adv Pediatr. 2019;66:263-280. 3. Antonara S, Leber AL. Diagnosis of Clostridium difficile infections in children. J Clin Microbiol. 2016;54(6):1425-1433. 4. Miranda-Katz M, Parmar D, Dang R, Alabaster A, Greenhow TL. Epidemiology and risk factors for community associated Clostridioides difficile

Antibiotic Stewardship Another important aspect of pediatric CDI prevention is eliminating antibiotic exposure. Antibiotic stewardship programs (ASPs) are coordinated programs that aid reduction of unnecessary antibiotic prescribing, thus helping to control pediatric CDI rates.2,8,9 Co-implementation of infection control measures with ASPs have been shown to be more efficacious than ASPs alone.2,7 These programs have been shown to significantly reduce the incidence of CDI infections

in children. J Pediatr. 2020;221:99-106. 5. Centers for Disease Control and Prevention. 2018 annual report for the emerging infections program for Clostridioides difficile infection. Accessed December 16, 2021. 6. Brumbaugh DE, De Zoeten EF, Pyo-Twist A, et al. An intragastric fecal microbiota transplantation program for treatment of recurrent Clostridium difficile in children is efficacious, safe, and inexpensive. J Pediatr. 2018;194:123-127.e1. 7. Hoffenberg EJ, Furuta GT, Kobak G, et al. Gastrointestinal tract. In: Hay WW, Levin MJ, Deterding RR, Abzug MJ. Current Medical Diagnosis and

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Treatment: Pediatrics. 24th ed. New York, New York: McGraw Hill Education;

26. Ng QX, Loke W, Foo NX, Mo Y, Yeo WS, Soh AYS. A systematic

2018:647-648.

review of the use of rifaximin for Clostridium difficile infections. Anaerobe.

8. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines

2019;55:35-39.

for Clostridium difficile infection in adults and children: 2017 update by the

27. Nicholson MR, Thomsen IP, Slaughter JC, Creech CB, Edwards KM.

Infectious Diseases Society of America (IDSA) and Society for Healthcare

Novel risk factors for recurrent Clostridium difficile infection in children.

Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48.

J Pediatr Gastroenterol Nutr. 2015;60(1):18-22.

9. Baur D, Gladstone BP, Burkert F, et al. Effect of antibiotic stewardship on

28. Gurram B, Sue PK. Fecal microbiota transplantation in children: current

the incidence of infection and colonisation with antibiotic-resistant bacteria

concepts. Curr Opin Pediatr. 2019;31(5):623-629.

and Clostridium difficile infection: a systematic review and meta-analysis.

29. Groves HE, Allen UD. Winning with poo? Fecal microbiome transplanta-

Lancet Infect Dis. 2017;17(9):990-1001.

tion as an emerging strategy for the management of recurrent Clostridioides

10. Bauer MP, Kuijper EJ. Potential sources of Clostridium difficile in human

difficile infection in children. Pediatr Transplant. 2020;24(1):e13651.

infection. Infect Dis Clin North Am. 2015;29(1):29-35.

30. Nicholson MR, Mitchell PD, Alexander E, et al. Efficacy of fecal microbiota

11. Noor A, Krilov LR. Clostridium difficile infection in children. Pediatr Ann.

transplantation for Clostridium difficile infection in children. Clin Gastroenterol

2018;47(9):e359-e365.

Hepatol. 2020;18(3):612-619.e1.

12. Clayton JA, Toltzis P. Recent issues in pediatric Clostridium difficile infection.

31. Hourigan SK, Nicholson MR, Kahn SA, Kellermayer R. Updates and chal-

Curr Infect Dis Rep. 2017;19(12):49.

lenges in fecal microbiota transplantation for Clostridioides difficile infection in

13. Borali E, Ortisi G, Moretti C, et al. Community-acquired Clostridium difficile

children. J Pediatr Gastroenterol Nutr. 2021;73(4):430-432.

infection in children: a retrospective study. Dig Liver Dis. 2015;47(10):842-846.

32. Tschudin-Sutter S, Tamma PD, Milstone AM, Perl TM. The prediction

14. Manthey CF, Eckmann L, Fuhrmann V. Therapy for Clostridium difficile

of complicated Clostridium difficile infections in children. Infect Control Hosp

infection - any news beyond metronidazole and vancomycin? Expert Rev Clin

Epidemiol. 2014;35(7):901-903.

Pharmacol. 2017;10(11):1239-1250.

33. Crews JD, Anderson LR, Waller DK, Swartz MD, DuPont HL, Starke JR.

15. Adams DJ, Eberly MD, Rajnik M, Nylund CM. Risk factors for community-

Risk factors for community-associated Clostridium difficile-associated diarrhea

associated Clostridium difficile infection in children. J Pediatr. 2017;186:105-109.

in children. Pediatr Infect Dis J. 2015;34(9):919-923.

16. Hourigan SK, Sears CL, Oliva-Hemker M. Clostridium difficile infection in pedi-

34. Goldenberg JZ, Yap C, Lytvyn L, et al. Probiotics for the prevention

atric inflammatory bowel disease. Inflamm Bowel Dis. 2016;22(4):1020-1025.

of Clostridium difficile-associated diarrhea in adults and children. Cochrane

17. Kim J. Editorial commentary: Clostridium difficile in pediatric oncology

Database Syst Rev. 2017;12(12):CD006095.

patients: more questions than answers. Clin Infect Dis. 2014;59(3):404-405.

35. Goldenberg JZ, Mertz D, Johnston BC. Probiotics to prevent Clostridium

18. Luo R, Weinberg JM, Barlam TF. The impact of Clostridium difficile infection

difficile infection in patients receiving antibiotics. JAMA. 2018;320(5):499-500.

on future outcomes of solid organ transplant recipients. Infect Control Hosp

36. Zetts RM, Garcia AM, Doctor JN, Gerber JS, Linder JA, Hyun DY.

Epidemiol. 2018;39(5):563-570.

Primary care physicians’ attitudes and perceptions towards antibiotic

19. De Giacomo C, Borali E. Clostridium difficile in children: a multifaceted

resistance and antibiotic stewardship: a national survey. Open Forum Infect

infection. J Pediatric Infect Dis. 2016;1:12.

Dis. 2020;7(7):ofaa244.

20. McConnie R, Kastl A. Clostridium difficile, colitis, and colonoscopy: pediatric perspective. Curr Gastroenterol Rep. 2017;19(8):34. 21. Campbell CT, Poisson MO, Hand EO. An updated review of Clostridium difficile treatment in pediatrics. J Pediatr Pharmacol Ther. 2019;24(2):90-98. 22. Skinner AM, Scardina T, Kociolek LK. Fidaxomicin for the treatment of Clostridioides difficile in children. Future Microbiol. 2020;15(11):967-979. 23. Wolf J, Kalocsai K, Fortuny C, et al. Safety and efficacy of Fidaxomicin and vancomycin in children and adolescents with Clostridioides (Clostridium) difficile infection: a phase 3, multicenter, randomized, single-blind clinical trial (SUNSHINE). Clin Infect Dis. 2020;71(10):2581-2588. 24. Okumura H, Fukushima A, Taieb V, Shoji S, English M. Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: a network meta-analysis. J Infect Chemother. 2020;26(1):43-50. 25. Gawronska A, Banasiuk M, Lachowicz D, Pituch H, Albrecht P, Banaszkiewicz A. Metronidazole or rifaximin for treatment of Clostridium

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difficile in pediatric patients with inflammatory bowel disease: a randomized clinical trial. Inflamm Bowel Dis. 2017;23(12):2209-2214.

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LEGAL ADVISOR CASE

NP Sued for Missed Hip Fracture A litigious patient mistakenly believes that a misdiagnosis is grounds for malpractice.

ANN W. LATNER, JD

In early January, a 76-year-old patient, Mrs R, was brought by her husband to the emergency department (ED) of a local hospital after sustaining a fall outside her home.Working in the ED that night was Ms W, a family nurse practitioner, and Dr T, the ED physician. Ms W went into the examination area to speak with Mrs R, who complained of left groin pain that radiated to her lower back. When Ms W asked if anything triggered the pain, Mrs R said that several packages were left outside her door and when she leaned over to pick them up, she fell and has experienced pain since. Ms W took a medical history and then performed a physical examination of the patient. She noted that Mrs R’s lower back was tender toward the sacral area and that the patient was unable to perform a straight leg raise because of pain.The differential diagnosis included hip fracture, and Ms W ordered radiographs of the patient’s pelvis, including the femoral neck and knee. After the radiograph results were back, Ms W conferred with Dr T, the ED physician. Dr T interpreted the images as showing no indication

A medical malpractice case requires a duty owed to the patient, breach of that duty, injury caused by the breach, and damages

of a fracture and Ms W concurred. Meanwhile, the patient had been given pain medication and was doing better. Mrs R was told that she would be discharged with pain medication and Ms W instructed her to follow up with her primary care provider. Ms W noted in the medical record that the patient’s condition had improved and that she advised the patient to contact her doctor for follow-up. Two hours after she left the first hospital, the patient had her husband take her to another hospital where she complained about the same pain that she had sought treatment for at the first hospital. At the second hospital, a computed tomography (CT) scan of Mrs R’s pelvis was conducted. The CT scan revealed a hip fracture. An orthopedist who was consulted recommended that Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2022 29

LEGAL ADVISOR Mrs R be admitted to the hospital for pain medication and physical therapy but advised that nothing should be done surgically. A few days later, Mrs R was admitted to a physical rehabilitation institute for continued physical therapy and treatment, which consisted of stretching , strengthening, and range of motion exercises as well as bone stimulation. According to the rehabilitation facility, she made progressive improvements and was discharged 2 weeks later. Some months later, Mrs R filed a medical review board complaint alleging medical malpractice by Ms W and Dr T for her treatment at the first hospital. The medical review panel found the defendants did not breach the standard of care or cause the damages Mrs R alleged and dismissed the complaint. Mrs R then filed a lawsuit against Ms W and Dr T in state court.

There was nothing in the affidavit to show that the breach of standard of care was linked to the patient’s injuries. Legal Background

The defendant clinicians made a motion for summary judgment asking that the case be dismissed. A hearing was held and the trial court dismissed the case. Mrs R appealed. On appeal, the appellate court was asked to decide whether dismissing the case was a proper action by the lower court. The court noted Mrs R would have the burden to prove 3 things at trial: • The standard of care • That the defendants breached that standard of care • That a causal connection existed between the defendants’ breach and the patient’s alleged injuries The court pointed out that the only thing Mrs R presented at the hearing on the summary judgment motion was the affidavit of a Dr O. In his affidavit, Dr O stated that the standard of care for an older patient who presents with continued pain in the pelvic and hip areas despite negative radiographs is to order a CT scan or magnetic resonance imaging (MRI) of the pelvis to detect fractures that radiographs may miss. He also said that, in his opinion, Ms W and Dr T had breached that standard of care by not ordering a CT or MRI of Mrs R’s pelvis. This is evidence that supports Mrs R’s burden of proof for 2 of the 3 elements in the medical malpractice claim, said the judge in the decision.

Still, Dr O’s affidavit made no mention of what, if any, injuries Mrs R had experienced. At the trial, the court found nothing in the affidavit to show that the breach of standard of care was linked in any way to the patient’s injuries. In fact, Mrs R never alleged that she experienced any injuries at all from the 2-hour delay in her diagnosis. This was a flaw in her argument: if there are no injuries, there is no medical malpractice case. Even if the treatment by the practitioners had fallen below the standard of care, if it did not result in injuries that could be causally tied to the breach, then there is no valid medical malpractice case. Protecting Yourself

It is extremely important to be familiar with the 4 required elements of a medical malpractice case: • A duty owed to the patient • Breach of that duty (of the accepted standard of care) • Injury caused by the breach • Damages Without each of these elements, a medical malpractice case will fail. Litigious patients sometimes mistakenly believe that just because a clinician made an error there is ground for a malpractice case.Without the other required elements, simply making an error (such as failing to order a CT or MRI for the patient) does not rise to the level of medical malpractice. ■ Ann W. Latner, JD, a former criminal defense attorney, is a freelance medical writer in Port Washington, New York.

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Clinical Advisor January/February 2022 Issue

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Dermatology Clinic

Legal Advisor

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