February 2014 Clinical Advisor

THE CLINICAL ADVISOR • FEBRUARY 2014

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■■Tailored diabetes care ■■Anxiety and stroke risk ■■New Alzheimer screening

ADVISOR FORUM

■■Epiploic appendagitis ■■Low amniotic fluid ■■Hirsutism in women

|

FEBRUARY 2014

| www.ClinicalAdvisor.com

CE: HOW TO MANAGE

FOOD ALLERGY Angioedema of the lips (shown) and face is often caused by allergy to shellfish, dairy, or nuts.

LEGAL ADVISOR

A missed diagnosis results in permanent blindness.

✶ FREE CE COURSES!

n Dermatology Clinic

PAINFUL AND ITCHY SHIN LESIONS PAGE 83

n Dermatologic Look-Alikes VOLUME 17, NUMBER 2

BLISTERING RASH IN THE GROIN PAGE 87 Take the Scavenger Hunt Challenge and win an iPad! Turn to p. 51 for details

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Editor Joe Kopcha, editor@clinicaladvisor.com Managing editor Marina Galanakis Senior editor Delicia Yard Web editor Nicole Blazek Contributing editors Bruce D. Askey, MSN, CRNP; Rebecca H. Bryan, APRN, CNP; Eileen F. Campbell, MSN, CRNP; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP-BC; Sharon Dudley-Brown, PhD, FNP-BC; Maria Kidner, DNP, FNP-C; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Claire B. O’Connell, MPH, PA-C; Kathy Pereira, MSN, FNP-BC; Sherril Sego, FNP, DNP; Julee B. Waldrop, MS, PNP; Kim Zuber, PA-C Art director Andrew Bass Group art director, Haymarket Medical Jennifer Dvoretz Production director Kathleen Millea Circulation manager Paul Silver Audience development director John Crewe National accounts manager Alison McCauley, 646.638.6098 alison.mccauley @ haymarketmedical.com Group publisher Thomas P. Hennessy, 646.638.6085 tom.hennessy @ haymarketmedia.com Editorial director Jeff Forster Vice president, medical magazines and digital products Jim Burke CEO, Haymarket Media, Inc. Lee Maniscalco All correspondence to: The Clinical Advisor 114 West 26th Street, 4th Floor, New York, NY 10001 For advertising sales, call 646.638.6085.

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CONTENTS FEBRUARY 2014

NEWS AND COMMENT

61 The facts and fictions of chelation therapy Originally used to treat lead poisoning and hypercalcemia, chelation has shown promise among individuals with heart disease and other conditions.

16 Newsline ■■ADA calls for more tailored diabetes care ■■New advice on menopause symptoms ■■Disc surgery is good but no surgery is not bad ■■Migraine message matters ■■Anxiety may raise stroke risk ■■FDA sets acetaminophen max in combo drugs ■■Mammography pros and cons quantified ■■New tests to detect early Alzheimer disease ■■Constipation does not cause diverticulosis ■■Better cutoffs given for respiratory symptoms

Satisfaction after back surgery for pain 25

DEPARTMENTS 78 Legal Advisor Significant facial edema and redness is misdiagnosed as an allergic reaction— with drastic consequences.

43 Drug Update ■■Therapy for chronic hepatitis C infection ■■Treatment against MDD in adults

The controversy over chelation therapy 61

101 Commentary

and hypothyroidism presented with shin lesions that were intensely itchy, painful, and exquisitely tender when bumped.

52 CME/CE Managing food allergies in primary care As gatekeepers, primary-care clinicians are able to provide education on the recognition and treatment of potentially fatal complications.

Continues on page 11

Misdiagnosed infection leads to blindness 78

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Follow us on Twitter @ClinicalAdvisor

82 CME/CE Dermatology Clinic n Over the course of one year, a man developed numerous reddish-brown, crusted, and nonpruritic papules on his chest, back, and extremities. n A man with cardiovascular disease

FEATURES

MAKING CONTACT

71 Controversy surrounds new JNC 8 guidelines In a departure from previous treatment guidelines, JNC 8 recommends that clinicians raise BP goals and use fewer antihypertensive medications.

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CONTENTS 87 CME/CE Dermatologic Look-Alikes Two patients presented with a pruritic inguinal rash that featured tense serous and hemorrhagic bullae.

n Testosterone therapy is associated

with increased cardiovascular events in men with low testosterone levels and high cardiovascular risk n Steroids reduce time to discharge from observation unit in infants with acute bronchiolitis and suspected asthma

91 CME/CE Posttest 92 Derm Dx Read the clinical descriptions, view the images, and make your diagnosis at ClinicalAdvisor.com.

Blistering rash with no oral erosions 87

74 Consultations ■■Relieving the pain of epiploic appendagitis ■■Is low amniotic fluid preventable?

■■Do surgical metals affect security or MRI scans?

■■And more

93 Alternative Meds Update Magnet therapy is based on the concept that, when placed on the skin, such devices increase blood flow and oxygenation and promote the removal of pain-producing prostaglandins.

96 Evidence-Based Medicine n Multivitamin plus selenium supplement may slow progression of HIV in treatment-naïve adults in low-resource settings n Clarithromycin might increase all-cause mortality and hospitalization for acute kidney injury compared with azithromycin in older adults receiving calcium channel blockers

ADVISOR FORUM

Drug reaction may lead to hypotension 96

76 Clinical Pearls ■■Cold comfort for recurrent nosebleeds ■■With multiple dermatofibromas, think lupus ■■Eliminate earwax with olive oil ■■Detecting abnormal heart sounds 76 Your Comments ■■A correction on the treatment of vaginal atrophy

HOW TO CONTACT US

TO CONTACT AN EDITOR: • Editor@ClinicalAdvisor.com • Call 646.638.6077

CA0214_TOC.indd 11

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■ Tailored diabetes care ■ Anxiety and stroke risk ■ New Alzheimer screening ADVISOR FORUM

■ Epiploic appendagitis ■ Low amniotic fluid ■ Hirsutism in women

|

FEBRUARY 2014

| www.ClinicalAdvisor.com

CE: HOW TO MANAGE

FOOD ALLERGY Angioedma of the lips (shown) and face is often caused by allergy to shellfish, dairy, or nuts.

LEGAL ADVISOR

A missed diagnosis results in permanent blindness.

✶ FREE CE COURSES!

■ Dermatology Clinic

PAINFUL AND ITCHY SHIN LESIONS PAGE 83

■ Dermatologic Look-Alikes VOLUME 17, NUMBER 2

TO SUBMIT AN ARTICLE: • Editor@ClinicalAdvisor.com • Fax it to 646.638.6117

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BLISTERING RASH IN THE GROIN PAGE 87 Take the Scavenger Hunt Challenge and Win an iPad! Turn to p. 46 for details

1/28/14 11:26 AM

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ClinicalAdvisor.com Web Exclusives

Videos

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Pediatric AOM hikes U.S. health-care costs Children with acute otitis media have more office visits, increased outpatient health care costs and higher patient ­medication costs.

Obese, overweight adults consume more diet drinks Calories from sugar sweetened beverages lower in obese, overweight compared with healthy weight, but solid food calories up.

Direct-acting hepatitis C antivirals effective without interferon All-oral combination therapies achieve ­sustained virologic responses in patients with difficult to treat hepatitis C infections.

Is it time for his and hers health care?

Every cell in the human body has a sex, which means that men and women are different right down to the cellular level. Yet too often, research and medicine often ignore this insight. Paula Johnson, MD, MPH, founder of the the Center for Cardiovascular Disease in Women at Brigham and Women’s Hospital in Boston, describes how lumping everyone in together essentially leaves women’s health to chance.

Perhaps it is time to rethink.

The benefits of mental exercise persist 10 years after training Older adults who received as few as 10 sessions of mental training show long-lasting improvements in reasoning and speed of processing skills 10 years after the intervention, according to University of Florida Health researchers with the Advanced Cognitive Training for Independent and Vital Elderly, or ACTIVE, study.

Derm Dx

The Waiting Room

Interact with your peers by viewing the images and offering your diagnosis and comments.

Official Blog of The Clinical Advisor

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Jim Anderson, MPAS, PA-C, ATC Are AAPA elections relevant to members?

During the past few years, voting ­numbers have ­continued to fall with recent annual elections attracting less than 10% of the eligible AAPA voters.

Hepatology Information Center CliniAd.com/1n7cSA2

Blue sclera in a patient with skeletal fractures A woman with a history of multiple skeletal fractures came in for a routine checkup.

Physical examination revealed bluish sclera.

MAKING CONTACT

Follow us on Twitter @ClinicalAdvisor

CDC updates HBV vaccination guidelines for HCWs All should be vaccinated and undergo serologic testing.

FDA approves Sovaldi for chronic hepatitis C Breakthrough drug does not need combined interferon.

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Newsline

ACOG updates menopause guidelines page 25

F E B R U A R Y 2 014

FDA limits acetaminophen to 325 mg page 31

The benefits and harms of mammography page 36

© CMSP

ADA calls for more tailored diabetes care

The update addresses screening, diagnosis, and treatment.

The ADA standards advise screening for gestational diabetes at 24 to 28 weeks of pregnancy in women not previously known to have diabetes. Separately, the United States Preventive Services Task Force (USPSTF) has just issued a recommendation for screening asymptomatic pregnant women for gestational diabetes after 24 weeks’ gestation, having found insufficient evidence to assess the balance of benefits and harms of such screening before that time. This updates a 2008 USPSTF recommendation that found insufficient evidence to recommend for or against gestational diabetes screening in asymptomatic pregnant women.

The full recommendation can be found at the USPSTF website (www.uspreventiveservicestaskforce.org/uspstf/uspsgdm.htm; accessed January 15, 2014).

Percentage of youths who are physically active daily “Physically active” is defined as engaging in any kind of activity for at least 60 minutes that increases heart rate and makes breathing harder.

Source: CDC/NCHS, National Health and Nutrition Examination Survey and National Youth Fitness Survey, 2012.

30

29.5

29.5 24.1

25 Percent

IN its annual update to its Standards of Medical Care, the American Diabetes Association (ADA) urges clinicians to evaluate individual patient needs rather than take a one-size-fits-all approach to diabetes management (Diabetes Care. 2014;37 Suppl 1:S5-S13).

Based on the most current scientific evidence, the revised standards address screening, diagnostic, and therapeutic actions expected to improve the health of persons with type 1, type 2, or gestational diabetes, or additional specific types of diabetes stemming from other causes.

The following recommendations are supported by clear A-level evidence (from wellconducted, generalizable randomized controlled trials): • Most people with type 1 diabetes should use insulin analogs to reduce hypoglycemia risk.

• Metformin is the preferred initial agent for type 2 diabetes. If noninsulin monotherapy does not achieve or maintain the hemoglobin A1c target over three months, add a second oral agent, a glucagon-like peptide 1 receptor agonist, or insulin.

• Individuals who have prediabetes or diabetes should receive individualized medical nutrition therapy (MNT) as needed to achieve treatment goals, preferably from a registered dietitian familiar with the components of diabetes MNT. B-level evidence suggests that there is no ideal percentage of calories from carbohydrate, protein, and fat for all people with diabetes, and that among persons with both diabetes and hypertension, reductions in sodium intake beyond <2,300 mg/day should be individualized.

18.0

20

n Normal-weight n Overweight n Obese 20.1

19.6

15 10 5 0

Boys

Girls

16 THE CLINICAL ADVISOR • FEBRUARY 2014 • www.ClinicalAdvisor.com

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Newsline New advice on menopause symptoms THE American Congress of Obstetricians and Gynecologists (ACOG) has issued several recommendations regarding the management of vasomotor and vaginal symptoms related to menopause in a new practice bulletin (Obstet Gynecol. 2014;123[1]:202-216).

ACOG affirmed that vasomotor (hot flush) symptoms can be particularly troubling to women and are the most commonly reported menopausal symptoms. Among the recommendations and conclusions based on good or consistent scientific evidence (level A) are the following: • The most effective treatment for vasomotor symptoms related to menopause is systemic hormone therapy (HT), with estrogen alone or in combination with progestin.

• Low-dose and ultra-low systemic doses of estrogen have a better adverse-effect profile than do standard doses, and may reduce vasomotor symptoms in some women.

Clinicians should prescribe the lowest effective dose of HT for the shortest duration necessary.

• The risks of combined systemic HT include thromboembolic disease and breast cancer.

• Alternatives to HT for the treatment of menopauserelated vasomotor symptoms are selective serotonin reuptake inhibitors, selective serotonin norepinephrine reuptake inhibitors, clonidine (Catapres, Kapvay), and gabapentin (Horizant, Neurontin).

• Estrogen therapy effectively alleviates atrophic vaginal

Hot flushes are one of the most common symptoms of menopause.

symptoms related to menopause. Women who only have vaginal symptoms should receive local therapy.

• Ospemifene (Osphena) was approved in February 2013 for the treatment of moderateto-severe dyspareunia in postmenopausal women.

CAREFULLY selected patients who underwent surgery for a lumbar disc herniation had greater improvements in pain, functioning, and disability than did patients who were treated nonoperatively, but the latter group also fared relatively well, a recent analysis showed (Spine.

2014;39[1]:3-16).

Researchers analyzed follow-up data from 1,244 participants in the Spine Patient Outcomes Research Trial (SPORT). All were surgical candidates with imagingconfirmed lumbar intervertebral disc herniation.

Pain scores were lower in people who had had surgery.

The 501 randomized participants and observational cohorts (743 persons) had been treated at 13 U.S. spine clinics with standard open discectomy or usual nonoperative care, the latter of which was recommended to include, at least, active physical therapy, education/counseling with homeexercise instruction, and nonsteroidal anti-inflammatory drugs if tolerated. The study subjects had been allowed to cross over to the treatment not originally assigned.

Mean scores of post-treatment pain were approximately 11 points lower in the people who

had undergone surgery compared with those who had not. Measures of physical functioning and disability were similarly better for the surgery patients.

Many of the nonsurg ical patients, however, experienced significant improvements following therapy. After eight years, approximately one-third of the participants who were clinically indicated for surgery had chosen not to have the operation; 54% of the nonsurgical group reported being satisfied with their symptoms and 73% were satisfied with their care eight years later.

© SCIENCE SOURCE / LAURENT / ANNETTE PRI

Disc surgery is good but no surgery is not bad

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2014 25

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Newsline

PATIENTS suffer ing from migraine got better results from medication as well as placebo after receiving positive information about each therapy from their health-care provider.

To determine how the treatment i n for m at ion a ltered reported headache pain, investigators evaluated 459 episodic migraine attacks in 66 patients (seven separate migraine episodes per person) (Sci Transl Med. 2014;6[218]:218ra5). An initial attack with no treatment served as the control. In the six subsequent migraine attacks, patients received either rizatriptan (Maxalt) 10 mg or a placebo, administered under three different information conditions applied randomly.

Patients derived more benefit from the rizatriptan when they were told that they would be receiving a drug effective against acute migraine.

When rizatriptan labels were switched with labels for placebo pills, patients reported similar reductions in pain for each pill.

In a third approach, patients were told outright that they would be receiving a placebo pill.

They nonetheless reported more pain relief than they did when receiving no therapy at all.

“The information provided to patients and the ritual of pill taking are important components of care,” concluded the researchers.

Anxiety may raise stroke risk HIGHER anxiety-symptom levels were associated prospectively with increased risk for incident stroke in a recent study.

Higher levels of anxiety are linked with heightened risk for coronary heart disease, acknowledged Maya J. Lambiase, PhD, and colleagues in their writeup for the journal Stroke. However, they noted, few have examined whether anxiety is related to stroke.

Lambiase and team followed 6,019 participants in the First National Health and Nutrition Examination Survey, aged 25 to 74 years. A total of 419 strokes occurred in the study group over the course of 22 years.

People who reported more anxiety symptoms at baseline had an increased risk of incident stroke after data were adjusted for standard biological and behavioral cardiovascular risk factors and for depression. People in the highest third of anxiety symptoms had a 33% greater risk of stroke than did those in the lowest third.

Those with the highest anxiety had a 33% greater risk of stroke.

Another study uncovered an additional risk factor for stroke: the use of warfarin (Coumadin, Jantoven). Dr. Laurent Azoulay and associates repor ted in European Heart Journal that warfarin initiation increased stroke risk by 71% during the first 30 days of treatment compared with persons taking no anticoagulant agents, but after the first 30 days, the risk of stroke declined by half.

The 30-day risk was particularly high for people who had had a previous ischemic stroke.

FDA sets acetaminophen max in combo drugs PROVIDERS should no longer prescribe or dispense prescription combination drug products containing more than 325 mg of acetaminophen per tablet, capsule, or other dosage unit, the FDA has announced.

The FDA requested three years ago that manufacturers of prescription drug products containing acetaminophen limit the amount to 325 mg or less by January 14, 2014, to lower the user’s risk of severe liver damage.

In the latest directive, the agency recommends that providers consider prescribing combination drug products that contain no more than 325 mg of acetaminophen, stating that there are no available data to show that taking more than this amount per dosage unit provides additional benefit that outweighs the added risks for liver injury.

A two-tablet or two-capsule dose totaling 650 mg of acetaminophen may still be prescribed if appropriate.

© THINKSTOCK

Migraine message matters

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Newsline TWO researchers have put rough estimates to the benefit/ harm trade-off for screening mammography.

In a study published in in JAMA Internal Medicine, H. Gilbert Welch, MD, MPH, and Honor J. Passow, PhD, of the Dartmouth Institute for Health Policy and Clinical Practice, evaluated the absolute frequency of three outcomes important to the mammography decision: breast cancer deaths avoided, false alarms, and overdiagnosis. The data revealed that among 1,000 U.S. women aged 50 years who are screened annually for a decade, 0.3 to 3.2 will avoid death from breast cancer, 490 to 670 will have at least one false alarm, and 3 to 14 will be overdiagnosed and will undergo unnecessary treatment.

The authors acknowledged that many women will find these ranges insufficiently precise to make an informed decision about screening, and that women will likely desire more precise estimates regarding benefits and harms.

In other breast-cancer screening news, the United States Preventive Services Task Force (USPSTF) now recommends that primarycare providers screen asymptomatic women who have a family history of breast, ovarian, tubal, or peritoneal cancers with one of several tools designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in the breast-cancer susceptibility genes BRCA1 and BRCA2. Writing in Annals of Internal Medicine on behalf of

© CMSP / BEEBE

Mammography pros and cons quantified

The USPSTF advises genetic counseling after a positive screening test.

the USPSTF, guideline author Virginia A. Moyer, MD, MPH, advises that women with positive screening results should receive genetic counseling, to be followed

by BRCA testing if indicated after counseling (available at annals. org/article.aspx?articleid=1791499, accessed January 15, 2014).

TWO new cognitive screening assessment tools appear to be useful additions to the arsenal of Alzheimer testing.

The Sel f-Ad m in istered Gerocognitive Examination (SAGE) was used to screen 1,047 persons aged 50 years and older at community events. The test, which takes less than 15 minutes to complete and is simple enough for people to perform at home, assesses participants on orientation, language, reasoning/ computation, visuospatial ability, executive ability, and memory.

Douglas W. Scharre, MD, and his

The SAGE test takes less than 15 minutes to complete.

SAGE co-developers reported in The Journal of Neuropsychiatry and Clinical Neurosciences that the test identified cognitive impairment in 28% of the individuals tested.

Scharre pointed out in a separate statement that although SAGE cannot be used to diagnose Alzheimer disease (AD), it does provide clinicians with a baseline of cognitive function for patients, which can result in more rapid intervention if changes are noted.

In another study, investigators predicted with 90% accuracy which persons with mild cognitive impairment would receive a

clinical diagnosis of AD within two years, and which persons would not develop the disease ( J Alzheimers Dis. 2014;38[2]:307318). Brain neuroimaging and neuropsychological measures showed the strongest neuroimaging predictors of progression to dementia to be baseline cortical thickness in the right anterior cingulate and middle frontal gyri of the brain. In terms of cognitive predictors, deficits in both free recall and recognition episodic memory tasks were highly suggestive of progression to dementia.

© SCIENCE SOURCE / JESSICA WILSON

New tests to detect early Alzheimer disease

36 THE CLINICAL ADVISOR • FEBRUARY 2014 • www.ClinicalAdvisor.com

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Newsline ALTHOUGH asymptomatic diverticulosis is commonly attributed to constipation caused by a low-fiber diet, the already limited evidence of this relationship received no support from a crosssectional, colonoscopy-based study involving 539 persons with diverticulosis and 1,569 without (Clin Gastroenterol Hepatol.

2013;11[12]:1622-1627).

Colonoscopy results and assessment of diet, physical activity, and bowel habits revealed no association between constipation and an increased risk of diverticulosis.

In fact, participants who had less frequent bowel movements (fewer than seven per week) had reduced odds of diverticulosis compared with persons who had regular bowel movements (seven per week). Individuals who reported

hard stools also had reduced odds of diverticulosis.

Investigators also found no association between the development of diverticulosis and straining during bowel movements or having incomplete bowel movements. Finally, the researchers found no connection between dietary fiber intake and divertuculosis when comparing the highest quartile of such intake (mean 25 g/day) with the lowest (mean 8 g/day).

In a statement announcing the publication of the study, the American Gastroenterological Association asserted that diverticulosis is increasing in frequency, affecting the majority of those who reach age 80 years. In this condition, small pouches, or sacs, known as diverticula form and

In colonic diverticulosis, small pouches develop in the walls of the colon (shown).

push outward through weak spots in the colon wall.

Diverticular bleeding occurs when a small blood vessel within the wall of a diverticulum bursts, and diverticulitis develops when diverticula become inflamed and infected. Another study published in the same issue determined that only about 4% of persons with diverticulosis develop acute diverticulitis, contradicting the common belief that diverticulosis has a high rate of progression (Clin Gastroenterol Hepatol.

2013;11[12]:1609-1613).

© CSMP

Constipation does not cause diverticulosis

NEW research can help clinicians better answer one of the most frequently asked questions by adults caring for children with respiratory tract infections: “How long will the symptoms last?”

Typically used estimates of the expected time course of symptoms of common respiratory tract infections are not always evidence-based (BMJ. 2013;347:f7027; available at www.bmj.com/content/347/ bmj.f7027, accessed January 15, 2014). Researchers performed a systematic review of the literature, focusing on symptom duration of the most common respiratory tract

In 90% of children, sore throat resolved by two to seven days.

infections in children presenting to primary-care settings: earache (acute otitis media), common cold, sore throat, and cough.

The analysis of 23 randomized controlled trials and 25 observational studies showed that in 90% of children, earache resolved by seven to eight days, and the common cold by 15 days. The authors

noted that information for patients distributed by the CDC describes earache as lasting for an average of two days and the common cold as lasting up to 14 days.

The CDC puts the duration of sore throat at one to two weeks, and the duration of cough at two to eight weeks. Investigators found that in 90% of the children represented in the evaluated studies, sore throat resolved by two to seven days, croup by two days, bronchiolitis by 21 days, acute cough by 25 days, and nonspecific respiratory tract infection symptoms by 16 days. n

©THINKSTOCK

Better cutoffs given for respiratory symptoms

40 THE CLINICAL ADVISOR • FEBRUARY 2014 • www.ClinicalAdvisor.com

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DrugUpdate New drug information from the publishers of MPR

Therapy for chronic hepatitis C infection Product: Olysio

values of 0.5 nM and 1.4 nM, respectively.

Company: Janssen

Therapeutics Pharmacologic class:

Hepatitis C virus (HCV) NS3/4A protease inhibitor.

Active ingredient:

Simeprevir 150 mg; caps.

Indication: Chronic

hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin in patients with compensated liver disease, including cirrhosis. Not for use as monotherapy. Screen for presence of virus with NS3Q80K polymorphism at baseline; consider alternative therapy if Q80K polymorphism is present.

Pharmacology: Simeprevir is an inhibitor of the HCV NS3/4A protease. In a biochemical assay, simeprevir inhibited the proteolytic activity of recombinant genotype 1a and 1b HCV NS3/4A proteases, with median Ki

Clinical trials: The effi-

cacy of Olysio in patients with HCV genotype 1 infection was evaluated in three Phase 3 trials— QUEST-1 and QUEST-2 in treatment-naïve patients and PROMISE in patients who have relapsed after prior interferon-based treatment—as well as one Phase 2b ASPIRE study in prior nonresponder patients.

Results from a pooled analysis of QUEST-1 and QUEST-2 demonstrated

Olysio is a component of a combination treatment regimen for HCV.

that 80% of treatmentnaïve patients in the group receiving Olysio achieved sustained virologic response 12 weeks after the end of treatment (SVR12), vs. 50% in the placebo groups. In PROMISE, 79% of prior relapsers in the Olysio group achieved SVR12 vs. 37% in the placebo group. Results from ASPIRE demonstrated that use of Olysio led to SVR24 after the end of treatment in 65% of prior partial-responders and 53% of prior null-responders vs. 9% and 19% of prior partial- and null-responder patients in the placebo groups, respectively.

For more clinical trial data, see full labeling.

Adults: Swallow whole.

Take with food. 150 mg once daily. Treat for 12 weeks (with peginterferon + ribavirin).

Treatment-naïve and prior relapsers, including cirrhosis: give additional 12 weeks of peginterferon + ribavirin (total treatment + 24 weeks). Prior nonresponders (partial and null), including cirrhosis: Give additional 36 weeks of peginterferon + Continued pg. 49

Treatment against MDD in adults Product: Brintellix Companies: Takeda and Lundbeck Pharmacologic class: Serotonergic

antidepressant.

Active ingredient:

Vortioxetine 5 mg, 10 mg, 20 mg; tabs.

Indication: Treatment of

adults with major depressive disorder (MDD).

Pharmacology: The antidepressant effect of vortioxetine is not fully understood but is thought to be related to its enhancement of serotonergic activity in the central nervous system through inhibition of the reuptake of serotonin (5-HT).

It also has several other activities including 5-HT3 receptor antagonism and 5-HT1A receptor agonism.

Clinical trials: The effi-

cacy of Brintellix was Continued pg. 49

For more products, visit www.eMPR.com

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2014 43

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DrugUpdate Olysio from pg. 43

ribavirin (total treatment + 48 weeks). Do not reduce simeprevir dose or interrupt therapy; if discontinued, do not reinitiate. Discontinue if HCV-RNA levels indicate futility (see full labeling). If peginterferon or ribavirin is discontinued, simeprevir must also be discontinued.

Children: <18 years: not

established.

Contraindications:

Pregnant women and men whose partners are pregnant (note: ribavirin is Category X). Peginterferon and ribavirin contraindications also apply to combination therapy with simeprevir.

Warnings/Precautions:

Female patients and

Brintellix enhances serotonergic activity in the central nervous system.

partners must have negative pregnancy test before therapy; use two effective forms of contraception during and six months after treatment completion; perform routine monthly pregnancy test.

Avoid sun exposure, tanning devices; consider discontinuing if photosensitivity or rash occurs.

Sulfa allergy. Monitor HCV-RNA levels as clinically indicated.

East Asian ancestry.

Severe renal impairment, end-stage renal disease, or dialysis.

Moderate or severe hepatic impairment.

Liver transplant patients.

Other HCV genotypes.

Pregnancy (Category C).

Nursing mothers: not recommended.

Interactions:

Brintellix from pg. 43

primary efficacy measures were the Hamilton Depression Scale total score in Study 2 and the Montgomery-Asberg Depression Rating Scale total score in all others.

In Study 1, the difference in least-squares mean change from baseline for the Brintellix 5-mg arm was −5.9 (95% CI: −8.6, −3.2) and for the 10-mg arm was −5.7 (95% CI: −8.5, −2.9). Both treatment groups were

established in six six- to eight-week randomized, double-blind, placebocontrolled, fixed-dose studies (including one study in the elderly) and one maintenance study in adult inpatients and outpatients who met the DSM-IV-TR criteria for MDD. In five of the efficacy studies, patients were randomized to 5 mg, 10 mg, 15 mg, 20 mg, or placebo once daily. The

Concomitant moderate or strong CYP3A inducers/ inhibitors: not recommended. Avoid use with macrolides, azole antifungals, cobicistat-containing products, milk thistle, delavirdine (Rescriptor), darunavir (darunavir), ritonavir (Norvir), other HIV protease inhibitors.

May be antagonized by anticonvulsants, rifabutin (Mycobutin), rifampin (Rifadin, rifapentine (Priftin), dexamethasone (Decadron, Dexamethasone Intensol, Dexpak), efavirenz (Sustiva), etravirine (Intelence), nevirapine (Viramune), St. John’s wort; avoid. May potentiate cisapride (Propulsid) (avoid), antiarrhythmics (caution), digoxin (Cardoxin,

Digitek, Lanoxicaps, Lanoxin), calcium channel blockers, statins (use lowest dose), PDE-5 inhibitors for pulmonary arterial hypertension, oral midazolam (Versed), or triazolam (Halcion). Monitor warfarin (Coumadin, Jantoven), immunosuppressants.

Adverse reactions: Rash, photosensitivity, pruritus, nausea, myalgia, dyspnea.

Note: For peginterferon alfa and ribavirin specific dosing and safety information, refer to their respective prescribing information.

How supplied: Caps—7, 28 For more information, call 800.526.7736 or visit www.Olysio.com.

statistically significantly superior to placebo.

Across all studies, at least one dose group of Brintellix was superior to placebo in the improvement of depressive symptoms as measured by mean change from baseline to end-point visit.

For more clinical trial data, see full labeling.

Adults: Initially, 10 mg

once daily; then increase to 20 mg/day, as tolerated.

For more products, visit www.eMPR.com

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2014 49

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DrugUpdate Contraindications:

May consider 5 mg/day if the patient is unable to tolerate. Discontinuing treatment: may reduce to 10 mg/day for one week before full discontinuation of 15 mg/day or 20 mg/day. CYP2D6 poor metabolizers: maximum 10 mg/day. Concomitant strong CYP2D6 inhibitors: Reduce vortioxetine dose by half; increase to original level when inhibitor is discontinued. If concomitant strong CYP inducers for more than 14 days: consider increasing vortioxetine dose up to maximum three times original dose; reduce to original level within 14 days when inducer is discontinued.

Concomitant monoamine oxidase inhibitors (MAOIs) during or within 21 days of discontinuing vortioxetine. Within 14 days of discontinuing an MAOI. Concomitant linezolid (Zyvox) or IV methylene blue.

Children: <18 years: not

established.

“We raise our beef humanely.”

Warnings/Precautions:

Increased risk of suicidal thinking and behavior in children, adolescents, and young adults; monitor for clinical worsening or changes. Monitor for serotonin syndrome; discontinue if occurs. History of mania/hypomania.

Screen patients for bipolar disorder prior to starting.

Severe hepatic impairment: not recommended.

Volume depletion. Elderly.

Pregnancy (Category C; avoid in third trimester; see

full labeling for effects on neonate). Nursing mothers: not recommended.

Interactions: See Contraindications. Do not start with concomitant linezolid or IV methylene blue; if necessary, discontinue vortioxetine before starting; monitor for serotonin syndrome for 21 days or until 24 hours after last dose of linezolid or IV methylene blue, whichever comes first. Caution with concomitant triptans, tricyclic antidepressants, fentanyl, lithium (Lithobid), tramadol (ConZip, Rybix ODT, Ultram), tryptophan, buspirone, St. John’s wort, linezolid, IV methylene blue; may cause serotonin syndrome. Increased risk of bleeding with nonsteroidal anti-inflammatory drugs, aspirin, warfarin

“Business doesn’t take a summer vacation.”

(Coumadin, Jantoven), others that affect coagulation. May be affected by strong CYP2D6 inhibitors (e.g., bupropion, fluoxetine [Prozac, Rapiflux, Sarafem, Selfemra], paroxetine [Paxil, Pexeva], quinidine) or strong CYP inducers (e.g., rifampicin, carbamazepine, phenytoin [Dilantin, Phenytek]); adjust doses (see Adults).

May potentiate proteinbound drugs.

Adverse reactions:

Nausea, constipation, vomiting, dizziness; hyponatremia (especially in the elderly), mania/hypomania, sexual dysfunction.

How supplied: Tabs—30 n For more information, call 877.825.3327 or visit www.Brintellix.com.

“It’s the bottom of the ninth, with two outs and bases loaded, and you’re in the batter’s box doing situps for some reason.”

© The New Yorker Collection 2014 from cartoonbank.com. All Rights Reserved.

Brintellix from pg. 49

For more products, visit www.eMPR.com

50 THE CLINICAL ADVISOR • FEBRUARY 2014 • www.ClinicalAdvisor.com

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1/28/14 11:23 AM

Take the Scavenger Hunt Challenge February edition

Correctly answer the questions below— all of which can be found within this issue of The Clinical Advisor—and you’ll be entered into a random drawing to win an Apple iPad mini.

To submit your responses, simply go to CliniAd.com/LghLbf. QUESTIONS 1. According to the CDC, what percentage of normal-weight girls are physically active daily? (p. 16) 2. What is the first-line treatment for anaphylaxis in all patients with food allergy? (p. 55) 3. In what year did the Trial to Assess Chelation Therapy begin? (p. 62) 4. For individuals younger than age 60 years, JNC 8 advises initiating antihypertensive medication for BP over what level? (p. 72) 5. How much amniotic fluid is typically present at 42 weeks’ gestation? (p. 75) 6. In which sex is pityriasis lichenoides more common? (p. 84) 7. What part of the body is most commonly affected by lichen planus? (p. 85) 8. What is the estimated incidence of linear immunoglobulin A bullous dermatosis in the United States? (p. 88) 9. What is the most common autoimmune blistering disorder to occur in the skin? (p. 89) 10. By age 2 years, how big should a child’s vocabulary be? (p. 101)

WHO MAY ENTER All nurse practitioners and physician assistants 21 and over who are on The Clinical Advisor’s subscriber list. Employees and families of employees of Haymarket Media Inc., its affiliates, printer, agencies, mailers, and advertisers are not eligible.

RULES No purchase necessary. Entries are limited to one per person.Void where prohibited. All entries must be received by March 15, 2014.

Entries become the property of The Clinical Advisor and will not be acknowledged or returned. The Clinical Advisor is not responsible for late or misdirected entries, illegible entries, or electronic malfunctions. Entry constitutes acceptance of all rules.

PICKING WINNERS Winners will be randomly selected from all accepted entries received by the deadline.

Winners will be notified no later than April 1, 2014. Winners will be required to sign an affidavit of eligibility within 14 days of notification, or another winner will be chosen. Where permitted by law, winners agree to the use of their names, likenesses, and photographs for promotional purposes, without additional compensation. Odds of winning depend on the number of entries received.

Winners agree to release and hold harmless The Clinical Advisor and Haymarket Media, Inc. from any liability arising from participation in this contest or acceptance and use of a prize.

Names of winners will be published in a future issue of The Clinical Advisor. The winners’ names will be available upon written request after April 1, 2014, to individuals who send a stamped, self-addressed, business-sized envelope to Clinical Advisor Contest Winners, 114 W. 26th St., 4th Floor, New York, NY 10001.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2014 51

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CME CE

n LEARNING OBJECTIVES • Define the symptoms of common food allergies.

• Review diagnostic measures including skin-prick testing and oral food challenge protocols.

• Identify and mediate the signs and symptoms of anaphylaxis.

• Describe select vaccine constituents and their roles in food allergies.

• Discuss management and prevention strategies, focusing on patient education. n COMPLETE THE POST TEST: Page 91

FEATURED COURSE

n ADDITIONAL CME/CE CREDIT: Pages 83, 87

This activity is jointly sponsored by Medical Education Resources (MER) and Haymarket Medical Education (HME).

Release Date: February 2014 Expiration Date: February 2015 Estimated time to complete the educational activity: 30 minutes Statement of Need: There is consensus that the current prevalence of food allergy is increasing, affecting adults as well as children. Due to a number of potentially life-threatening complications stemming from food allergies, primary-care clinicians need to be able to identify and appropriately manage patients affected by food allergies. This includes the ability to provide patients with education on avoidance and preventive management strategies.

Target Audience: This activity has been designed to meet the educational needs of primary-care physicians, physician assistants, and nurse practitioners who treat patients with food-related allergies.

Faculty Karen Rance, DNP, CPNP Allergy Partners of Central Indiana, Indianapolis Mary O’Laughlen, PhD, FNP-BC Nurse researcher and educator University of Virginia Charlottesville Accreditation Statements Physician Credit: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of MER and HME. MER is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: MER designates this educational activity for a maximum of 0.5 AMA PRA Category 1 creditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nursing Credit: MER is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

Credit Designation: This CE activity provides 0.5 contact hour of continuing nursing education.

MER is a provider of continuing nursing education by the California Board of Nursing Registered Nursing, Provider #CEP 12299, for 0.5 contact hours.

American Academy of Physician Assistants AAPA accepts certificates of participation for educational activities certified for Category I credit from AOACCME, Prescribed credit from AAFP, and AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 1 hour of Category I credit for completing this program.

Accreditor Disclosure of Conflicts-of-Interest Policy MER ensures balance, independence, objectivity, and scientific rigor in all our educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts are resolved by MER to ensure all scientific research referred to, reported,

0214_CME Feature disclosure page.indd 52

or used in a CME/CE activity conforms to the generally accepted standards of experimental design, data collection, and analysis. MER is committed to providing its learners with high-quality CME/CE activities that promote improvements or quality in health care and not a commercial interest.

Faculty Disclosures The faculty reported the following financial relationships or relationships to products or devices that they or their spouse/life partner have with commercial interests related to the content of this CME/CE activity: Karen Rance, DNP, CPNP, and Mary O’Laughlen, PhD, FNP-BC, have no relevant financial relationships to disclose.

Staff/Planners’ Disclosures The planners and managers reported the following financial relationships or relationships to products or devices that they or their spouse/life partner have with commercial interests related to the content of this CME activity: The following HME planners and managers hereby state the following financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months: Joseph Kopcha, Editor; Marina Galanakis, Executive Editor; and Nicole Blazek, Web Editor have no real or apparent conflicts of interest to report.

The MER planners and managers, and Veronda Smith, BC-FNP, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

Method of Participation: There are no fees for participating in and receiving CME/CE credit for this activity. During the period of February 2014 through February 2015, participants must: 1) read the learning objectives and faculty disclosures; 2) study the educational activity; 3) complete the posttest and submit it online (physicians may register at www.myCME.com); and 4) complete the evaluation form online.

A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed posttest with a score of 70% or better.

Disclaimer: The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of MER or HME. The authors have disclosed if there is any discussion of published and/or investigational uses of agents that are not indicated by the FDA in their presentations. The opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of MER or HME. Before prescribing any medicine, primary references and full prescribing information should be consulted. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. The information presented in this activity is not meant to serve as a guideline for patient management.

1/28/14 10:32 AM

KAREN RANCE, DNP, CPNP, AND MARY O’LAUGHLEN, PhD, FNP-BC

Managing food allergies in primary care As gatekeepers, primary-care clinicians are able to provide education on the recognition and treatment of potentially fatal complications.

F

© SCIENCE SOURCE / DR. P. MARAZZI

ood allergy is a growing public health concern for which there is no cure. Although a discussion of food allergy often focuses on children, adults of all ages are affected as well.

Receiving a diagnosis of food allergy requires significant changes to be made in an individual’s daily routine. Patients cannot always easily avoid the foods to which they are allergic, but the risks of not doing so are high. Food allergy is the most frequent cause of anaphylaxis seen either inside or outside of the emergency department. Fatal allergic reactions are most likely to be associated with peanuts, tree nuts, or seafood. However, fatal reactions to milk, eggs, seeds, and other foods have also been reported. Being a teenager or young adult, having asthma, or delaying the use of epinephrine for the treatment of anaphylaxis are factors that increase the risk of death from a food allergy. Because of the potentially life-threatening complications of food allergies, primary-care providers must know how to identify and appropriately manage affected patients. This article will review an evidence-based approach to the diagnosis and management of food allergies in primary care.

Overview

The most common cause of angioedema (shown) is a sudden allergic reaction to certain foods.

There is consensus among professionals that the current prevalence of food allergy in adults and children is increasing, but the exact rates vary. The most recent overall prevalence of self-reported food allergy is 8.96%, consisting of 6.53% in children and 9.72% in adults.1 It is estimated that 2 children in every classroom of 25 children have food allergies. Children with food allergies are more likely www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2014 53

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CME CE

FOOD ALLERGY

to have asthma or other allergic conditions than those without food allergies.

While more than 170 foods have been identified as triggers of food allergy, the 8 most common food allergens are peanuts, tree nuts, fish, shellfish, milk, eggs, wheat, and soy. Those 8 foods are responsible for causing 90% of all food allergies.2 Peanut allergy receives the most attention from patients, health-care providers, and the media. The most obvious reason for that increased attention is the fact that the prevalence of peanut allergy has risen 300% over the past 15 years.3 In an effort to keep pace with the growing needs of providers and patients, the National Institute of Allergy and Infectious Diseases (NIAID) published Guidelines for the Management and Diagnosis of Food Allergy in the United States.2 The guidelines offer a comprehensive review of research and expert opinion.

The NIAID is one of 27 institutes that make up the National Institutes of Health.

The Joint Task Force on Practice Parameters—representing the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma & Immunology; and the Joint Council of Allergy, Asthma & Immunology— recently drafted Food Allergy: A Practice Parameter Update to be published in 2014. The Practice Parameter was last updated in 2006.4 The 2014 document promises to highlight new research on food allergens, diagnostic testing, nonimmunemediated disorders, and the management of various food allergic reactions.

Theories behind the rising prevalence of food allergy

Food allergies are increasing as a part of the overall rising trend of all allergies. The cause of this phenomenon is not known, but two common theories exist. 5 According to the dietary hypothesis, patients consuming the standard American diet, which contains 61% refined carbohydrates, added fats, TABLE 1. Common food allergy symptoms Abdominal pain, diarrhea, nausea, or vomiting Anaphylaxis

and added sugars, have less biodiversity of organisms in their gut compared with people of previous generations, who ate a less refined and more natural diet. Less biodiversity in gut organisms is believed to contribute to increased sensitivities and lead to to more food allergies.

The hygiene hypothesis theorizes that the development of our modern immune systems has been suppressed by a lack of early-childhood exposure to bacteria and parasitical infections. Cultural changes over the course of generations have favored measures that prioritize being “germ free.”

This, coupled with the continued development and use of vaccines, has made our modern immune systems more sensitive to allergens.

Pathophysiology

Allergy is a specific, acquired immune response to a nonpathogenic antigen that results in the production of specific immunoglobulin E (IgE) antibodies. Food allergy is defined as an abnormal IgE-mediated immune-system response to a food protein. A food allergy reaction can provoke a local response in the mucosal immune system, a systemic process, or both.

Symptoms of food allergy (Table 1) can vary widely among patients, and one reaction can vary widely from the next in the same patient. The intensity of a patient’s symptoms is often related to the amount of the food allergen eaten.

Younger patients with food allergies typically present with vomiting and urticaria, whereas older patients typically present with abdominal symptoms, angioedema of the lips and face, and urticaria.

Oral allergy syndrome (OAS) is an IgE-mediated immune response occurring when individuals who are allergic to tree or weed pollen eat (typically, fresh) fruits and vegetables.

OAS occurs because of the similar protein complexes and cross-reactivity between the proteins in tree or weed pollen and certain fruits and vegetables. OAS symptoms are limited to the oropharynx area and, as with other food allergy reactions, places patients at risk for anaphylaxis. It is estimated that 9% of persons with food allergy have OAS symptoms.6

Angioedema of the lips, tongue, eyelids, or whole face Dizziness or fainting

Diagnosis

Dysphagia

Diagnosing a food allergy requires a thorough patient history, positive food-test results, and confirmation with an oral food challenge (OFC). The patient’s medical history with the suspected food is perhaps the most useful component in making an accurate diagnosis (Table 2). Current practice guidelines favor skin-prick tests (most often performed by an allergy specialist) over serum-specific immunoglobulin

Flushing of skin Pruritus of the mouth, lips, tongue, throat, eyes, skin, or other areas Rhinorrhea Urticaria Wheezing, coughing, or shortness of breath

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E (ssIgE) tests because of their increased sensitivity, greater validity, and lower costs.2 Use of allergen-specific IgG testing, cytotoxicity assays, applied kinesiology, provocation neutralization, or hair analysis is not recommended because of insufficient evidence in the literature of their value.

A positive skin-prick or ssIgE test should be followed by an OFC to establish a diagnosis. An OFC corroborates or excludes a suspected food allergy by having the patient eat small, but increasing, amounts of a suspect food.

The OFC begins with the introduction of a suspicious food every three to five days. If the food eaten during the OFC elicits an allergic symptom, the diagnosis of food allergy is confirmed. If the patient eats the food without any symptoms produced, the diagnosis of food allergy is ruled out.

If the patient’s history of food reaction is mild, the OFC can be conducted at home with proper education and an emergency treatment plan in place. Otherwise, the OFC is conducted in an allergy specialist’s office.

An OFC is preceded by a one- to two-week elimination diet in which all suspected foods (i.e., those with positive skin-prick or ssIgE test results) are excluded from the diet.

This process is used to identify foods that may be causing an adverse effect in patients. The goal of the elimination diet is to return the individual’s food allergy symptoms to baseline if possible. It is important that the patient symptoms normalize prior to starting the OFC to allow a means of objective measurement. If the patient’s symptoms do not return to baseline with the elimination diet, further evaluation is needed.

It is uncommon for a person to be allergic to a food he or she has previously eaten successfully. Food allergies usually follow a predictable path, so if a patient has allergy-type symptoms to a previously tolerated food, consideration should be given to an alternative diagnosis. Differential diagnoses for food allergy include bacterial infection, eczema flare from nonfood exposure, eosinophilic esophagitis, food intolerance (a non-IgE-mediated reaction to food that can cause the same symptoms as a food allergy), gallbladder disease, gustatory rhinitis, Heiner syndrome, infection from contaminated foods, pancreatic insufficiency, parasitic infection, protein-induced proctocolitis/enterocolitis, and pyloric stenosis.4

TABLE 2. Key questions for patients What particular food do you suspect caused the reaction?

How much of the suspected food did you eat?

What other foods did you also eat at the time the reaction occurred?

Do you know (or can you get a list of) all the ingredients in the food product?

How was the food prepared and served?

Did you have similar symptoms on other occasions when the food was eaten?

What was the time lapse between eating the food and the reaction beginning?

Do you have a history of avoiding or refusing to eat the suspected food?

(Table 3).7 The first-line treatment for anaphylaxis in all patients is epinephrine (Adrenaclick, Adrenalin, Epi-Pen, Twinject). A delay in the use of epinephrine will increase the risk of death.

Onset of anaphylaxis may occur as quickly as several minutes postexposure or up to 72 hours later. In 20% of all anaphylactic reactions, patients may experience a biphasic anaphylactic reaction, with the second phase occurring shortly after the first without further exposure to the provoking allergen.8 Because a second dose of epinephrine is the preferred treatment in biphasic reactions health-care providers should prescribe epinephrine injectors in packs of two and instruct the patient to carry both doses at all times.

Several types of epinephrine auto-injectors are available.

Regardless of the type used, the dose is 0.3 mg for individuals weighing more than 66 lb and 0.15 mg for those weighing between 33 lb and 66 lb.7 Patient resources detailing the identification, treatment, and management of anaphylaxis are available from Food Allergy Research and Education (FARE) (www.foodallergy.org/anaphylaxis, accessed January 15, 2014).

A written action plan that details emergency actions should anaphylaxis occur needs to be provided to all patients with food allergy.7 A child’s school, day-care facility, and extended family members need to be aware of the emergency plan. An TABLE 3. Signs and symptoms of anaphylaxis Angioedema of conjunctiva, face, lips, mouth, tongue, or throat Cardiac—tachycardia, hypotension Central nervous system—loss of consciousness, confusion, headache, anxiety Epidermis—urticaria, pruritus, flushing Gastrointestinal—abdominal pain, diarrhea, vomiting Nasal rhinorrhea

Food allergy anaphylaxis

Anaphylaxis is a serious, generalized immune-mediated hypersensitivity reaction that may result in death if not promptly treated. The signs and symptoms of anaphylaxis vary from person to person and from reaction to reaction

Respiratory—shortness of breath, wheezing, dysphagia, cough Urinary incontinence Adapted from Sampson HA. Anaphylaxis and emergency treatment. Pediatrics. 2003;111:16011608. Available at pediatrics.aappublications.org/content/111/Supplement_3/1601.long, accessed January 15, 2014.

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CME CE

FOOD ALLERGY

Food-dependent exercise-induced anaphylaxis only develops when a person engages in physical activity a few hours after eating an allergenic food. example of a food allergy action plan can also be found at the FARE website (www.foodallergy.org/document.doc?id=234, accessed January 15, 2014).

Food-dependent exercise-induced anaphylaxis (FDEIA) is a type of anaphylaxis that develops only when a person engages in physical activity within a few hours after eating an allergenic food.9 Wheat, shellfish, tomatoes, peanuts, and corn are the most common foods that provoke FDEIA. Most often, patients who experience FDEIA can tolerate the same food if they are not physically active soon after eating; it is only the combination of the two that causes anaphylaxis.

The exact cause for FDEIA is not known, but the physical activity may increase intestinal absorption of the food protein; the higher concentrations of the protein circulating through the body may then cause the allergic reaction. FDEIA is of great concern in the school setting, as affected children may have recess or gym class soon after lunch. School staff should always be attentive to any signs or symptoms of anaphylaxis in students, especially in the hours that follow lunch.

Although meat allergy is uncommon in the developed world, recent findings have linked the consumption of red meat to an alpha-gal allergic reaction. The reaction occurs after a tick bite and may lead to anaphylaxis.10 The link is galactose-alpha1,3-galactose—commonly referred to as alpha-gal—a sugar found in the meat of all non-primate mammals, including cows, pigs, sheep, and goats. Research indicates that a tick bite—specifically, a bite from the tick Amblyomma americanum— is a cause, if not the only significant cause, of IgE production related to alpha-gal.11 Amblyomma americanum, also known as the lone star tick, is indigenous to the southeastern United States. The tick bite introduces alpha-gal into the person’s skin of, causing the creation of specific IgE in some people.

After the patient is sensitized, the consumption of red meat then produces a delayed allergic reaction that may be severe enough to cause anaphylaxis. The good news is that the allergy usually resolves within eight months to three years, as long as the patient is not exposed again through another tick bite.

Gelatin is added to vaccines as a stabilizer and may cause anaphylaxis in gelatin-allergic individuals. Vaccines that contain gelatin include those for measles, mumps, and rubella (MMR), influenza, and varicella. An allergy specialist should further evaluate patients who are allergic to gelatin before such patients receive any of these vaccines.

Egg protein is present in vaccines for yellow fever and MMR as well as some influenza and rabies vaccines. In 20132014, an egg-free influenza vaccine was offered for the first time but with limited availability in some parts of the United States.13 According to the CDC, a person who can eat lightly cooked egg (e.g., scrambled) without reaction is unlikely to be allergic and can receive the influenza vaccine per usual protocol.14 Individuals with a history of egg allergy who have experienced only hives after exposure should receive the inactivated influenza vaccine and be observed for at least 30 minutes for signs of a reaction after each vaccine dose.

Someone who experiences such symptoms as cardiovascular changes (e.g., hypotension), respiratory distress, nausea/ vomiting, or a reaction requiring epinephrine or emergency medical attention after eating eggs or egg-containing foods should receive the trivalent formulation of the recombinant hemagglutinin influenza vaccine (RIV3) if aged 18 to 49 years. Alternatively, these patients can be referred to an allergy specialist for further evaluation.

The cow’s milk protein casein has been linked to anaphylaxis following administration of diphtheria, tetanus, and pertussis (DTaP, Tdap) vaccine in severely milk-allergic children.15 The DTaP and Tdap vaccines are prepared in a cow’s milk medium containing casein. The overwhelming majority of severely milk-allergic children do not react to the vaccine.

However, these children should be evaluated by an allergy specialist prior to receiving the DTaP or the Tdap vaccine.

Yeast protein is found in the hepatitis B and human papillomavirus vaccines and has been known, albeit rarely, to cause anaphylaxis in yeast-allergic individuals.16 A patient who is allergic to yeast should be skin tested by an allergy specialist prior to receiving these vaccines.

Vaccine constituents and food allergy

Certain vaccines can cause allergic reactions in food-allergic patients and may lead to anaphylaxis. Potential sources of food proteins in vaccines include gelatin, egg, chicken, and yeast.12 Nonfood preservatives, natural rubber latex, and antimicrobials have also been linked to allergic reactions to vaccines but will not be discussed here.

Management of food allergies

Patient education is the central element of food allergy management. The treatment is limited to strict dietary avoidance, nutritional counseling, and emergency treatment of adverse reactions. When patients have multiple food allergies, strict avoidance can be complicated. Patients often

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Patients often need advice on how to maintain adequate nutrition and caloric intake while meeting the goals of food avoidance. need advice on how to maintain adequate nutrition and caloric intake while meeting the goals of food avoidance.

The FDA’s Food Allergen Labeling and Consumer Protection Act of 2004 requires food labels to list any of the eight major food allergens contained in the product, regardless of the amount.17 The label of any food product that contains nuts or seafood must list the specific type.

Food-allergic individuals should avoid all products with any precautionary labeling (e.g., “This product may contain trace amounts of peanuts”). The astute clinician will advise food-allergic patients to avoid any food product whenever uncertain of its contents.

Hidden allergens contribute to the complexities of managing food allergies (Table 4).18 For example, patients with egg allergies must recognize that mayonnaise contains eggs and should be avoided. Patients should be provided with a list of possible covert sources of their food allergens. Additionally, food allergens often have several different names, and patients must be familiar with them. For example, milk can also be referred to as casein, hydrolysate whey, ghee, curds, and/or lactalbumin phosphate on a food label, and wheat can come in the forms of couscous, durum, farina, kamut, spelt, and/or modified starch.

Changing the allergenicity (the capacity to elicit an IgE response) of a food may affect how provoking the food is to the patient. Heat from the manufacturing or baking process destroys the protein structure of food and decreases its allergenicity. Some milk-allergic patients may be able to tolerate milk in baked products but not when drinking it cold. Raw fruits and vegetables may cause reactions in some allergic patients, but such an indvidual may be able to tolerate those same fruits or vegetables after they have been cooked.

Cooking oils are commonly derived from soy, corn, peanut, and sesame and may provoke food allergy symptoms. Oils range in their allergenicity depending on how much of the food protein is removed during the manufacturing process.

Occasionally, small amounts of protein from the grain, nut, or seed remain in the oil. Pure oils are nonallergenic because these products do not contain a protein. Consuming highly refined oils developed from major allergenic food sources does not appear to be associated with allergic reactions for most patients. It is recommended that persons with peanut allergy avoid peanut oil since it is often quite difficult to ascertain the degree of oil refinement in the product. Sesame oil is often largely unrefined and should be avoided. Canola

oil (made from rapeseeds) appears to be the safest oil for patients to consume because it does not contain a protein.

If a patient has only been skin-prick-tested or ssIgE-tested for a few select foods, questions may arise as to whether to avoid similar foods not subject to testing. Patients should be aware of foods that commonly cross-react with their food allergen and approach these foods with caution until the tolerability for the food is known (Table 5). For example, if a patient is allergic to peanuts (a member of the legume family), there is an increased risk of cross-reactivity with other legumes (e.g, peas, lentils, beans). Similarly, a patient who is allergic to latex faces an increased risk of cross-reactivity with banana, kiwi, and avocado. All patients should take appropriate care when consuming products that are known to cross-react with their allergens.

Such food additives as dyes, preservatives, and artificial sweeteners are common causes of concern as potential triggers of food allergies and should be avoided by individuals who have TABLE 4. Hidden food allergens Allergen

Suspect foods

Egg

Bagels, pretzels, baked goods, bouillon, cereals, cakes, chocolate, custard, butter, pancakes, waffles, ice cream, mayonnaise, marshmallows, salad dressings, sherbets

Fish

Caesar salads, hot dogs, pizza toppings, imitation crab, Worcestershire and marinara sauces

Milk

Yogurt, butter, margarine, cheese, creams, custards, meatballs, pizza, frozen desserts, coffee, whey, caramel flavoring, ghee

Peanut

Artificial nuts, imitation nuts, beer nuts, praline, cakes, pastries, biscuits, ice cream, cereal bars, meat products, egg rolls, granola, cereals, candy

Shellfish

Shrimp, crab, lobster, oysters, octopus, scallops, escargot, fish stock

Soy

Soy flour, tofu, soy nuts, imitation seafood, dairy substitutes, textured vegetable protein, vegetable starch, vegetable broth, Asian cuisine

Tree Nuts

Pesto sauce, popcorn, doughnuts, desserts, cookies, candy, cereals, cheese spreads, chocolates, ice cream, granola, marzipan

Wheat

Breads, baked goods, pastries, pasta, cereals, crackers, cakes, cookies, snacks, processed meat, modified food starch, salad dressings, flour

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CME CE

FOOD ALLERGY

Such food additives as dyes, preservatives, and artificial sweeteners are common causes for concern as potential triggers of food allergies. a history of reactivity to such products. There is no research that supports the avoidance of food additives in patients with attention-deficit/hyperactivity disorder.19 Patients with food allergies should undergo regular followup. The majority of children (85%) will outgrow their food allergy to milk, egg, wheat, and soy, and substantially fewer youths (15% to 20%) will outgrow their allergy to peanuts, tree nuts, fish, and shellfish.20 Children with food allergies should be re-evaluated every one to two years to determine the status of their condition. For adults, follow-up evaluation is recommended every two to five years, depending on the food allergy.

Prevention strategies

Food allergy prevention strategies include: (1) exclusive breastfeedingfor at least the first four to six months of a child’slife; (2) maternal dietary restrictions during breastfeeding, when the probability of inherited allergy is high; and (3) the use of hydrolyzed formula for infants at increased risk of allergic disease who cannot be exclusively breast-fed for the first four to six months of life.21 There is no benefit to pregnant women avoiding such allergenic foods as dairy, egg, and peanuts during pregnancy or lactation in an effort to prevent the development of food allergy in their children.

For decades, parents have been advised to delay the introduction of solid foods into the child’s diet in the hopes of reducing the risks of a child developing food allergies.

However, both the American Academy of Pediatrics and the American Academy of Allergy, Asthma & Immunology TABLE 5. Allergen risk of cross-reaction Allergen (example):

May react with (example):

Legume (peanut)

Other legumes (peas, lentils, beans)

Tree nut (walnut)

Other tree nuts (brazil, cashew, hazelnut)

Fish (salmon)

Other fish (swordfish, sole)

Shellfish (shrimp)

Other shellfish (crab, lobster)

Grain (wheat)

Other grains (barley, rye)

Cow’s milk

Beef, goat’s milk, mare’s milk

Pollen (birch, ragweed)

Fruits/vegetables (apple, peach, honeydew)

Peach

Other Rosaceae (apple, plum, cherry, pear)

Melon (cantaloupe)

Other fruits (watermelon, banana, avocado)

Latex (latex glove)

Fruits (kiwi, banana, avocado)

Fruits (kiwi, avocado, banana)

Latex (latex gloves)

currently note that delaying the introduction of foods may actually result in an increased risk of food allergy.21 Once an infant is at least age 4 months and has tolerated a few nonallergenic solid foods (e.g., rice cereal, oatmeal, sweet potatoes, carrots, bananas, apples, pears), parents can add other, more allergenic foods without delay (e.g., wheat, cow’s milk dairy, eggs, fish, nuts). It is advisable to introduce such foods at home rather that at a day-care program or in a restaurant.

Only one new food should be introduced every three days to allow easy recognition of any adverse reaction.

Special concerns for schoolchildren

Studies show that the accidental ingestion of food allergens in school occurs in 16% to 18% of children with food allergies.22 In one study, approximately 25% of food-related anaphylaxis struck children with no previous diagnosis of food allergy.23 Recently published CDC guidelines provide a road map for schools to ensure proper care of students with food allergies by shifting the focus from response to prevention.24 Bullying is a growing issue for children living with food allergies. In a survey of food-allergic children, 24% reported having been bullied, teased, or harassed because of food allergy (86% of those children reported multiple episodes), with more than 20% of the cases perpetrated by a teacher or a school employee.25 Parents, school staff, and community members should be made aware that food-allergic students are high-risk targets for harassment and/or bullying.

Parents may be given the option of choosing an allergyfree table for their child at lunch. This option adds a degree of safety by increasing the focus and attention on strict avoidance. In some cases, however, this action may ostracize the child from his or her classmates and increase the risk for bullying.

To prevent cross-contact of food allergens through saliva exchange, the sharing of straws, cups, and utensils should be avoided by children with food allergies.

Parents should know that the ingestion of an allergen, rather than casual exposure through the skin or being in close proximity to that allergen, is almost the only route for triggering an anaphylactic reaction. Parents can work with their health-care providers to determine the best location in the cafeteria for the child to eat lunch. If an allergy-free table is not available, parents should be encouraged to become advocates for their child. Excellent resources to help schools manage food allergies can be found at the Allergy

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Because there is currently no cure for food allergy, education on avoidance and prevention is crucial in the management of this condition.

Home website (www.allergyhome.org/schools/, accessed January 15, 2014).

nutritional, and/or pulmonary-care specialists will improve patient outcomes and should be considered. n

The future of food allergy

Dr. Rance is a nurse practitioner specializing in allergy, asthma, and immunology at Allergy Partners of Central Indiana in Indianapolis. Dr. O’Laughlen is a nurse researcher and educator at the University of Virginia in Charlottesville.

Researchers continue to seek safe and effective methods for desensitizing or permanently producing a state of oral tolerance in food-allergic patients. The protective effect in a food-allergic person who is desensitized to the food to which he or she is allergic depends on the daily, uninterrupted ingestion of the food allergen. If the daily ingestion is interrupted, the protective benefit may be lost or significantly decreased. In cases of oral tolerance, there is an actual decrease in the related food-specific IgE. When permanent oral tolerance is achieved, the food may be ingested without allergy symptoms developing, even after periods of not having eaten the food.

Some current research methodologies appear only to desensitize patients temporarily while others show promise in producing a permanent tolerance to the food allergen.

Potential future treatments specific for individuals with food allergy include oral, sublingual, and subcutaneous immunotherapy.26 There is a wide gap between the number of individuals who believe they have an IgE-mediated food allergy and those who actually do. Some of this discrepancy is attributable to the limitations of current diagnostic testing, which has low specificity. Researchers are focusing on improving the predictive capacity of diagnostic tools. There has been a substantial effort to recognize, clone, and produce major allergens from hundreds of sources in the hopes of increasing the specificity of diagnostic testing.

References 1. American Academy of Allergy, Asthma & Immunology. Updated prevalence of food allergy in the United States. Available at www.aaaai.org/global/ latest-research-summaries/Current-JACI-Research/food-allergy-in-us.aspx.

2. NIAID-Sponsored Expert Panel, Boyce JA, Assa’ad A, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol.

2010;126(6 Suppl):S1-S58. Available at www.niaid.nih.gov/topics /foodallergy/clinical/Pages/default.aspx.

3. Sicherer SH, Muñoz-Furlong A, Godbold JH, Sampson HA. US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year followup. J Allergy Clin Immunol. 2010;125:1322-1326.

4. American College of Allergy, Asthma & Immunology. Food allergy: a practice parameter. Ann Allergy Asthma Immunol. 2006;96(3 Suppl 2):S1-68.

5. Lack G. Epidemiologic risks for food allergy. J Allergy Clin Immunol.

2008;121:1331-1336.

6. American College of Allergy, Asthma & Immunology. Oral allergy syndrome. Available at www.acaai.org/allergist/allergies/Types/food-allergies/ types/Pages/oral-allergy-syndrome.aspx.

7. Sampson HA. Anaphylaxis and emergency treatment. Pediatrics.

2003;111:1601-1608. Available at pediatrics.aappublications.org/content/111/Supplement_3/1601.long 8. Tole JW, Lieberman P. Biphasic anaphylaxis: Review of incidence, clinical predictors, and observation recommendations. Immunol Allergy Clin N Am.

Summary

2007;27:309-326.

It is widely acknowledged that food allergies cause significant distress in the lives of patients. Because there is currently no cure for food allergy, education on avoidance and prevention is crucial in the management of this condition. Patients should be taught how to recognize and treat anaphylaxis and have a written allergy action plan that details how and when to use epinephrine. Primary-care providers are the gatekeepers and must be able to identify and appropriately manage their food-allergic patients. In situations in which the patient has a history of anaphylaxis, more than one food allergy, or unexplained food-related symptoms, collaboration with allergy, dermatology, GI,

9. Morita E, Kunie K, Matsuo H. Food-dependent exercise-induced anaphylaxis. J Dermatol Sci. 2007;47:109-117.

10. Commins SP, Platts-Mills TA. Tick bites and red meat allergy. Curr Opin Allergy Clin Immunol. 2013;13:354-359.

11. Commins SP, James HR, Kelly LA, et al. The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose. J Allergy Clin Immunol. 2011;127:1286-1293.

Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3085643/.

12. Nokleby H. Vaccination and anaphylaxis. Curr Allergy Asthma Rep. 2006;6:9-13.

13. Campos-Outcalt D. Influenza: Update for the 2013-2014 season. J Fam Pract. 2013;62:494-498.

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FOOD ALLERGY

14. Centers for Disease Control and Prevention (CDC). Prevention and

21. Fleischer DM, Spergel JM, Assa’ad AH, Pongracic JA. Primary preven-

control of seasonal influenza with vaccines. Recommendations of the

tion of allergic disease through nutritional interventions. J Allergy Clin

Advisory Committee on Immunization Practices—United States, 2013–

Immunol Pract. 2013;1:29-36.

2014. MMWR Recomm Rep. 2013;62(RR-07):1-43. Available at www.cdc.

22. Sicherer SH, Mahr T; American Academy of Pediatrics Section on

gov/mmwr/preview/mmwrhtml/rr6207a1.htm.

Allergy and Immunology. Management of food allergy in the school setting.

15. Kattan JD, Konstantinou GN, Cox AL, et al. Anaphylaxis to diphtheria,

Pediatrics. 2010;126:1232-1239. Available at pediatrics.aappublications.org/

tetanus, and pertussis vaccines among children with cow’s milk allergy. J

content/126/6/1232.full.

Allergy Clin Immunol. 2011;128:215-218.

23. McIntyre CL, Sheetz AH, Carroll CR, Young MC. Administration

16. DiMiceli L, Pool V, Kelso JM, et al. Vaccination of yeast sensitive indi-

of epinephrine for life-threatening allergic reactions in school settings.

viduals: review of safety data in the US vaccine adverse event reporting

Pediatrics. 2005;116:1134-1140. Available at http://pediatrics.aappublica-

system (VAERS). Vaccine. 2006;24:703-707.

tions.org/content/116/5/1134.long.

17. U.S. Food and Drug Administration. Food Allergen Labeling and

24. Centers for Disease Control and Prevention. Voluntary guidelines for

Consumer Protection Act of 2004 (Public Law 108-282, Title II). Available

managing food allergies in schools and early care and education programs.

at www.fda.gov/downloads/Food/GuidanceRegulation/UCM179394.pdf.

Available at www.cdc.gov/healthyyouth/foodallergies/pdf/13_243135_A_

18. Steinman HA. “Hidden” allergens in foods. J Allergy Clin Immunol.

Food_Allergy_Web_508.pdf.

1996;98:241-250.

25. Lieberman JA, Weiss C, Furlong TJ, et al. Bullying among pediatric

19. Nigg JT, Lewis K, Edinger T, Falk M. Meta-analysis of attention-deficit/

patients with food allergy. Ann Allergy Asthma Immunol. 2010;105:282-286.

hyperactivity disorder or attention-deficit/hyperactivity disorder symp-

26. Narisety SD, Keet CA. Sublingual vs oral immunotherapy for food

toms, restriction diet, and synthetic food color additives. J Am Acad Child

allergy: identifying the right approach. Drugs. 2012;72:1977-1989. Available

Adolesc Psychiatry. 2012;51:86-97.

at www.ncbi.nlm.nih.gov/pmc/articles/PMC3708591/.

20. Thong BY, Hourihane JO. Monitoring of IgE-mediated food allergy in All electronic documents accessed January 15, 2014.

“She’s so Jersey.”

“Does your waitress have any identifying marks or tattoos?”

© The New Yorker Collection 2014 from cartoonbank.com. All Rights Reserved.

childhood. Acta Paediatr. 2004;93:759-764.

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FEATURE: RONALD L. HOFFMAN, MD

The facts and fictions of chelation therapy Originally used to treat lead poisoning and hypercalcemia, chelation has shown promise among individuals with heart disease and other conditions.

C

helation therapy, a type of intravenous (IV) treatment promoted by some members of the complementary and alternative medicine community, has long been mired in controversy. Often dismissed as quackery, chelation therapy was the subject of a recently completed NIH study (Trial to Assess Chelation Therapy [TACT]) that showed the practice to be of moderate benefit to heart-attack survivors. Yet the controversy continues unabated, with some calling the study misguided or flawed and few in the conventional-medicine community willing to embrace chelation therapy as a legitimate option for patients with cardiovascular problems.

© CMSP / J CAVALLINI

How chelation therapy works

Chelation therapy reduced the risk of adverse outcomes in patients with a history of MI (blue).

Chelation therapy consists of a series of IV administrations of disodium or calcium ethylenediaminetetraacetic acid (EDTA) mixed with minerals and vitamins. Patients aret treated in the clinician’s office for one to four hours once to three times weekly for a series of 20 to 80 chelations. “Booster” chelations may be administered on a monthly basis or intermittently for years.

The purported benefits of chelation therapy vary, but the treatment typically is credited with: • Improving such circulatory disorders as coronary artery disease (CAD), cerebrovascular disease, or peripheral vascular disease • Detoxifying the body of such heavy metals as lead, cadmium, and mercury • Combating degenerative diseases and slowing the aging process.

Continues on page 62

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CHELATION THERAPY

Until the TACT study, chelation therapy for conditions other than acute lead intoxication was considered unwarranted and dangerous.

The procedure is usually not covered by Medicare or private insurance. The out-of-pocket costs are borne by patients and may total thousands of dollars for a single course of treatment.

History

The term chelation (derived from the Greek chelos, meaning “claw”) refers to the mineral- or metal-binding properties of certain compounds that can hold a central cation in a pincerlike grip. Developed in Germany in 1935, EDTA was originally used as a means of binding and extracting calcium in the dye industry.

In the 1940s, Martin Rubin, professor emeritus of biochemistry at Georgetown University Medical Center in Washington, D.C., discovered EDTA’s effects on calcium in biologic systems. This finding led to the product’s use as an anticoagulant and is still used in “purple top” blood-collection tubes. Professor Rubin’s research led him to advance the use of EDTA for the treatment of hypercalcemia and, eventually, lead poisoning.

In the 1950s and 1960s, some clinicians began to observe that patients treated for lead poisoning with IV EDTA experienced improvements in their cardiovascular conditions. This observation led to the widespread, but mostly empirical, use of EDTA therapy for heart patients within a growing community of alternative-medicine practitioners.

Studies were undertaken, but these were mostly observational or uncontrolled and involved only small numbers of patients. Chelation therapy for other than the approved indications of refractory hypercalcemia and severe lead toxicity remained highly touted but poorly substantiated.

Clinicians practicing chelation therapy were sometimes targeted by medical boards for disciplinary action, irrespective of whether specific patient harm had occurred. Some states adopted regulations prohibiting the practice of chelation therapy. To this day, disodium EDTA is not approved by the FDA to treat any diseases. However, disodium EDTA is produced by compounding pharmacies for individual patients, so the treatment can still be obtained.

In 1998, the U.S. Federal Trade Commission (FTC) targeted the American College for Advancement in Medicine (ACAM), an organization that has trained and certified physicians in methods of safe administration of chelation therapy since the 1970s, for allegedly exaggerated advertising claims made regarding the treatment of atherosclerosis.

The FTC concluded that there was a lack of scientific studies

to support these claims and that pro-chelation statements made by ACAM were false. As an alternative to litigation, ACAM stipulated that it would curtail public pronouncements presenting chelation therapy as an effective treatment for heart disease.

The public’s enthusiasm for chelation therapy remained undiminished, however. Between 2002 and 2007, users of chelation therapy as a treatment for heart disease and other conditions grew in the United States by nearly 68%, to 111,000 people.1 As of the start of the TACT study in 2001, it was estimated that patients received 800,000 individual EDTA infusions per year.2 Until the TACT study, mainstream clinicians widely believed that EDTA chelation therapy for conditions other than acute lead intoxication was an unwarranted and dangerous modality. This is true to the extent that excessive doses of EDTA can be nephrotoxic; cases of renal failure resulting in dialysis or death have been recorded. Additionally, transient hypocalcemia provoked by EDTA calcium sequestration can trigger cardiac arrhythmias or sudden death. But these outcomes have generally occurred only in rare instances in which EDTA is administered in too high a dose and/or too rapidly, or without regard to a patient’s glomerular flow rate.

In 1989, a protocol for the safe and effective administration of EDTA was developed and subsequently updated.3 The detailed protocol provides strict criteria for patient selection and cautions clinicians to perform an initial evaluation of renal function using the Cockcroft-Gault equation and to monitor renal function frequently throughout a series of chelation treatments. Emergency procedures for managing adverse reactions are outlined.

Designing TACT

When TACT began in 2002, Stephen Straus, MD, director of the National Center for Complementary and Alternative Medicine (NCCAM), opined, “The public health imperative to undertake a definitive study of chelation therapy is clear.

The widespread use of chelation therapy in lieu of established therapies, the lack of adequate prior research to verify its safety and effectiveness, and the overall impact of CAD convinced NIH that the time is right to launch this rigorous study.”4 TACT was the brainchild of Gervasio Lamas, MD, a Miami cardiologist and experienced NIH trialist. In 1999, a patient asked Lamas about undertaking chelation with a local alternative-medicine practitioner. Lamas initially

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CHELATION THERAPY

Extensive debate preceded the initiation of TACT with regard to whether trial participants should receive oral vitamins typical of chelation practice. discouraged the patient but later realized there was no clinical-trial information upon which to base his opinion, and TACT was soon born.

Practitioners of chelation therapy were delighted at the prospect of a large study underwritten by the U.S. government, but the community was not without reservations.

Some seasoned chelation practitioners, harried by years of perceived persecution by the medical establishment, were wary of a trap and did not trust Lamas. Others questioned whether it would be wise to cooperate with Lamas in view of the fact that, with or without a big study, chelation was performed anyway, albeit with the disapproval of mainstream medicine. Why risk a negative outcome?

There was even concern that if the trial were successful, the therapy might be co-opted by conventional cardiologists or adopted by Medicare and private insurers with strict caps on reimbursement.

Many raised concerns over the possibility that the study might not be robust enough statistically. Even with a hefty allocation of $31.6 million from the NIH, could enough patients of the right type be recruited and treated adequately to capture and highlight—under artificial experimental conditions—the benefits of chelation therapy?

There were also methodology-related concerns regarding which end points would be measured. Would the study track such hard statistics as coronary deaths or cardiac events, or would more subtle markers based on changes in circulation be needed to delineate subtle effects of chelation (e.g., angiography, radionuclide stress tests, positron emission tomography scans, coronary artery calcium scoring)?

In terms of determining the types of patients to be recruited for the trial, there was concern that the benefits of chelation might not be easily discerned if the participants were too healthy. Conversely, patients who were very sick might be too far gone to experience disease reversal with chelation. In addition, ethical considerations would mandate that sick heart patients be correctly medically managed on a proper array of cardiovascular drugs; the efficacy of chelation might be blunted if the treatment were not applied as a stand-alone therapy.

The number of chelations each patient in the trial would undergo was another factor to be considered. Many individuals with advanced heart disease have succeeded with 60 to 100 or more chelations, but the practical dictates of a large-scale study argued for a more manageable number (i.e., 40). However, with such a low number of chelations,

many proponents were worried that the treatment’s upside would not be sufficiently reflected.

Debate also centered on how best to study chelation in isolation when the therapy is typically administered as the anchor of a transformational experience that includes lifestyle modification (healthful diet, adequate exercise, reduced stress) and a regimen of numerous vitamins and supplements. The investigators also had to determine how chelation therapy could be subjected to a double-blind, placebo-controlled study, the gold standard of scientific inquiry.

The final hurdle was to determine how to recruit a sufficient number of patients to participate in an arduous (albeit free) regimen of IV treatments that gave them a 50/50 chance of being infused with inactive colored water as part of the placebo group.

Lamas and his research team took great care to address these challenging questions. It was decided that the trial subjects would be patients aged 50 years and older who had suffered an MI at least six weeks prior to the initiation of chelation. Exclusion criteria included chronic renal failure (creatinine ≥2.0 mg/dL), liver disease, current smoking, or a revascularization procedure within the past six months.

Placebo and control arms alike were to be carefully managed with maximal medical therapy (i.e., anticoagulants, statins, beta blockers, and antihypertensive medications). In fact, 90% of the participants were taking anticoagulants, and 83% had undergone revascularization. The median age of the patients was 65 years; the majority were obese (average BMI 30), and many had diabetes.2

POLL POSITION

Do you consider chelation a legitimate form of therapy for patients with heart disease? n=208 40%

n Yes: 40% n No: 60%

60%

For more polls, visit CliniAd.com/10TDwDb.

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Approximately half of the patients in TACT were recruited from alternative-medicine practitioners and treated in their offices; the others were treated at conventional medical centers. To solve the placebo conundrum, after randomization, active and placebo infusions were prepared off-site and delivered in blinded fashion to trial sites.

Extensive debate preceded the initiation of TACT with regard to whether trial participants should receive oral vitamins typical of chelation practice. Some trial designers were concerned that this would confuse the issue given the fact that previous studies assessing the merits of multivitamins in the prevention of cardiovascular disease have yielded conflicting results (some even suggesting harm). Chelation practitioners argued that giving vitamins with chelation more accurately reflects real-world chelation practice. Besides, it was argued, EDTA reacts with calcium, zinc, copper, and other micronutrients, thereby raising at least the theoretical specter of iatrogenic depletion if supplements are not included in the study.

The pro-multivitamin faction ultimately won out, resulting in a two-by-two factorial design: active chelation plus vitamins; active chelation plus placebo vitamins; placebo chelation plus vitamins; and placebo chelation plus placebo vitamins.

Opposition to TACT

Soon after the TACT study was underway, critics of “unscientific” medicine harshly assailed the project. In 2008, a group authored an article that argued for the abandoning of TACT.5 The authors cited a variety of reasons for their opposition to the study and leveled accusations of conflict of interest and scientific impropriety against some of TACT’s investigators. The article claimed that the inefficacy of chelation had already been sufficiently adjudicated by previous studies. The authors concluded that the trial posed unacceptable risk to its subjects and was a waste of money.

In a rebuttal that appeared in the Journal of American Physicians and Surgeons, Beth Clay, a former member of the U.S. House of Representatives, Committee on Government Reform, pointed out that the authors of the anti-TACT article “derive income from legal compensation for testifying against medical professionals who use chelation or other alternative or complementary therapies in their practices.”6 Ms. Clay also claimed that investigation of off-label uses of FDA-approved drugs is essential for progress in medicine.

TACT was beset by other problems as well. Enrollment proceeded slowly, and inadequate patient recruitment threatened to compromise the study’s statistical strength. In 2003

CLINICAL SLIDESHOW For more information on hypertension and associated complications, view the slideshow at CliniAd.com/LeDIYA.

and 2004, the deaths of two children were attributed to EDTA chelation, resulting in an unfavorable series of press reports highlighting the hazards of chelation.7 Defenders of the therapy argued that these tragedies resulted from dangerously rapid administration of disodium EDTA, which should be infused gradually over the course of three to four hours, as the TACT protocol dictated.

The low-water mark for TACT occurred in 2008 when the trial was temporarily halted after critics persuaded the Office for Human Research Protections of the U.S. Department of Health and Human Services to launch an investigation.

After nearly a one-year delay, the trial was exonerated and allowed to proceed.

Despite many obstacles, TACT was finally completed in 2011 and presented at the American Heart Association’s 2012 Scientific Sessions in Los Angeles.

TACT results

Overall, those receiving chelation had an 18% reduced risk of such subsequent cardiovascular events as heart attack, stroke, hospitalization for angina, or coronary revascularization, or death from any cause. A cardiovascular event occurred in 222 patients (26%) in the chelation group and in 261 patients (30%) in the placebo group. This benefit achieved statistical significance.

Of particular note was a subgroup analysis revealing that two cohorts of participants enjoyed an exceptional reduction in risk for cardiovascular events: Those with diabetes had a 39% reduction in risk, and those who had experienced a specific type of heart attack—an anterior MI—had a 37% reduction in risk.

A NIH-appointed data and safety monitoring board oversaw the trial throughout its entirety, providing ongoing review of patient safety. Roughly comparable numbers of chelation and control patients cited “adverse reactions” as a reason for leaving the study. There were two severe unanticipated adverse reactions in each group, which resulted in one death in each group. One patient in the chelation group

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CHELATION THERAPY

required hospitalization for transient hypocalcemia, but the much-feared side effect of renal failure did not develop in chelation patients, despite thousands of infusions. The rate of heart failure was not increased by chelation.

Although cardiac end points were affected by chelation therapy, no overall enhancement of quality of life was found.

Patients’ daily functioning and sense of mental well-being remained unchanged while receiving chelation therapy.

diabetes.11 Researchers reported a 51% reduction in cardiovascular risk in the subgroup of persons with diabetes in the treatment arm who received chelation plus vitamins vs. persons with diabetes treated with placebo. According to the study authors, “These findings, if replicable, would have an impact on the health of patients with diabetes. We emphasize, however, that these results are based on a subgroup of the overall trial, albeit prespecified, and therefore must be interpreted with caution.”

Reactions to TACT

There was no shortage of editorials in the aftermath of TACT. Steven Nissen, MD, a cardiologist at the Cleveland Clinic, wrote, “Given the numerous concerns with this expensive, federally funded clinical trial, including missing data, potential investigator or patient unmasking, use of subjective end points, and intentional unblinding of the sponsor, the results cannot be accepted as reliable and do not demonstrate a benefit of chelation therapy.” Nissen concluded, “The findings of TACT should not be used as a justification for increased use of this controversial therapy.”8 In an unprecedented step, the editors of The Journal of the American Medical Association ( JAMA) wrote a letter defending their decision to publish the findings of the TACT study, highlighting the fact that their review went above and beyond the routine due diligence accorded to studies that appear in the journal. “Because articles published in journals like JAMA can influence the practice of medicine, this level of scrutiny of TACT reflects our commitment to fulfilling the responsibility to try to ensure that every article published in JAMA is valid and is reported accurately,” the editors wrote in a letter accompanying the published trial.9 In the end, the editor conceded that TACT was “a positive, if perplexing, study [that] suggested that chelation therapy may modestly improve clinical outcomes in patients after an acute MI.” Even TACT researchers did not recommend the routine use of chelation therapy in post-MI patients. These investigators believed that the study results should have been used only to guide future research. Noted cardiologist Eric Topol, MD, of the Scripps Translational Science Institute in San Diego, struck a conciliatory note. “Back in 2003, when this trial was announced, I thought it was a crazy notion,” affirmed Topol. “At the end of the day, after all this work of all these investigators, I give them credit, and I give the JAMA editors credit for publishing it.”10 However, the most recently published analysis of the TACT data uncovered an even more robust protective effect of chelation, specifically for post-MI patients with

Multivitamins and heart disease

Although TACT was not empowered to address properly the question of whether multivitamins impact CAD, the study did deliver provocative data on supplement usage. Owing to its two-by-two factorial design, half of the TACT participants received multivitamins (with or without active chelation).

In the vitamin arm of TACT, treatment with high-dose vitamin therapy resulted in a statistically nonsignificant 11% relative reduction in the risk of death, MI, stroke, coronary revascularization, and hospitalization for angina when compared with patients who received placebo vitamins.

However, the addition of high-dose multivitamins was found to boost the efficacy of chelation, suggesting synergy between chelation and supplements in conferring protection from adverse cardiovascular end points. This contrasts with previous studies that suggested an adverse effect of certain supplement regimens on circulatory disease.

The future of chelation therapy

It is still unclear whether the benefits of chelation therapy are derived from EDTA or from some of the other components

Can oral chelation therapy be trusted?

The promise of IV chelation therapy has spawned a host of “oral chelation” products of dubious worth. A number of these products claim to remove plaque from the blood vessels with a variety of ingredients, including oral EDTA, without the expense and bother of undergoing medical treatment.

To date, no compelling evidence suggests that oral chelation products confer anything other than minor benefit due to the “heart-healthy” nutrients they contain. Claims that the heavy-metal chelating effects of IV EDTA can be replicated by means of oral administration are unsubstantiated and an unwarranted extrapolation of the TACT results—which themselves remain hotly contested.

68 THE CLINICAL ADVISOR • FEBRUARY 2014 • www.ClinicalAdvisor.com

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CHELATION THERAPY

Conventional pharmaceutical research is unlikely to materialize due to the vague proprietorship and regulatory status of disodium EDTA. of the IV cocktail, such as magnesium, vitamin B, vitamin C, or procaine. TACT was not designed to determine chelation therapy’s mechanism of action. Lamas hypothesizes that chelation therapy eliminates heavy metals associated with damage to systems in the blood that combat reactive oxygen species. He points out that lead and cadmium are associated with higher incidences of such vascular events as stroke, heart attack, and renal insufficiency.

Could chelation therapy join the armamentarium of treatments offered by conventional cardiologists? Lamas does not see this happening any time soon. “Receiving IV chelation is such a time-consuming and expensive treatment for patients,” he explained. “The ideal would be for a pharmaceutical company to research and develop an oral version of this therapy for patients who have had a heart attack and those with diabetes.” (See box: “Can oral chelation therapy be trusted?”)

More extensive analysis of the TACT data will allow researchers to tease out potential relationships between chelation and such surrogate markers as cholesterol and cholesterol subfractions, homocysteine, and C-reactive protein.

This analysis might provide clues to chelation’s benefits.

Because of federal budgetary constraints and the chorus of criticism that “soft” research into alternative therapies incites, it is unlikely that another government-sponsored study of chelation will be undertaken in the near future.

Industry funding, along the lines of conventional pharmaceutical research, is unlikely to materialize due to the vague proprietorship and regulatory status of disodium EDTA, whose marketability may lie only in the niche realm of a small number of alternative practitioners treating a relatively small population of patients. n

use among adults and children: United States, 2007. Natl Health Stat Report.

2008;12:1-23. Available at www.cdc.gov/nchs/data/nhsr/nhsr012.pdf.

2. Lamas GA, Goertz C, Boineau R, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA. 2013;309:1241-1250.

Available at jama.jamanetwork.com/article.aspx?articleid=1672238.

3. Rozema TC. The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity. J Advancement Med. 1997;10:5-100.

4. National Center for Complementary and Alternative Medicine. NIH launches large clinical trial on EDTA chelation therapy for coronary artery disease. Available at nccam.nih.gov/news/2002/chelation/pressrelease.htm.

5. Atwood KC, Woeckner E, Baratz RS, Sampson WI. Why the NIH Trial to Assess Chelation Therapy (TACT) should be abandoned. Medscape J Med. 2008;10:115. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2438277/.

6. Clay B. Study of chelation therapy should not be abandoned. J Am Physicians Surg. 2009;14:51-57. Available at www.jpands.org/vol14no2/clay.pdf.

7. Brown MJ, Willis T, Omalu B, Leiker R. Deaths resulting from hypocalcemia after administration of edetate disodium: 2003-2005. Pediatrics.

2006;118:e534-e536. Available at pediatrics.aappublications.org /content/118/2/e534.long.

8. Nissen SE. Concerns about reliability in the Trial to Assess Chelation Therapy (TACT). JAMA. 2013;309:1293-1294. Available at ama .jamanetwork.com/article.aspx?articleid=1672219.

9. Bauchner H, Fontanarosa PB, Golub RM. Evaluation of the Trial to Assess Chelation Therapy (TACT): the scientific process, peer review, and editorial scrutiny. JAMA. 2013;309:1291-1292. Available at jama.jamanetwork.com/article.aspx?articleid=1672221.

10. Medscape. Chelation therapy in TACT: Daring to challenge dogma (and suspend disbelief). Available at www.medscape.com/viewarticle/802786.

11. Escolar E, Lamas GA, Mark DB, et al. The effect of an EDTAbased chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the trial to assess chelation therapy (TACT).

Dr. Hoffman is the founder and medical director of the Hoffman Center in New York City.

Circ Cardiovasc Qual Outcomes. 2013 Nov 19. [Epub ahead of print.]

Available at circoutcomes.ahajournals.org/content/early/2013/11/19/ CIRCOUTCOMES.113.000663.

References 1. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine

All electronic documents accessed January 15, 2013.

For more news, opinion, and clinical features on heart attack and stroke, visit our Cardiovascular Disease Information Center at

CliniAd.com/1d7soD5.

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FEATURE: CARL SHERMAN

Controversy surrounds new JNC 8 guidelines In a departure from previous treatment guidelines, JNC 8 recommends that clinicians raise BP goals and use fewer antihypertensive medications.

© SCIENCE SOURCE / JOHN GREIM

T

Drug teatment should be initiated when BP is above 150/90 in a patient aged 60 years and older.

he panel members of the Eighth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8) released the Evidence-Based Guideline for the Management of High Blood Pressure in Adults in December 2013,1 and controversy quickly followed.

Based on a more stringent selection of evidence than its predecessor, the JNC 7 guideline of 2003,2 the more focused JNC 8 version addresses only treatment thresholds, goals, and medication choice, without detailed discussion of diagnosis and evaluation, secondary causes of hypertension, adherence, or treatment resistance.

The new document is also looser in its recommended treatment targets, particularly for older patients and for persons with comorbid conditions, and in its endorsement of drugs for uncomplicated hypertension.

According to the authors, particular attention was paid to the needs of primary-care clinicians during the development of the guidelines. “We have not reclassified hypertension, but we think we have simplified it,” said Paul James, MD, chair of the JNC 8 and head of the Department of Family Medicine at the University of Iowa Carver College of Medicine in Iowa City.

“We are saying to the clinician: When BP is elevated, you have to get to these goals, and these are medications proven to get there and to improve outcome.”

Whereas the JNC 7 recommendations were based on varied research, including observational studies, the 2014 version included only

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JNC 8 GUIDELINES

JNC 8 calls for a threshold and goal of 140/90 for persons of any age with diabetes and CKD; JNC 7 advocated a more aggressive approach. large, multicenter, randomized controlled trials in its deliberations. “As clinicians and scientists, we considered what would be the best evidence available, and found very good randomized controlled trials [RCTs] to guide primary-care clinicians as to the appropriate threshold and goal for treatment,” James explained.

Where RCT evidence was lacking, the panel made recommendations based on expert judgment, and indicated as much.

It is worth noting that the JNC 8 panel, like its predecessors, was initially convened by the National Heart, Lung and Blood Institute (NHLBI). But when the Institute announced in mid-2013 that it was discontinuing its role in guideline development and collaborating henceforth with other professional organizations, the panel chose to finish its work independently. Therefore, the document is “not an NHLBI sanctioned report and does not reflect the views of NHLBI,” the authors clarified in the new document.

Thresholds and targets for older patients

Perhaps the most contentious point in the JNC 8 is the recommendation that, for individuals aged 60 years and older without diabetes or chronic kidney disease (CKD), drug treatment should be initiated when BP exceeds 150 mmHg systolic or 90 mmHg diastolic, a departure from the usual threshold of 140/90 for most patients up to age 80 years.

The treatment goal for this group is 150/90.

“There’s irrefutable evidence that lowering systolic BP below 150 is of proven benefit for patients older than age 60 years,” James said. “But studies comparing 140 to 150 have shown no clearly improved outcome.”

The potential downside of aggressive attempts to bring systolic pressure lower should not be ignored, he added.

“We are concerned about the problems of polypharmacy in the elderly: Some patients are on 10 to 15 medications, and compounding that by adding antihypertensives could bring about dizziness and unsteadiness, increasing the risk of falls.”

Reducing systolic pressure below 140 may bring some patients’ diastolic pressure down under 60, “causing side effects that we think can be very detrimental in primary care,” James said.

Thresholds and targets for younger patients

For individuals younger than age 60 years, the standard advice remains unchanged: Initiate antihypertensive medication for BP over 140/90, and treat to achieve that level. But the

JNC 8 report makes the distinction that the diastolic reduction is a “strong recommendation,” backed by RCT data, while the systolic threshold and goal are based on “expert opinion” in the absence of convincing evidence.

Diastolic pressure is likely to be the one that counts in any case, James noted. “Hypertension is a little bit of a different disease in older and younger patients. In the under-60 age group, systolic pressure is not usually the problem. If the clinician is getting diastolic pressure below 90, for the most part, systolic pressure will be 140 or less.”

Because there are few data for individuals younger than age 30 years, both diastolic and systolic targets for this age group are based on expert opinion.

Diabetes and kidney disease

The 2014 guideline’s recommendations for patients with diabetes and CKD represent another departure from the previous version. The JNC 8 report calls for a threshold and goal of 140/90 for persons of any age with diabetes and CKD; JNC 7 advocated a more aggressive approach (down to a target of 130/80).

According to the panel, these more relaxed goals are based on expert opinion rather than evidence of improved outcome.

In raising threshold and goal BPs, JNC 8 is following a contemporary trend. Other recent guidelines, including a 2013 publication of the American Diabetes Association,3 also endorse the 140/90 standard for patients with these comorbidities.

Treat lifestyle first

Although its evidence review and recommendations focus on medication, the new guideline, like the earlier version, prioritizes a nonpharmacologic approach to BP reduction.

“Our algorithm indicates lifestyle modification as the first line of treatment,” affirmed James.

The guideline does not detail a timetable, but James pointed out that most clinicians require elevated BP at three separate visits for a firm diagnosis of hypertension. “Lifestyle modification should be started at the first visit,” James said, with pharmacotherapy indicated only if BP remains above threshold values.

The importance of a healthy diet, weight control, and regular exercise cannot be overemphasized, the authors wrote, and suggested patients consult the AHA/ACC 2013 Guideline on Lifestyle Management to Reduce Cardiovascular Risk for more detailed direction.4

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Especially when combining medications, the JNC 8 panel does not encourage efforts to achieve BPs below recommended levels.

Choosing medication

For initial treatment of uncomplicated hypertension in most nonblack patients, JNC 8 advises clinicians to prescribe any approved drug from one of four classes: thiazide-type diuretics, angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs). Combination treatment with agents from two of these classes is also an option. Black patients should generally be prescribed a CCB or thiazide diuretic as initial treatment.

These recommendations apply to individuals of any age, with and without diabetes or most other comorbidities. For those with CKD, an ACEI or ARB—drugs linked strongly to improved kidney outcome—should be included from the outset of treatment.

Black patients with CKD represent a difficult clinical situation. Based on expert opinion, the panel advises initial ACEI or ARB therapy for individuals with proteinuria, but otherwise expands the choice to all four classes (although an ACEI or ARB should always be included in combination treatment, which is usually necessary).

The JNC 7 guidelines recommended thiazide diuretics as initial treatment for most patients and specified an array of options to address diverse comorbidities and clinical situations.

However, “We wanted to simplify treatment and give flexibility to primary-care clinicians, and to suggest that they could follow many different pathways to achieve goal BP,” James said of the new recommendations. “The evidence in general is very positive for all four classes, and there is no evidence that one is better than another, except in cases featuring black patients and those with CKD.” Other drug classes, including some recommended in earlier guidelines, are not included in the core group named

by JNC 8. There is less evidence supporting the efficacy of those drug classes, said James, who went on to note that these drugs may be indicated for other reasons (e.g., a beta blocker for a hypertensive patient with recent MI).

The JNC 8 guideline includes a chart of evidence-based dosing that lists ranges for agents shown to be efficacious in the RCTs on which the recommendations are based.

According to James, the purpose of this chart was to encourage adequate prescribing (for diuretics in particular), because clinicians have become overly conservative in recent years.

The recommendations are no substitute for clinical judgment, the JNC 8 authors emphasized. “These are broad guidelines meant to address the problems of the majority

of patients,” said Dr. James. “The primary-care clinician is applying these recommendations in the face of unique situations and individual circumstances,” such as comorbidity and possible drug-drug interactions.

Beyond initial treatment

When treatment with a single antihypertensive medication does not achieve BP goals within one month, the JNC 8 guideline recommends increasing dosage to the maximum tolerated level or adding a second agent from another of the core classes listed for initial treatment. The clinician also should assess adherence to medication and lifestyle modification.

Repeat the process if two drugs are not effective, the authors advise. If target values remain elusive, the provider should consider adding a drug from a class outside the core group (e.g., beta blocker, aldosterone antagonist), or referral to a clinician with expertise in treating hypertension.

Especially when combining medications, the panel does not encourage efforts to achieve BPs below recommended levels.

“One of the things this guideline is really questioning is the core belief that lower BP is better BP,” James said.

“Whenever we give medication, we have to be asking hard questions about benefits versus harms.” n Mr. Sherman is a freelance medical writer in New York City.

References 1. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).

JAMA. 2013 Dec 18. [Epub ahead of print]. Available at jama.jamanetwork. com/article.aspx?articleid=1791497.

2. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.

3. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36 Suppl 1:S11-S66. Available at care.diabetesjournals.org/content/36/Supplement_1/S11.long.

4. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Nov 7. [Epub ahead of print].

All electronic documents accessed January 15, 2014

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Advisor Forum These are letters from practitioners around the country who want to share their clinical problems and successes, observations, and pearls with their colleagues. Responding consultants are identified below. We invite you to participate.

Inside the Forum FEBRUARY 2014

Consultations Is low amniotic fluid preventable?. . . . 74 Do surgical metals affect security or MRI scans?. . . . . . . . . . . . . . . . . 75 Blood glucose test reliability. . . . . . . . 75 Treatment options for women with facial hair . . . . . . . . . . . . . . . . . . . . 75

Clinical Pearls Cold comfort for recurrent nosebleeds . . . . . . . . . . . . 76 With multiple dermatofibromas, think lupus. . . . . . . . . . . . . . . . . . . 76 And more. . . . . . . . . . . . . . . . . . . . . 76

Your Comments

Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001.

You may also fax (646) 638-6117, or contact us by e-mail at letters@ clinicaladvisor.com.

If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter.

No anonymous contributions will be accepted.

A correction on the treatment of vaginal atrophy . . . . . . . . . . . . . . . . 76

CONSULTATIONS RELIEVING THE PAIN OF EPIPLOIC APPENDAGITIS How would you recommend treating a woman, aged 30 years, who has intermittent right-lower-quadrant abdominal pain diagnosed on CT scan as epiploic appendagitis?

The patient’s pain is frequently so incapacitating that she is forced to leave work.—JOANNE L. TANNER, FNP-C, Cortland, N.Y. Epiploic appendagitis is a fairly rare occurrence, but it is not usually serious (Med Sci Monit. 2012;18:CS48-CS51; available at www. ncbi.nlm.nih.gov/pmc/articles/PMC3560724/, accessed January 15, 2014). Unlike appendicitis, in which the structure is anatomically normal, epiploic appendages are made of inflamed malformations of the serosal layers of the outer colonic wall. Most cases resolve as the inflammation dissipates, and occasionally, the appendage will self-destruct through ischemia. Patients usually recover with conservative nonsurgical treatment. Laparoscopic removal results in complete healing and may be necessary in persistent cases.—Sherril Sego, FNP-C, DNP (184-1)

IS LOW AMNIOTIC FLUID PREVENTABLE? As a women’s health nurse practitioner in a prenatal clinic, I have seen several patients with oligohydramnios. Why does

OUR CONSULTANTS

Rebecca H. Bryan, APRN, CNP,

Eileen Campbell, MSN, CRNP,

Philip R. Cohen, MD,

is a lecturer in the Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia.

is associate program director, Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia.

is clinical associate professor of dermatology, University of Texas Medical Center, Houston.

Deborah L. Cross, MPH, CRNP, ANP-BC, is associate program

director, Gerontology NP Program, University of Pennsylvania School of Nursing, Philadelphia.

Maria Kidner, DNP, FNP-C,

is a nurse practitioner with Cheyenne Cardiology Associates in Cheyenne, Wyo.

74 THE CLINICAL ADVISOR • FEBRUARY 2014 • www.ClinicalAdvisor.com

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low amniotic fluid occur so late in pregnancy despite regular prenatal visits and good prenatal care?—VISHNU MAYA UPADYHAY, WHCNP, Mesquite, Tex.

In which disease states or at what stages of chronic kidney disease is the HbA1c test no longer reliable?—PAMELA A. TETRO, MSN, FNP, NDE, Charlottesville, Va.

There is a normal decline in amniotic fluid from about 800mL at 28 weeks’ gestation to 400 mL at 42 weeks’ gestation (J Perinatol.

2005;25:341-348). Amniotic fluid index (AFI) levels are available for each gestational week between 28 and 42 (Int J Gynaecol Obstet.

2005;91:132-136). Remember, the AFI is only one parameter to use when making a judgment about maternal or fetal well-being.—Julee B. Waldrop, DNP (184-2)

Since the HbA1c assay is dependent on a naturally functional and structural Hb molecule, any alteration in that molecule or its integrity will diminish the assay’s accuracy. Similarly, any condition altering the size or longevity of the red blood cells (RBCs) will also change the results because the assay measures the amount of glycosylation (or binding) of serum glucose and the hemoglobin molecules in the red corpuscle. Since these cells live an average of 60 to 90 days in a healthy person, an index is derived to infer a daily glucose level based on the degree of saturation (or binding) that exists.

When either the hemoglobin or the RBC itself is impaired, the result can be erroneously high or low. Conditions known to interfere with hemoglobin glycosylation include genetic variants or hemoglobinopathies, renal failure, and large amounts of ingested aspirin.

Conditions affecting RBC survival include recovery from acute blood loss, anemia (specifically, the iron-deficient variety), hemolytic anemia, and increased RBC turnover attributable to other pathologies.

Additional factors affecting the HbA1c assay are ingestion of large amounts of vitamin C and/or vitamin E, chronic alcoholism, and chronic opiate use. There is no direct linear scale to use for correlation of values, so clinical assessment is key. Consistently elevated serum glucoses that seem to oppose a low or normal HbA1c should be given consideration in light of any other compounding factors, and the HbA1c assay should not be used as the sole diagnostic indicator.—Sherril Sego, FNP-C, DNP (184-4)

DO SURGICAL METALS AFFECT SECURITY OR MRI SCANS? Does the hardware used in surgery (orthopedic, plastic, neurosurgical, etc.) set off the metal detectors used in airport security or affect MRI scans?—CRAIG LIPPIT, PA-C, Cooperstown, N.Y. All heavy metals, including titanium and aluminum, will cause distortion of the waves used in scanning, including MRI and metal detectors. The degree of distortion depends on the size of the metal piece. Researchers are working to develop MRI scanners that perform using thinner sections and/or increased frequency gradient strength. Specialized fast-scan sequencing may also cut down on distortions.—Claire Babcock O’Connell, MPH, PA-C (184-3)

BLOOD GLUCOSE TEST RELIABILITY As a diabetes specialist, I frequently assess hemoglobin (Hb) A1c values. It is well known that anemia of chronic disease associated with end-stage renal disease renders the HbA1c test invalid. At what level of anemia is the HbA1c affected?

Debra August King, PhD, PA,

is senior physician assistant at New York-Presbyterian Hospital, New York City.

Mary Newberry, CNM, MSN

provides well-woman gynecologic care as a midwife with Prima Medical Group, Greenbrae, Calif.

TREATMENT OPTIONS FOR WOMEN WITH FACIAL HAIR I provide care in a women’s prison and have noted a number of patients with excess body hair. These women are tired

Claire O’Connell, MPH, PA-C,

teaches in the PA Program at the New Jersey Medical School and Rutgers University, Piscataway, N.J.

Sherril Sego, FNP-C, DNP,

is a primary-care nurse practitioner at the Department of Veterans Affairs Medical Center in Kansas City, Mo.

Julee B.Waldrop, DNP,

is associate professor at the University of Central Florida (UCF), and practices pediatrics at the UCF Health Center.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2014 75

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Advisor Forum every hour to provide vasoconstrive effects.—MICHELE CORRICE, APN-C, Mt. Arlington, N.J. (184-6)

© CMSP / SPL

WITH MULTIPLE DERMATOFIBROMAS, THINK LUPUS When a patient presents with six or more dermatofibromas, consider systemic lupus erythematosus in your differential.

—KATHLEEN HAYCRAFT, DNP, FNP/PNP-BC, DCNP, Hannibal, Mo. (184-7)

Hirsutism in women (shown) can be caused by hyperandrogenism.

of shaving facial hair and discouraged by the ridicule it engenders from other inmates. What is the best, safest, and most cost-effective treatment for these patients?—LANA K. FOWLER, FNP, Kansas City, Mo. Hair growth that is abnormal for the age, sex, or race of an individual or a particular area of the body is referred to as hypertrichosis. Malepattern hair growth in a woman or a child is known as hirsutism. In addition to shaving, cosmetic approaches for treating hirsutism include bleaching the hair, using depilatory creams, waxing, threading, and electrolysis. Photodynamic treatment and laser hair removal are also effective (Am Fam Physician. 2012;85:373-380; available at www. aafp.org/afp/2012/0215/p373.html, accessed January 15, 2014).

Pharmacologic management (e.g., gonadotropin-releasing hormone agonists, combined oral contraceptives, and steroidal or nonsteroidal antiandrogens) is also available for treating hirsutism in women with hyperandrogenism (polycystic ovary syndrome) or with normal serum androgen levels and regular ovulatory menstrual cycles (idiopathic hirsutism).—Philip R. Cohen, MD (184-5)

CLINICAL PEARLS COLD COMFORT FOR RECURRENT NOSEBLEEDS For recurrent epistaxis, advise the patient to buy saline mist and store it in the refrigerator. Use the cold mist daily and during any acute episode of bleeding. The saline solution provides moisture, and the cold temperature promotes vasoconstriction. Chemotherapy patients who experience epistaxis with treatment should bring the saline mist packed in ice to the infusion treatment and use two to three sprays

ELIMINATE EARWAX WITH OLIVE OIL To minimize the recurrence of cerumen impaction, advise patients to place two drops of olive oil in the affected ear one or two times a month. After letting the oil soak in for 15 minutes, the person should shower and let the water gently enter the ear canal to rinse out the olive oil and any accumulated wax.—KRISTEN CURTIS, CRNP, Bensalem, Pa. (184-8) DETECTING ABNORMAL HEART SOUNDS Picking up such low-pitched heart sounds as S3 and S4 can be difficult. To clarify what you are hearing, convert the bell of your stethoscope into a diaphragm by pressing down. If the sound disappears, it is most likely an S3 or S4.—ZIEMOWIT MAZUR, PA-C, North Chicago, Ill. (184-9)

YOUR COMMENTS A CORRECTION ON THE TREATMENT OF VAGINAL ATROPHY In a recent discussion of vaginal atrophy (Item 182-3), you stated that Femring is a low-dose regimen for vaginal use.

The correct low-dose regimen for vaginal use is Estring.

For therapy of menopausal symptoms beyond vulvovaginal atrophy, Femring is available in two doses (0.1 mg/day and 0.05 mg/day). Both of these dosages exceed the threshold for endometrial proliferation and require progesterone use if an intact uterus is present.—TERRI TWENHAFEL, APN-C, NCMP, Carbondale, Ill. Ms. Twenhafel is correct. Femring is a systemic dose and requires opposing progesterone, whereas Ering is a local dose that does not need opposing progesterone. This was an error made by the editors during the production process. I apologize for the confusion.—Joe Kopcha, Editor (184-10) n

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KEYNOTE SPEAKER:

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LEGAL ADVISOR CASE

An infection leads to blindness

BY ANN W. LATNER, JD

Long days were nothing new for Mr. D, a physician assistant working for a family practitioner, Dr. M. To keep the clinic open for as many days as possible, the two providers took turns staffing the office. But over the past few months, Mr. D had noticed that his “on” days seemed to be getting more numerous, and Dr. M’s hours were getting shorter.

On some level, Mr. D understood. He had been working for the physician since graduating school in his late 20s, and the doctor had been his mentor in many ways. But Dr. M was getting older and did not like working such long hours anymore. At first, the physician had started scheduling Mr. D for all the evening hours because he claimed he could no longer drive at night. Then, Mr. D got stuck working every weekend, because Dr. M was busy on the golf course preparing for his looming retirement. And while Dr. M and Mr. D sometimes worked together in the office, it seemed to Mr. D that he was coming in far earlier and leaving far later than his employer, and the long hours were starting to catch up with him.

© SCIENCE SOURCE

Significant facial edema and redness is misdiagnosed as an allergic reaction—with drastic consequences.

Ms. B’s face was swollen and red, and she complained of two to three days of fever and runny nose, which she had treated with an OTC decongestant.

Adding to Mr. D’s frustration was the fact that his wife had just had their second child and needed his help at home, but he was often too tired to be of much use at the end of his shift. If it were not for the combination of his ambition and a terrible fear that he would not be able to find a new job, Mr. D would have quit long ago. But Mr. D felt loyal to Dr. M, and needed to maintain his steady income, so he lived with the increasingly long hours.

Mr. D was working one evening when Ms. B came in. Although Dr. M had been in the office for a few hours earlier in the day, Mr. D was now covering the evening hours alone, and the waiting room was full of patients. Scanning the room, he could feel his stress level increasing as he asked the nurse to send Ms. B into the examination room.

Continues on page 80

Cases presented are based on actual occurrences.

Names of participants and details have been changed.

Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

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Download the new app for the iPhone, iPad,and Android— created specifically for nurse practitioners and physician assistants from the publishers of the highest rated journal for these health-care professionals.

With the Clinical Advisor app you can: • Take Derm Dx quizzes to learn about difficultto-identify dermatology conditions, and then see how you performed against your peers.

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LEGAL ADVISOR Ms. B’s face was swollen and red, and she complained of two to three days of fever and runny nose, which she treated herself with an OTC decongestant. Mr. D looked at her face again. He diagnosed her with a viral infection and told her that it would go away in a day or two.

“Why is my face so swollen?” Ms. B asked.

“You are likely having an allergic reaction to a dye in the decongestant,” Mr. D explained. “It’s not uncommon.

I will prescribe a mild steroid to help relieve the effects.”

He wrote the prescription and quickly ushered Ms. B out of the office, motioning for the next patient.

One day later, Ms. B called the office complaining that the facial swelling had not resolved. Dr. M, who was in

Settling out of court is a good way to lower costly attorney fees when the odds of winning the case are slim. the office at the time, took the call. He looked at the notes that Mr. D had written in the file, and told the patient that he would adjust her dose and call in another prescription.

Two days after that, Mr. D got another phone call from the patient, still complaining of severe facial swelling, especially around the eyes. Mr. D increased her steroid dosage, and told her to call back in a few days.

Ms. B never called back. In fact, Mr. D and Dr. M never heard from her again until several months later, when they received papers notifying them that they were being sued for medical malpractice for the failure to diagnose a bacterial infection.

The lawsuit alleged that after the second call to the physician’s office, and despite the increased dosage of steroids, Ms. B’s face continued to swell as a result of an undiagnosed case of orbital cellulitis. By the time Ms. B arrived for treatment at the emergency department of her local hospital, she had lost sight in both eyes. Ms. B was later declared permanently blind as a result of the extensive untreated bacterial infection around her eyes. When she found out her diagnosis, she hired an attorney and sued Dr. M’s practice and Mr. D. The two clinicians were horrified—Dr. M, because he’d managed to go his entire career without a malpractice lawsuit until now, and Mr. D because he was stricken with guilt. The pair met with the attorney provided by their malpractice insurer. She advised that they wait for

the discovery process and then decide whether or not to settle out of court. During the discovery process, it was revealed that Mr. D had spent only five minutes with the patient when she first came in for treatment. Ms. B was alleging that if Mr. D had ordered a simple blood test, it would have been obvious that she was suffering from a bacterial rather than a viral infection.

“I believe we would be better off settling this case,” said the attorney. “Based on what I’ve seen, you do not stand a good chance of winning, and it would be better to avoid the bad publicity.”

Dr. M was reluctant to settle. He didn’t want this blemish on his record, and he didn’t feel as responsible, since he had only spoken with the patient once. The attorney explained the situation.

“As the supervisor of Mr. D, you are still responsible,” the attorney told Dr. M. “As the owner of the practice, you are still responsible. And if that weren’t enough, you never suggested that the patient come in for further evaluation when you spoke to her.”

Despite Dr. M’s grumbling, the attorney negotiated an out-of-court settlement of $2.4 million, the upper limits of the malpractice policy.

Legal background

As has been mentioned many times before, settling out of court is a good way to lower costly attorney fees when the odds of winning a case are slim.

Defense attorneys who work for insurance companies are really working on behalf of the insurance company, not necessarily the physician. They will suggest whatever they think is most beneficial for the insurance company, and if settling prior to trial for a lump sum will be financially better for the insurer, the attorney will push for that.

Protecting yourself

Mr. D let the pressure of his job distract him to the point that he was not focused on his patient. Practitioner appointments are getting shorter and shorter, but five minutes is really too short to completely assess a patient. Had Mr. D spent more time with Ms. B, ordered a simple blood test, or even just responded with more urgency and thought to her phone calls, Ms. B might still have her vision.

While diagnoses need to be made, and often quickly, that’s no excuse to pay minimal attention to a patient’s symptoms. n Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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d

CME CE

n LEARNING OBJECTIVES

For Dermatology Clinic

• Identify and diagnose dermatologic conditions and review up-to-date treatment.

For Dermatologic Look-Alikes

• Distinguish and properly treat dermatologic conditions with similar presentations. n COMPLETE THE POST TEST: Page 91

DERMATOLOGY COURSES

n ADDITIONAL CME/CE CREDIT: Pages 53, 87

This activity is jointly sponsored by Medical Education Resources (MER) and Haymarket Medical Education (HME).

Release Date: February 2014 Expiration Date: February 2015 Estimated time to complete the educational activity: 30 minutes Statement of Need: Undertraining in dermatology for primary-care providers is a common phenomenon. Thus, primary care clinicians need additional educational outlets devoted to identifying and treating dermatologic conditions. For clinicians out of training, CME becomes the most accessible route.

Target Audience: This activity has been designed to meet the educational needs of primary care clinicians who treat patients with various dermatologic conditions.

Faculty Audrey Chan, MD Resident, Department of Dermatology Baylor College of Medicine Houston, TX Esther Stern, NP-C Advanced Dermatology & Skin Surgery, P.C. Lakewood, N.J. Kerri Robbins, MD Instructor, Department of Dermatology Baylor College of Medicine Houston, TX Accreditation Statements Physician Credit: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of MER and HME. MER is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: MER designates this educational activity for a maximum of 0.5 AMA PRA Category 1 creditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nursing Credit: MER is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

Credit Designation: This CE activity provides 0.5 contact hour of continuing nursing education.

MER is a provider of continuing nursing education by the California Board of Nursing Registered Nursing, Provider #CEP 12299, for 0.5 contact hour.

American Academy of Physician Assistants AAPA accepts certificates of participation for educational activities certified for Category I credit from AOACCME, Prescribed credit from AAFP and AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician Assistants may receive a maximum of 1 hour of Category I credit for completing this program.

Accreditor Disclosure of Conflicts of Interest Policy MER ensures balance, independence, objectivity, and scientific rigor in all our educational programs. In accordance with this policy, MER identifies

0214_CME derm disclosure page.indd 82

conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts are resolved by MER to ensure all scientific research referred to, reported, or used in a CME/CE activity conforms to the generally accepted standards of experimental design, data collection, and analysis. MER is committed to providing its learners with high-quality CME/CE activities that promote improvements or quality in health care and not a commercial interest.

Faculty Disclosures The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Audrey Chan, MD, Esther Stern, NP-C, and Kerri Robbins, MD, have no relevant financial relationships to disclose.

Staff/Planners’ Disclosures The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: The following HME planners and managers hereby state the following financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months: Joseph Kopcha, Editor, Marina Galanakis, Executive Editor, and Nicole Blazek, Web Editor have no real or apparent conflicts of interest to report.

The MER planners and managers, and Veronda Smith, BC-FNP, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

Method of Participation: There are no fees for participating in and receiving CME/CE credit for this activity. During the period of February 2014 through February 2015, participants must: 1) read the learning objectives and faculty disclosures; 2) study the educational activity; 3) complete the posttest and submit it online (physicians may register at www.myCME.com); and 4) complete the evaluation form online.

A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed posttest with a score of 70% or better.

Disclaimer: The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of MER or HME. The authors have disclosed if there is any discussion of published and/or investigational uses of agents that are not indicated by the FDA in their presentations. The opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of MER or HME. Before prescribing any medicine, primary references and full prescribing information should be consulted. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. The information presented in this activity is not meant to serve as a guideline for patient management..

1/28/14 10:32 AM

CME CE

Dermatology Clinic n LEARNING OBJECTIVES: To identify and diagnose dermatologic conditions and review up-to-date treatment. n COMPLETE THE POSTTEST: Page 91

n ADDITIONAL CME/CE: Pages 52, 87

CASE #1

Itchless, red, and crusted trunk papules AUDREY CHAN, MD

A Hispanic man, aged 32 years, presented with a rash that started one year earlier. Over that time, the man had developed crops of reddish-brown, crusted, and nonpruritic papules on his trunk. The patient’s medical history was noncontributory, and his social history was negative for family members with similar lesions. The man denied the use of any medications. A review of systems was negative for fever, chills, and weight loss. Physical exam was notable for scattered, discrete, red-brown papules—some with scale-crust—located mostly on the chest and back, with a few lesions on the extremities.

What is your diagnosis? Turn to page 84

CASE #2

Thick and keratotic lesions on both shins ESTHER STERN, NP-C

A man, aged 83 years, presented with thick bumps on his legs. The man had noticed a hard growth on his leg four weeks earlier and had no recollection of previous trauma to the area. Over the next week, more bumps appeared on the anterior surface of both legs.

These growing lesions were described as intensely itchy, painful, and exquisitely tender when bumped. Medical history included cardiovascular disease and hypothyroidism. Physical exam revealed approximately 15 keratotic papules, plaques, and nodules on both anterior shins. No evidence of any other lesions or dermatitis was seen elsewhere on the skin or in the mouth.

What is your diagnosis? Turn to page 85 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2014 83

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CME CE

CASE #1

Dermatology Clinic

Pityriasis lichenoides chronica

Pityriasis lichenoides (PL) is an acquired papulosquamous eruption. The two variants of PL are pityriasis lichenoides et varioliformis acuta (PLEVA) and pityriasis lichenoides chronica (PLC). Some clinicians distinguish between the two variants based on chronicity or morphology of the lesions; however, most dermatologists now appreciate that these entities exist on a clinical and histologic spectrum.

The incidence and prevalence of PL is unknown, but it may be as frequent as 1 in 2,000 persons.1 PL typically affects patients before age 30 years but can strike patients of any age, including young children and the elderly. This disease is more common in males.2 The pathogenesis of PL is unknown. The primary hypotheses include: (1) an atypical immune response in genetically susceptible individuals to foreign agents, including infections and medications; (2) a precursor to a lymphoproliferative disorder; and (3) a manifestation of systemic illness or pregnancy.2,3 The development of PL has been linked to various viruses (e.g., HIV, varicella-zoster, Epstein-Barr, cytomegalovirus, parvovirus B19, adenovirus, hepatitis C) and bacteria (e.g., Staphylococcus, Streptococcus, Mycoplasma, and Toxoplasma).3 There have been case reports of resolution of PL after tonsillectomy, lending evidence to the atypical-immune-response hypothesis.4 Medications that have been linked to PL include chemotherapeutic agents, estrogen-progesterone therapy, astemizole, tumor necrosis factor-a inhibitors, radiocontrast dye, certain herbs used in Japanese traditional medicine, and the measles vaccine.3 Because the histology of PL lesions can reveal a monoclonal lymphocytic proliferation and clonal T-cell receptor gene arrangements, PL has been thought to be a precursor to a lymphoproliferative disorder; however, it is important to note that T-cell clonality is not synonymous with malignancy and can be seen in benign reactive processes.3 PL also has been reported in association with such systemic illnesses as malignancies (e.g., mycosis fungoides, lymphomas), autoimmune disorders (e.g., rheumatoid arthritis, hypothyroidism, and pernicious anemia), and pregnancy.2,3 As a group, PL presents with recurrent crops of red-brown to erythematous papules. The two variants, PLEVA and PLC, exist on a clinical and histologic spectrum.2 PLC is characterized by red to red-brown and scaly scattered flat

papules. These lesions tend to take a more indolent course, regressing over months.2 Typically, PLC patients have fewer than 50 lesions, but the number can range from as few as 10 to as many as 100.5 The most common location for PLC is the lateral trunk and proximal extremities; however; lesions can also be diffuse, located primarily on the trunk, or located primarily on the extremities.2,4 The face is typically spared.

Individuals who fall more on the PLEVA side of the disease have polymorphic lesions with intermixed crusts, ulcers, vesicles, or pustules. Lesions on the PLEVA end of the spectrum tend to resolve within weeks. The distribution of lesions may be a more accurate predictor of the course of disease than the lesions’ acute or chronic nature:6 Patients with diffuse distribution may have the shortest average course of disease (11 months). Patients with lesions primarily on the extremities are thought to have the longest course of disease (33 months, on average).2 PLEVA in a central distribution typically has an intermediate course, lasting longer than the diffuse distribution but shorter than the peripheral distribution.2 Lesions of PLEVA fade leaving behind persistent areas of hypopigmentation.4 In some cases, the hypopigmented macules may be the most prominent finding.5 Red-brown, scaly, flat papules that recur in crops indicate the diagnosis of PLC; however, a skin biopsy is typically performed for confirmation. Just as PLC lies on a clinical spectrum with PLEVA, the histopathologic findings of PLC also lie on a spectrum with PLEVA, with PLC usually representing a more blunted histologic version of PLEVA. Histopathology of PLC reveals a superficial perivascular interface dermatitis.2 The perivascular infiltrate is predominantly lymphocytes, although a few neutrophils may be seen. The epidermis is often notable for parakeratosis and only focal keratinocyte necrosis.

Erythrocyte extravasation is often noted. The histopathologic findings on the PLEVA end of the spectrum are much more robust, with a denser perivascular infiltrate that is often wedgeshaped. In contrast to the focal keratinocyte necrosis seen in PLC, there can be extensive epidermal necrosis in PLEVA. There are no serologic tests for either variant of PL. The differential diagnosis of PL includes guttate psoriasis, folliculitis, Grover disease, and lymphomatoid papulosis.

Guttate psoriasis is most commonly seen in children and adolescents and is frequently preceded by an upper respiratory infection.2 Lesions of guttate psoriasis are small, discrete, and erythematous papules and plaques with overlying silvery scale. Psoriasis can demonstrate the Koebner phenomenom, whereby lesions can form linear configurations.

This feature is not seen in PLC. Folliculitis manifests as pustules on an erythematous base. Because PLC can lie on

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a clinical spectrum with PLEVA, occasional pustules may be seen. In folliculitis, however, all lesions by definition should be noted in association with a hair follicle. PL is not a folliculocentric process, and therefore lesions should be more scattered and randomly distributed. Grover disease is most commonly seen in white men older than age 40 years.2 The papules and papulovesicles in Grover disease tend to be pink rather than the red-brown papules seen in PL. Lymphomatoid papulosis, like PL, is a chronic and recurrent skin disease that occurs in crops. The papules in lymphomatoid papulosis are also red-brown, but there are often concomitant larger nodules, which are not seen in PL. A biopsy can easily distinguish among all of these entities.

PL treatment depends on disease severity. For mild disease, topical corticosteroids are frequently used. For more extensive disease, methotrexate (Rheumatrex, Trexall) is often initiated. Low doses of methotrexate (typically 5 mg to 15 mg, orally once weekly) may lead to partial to complete resolution of skin lesions; however, there are no specific guidelines on dose and duration of treatment.

Methotrexate is typically continued six to eight weeks after cutaneous lesions stop developing. If lesions recur after drug discontinuation, methotrexate can be restarted.

Other treatment regimens that have shown some efficacy include oral erythromycin, oral tetracycline (Sumycin), UVB phototherapy, and psoralen UVA phototherapy.

The chronic nature of this patient’s disease and the fairly uniform appearance of the red-brown papules indicated a diagnosis of PLC. The man elected to start methotrexate, but he was lost to follow-up.

Dr. Chan is a third-year dermatology resident at Baylor College of Medicine in Houston.

References 1. Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 6th ed. New York, N.Y.: McGraw-Hill; 2003:456-62.

2. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008:139-141.

3. Khachemoune A, Blyumin ML. Pityriasis lichenoides: pathophysiology, classification, and treatment. Am J Clin Dermatol. 2007;8:29-36.

4. Takahashi K, Atsumi M. Pityriasis lichenoides chronica resolving after tonsillectomy. Br J Dermatol. 1993;129:353-354.

5. James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, Pa.: Saunders Elsevier; 2011:729-730.

6. Gelmetti C, Rigoni C, Alessi E, et al. Pityriasis lichenoides in children: a long-term follow-up of eighty-nine cases. J Am Acad Dermatol.

1990;23:473-478.

CASE #2

Hypertrophic lichen planus

Hematox yl in and eosin (H&E) stains performed on a deep-shave biopsy specimen revealed a lichenoid infiltrate at the tips of the rete ridges with dyskeratosis, pigment incontinence, and lack of cytologic atypia in the lesion.

These f indings conf irmed the diagnosis of hypertrophic lichen planus (LP), also known as lichen planus verrucosus.

LP is an inflammatory disease with no known cause; however, an immunologic pathogenesis has been discussed.

In addition, studies have indicated a link between LP and infection with the hepatitis C virus,1 as well as lichenoidtype dermatitis in response to certain medication. LP occurs worldwide and may have a small familial predisposition.

Men and women are affected equally; patients are typically aged 20 years to 60 years.

LP usually presents with a rash consisting of characteristic shiny, polygonal, flat-topped, and violaceous papules. A reticulated white scale, known as Wickham’s striae, may be noted on close inspection. Although LP can appear anywhere on the skin and mucous membranes, the flexor surfaces of the extremities, particularly the wrists, are most commonly affected.

Hypertrophic LP, an uncommon variant of LP, presents with large hypertrophic or verrucous plaques with varying amounts of scale. The more classic violaceous, flat-topped papules may be noted at the edge of the lesion. These papules can range in size from several millimeters to several centimeters, with lesion spread and confluence encouraged by habitual scratching. Hypertrophic LP most commonly appears on the dorsal surface of the shins, ankles, and feet, often in a symmetric pattern. Frequently, hypertrophic LP appears against a background of chronic stasis dermatitis.

The condition may develop in isolation or as part of a generalized LP eruption. Other variants of LP affect the oral mucosa, nails, and scalp.

The diagnosis of hypertrophic LP usually requires histopathologic confirmation, as this condition may resemble a verrucous psoriasis, hypertrophic lupus erythematosus, keratoacanthoma, or squamous cell carcinoma.

Classic LP usually lasts one to two years, but the hypertrophic variant often has a more protracted course, with one source reporting an average duration of six years in those whose

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Dermatology Clinic

lesions cleared.2 The goal of LP treatment is control, as there is no curative treatment. Treatment for classic LP involves topical therapy for more limited disease and systemic therapy for more generalized disease. Local treatment includes topical corticosteroids, such topical immunomodulators as tacrolimus (Prograf) and pimecrolimus (Elidel), and intralesional triamcinolone acetonide (Kenalog) injections. Systemic therapy may involve oral or intramuscular prednisone; an oral retinoid, such as isotretinoin 20 mg to 60 mg daily or acitretin (Soriatane) 0.5 mg/kg/day to 1.0 mg/kg/day; or, less commonly, an immunosuppressant, such as mycophenolate mofetil (CellCept) or cyclosporine (Gengraf, Neoral, Sandimmune). Phototherapy with psoralen plus UVA (PUVA) light or narrow-band UVB may also be considered.

For scattered individual lesions of hypertrophic LP, intra­ lesional triamcinolone acetonide injections are the preferred treatment. Dosage ranges from 10 mg/mL to 40 mg/mL, with 0.1 mL to 0.3 mL per lesion, depending on lesion thickness and previous response. Alternatively, application of a potent topical corticosteroid under occlusion may be used. Caution must be used to avoid the adverse effect of cutaneous atrophy.

Many patients may require antipruritic therapy for comfort. Such nonsedating antihistamines as fexofenadine (Allegra) and/or hydroxyzine (Vistaril) may be useful adjuvant therapy, and diphen­hydramine may be recommended for nighttime relief.

If localized therapy fails to control the lesions and symptoms of hypertrophic LP, consider systemic treatment as indicated for generalized LP.

Rare cases of squamous cell carcinoma have been reported to evolve in lesions of hypertrophic LP on the lower leg.3 Clinicians should have a low threshold for biopsy of isolated resistant or growing lesions.

Even with treatment, hypertrophic LP often resolves with scarring and hyperpigmentation. Patients should be made aware of expected and realistic outcomes of this condition, which may be chronic or recurrent.

The man in this case was treated with once-monthly triamcinolone acetonide injections, starting at a concentration of 10 mg/mL. The patient ultimately benefited most from 0.1 mL to 0.3 mL at a concentration of 40 mg/mL injected into each lesion. Most of the papules, plaques, and nodules on his shins responded well and resolved with postinflammatory hyperpigmentation. On follow-up, the patient reported a significant decrease in itching and pain and was satisfied with the treatment outcome. n Ms Stern is a family nurse practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J. References 1. Chuang TY, Stitle L, Brashear R, Lewis C. Hepatitis C virus and lichen planus: A case-control study of 340 patients. J Am Acad Dermatol.

1999;41:787-789.

2. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008:190.

3. James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, Pa.: Saunders Elsevier; 2011:214-215.

“Don’t you have any sexual fantasies that don’t involve me cleaning?”

“I’m sorry, but this beach is for residents only.”

© The New Yorker Collection 2014 from cartoonbank.com. All Rights Reserved.

CME CE

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CME CE

Dermatologic Look-Alikes n LEARNING OBJECTIVE: To distinguish and properly treat dermatologic conditions with similar presentations. n COMPLETE THE POSTTEST: Page 91

n ADDITIONAL CME/CE: Pages 52, 83

Blistering rash in the groin KERRI ROBBINS, MD

CASE #1

CASE #2

A man, aged 64 years, presented with pruritic blisters in the groin and bilateral axillae. The blisters began two weeks ago during a hospital stay in which he received IV vancomycin (Vancocin) for an infection. No oral erosions were reported. The man was not currently taking any medications. Physical examination revealed tense serous and hemorrhagic bullae on an erythematous base in the groin and bilateral axillae. A punch biopsy was performed and sent for hematoxylin and eosin (H&E) staining and direct immunofluorescence (DIF).

For three weeks, a black woman, aged 71 years, had experienced a pruritic and blistering rash. No oral erosions were reported. The woman was not under any current treatment. Review of systems was otherwise negative.

On physical exam, tense serous and hemorrhagic bullae on normal and erythematous skin were appreciated on the trunk, bilateral axillae, abdomen, back, groin, and proximal lower extremities. Superficial erosions and crusting were seen in a similar distribution. A punch biopsy was performed and sent for H&E staining and DIF.

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CME CE

CASE #1

Dermatologic Look-Alikes

Linear IgA bullous dermatosis

Linear immunoglobulin (Ig) A bullous dermatosis (LABD) was previously thought to be a variant of dermatitis herpetiformis (DH). It wasn’t until 1969 that researchers recognized that patients with vesiculobullous lesions that had histologic findings similar to DH had linear rather than granular deposits of IgA along the basement membrane zone.

In 1975, Chorzelski and Jablonska were the first to make the suggestion that LABD was a separate entity.1 Today, it is widely agreed upon by dermatologists that LABD and DH are distinct disorders.

Both adults and children may develop the disease. In adults, the condition is most commonly termed LABD, whereas in children it is most often referred to as chronic bullous disease of childhood (CBDC). Histologically, the two diseases are indistinguishable. Clinically, however, LABD most closely resembles DH or bullous pemphigoid (BP) and is often drug-induced. In CBDC, the cutaneous features are unique and usually characterized by annular erythema and blisters (often referred to as a crown of jewels).

The exact incidence of LABD is unknown. In southern England, the incidence has been estimated to be 1 in 250,000 per year. In the United States, the incidence has been estimated to be 0.6 per 100,000 adults. Females are slightly more affected than males. The average age of onset of LABD is after age 60 years. Most children develop the disease by age 3 years and go into spontaneous remission by age 13 years.2 LABD is an acquired, autoimmune blistering disease. The target antigen is most commonly the carboxy terminus of bullous pemphigoid antigen 2 (BPAG2). More specifically, an IgA antibody reacts against a 97 kDa antigen that is a cleaved ectodomain of BPAG2, referred to as LABD97.3 Histologically, there is a less common subtype of LABD that binds to type VII collagen in anchoring fibrils. There are reports in the literature of LABD being associated with GI diseases (rarely, gluten-sensitive enteropathy),4 autoimmune diseases, malignancies, and infections. In adults, the dermatosis commonly occurs as a drug-induced disease and may be more severe than the spontaneously occurring form.

Commonly implicated drugs include vancomycin (most common), lithium (Lithobid), amiodarone (Cordarone,

Pacerone), captopril (Capoten), penicillin, amoxicillin, moxifloxacin (Avelox), carbamazepine, phenytoin (Dilantin, Phenytek), psoralen, furosemide (Lasix), oxaprozin (Daypro), interleukin 2, interferon alfa-2a (Roferon-A), diclofenac (Cataflam, Voltaren, Zipsor), statins, tea tree oil, angiotensin receptor antagonists, glyburide (DiaBeta, Glynase), and ustekinumab (Stelara).5,6 Lesions may develop on normal or erythematous skin as individual tense bullae or herpetiform vesiculobullae.

The classic description is that of bullae that are arranged in an annular array or rosette (i.e., crown-of-jewels) configuration. Patients will often complain of severe pruritus.

Bullae preferentially develop on the lower trunk, buttocks, genitalia, and thighs. Up to 75% of patients may have oral mucous membrane involvement, and LABD may sometimes present as a variant of cicatricial pemphigoid.7 LABD may be difficult to diagnose clinically in adults because the condition may closely resemble DH or BP. To determine the exact diagnosis, a biopsy with both H&E stain and DIF is needed. Patients with LABD will demonstrate a subepidermal blister with neutrophils in the dermal papillae on H&E stains. This histologic picture may be seen not only in LABD but also in patients with DH or bullous lupus erythematosus. An antinuclear antibody panel may help to exclude a diagnosis of bullous lupus erythematosus.

A DIF will help to distinguish LABD from DH, and biopsies should be obtained from perilesional skin. While patients with LABD will show linear deposition of IgA along the basement membrane zone (BMZ) on a DIF, patients with DH will demonstrate granular IgA in the dermal papillae or along the BMZ. Patients with BP will most commonly display a subepidermal bullae with eosinophils on H&E and linear deposition of C3 and IgG along the BMZ on DIF. Nearly 60% to 70% of patients with LABD will demonstrate circulating anti-BMZ antibodies of the IgA class.7 These antibodies most commonly bind to the epidermal side (roof ) of salt-split skin. However, those patients with the less common form of LABD that binds to collagen VII will have IgA antibodies that bind to the dermal side of salt-split skin.

Most patients with LABD will respond to either oral dapsone or sulfapyridine therapy. The results are impressive, with most patients having a clinical response within two to three days. Some cases respond to topical steroids alone, and in severe cases, oral prednisone may be added to achieve complete control of the disease. Other treatments that have been reported as effective include mycophenolate mofetil (CellCept), azathioprine (Azasan, Imuran),

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cyclosporine (Gengraf, Neoral, Sandimmune), topical calcineurin inhibitors, colchicine (Colcrys), dicloxacillin, trimethoprim/sulfamethoxazole (Bactrim, Septra, Sulfatrim), erythromycin, and IV immunoglobulin (IVIG).

All treatments are off-label. Rarely, those patients who have an associated gluten-sensitive enteropathy may respond to a gluten-free diet.

Drug-induced LABD is usually a self-limited eruption that resolves within two to six weeks after cessation of the drug. However, some cases have persisted for months.

The idiopathic form of the disease generally responds well to dapsone or sulfapyridine, and these cases tend to persist for years with spontaneous remission in several patients. In children, the untreated disease usually will resolve spontaneously by adolescence. Given the possibility for spontaneous remission in both adults and children, repeated attempts to taper medications should be made in case spontaneous remission has occurred.

The diagnosis of LABD was confirmed on H&E and DIF in this patient. The man was treated with dapsone, and the lesions resolved on follow-up. He was advised to avoid vancomycin.

CASE #2

Bullous pemphigoid

During the 18th century, every blistering disorder was termed pemphigus. In 1953, Lever was the first to recognize BP as a distinct disorder based on its specific clinical and histologic features.8 In the 1960s, Jordon, Beutner, and colleagues determined that patients with BP had tissuebound and circulating autoantibodies that were directed against the cutaneous BMZ.9 BP is the most common autoimmune blistering disorder to occur in the skin. It most commonly occurs in the elderly, with an average age of onset of 65 to 75 years. The disorder tends to be more predominant in males than females. The exact incidence is unknown, but it is estimated that there are at least 6 to 7 new cases per million population.10 The disease also occurs in children, but rarely.

BP is an autoimmune blistering disorder that is associated with both a humoral and cellular immune response.

The target self-antigens are the BP antigen 180 (BP180, BPAG2, or type XVII collagen) and the BP antigen 230 (BP230 or BPAG1). BPAG2 is a transmembrane protein, whereas BPAG1 is a cytoplasmic protein that belongs to the plakin family. Both of these antigens are an integral part of the hemidesmosome, which promotes epithelial-stromal adhesion of the stratified epithelia of the skin and mucous membranes. Nearly all individuals have circulating autoantibodies to BPAG2. More specifically, these autoantibodies are targeted against the noncollagenous NC16A domain that is located extracellularly but close to the transmembrane domain. Once these autoantibodies bind to their target antigen, a subepidermal blister forms, and a cascade of events involving complement activation, recruitment of inflammatory cells, and liberation of various chemokines and proteases ensues. BP may also be drug-induced; the most common offenders include furosemide, analgesics, D-penicillamine (Cuprimine, Depen), penicillin, sulfasalazine (Azulfidine), potassium iodide, gold, and captopril.

There is both a nonbullous and a bullous phase of BP. In the nonbullous phase, the clinical appearance can be very polymorphic. Patients most often complain of mild or severe pruritus that may be associated with excoriated, eczematous, and/or urticarial lesions. Tense blisters on an erythematous base predominate the bullous stage of the disease. The bullae are usually 1 cm to 4 cm in diameter, contain clear or hemorrhagic fluid, and may persist for several days. After the bullae rupture, large denuded areas that may become crusted are left behind. On healing, these lesions may leave residual postinflammatory hyper- and/or hypopigmentation and milia. Lesions tend to be symmetric and occur predominately within flexural areas of the limbs and lower trunk, including the abdomen. Approximately 10% to 30% of patients will have oral mucous membrane involvement.11 BP that occurs in pregnancy is called pemphigoid gestationis.

This eruption most commonly occurs during the second or third trimester of pregnancy and appears as pruritic papules and/or bullae that begin periumbilically and then generalize. Childhood BP more commonly involves the palms, soles, and mucous membranes.

The differential diagnosis of bullous pemphigoid may include LABD, DH, bullous lupus, pemphigus vulgaris, porphyria cutanea tarda, bullous impetigo, epidermolysis bullosa, drug reactions, contact dermatitis, urticaria, and arthropod reactions.

On H&E staining, a subepidermal bulla with perivascular lymphocytes and eosinophils is most commonly observed.

Eosinophilic spongiosis and dermal edema also may be

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CME CE

Dermatologic Look-Alikes

present. In rare cases, the inflammatory infiltrate may be sparse; this is termed cell-poor BP. If numerous eosinophils are found within the dermis of an elderly patient, even without blistering, a diagnosis of BP is highly likely. DIF of perilesional skin reveals C3 and IgG at the BMZ. On indirect immunofluorescence of salt-split skin, circulating autoantibodies bind to the roof of the blister. Epidermolysis bullosa acquisita (EBA) patients often demonstrate subepidermal cell-poor bullae on H&E staining, and DIF will also show linear deposition of complement and IgG along the BMZ. Since cell-poor BP and EBA may appear identical on H&E and DIF, EBA must be considered in a patient diagnosed with BP who is responding poorly to treatment. In contrast to BP, patients with EBA will have localization of autoantibodies to the floor of the blister on indirect immunofluorescence. BP 180 enzyme-linked immunosorbent assay (ELISA) and BP 230 ELISA may also be performed to aid in the diagnosis; these assays have a sensitivity of 72% and 59% and a specificity of 94.1% and 99.2%, respectively.12 However, DIF still remains the gold standard, with a sensitivity of 90.8% and a specificity of 98%.12 The mainstay of treatment is systemic corticosteroids at a dosage of 0.5 mg/kg/day to 1.0 mg/kg/day. The disease rapidly improves within one to two weeks, and steroids are then tapered over a period of months. Topical cortico­ steroids alone are also a well-accepted treatment option for mild disease. Other treatments are often used as secondline therapy and include azathioprine, mycophenolate mofetil, methotrexate (Rheumatrex, Trexall), chlorambucil (Leukeran), cyclophosphamide, cyclosporine, nicotinamide, tetracycline (Sumycin), IVIG, plasma exchange, and rituximab (Rituxan). All treatments are off-label.

BP is generally a self-limited disease that spontaneously remits within five to six years in adults and within one year in children. Approximately 10% to 15% of patients will relapse on discontinuation of therapy.13 The estimated death rate during the first year has varied between 10% and 40%, depending on the series.14,15 However, much of the morbidity and mortality is related to side effects of drug therapy; with better treatments, pemphigoid patients now have similar mortality to age-matched controls.

The H&E and DIF confirmed the diagnosis of BP in this patient. The woman was treated with systemic and topical corticosteroids. After remission, the systemic corticosteroids were tapered and the patient currently remains disease-free. n

References 1. Chorzelski TP, Jablonska S. Diagnostic significance of immunofluorescent pattern in dermatitis herpetiformis. Int J Dermatol. 1975;14:429-436.

2. Wojnarowska F, Marsden RA, Bhogal C, et al. Chronic bullous disease of childhood, childhood cicatricial pemphigoid, and linear IgA disease of adults: a comparative study demonstrating clinical and immunopathologic overlap. J Am Acad Dermatol. 1988;19:792-805.

3. Zone JJ, Taylor TB, Kadunce DP, et al. Identification of the cutaneous basement membrane zone antigen and isolation of antibody in linear immunoglobulin A bullous dermatosis. J Clin Invest. 1990;85:812-820.

Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC296499/.

4. Leonard JN, Griffiths CE, Powles AV, et al. Experience with a gluten free diet in the treatment of linear IgA disease. Acta Derm Venereol.

1987;67:145-148.

5. Becker JG, Mundi JP, Newlove T, et al. Development of linear IgA ­bullous dermatosis in a patient with psoriasis taking ustekinumab. J Am Acad Dermatol. 2012;67:e150-e151.

6. Fortuna G, Salas-Alanis JC, Guidetti E, et al. A critical reappraisal of the current data on drug-induced linear immunoglobulin A bullous dermatosis: A real and separate nosological entity? J Am Acad Dermatol.

2012;66:988-994.

7. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 3rd ed. St. Louis, Mo.: Elsevier-Mosby; 2012:496-499.

8. Lever WF. Pemphigus. Medicine. 1953;32:1-123.

9. Jordon RE, Beutner EH, Witebsky E, et al. Basement zone antibodies in bullous pemphigoid. JAMA. 1967;200:751-756.

10. Rzany B, Weller N. Epidemiology of autoimmune skin disorders. In: Hertl, M ed. Autoimmune Diseases of the Skin. New York, N.Y.: Springer Verlag; 2001:21-38.

11. Williams DM. Vesiculo-bullous mucocutaneous disease: benign mucous membrane and bullous pemphigoid. J Oral Pathol Med. 1990;19:16-23.

12. Sardy M, Kostaki D, Varga R. Comparative study of direct and indirect immunofluorescence and of bullous pemphigoid 180 and 230 enzyme-linked immunosorbent assays for diagnosis of bullous pemphigoid. J Am Acad Dermatol. 2013;69:748-753.

13. James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, Pa.: Saunders Elsevier; 2011:457.

14. Bystryn JC, Rudolph JL. Why is the mortality of bullous pemphigoid greater in Europe than in the US? J Invest Dermatol. 2005;124:xx-xxi.

Available at www.nature.com/jid/journal/v124/n3/full/5602722a.html.

15. Joly P, Benichou J, Lok C, et al. Prediction of survival for patients with bullous pemphigoid: a prospective study. Arch Dermatol.

2005;141:691-698. Available at archderm.jamanetwork.com/article. aspx?articleid=395851.

Dr. Robbins is an instructor in the Department of Dermatology at Baylor College of Medicine in Houston.

All electronic documents accessed January 15, 2014.

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CME

POSTTEST Expiration date: February 2015

Physician Credit This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Medical Education Resources (MER) and Haymarket Medical. MER is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Medical Education Resources designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Category I credit from AOACCME, Prescribed credit from AAFP and AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician Assistants may receive a maximum of 1 hour of Category I credit for completing this program.

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This CE activity provides 1 contact hour of continuing nursing education.

Medical Education Resources is a provider of continuing nursing education by the California Board of Registered Nursing, Provider #CEP 12299, for 1 contact hour.

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page 52

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Managing food allergies in primary care

Case #1

Case #1

1. Pityriasis lichenoides is associated with which systemic illness? a. Ulcerative colitis b. Pernicious anemia c. Sarcoidosis d. Gout

1. What is the most common drug associated with linear IgA bullous dermatosis (LABD)? a. Lithium (Lithobid) b. Furosemide (Lasix) c. Vancomycin (Vancocin) d. Phenytoin (Dilantin, Phenytek)

1. What is a common food allergy symptom? a. Abdominal pain b. Dysphagia c. Rhinorrhea d. All of the above 2. What is one of the most common foods that provoke food-dependent exercise-induced anaphylaxis? a. Soy b. Eggs c. Shellfish d. Milk

2. What is the most common location of pityriasis lichenoides chronica? a. Face b. Flexor surfaces c. Lateral trunk d. Genitalia Case #2

3. Yeast protein is found in which vaccine? a. Human papillomavirus b. Influenza c. Measles, mumps, rubella d. Rabies 4. A latex allergy may cross-react with a. Lentils b. Avocado c. Barley d. Peach

TO TAKE THE POSTTEST please go to CliniAd.com/M51Yw8

3. Hypertrophic lichen planus (LP) is associated with Wickham striae, a dermatologic sign described as a. Linear freckling b. Punctate bleeding spots c. Petechiae in skin creases d. A reticulated white scale

2. What is the classic description of LABD? a. Blisters in a rosette configuration b. Pruritic lesions distributed symmetrically c. Grouped vesicles in a continuous band d. Blisters on urticated plaque edges Case #2 3. Patients with bullous pemphigoid (BP) often complain of a. Blisters on mucous membranes b. Mild or severe pruritus associated with excoriated lesions c. Small blisters that rupture easily, leaving erosions d. Fluid-filled blisters preceded by fever and widespread redness

4. What is the preferred treatment for scattered individual lesions of 4. What is the mainstay of treatment hypertrophic LP? for BP? a. Intralesional triamcinolone a. Tetracycline (Sumycin) acetonide b. Cyclophosphamide b. Daily oral retinoid (isotretinoin) c. Plasmapheresis c. Narrow-band UVB phototherapy d. Systemic corticosteroids d. Surgical excision TO TAKE THE POSTTEST please go to CliniAd.com/1iDpApF

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Derm Dx

EXCLUSIVE TO THE WEB

INTERACT WITH YOUR PEERS by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit CliniAd.com/10KIbCF. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

Blue sclera in a patient with skeletal fractures A woman, aged 64 years, came in for a routine checkup.

A history of multiple skeletal fractures dating back to childhood was reported. Physical exam revealed sclera with a bluish hue.

WHAT IS YOUR DIAGNOSIS?

• Marfan syndrome • Ehlers-Danlos syndrome • Osteogenesis imperfecta • Tuberous sclerosis

● See the full case at CliniAd.com/1crkPKL

Nodular lesion on the nose of patient with dyspnea A 48-year-old black woman with dyspnea presented with a nodular lesion on the nose. Chest x-ray showed bilateral hilar lymphadenopathy, and a skin biopsy showed noncaseating granulomas.

WHAT IS YOUR DIAGNOSIS?

• Lupus pernio • Lupus vulgaris • Lupus profundus • Lupus miliaris disseminatus faciei ● See the full case at CliniAd.com/JLpCwM

Have you missed any recent Derm Dx cases? Go to CliniAd.com/10KIbCF for a complete archive of past quizzes as well as additional images of this month’s other cases.

Vesicles on the abdomen

Hair loss with scarring

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ALTERNATIVE MEDS UPDATE

What you should know about the herbs and supplements patients use

By Sherril Sego, FNP-C, DNP. Ms. Sego is a staff clinician at the VA Hospital in Kansas City, Mo., where she practices adult medicine and women’s health. She also teaches at the nursing schools of the University of Missouri and the University of Kansas.

Magnets

© THINKSTOCK

Magnetism can refer to the alteration of gravitational pull to the North Pole as well as to the invisible attraction two people feel toward one another. Both definitions, however, indicate a hidden but palpable force that pulls one object to another. Historically, magnetism was discussed as early as 625 bc. in the writings of Aristotle.1 Later, mariners learned that magnetic rocks known as lodestones acted dependably as compasses when suspended from a string. With unfailing accuracy, the stone would come to rest in a north-south line, thus indicating the direction of the ship.2

BACKGROUND All magnets have positively and negatively charged poles.

Magnets bond when opposing poles are placed next to each other and repel when like poles face each other.

The medical uses of magnets are still being explored. More than $1 billion worth of OTC therapeutic magnets have been sold worldwide to date.3 The gauss (G) is the unit of measurement of a magnetic field.

The earth’s magnetic field on its surface is approximately 0.5 G. Commercially available magnets usually claim strengths of anywhere from 300 G to 5,000 G; an electromagnet used in an MRI machine is 15,000 G or higher.

SCIENCE Basic research shows that when a magnet is placed on the skin, capillary walls relax, allowing for increased blood flow and oxygenation and removal of accumulated pain-producing

prostaglandins. Theoretically, these actions relieve muscle spasms and, subsequently, pain.4 Since pain transmission requires the electrical activity found in nerve and muscle cells, properly aligned magnets could either block that action or, in cases of injury, promote healing.5 Magnets can be used in a constant, uninterrupted application (static therapy) or with manipulation of the magnetic field (pulsed therapy).

A meta-analysis of published clinical trials testing the efficacy of magnet therapy for pain showed no clear, statistically significant differences.6 Of the 29 studies examined, nine were randomized, placebo-controlled trials that explored the use of magnets for musculoskeletal pain. Four of these trials demonstrated a measurable reduction in pain but were not consistent in the strength of magnet used, length of use, and positioning of the magnets.

Of the four studies showing positive results, one was a small trial examining the effect of magnet therapy on fibromyalgia pain.7 This trial utilized a magnetic mattress pad of 1,100 G. Participants were randomized either to a

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ALTERNATIVE MEDS UPDATE placebo pad or the magnetic pad, and slept on the same pad for 16 weeks. The patients were assessed for pain, fatigue, myalgia, physical function, and sleep quality using the Fibromyalgia Impact Questionnaire. The magnetic pad group had statistically significant improvement in all areas compared with little or no change in the placebo group.

A small clinical trial used pulsed electromagnetic therapy (PEMT) to treat chronic low back pain.8 A total of 36 patients were randomized to PEMT or placebo treatment performed three times a week for three weeks. Patients were then followed for four weeks and asked to rate their pain on a numerical scale. Individuals in the treatment group reported a statistically significant decrease in pain for the entire month.

Another unique trial evaluated the efficacy of magnet therapy for menstrual pelvic pain.9 A device in the underwear secured the magnets to assure contact with the pelvis. In this trial, 35 women with documented dysmenorrhea were randomized to wear either a strong magnet garment or a weaker magnetic placebo device for the two days prior to menses until the end of their cycle. Blinded results assessed by the McGill Pain Questionnaire showed a statistically significant reduction in pain in the group wearing the strong-magnet garment.

quality and strength and varies from as low as $10 to as much as $100 or more. Patients should thoroughly research any product before buying.

SUMMARY

Electromagnetic therapy has been used to treat chronic low back pain.

Redness of the skin in contact with the magnet has been reported, but most cases self-resolve within 24 hours of removal.

SAFETY

Magnet therapy is still on the outer fringe of any sort of evidence-based practice. However, even the studies that did not show benefit failed to show any negative safety issues. Consequently, health-care professionals should be aware of the emerging data and help their patients make informed decisions regarding magnet therapy. n References 1. Basford JR. A historical perspective of the popular use of electric and magnetic therapy. Arch Phys Med Rehabil.

2001;82:1261-1269.

2. Boyer TH. The force on a magnetic dipole. Am J Physics.

1988;56:688-692.

3. Kuipers NT, Sauder CL, Ray CA. Influence of static magnetic fields on pain perception and sympathetic nerve activity in humans. J Appl Physiol (1985). 2007;102:1410-1415.

Available at jap.physiology.org/content/102/4/1410.long.

4. Mayrovitz HN, Groseclose EE. Effects of a static magnetic field of either polarity on skin microcirculation. Microvasc Res. 2005;69:24-27.

5. McLean M, Engstrom S, Holcomb R. Static magnetic fields for the treatment of pain. Epilepsy & Behavior. 2001;2:S74-S80.

6. Pittler MH, Brown EM, Ernst E. Static magnets for reducing pain: systematic review and meta-analysis of randomized trials. CMAJ. 2007;177:736-742. Available at www.cmaj.

Redness of the skin in contact with the magnet has been reported, but most cases self-resolve within 24 hours of removal of the device.

Patients who use cardiac pacemakers, implanted automatic defibrillators, or insulin pumps should not use magnet therapy without consulting their health-care provider. Some manufacturers warn that magnets can interfere with the pharmacokinetics of transdermal medications, such as pain patches. Although this theory has not been proven, it warrants consideration.

COST, HOW SUPPLIED

ca/content/177/7/736.long.

7. Colbert AP, Markov MS, Banerji M, Pill AA. Magnetic mattress pad use in patients with fibromyalgia: a randomized double-blind pilot study. J Back Musculoskeletal Rehab.

1999;13: 19-31.

8. Lee PB, Kim YC, Lim YJ, et al. Efficacy of pulsed electromagnetic therapy for chronic lower back pain: a randomized, double-blind, placebo-controlled study. J Int Med Res. 2006;34:160-167. Available at imr.sagepub.com/ content/34/2/160.long.

9. Eccles NK. A randomized, double-blinded, placebocontrolled pilot study to investigate the effectiveness of a static magnet to relieve dysmenorrhea. J Altern

All electronic documents accessed January 15, 2014.

© CMSP

Complement Med. 2005;11:681-687.

The cost of magnet therapy is highly variable.

Generally, the cost of the device rises with the 94 THE CLINICAL ADVISOR • FEBRUARY 2014 • www.ClinicalAdvisor.com

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Evidence-Based Medicine This department uses the best available scientific findings to offer practice guidance on a wide range of conditions seen in primary care.The author, Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Mass., and assistant clinical professor in Family Medicine, University of Massachusetts Medical School in Worcester. DynaMed (www.ebscohost.com/dynamed/) is a database that provides evidence-based infor-­­ mation on more than 3,000 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.The most important evidence identified is summarized here.

MULTIVITAMIN PLUS SELENIUM SUPPLEMENT MAY SLOW P ­ ROGRESSION OF HIV IN TREATMENT-NAÏVE ADULTS IN LOW-RESOURCE SETTINGS Level 2: Mid-level evidence Micronutrient deficiencies are common in patients with HIV infection and may occur very early in the course of the disease, affecting immune function and disease progression.

In low-resource settings where availability of antiretroviral therapy can be limited, other interventions to slow disease progression may be particularly valuable. Previous studies have suggested that micronutrient supplements may improve HIV markers in patients with advanced disease. A recent randomized trial in Botswana evaluated the effects of supplementation in 878 treatment-naïve adults with early, asymptomatic HIV infection ( JAMA. 2013;310:2154-2163).

Patients with HIV infection subtype C were randomized to one of four daily treatments for two years: multivitamins plus selenium (in one tablet) vs. multivitamin only vs. selenium only vs. placebo. Vitamins included thiamin 20 mg, riboflavin 20 mg, niacin 100 mg, vitamin B6 25 mg, vitamin B12 50 mcg, folic acid 800 µg, vitamin C 500 mg, and vitamin E 30 mg. The selenium dose was 200 µg. All patients had a CD4 count >350/µL and no history of AIDSdefining conditions at baseline. The primary outcome was disease progression defined as CD4 count ≤250/µL, and the secondary outcome was a composite of disease progression, development of AIDS-defining conditions, and AIDS-related death.

A total of 24.9% of patients were lost to followup or dropped out of the trial (with 7.5% discontinuing due to pregnancy). The incidence

Micronutrient supplements may be an inexpensive way to improve treatment for HIV patients in low-resource settings.

of the composite outcome (progression plus AIDS outcomes) was significantly reduced in the multivitamin plus selenium group (6.48 per 100 person-years) compared with placebo (10.95 per 100 person-years, p=0.04). Incidence in the other two groups was not significantly different from placebo. For the primary outcome of disease progression, incidence in both the multivitamin-plus-selenium group and the multivitamin-only group were significantly reduced compared with placebo. The rates of adverse events were similar among groups, and there were no significant differences in HIV viral load among groups.

These results suggest an inexpensive way to improve treatment for HIV patients early in the course of the disease in low-resource settings. It remains to be seen whether the benefits would also be found in parts of the world where most patients have access to a diet that is more likely to supply all of the essential nutrients.

CLARITHROMYCIN MIGHT INCREASE ALL-CAUSE MORTALITY AND HOSPITALIZATION FOR ACUTE KIDNEY INJURY COMPARED WITH AZITHROMYCIN IN OLDER ADULTS RECEIVING CALCIUM CHANNEL BLOCKERS Level 2: Mid-level evidence Calcium channel blockers (CCBs) are metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. The macrolide antibiotic clarithromycin The quality of the evidence supporting each item is rated from Level 1 (highest) to Level 3 (lowest). Absolute risk reductions are presented as the number needed to treat (NNT) for one patient to benefit. Absolute risk increases are presented as the number needed to harm (NNH).

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(Biaxin) is an inhibitor of CYP3A4, potentially leading to a drug-drug interaction when coprescribed with CCBs, whereas azithromycin (Zithromax, Zmax) is not. In an observational study involving older patients, coprescription of CCBs with either clarithromycin or erythromycin (also a CYP3A4 inhibitor) was associated with increased risk of hospitalization for hypotension, but azithromycin did not significantly increase risk (CMAJ. 2011;183:303307; available at www.cmaj.ca/content/183/3/303.long, accessed January 15, 2014). Hospitalization for hypotension soon after coadministration of a CYP3A4 inhibitor and a CCB has also been described in several case reports.

Nevertheless, clarithromycin is often prescribed to patients who are chronically on CCBs, despite a warning in the prescribing information that serious adverse reactions may occur. A recent study has assessed the risk of mortality or hospitalization for acute kidney injury or hypotension in a large cohort of older adults when either clarithromycin or azithromycin was given to patients who were already being treated with CCBs ( JAMA. 2013;310:2544-2553).

A total of 190,309 older adults (mean age 76 years) receiving a CCB plus newly prescribed clarithromycin or azithromycin were retrospectively assessed for 30 days from the date of antibiotic prescription. Approximately 40% of clarithromycin prescriptions and 38% of azithromycin prescriptions were for treatment of respiratory infections. CCBs evaluated in the study included amlodipine (Norvasc) (53% of patients), diltiazem (22% of patients), nifedipine (Adalat, Afeditab, Nifeditab, Nifedical, Procardia) (17% of patients), verapamil (Calan, Covera, Isoptin, Verelan) (4% of patients), and felodipine (Plendil) (4% of patients). The study excluded patients who had been discharged from the hospital in the previous two days, those who had been prescribed potent CYP3A4 inhibitors (i.e., protease inhibitors or antifungals) in the previous 30 days, and those with a history of end-stage renal disease requiring chronic dialysis. Clinical outcomes for risk of acute kidney injury and hypotension were assessed by reviewing hospital-based diagnosis codes.

Clarithromycin was associated with an increased risk of all-cause mortality compared with azithromycin (1.02% vs.

0.59%, p <0.05), with a number needed to harm (NNH) of 232. Clarithromycin was also associated with an increased risk of hospitalization for acute kidney injury (0.44% vs.

0.22%, p <0.05, NNH 454), and hospitalization for hypotension (0.12% vs. 0.07%, p <0.05, NNH 2,000). The risk of acute kidney injury was significantly greater in patients receiving nifedipine (NNH 160) compared with those receiving amlodipine (NNH 663).

© SCIENCE SOURCE / ANNABELLA BLUESKY

Evidence-Based Medicine

Coprescription of a CYP3A4 inhibitor and a calcium channel blocker may increase risk of hypotension or acute kidney injury.

It is worth noting that azithromycin is not without its own concerns. In March 2013, the FDA issued a warning that azithromycin can cause abnormal changes in the electrical activity of the heart that may lead to a potentially fatal irregular heart rhythm. Patients at particular risk for developing this condition include those with such known risk factors as existing QT interval prolongation, hypophosphatemia or hypomagnesemia, bradycardia, or use of antiarrhythmic drugs (FDA Drug Safety Communication, available at www.fda.gov/drugs/drugsafety/ucm341822.htm, accessed January 15, 2014).

TESTOSTERONE THERAPY IS ASSOCIATED WITH INCREASED CARDIOVASCULAR EVENTS IN MEN WITH LOW TESTOSTERONE LEVELS AND HIGH CARDIOVASCULAR RISK Level 2: Mid-level evidence Testosterone replacement therapy has become increasingly common in recent years and has shown efficacy in improving sexual dysfunction, bone mineral density, exercise capacity, and metabolic parameters in men with androgen deficiency or chronic conditions, including heart failure and diabetes. However, efficacy trials have generally been of relatively short duration, which may limit the ability to assess potential harms. A six-month randomized trial evaluating testosterone gel in frail elderly men was terminated early due to increased rates of cardiovascular events in the testosterone group (N Engl J Med. 2010;363:109-122; available at www.nejm.org/doi/full/10.1056/NEJMoa1000485, accessed January 15, 2014), raising concerns that this might reflect a larger problem. Now, a new retrospective cohort study has assessed the long-term risks of testosterone therapy

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Evidence-Based Medicine in men with low testosterone levels and high cardiovascular risk ( JAMA. 2013;310:1829-1836).

A total of 8,709 men who visited a Veterans Affairs facility for coronary angiography from 2005 to 2011 and subsequently had serum testosterone <300 ng/dL (<10.4 nmol/L) were followed for a mean of 27.5 months. At the time of angiography, 20% had had a previous MI and 50% had diabetes. More than 80% had at least 20% stenosis in at least one epicardial vessel on angiography. Following angiography, 14% began testosterone therapy at some point during the follow-up period (63.2% testosterone patch, 35.7% injection, and 1.1% gel). The median time from angiography to beginning of therapy was 531 days. The primary outcome was a composite of all-cause mortality, MI, and ischemic stroke.

There were a number of baseline differences between men who had testosterone therapy and men who did not.

The no-testosterone group was older (mean difference, three years) and had significantly higher rates of coronary artery obstruction, hypertension, hyperlipidemia, heart failure, previous MI, chronic obstructive pulmonary disease, peripheral vascular disease, and cerebrovascular disease. In an analysis weighted by the probability of treatment with testosterone and adjusted for comorbidities, testosterone therapy was associated with an increased risk of primary outcome events (adjusted hazard ratio 1.29, 95% CI 1.041.58). At three years, the cumulative event rates were 25.7% in the testosterone group vs. 19.9% in the no-testosterone group. These data are consistent with the results of a recent systematic review assessing the effects of testosterone therapy in 2,994 patients with low testosterone or chronic diseases (BMC Med. 2013;11:108; available at www.ncbi.nlm.nih. gov/pmc/articles/PMC3648456/, accessed January 15, 2014).

Although minimizing bias in an observational study of this type may be difficult, such findings will often prompt longer follow-up in subsequent randomized trials. That would certainly be helpful in this case. However, until such data are available, this information and its limitations should be part of the discussion for men considering testosterone replacement therapy.

STEROIDS REDUCE TIME TO DISCHARGE FROM OBSERVATION UNIT IN INFANTS WITH ACUTE BRONCHIOLITIS AND ­SUSPECTED ASTHMA Level 1: Likely reliable evidence Bronchiolitis commonly affects young children and is the most frequent cause of hospitalization among infants during winter months. A recent Cochrane review found

that systemic and inhaled corticosteroids do not reduce rates of hospital admissions or readmissions in children with acute bronchiolitis (Cochrane Database Syst Review.

2013;6:CD004878), and current guidelines do not recommend routine use of steroids in this patient population (Pediatrics. 2006;118:1774-1193; available at pediatrics.aappublications.org/content/118/4/1774.long, accessed January 15, 2014). However, some infants initially presenting with bronchiolitis are subsequently diagnosed with asthma, and corticosteroids are used for long-term symptom control. Data evaluating efficacy of steroids in infants with bronchiolitis who are at high risk for asthma have been limited thus far. A recent randomized trial has compared oral dexamethasone (Decadron, Dexamethasone Intensol, Dexpak) vs. placebo in 200 such infants (Pediatrics. 2013;132:e810-e816).

Infants (median age 3.5 months) presenting for emergency care with acute bronchiolitis were randomized to dexamethasone (1 mg/kg orally on day 1, followed by 0.6 mg/kg orally once daily for four more days) vs. placebo. All infants were at high risk for asthma based on either the presence of eczema or history of asthma in a first-degree relative. All infants received nebulized albuterol (Accuneb, Proair, Proventil, Ventolin) 2.5 mg four times over the first two hours and every two hours until discharge, and infants could receive nebulized epinephrine or other treatments at the discretion of the treating clinician. Infants were evaluated for readiness for discharge from an observation unit at least every six hours and were followed for one week after discharge.

A modified intention-to-treat analysis was used to assess the efficacy of dexamethasone. The mean time to readiness for discharge was 18.6 hours with dexamethasone vs. 27.1 hours with placebo (p=0.015), and the dexamethasone group had a lower rate of nebulized epinephrine use (19% vs. 34.4%, p=0.03, NNT 7). However, the frequency of return visit within one week of discharge was 22% for dexamethasone vs. 21% for placebo (not significant). No hospitalizations or adverse events occurred in either group.

Collectively, these results suggest that oral dexamethasone may be useful for treatment of bronchiolitis in the emergency department (ED) in this subpopulation by substantially decreasing the amount of time infants spend under observation. The increased turnaround associated with short-term dexamethasone treatment may be particularly beneficial during winter months, when cases of bronchiolitis in the ED are at their maximum frequency.

However, these data do not support continued treatment for five days, since there was no reduction in return visits in the week following discharge. n

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COMMENTARY Kelly Snively, BSN, RN, is a family nurse practitioner student at Carlow University in Greensburg, Pa.

Managing speech-delayed patients Speech deficiencies often are overlooked or underestimated in the health-care arena. Nurse ­practitioners (NPs) and physician assistants (PAs) who perform screenings at each visit can identify potential delays and target interventions to achieve milestones. Important language achievements range from babbling in the first few months of life, saying one to two words at age 12 months, imitating familiar sounds, and understanding simple instructions. By age 2 years a child should have a vocabulary of 150 to 300 words, and two-thirds of his or her speech should be intelligible.

Ask questions about the child’s speech and language to determine whether normal milestones are being met.

According to the American Speech-LanguageHearing Association’s “Speech Referral Guidelines for Pediatrics” (available at www. asha.org/public/speech/speech-referral/; accessed January 15, 2014), speech delay can affect a child’s ability to communicate his or her needs and can prevent the youngster from functioning at the expected level of independence, expressing feelings, engaging in socialization, and fulfilling his or her educational potential.

Speech delays can even put the child at risk for injury if he or she cannot convey information about a dangerous situation or call for help.

The United States Preventive Services Task Force (USPSTF) is in the process of updating its 2006 recommendations on screening for speech and language delay in preschool children, excluding children with hearing deficits, other medical problems, or craniofacial abnormalities (available at www.uspreventiveservicestaskforce.org/uspstf/uspschdv.htm#update; accessed January 15, 2014). In the 2006 document, the committee reported finding insufficient evidence to recommend for or against routine use of brief, formal screening instruments in primary care to detect speech and language delays in children aged 5 years and younger. Although inconsistent study results rendered the USPSTF unable to develop a list of specific risk factors to guide primary-care providers in performing selective screening, the most consistently reported risk

factors included family history of speech and language delay, male gender, and such perinatal factors as prematurity and low birth weight.

Providers need to rule out such causes of speech delay as hearing loss, developmental or neurologic disorders, genetic syndromes, or illness. However, speech delay can occur without any known cause.

Verbal communication skills should be evaluated at each well-child visit, with the clinician asking questions about the child’s speech and language to determine whether normal milestones are being met. The clinician should listen for specific sounds and for sounds that are substituted, left off, added, or changed.

Clinicians should advise parents or caregivers to read to the child, and help the child read aloud as well, if age-appropriate. Adults should urge the child to say what he or she wants rather than allow the child to grunt, point, or use other forms of nonverbal communication.

All children will make normal sound errors as they grow, but by age 8 years, they should have no appreciable deficiencies when speaking. A child should be referred to a speech-language pathologist when any of the following symptoms are noted: The child becomes frustrated when expressing wants or needs; the child cannot produce vowels or verbalize words beginning with the letters p, b, m, or w; and/or family members have difficulty understanding the child. n

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