November 2016 Clinical Advisor

THE CLINICAL ADVISOR • NOVEMBER 2016

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■ Prediabetes care ■ Preeclampsia screening ■ NSAIDs and heart failure FEATURE Child obesity intervention

Discussing weight issues with children and parents

|

NOVEMBER 2016

| www.ClinicalAdvisor.com

ADVANCES IN PEDIATRIC

NUTRITION In celiac disease, the lining of the small intestine is damaged by a reaction to gluten.

LEGAL ADVISOR

Outdated vaccine protocol leads to a lawsuit

■ Feature

BIOFILMS AND INFECTION PAGE 46

VOLUME 19, NUMBER 11

■ Dermatologic Look-Alikes

BLISTERS AND EROSIONS PAGE 77

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10/25/16 4:42 PM

THE CLINICAL ADVISOR • NOVEMBER 2016

A PEER-REVIEWED FORUM FOR PHYSICIAN ASSISTANTS

NEWSLINE

■ Prediabetes care ■ Preeclampsia screening ■ NSAIDs and heart failure FEATURE Child obesity intervention

Discussing weight issues with children and parents

|

NOVEMBER 2016

| www.ClinicalAdvisor.com

ADVANCES IN PEDIATRIC

NUTRITION In celiac disease, the lining of the small intestine is damaged by a reaction to gluten.

LEGAL ADVISOR

Outdated vaccine protocol leads to a lawsuit

■ Feature

BIOFILMS AND INFECTION PAGE 46

VOLUME 19, NUMBER 11

■ Dermatologic Look-Alikes

BLISTERS AND EROSIONS PAGE 77

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10/25/16 4:45 PM

Editor Colby Stong, editor@clinicaladvisor.com Senior editor Sandhya George Associate editor Lauren Grygotis Assistant editor Madeline Morr Contributing editors Mark P. Brady, PA-C; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP; Sharon Dudley-Brown, PhD, FNP; Abimbola Farinde, PharmD; Laura A. Foster, CRNP, FNP; Abby A. Jacobson, PA; Maria Kidner, DNP, FNP; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Mary Newberry, CNM, MSN; Claire Babcock O’Connell, MPH, PA; Kathy Pereira, DNP, FNP; Sherril Sego, DNP, FNP; Ann Walsh, PA-C, SCT(ASCP); Kim Zuber, PA-C Production editor Kim Daigneau Group art director, Haymarket Medical Jennifer Dvoretz Production director Ada Figueroa Circulation manager Paul Silver National accounts manager Alison McCauley, 973.224.6414 alison.mccauley @ haymarketmedical.com Publisher Kathleen Hiltz, 201.774.1078 kathleen.hiltz@haymarketmedia.com Editorial director Kathleen Walsh Tulley Senior vice president, digital products and medical magazines Jim Burke, RPh Senior vice president, medical communications John Pal CEO, Haymarket Media, Inc. Lee Maniscalco All correspondence to: The Clinical Advisor 275 7th Avenue, 10th Floor, New York, NY 10001 For advertising sales, call 646.638.6085.

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Ask our

EXPERTS If a patient has you stumped, write us and we’ll forward your query to one of our consultants and publish the response in Advisor Forum.You can also use this space to contribute a clinical pearl of your own or comment on another letter.

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.

CLINICAL PEARLS

It cannot be beat.—TERRI JORDAN, ARNP, Daytona Beach, Fla. (202-2)

NEUTROPHILS AND LYMPHOCYTES In interpreting a complete blood count with differential, anytime the neutrophils and lymphocytes are numerically close, it is a viral cause; when the neutrophils and lymphocytes are numerically distant, it is a bacterial cause.

This is very helpful in determining treatment.—DONNA CARTER, FNP-C, Scottsburg, Ind. (202-1) GENERIC “CAINE” IS EFFECTIVE FOR WOUND CARE For pain relief, most pharmacies offer a “caine” at 2-510%, and basically nothing higher, for between $5 and $30 per tube. I work in wound care and use Walmart’s

INTRA-ARTICULAR INJECTIONS FOR SEVERE OSTEOARTHRITIS Patients with severe osteoarthritis in the knees seem to do better with intra-articular injections if you have them sit up and dangle their legs off the examination table and distract the knee slightly when administering the injection.—ROSEMARY LEDBETTER, PhD, PA, Troy, Ill. (202-3)

YOUR COMMENTS SLIPPED CAPITAL FEMORAL EPIPHYSIS IN OBESE ADOLESCENTS I just read the CME/CE article by Marilou Shreve, DNP, APRN, entitled, “Assessing and treating pediatric obesity” [ June 2015]. I was concerned regarding the oversight of a critical issue in obese adolescents: the increased risk of slipped capital femoral epiphysis (SCFE). This was not addressed in the article.

The case study (p. 55) gave incomplete advice regarding the evaluation of an obese adolescent male with knee pain.

The most common etiology of the insidious onset of knee pain in children is the hip, due to referred pain from the

Equate brand—vagicaine 20% benzocaine. When using this before debriding a wound, give it three minutes to sedate the nerves, then perform the procedure. I get good results, as patients say. It relieves pain and burning for $1.88.

Advisor F

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 contact us by e-mail at editor@ 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.

orum

These are lette and successe rs from practitioners s, observat around the below. We ions, and country who OUR CONSULTANTS pearls with invite you want to shar to participa their colle e their clinic agues. Resp te. al problems onding cons ultants are identified CON SULTAT IONS

TREATM ENT FOR INFECT URINAR ION SGLT2 REC MALE CHI S IN THE UNC Y TRACT IRCUMCI LD FOR DIA EPTOR BLOCKE If a male SED child conti Deborah L. Cross, MPH, CRNP, Laura A.BET Foster,ES CRNP, FNP, Abby A. Jacobson, PA-C, RS Abimbola Farinde, PhD, PharmD, With the nues toassociate ANP-BC, is practices family medicine is a physician assistant is a professor redevprogram adven t ofPrimary circu SGLT2 recep at Delaware Valley urinaryattract director, Gerontology NP elop Program, mcisi Columbia Southern moda litywith Palmetto on be perfo for type tor infecPhysicians Dermatology University of Pennsylvania School blockersGroup University 2 diabe rmed? regarding inCare as a treatm in Wilmington, Del. in Orange Beach, Ala. useCharleston, S.C. tes, is there ent urology is of Nursing, Philadelphia. any evide NATHAN in patients with to protect the is well advise nce or data type 1 diabe GARDNE d tes mellitus?— R, PA-C, continues to to recommend a circum upper tracts, the kidne CPAAPA, ys. develo cision It p recurr•ent 44 THE ADVISOR AUGUST 2015 •on www.ClinicalAdvisor.com Castleton, severaCLINICAL l consideration urinary tract the male child who As it currently stands N.Y. , SGLT2 s that infections. for glycemic impede the receptor blocke There are control in ability to cleansenter into this decisio rs are FDA adults with n. Poor hygien should the e and quell -approved child have e may appro diet and exercise, but with type 2 diabetes phimosis, simpl infection potential. appropriate the in ved conjun FDA for use in patien Moreover, AdvisorForum_CA0815.indd urine 44 9/29/15ction 2:38 PM e cathet culture can ts with type has stated that they ketoacidosi steroid cream be a challenge. erization to obtain s, or those are not may tempo an FAR with severe 1 diabetes, patients with Having a short tion of the rarily solve renal functi diabetic steroid the trial of informINDE, PhD, Pharm these issues tenden , though after for infection D (See bottom on.—ABIMBOL ation about once again.—C cy redevelops, placin cessaA Dr. Farinde.) of this page Milwaukee g (203-2) for more , Wis. (203- OLEEN ROSEN, the child at risk 1) DNP, FNP -C, CLI Philip R. Cohen, MD,

is clinicaltions associate professor , shou ld of dermatology, University a of Texas Medical Center, The focus of Houston.

NICAL

Send us your letter Advisor Forum, The s with questions New York, and comm Clinical Advisor ents to: , 114 clinicaladvisoNY 10001. You may contacWest 26th Street , please indicatr.com. If you are writing in t us by e-mail at 4th Floor, each item. e so by including response editor@ to a the Letters are policy is edited for number in parent published letter, to heses at length and contribution print the author ’s name with clarity. The Clinicathe end of s will be accepted. l Advisor the letter.

No anonym ’s ous

Write us today.

OUR CO

NSULTA

PEARLS

NTS

VAGINA L RESULT DISCHARGE AND ING FRO If a female M TAMPON ODOR patient has USE a ask if she uses tamp history of vaginal disch ons. If she the pelvic arge with says “yes,” exam when cond odor, that you woul , do not enter ucting the rotating of d to take a pap smea vagina in the same the specu way r. Instead, the cervix. lum Most retain from side to side start shallow until reach ed tampons ing are lodge d in the fold

Philip R.

Cohen, MD, is clinical associa te profess of dermat or ology, of Texas MedicaUniversity l Center, Houston.

SEND TO The Clinical Advisor 275 7th Avenue, 10th floor New York, NY 10001

62 THE CLINI

Deborah L. Cross, MPH, ANP-B

CRNP, C, is associa te program director, Geronto logy NP Program University of Pennsyl vania School , of Nursing , Philadelphia.

CAL ADVI

AdvisorForum_

CA0915

SOR • SEPTE

MBER 2015

Abimbo la Farinde

, PhD,

is a profess PharmD, or at Columb ia Souther n Univers in Orange ity Beach, Ala.

• www.Clinic

alAdvisor.c

om

Laura A.

Foster,

practices familyCRNP, FNP, with Palmett medicine o Primary Care Physicia ns in Charles ton, S.C.

Abby A.

Jacobso

is a physicia n, PA-C, n at Delawa assistant re Dermatology Valley in Wilmington,Group Del.

.indd 62

9/29/15

2:44 PM

E-MAIL editor@clinicaladvisor.com

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2016 3

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CONTENTS NOVEMBER 2016

NEWS AND COMMENT 14

Newsline ■ Stepwise diabetes prevention is effective in prediabetes care.

■ NSAID use is linked to increased risk of hospitalization for heart failure.

■ USPSTF recommends screening for preeclampsia.

■ Reducing hepatitis C therapy duration may be effective.

■ Topical timolol maleate for treating infantile hemangiomas ■ Statin-based therapy is less effective in advanced chronic kidney disease.

■ Bipolar disorder treatment is more effective in earlier stages.

■ PA certification continues to increase, per NCCPA survey.

■ Reviewing treatment options for binge-eating disorder ■ Hormonal contraception use is associated with an initial diagnosis of depression.

■ FDA requires black box warning on HCV drugs regarding the risk of reactivating hepatitis B virus.

63

CME Feature posttest

nutrition Best practices for managing nutrition in neonatal and pediatric patients.

Screening advised for preeclampsia 18

12

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

71

Dermatology Clinic ■ Bilateral periorbital yellowbrown plaques ■ Six tan patches on a healthy teen

77

Dermatologic Look-Alikes Blisters and erosions

83

Conference Roundup News briefs from the American Thyroid Association

86

Stat Consult A clinical review of celiac disease

Six tan patches on a healthy teen 71

Continues on page 10

30

Interventions in childhood obesity A role for clinicians in dealing with the growing epidemic of pediatric obesity.

46

Biofilms and chronic infections A new understanding of how pathogens thrive in human hosts.

TOC_CA1116.indd 4

CME Advances in pediatric

DEPARTMENTS

FEATURES

MAKING CONTACT

52

Follow us on Twitter @ClinicalAdvisor

Alt Meds Update on Vitamin K 95

Like us on Facebook facebook.com/TheClinicalAdvisor

www.ClinicalAdvisor.com

Visit us on the web ClinicalAdvisor.com

Download the app ClinicalAdvisor.com/App

10/26/16 11:55 AM

CONTENTS Legal Advisor Outdated vaccine protocol

95

Alternative Meds Update Vitamin K

98

Commentary Recertifying from inactive status

ADVISOR FORUM 64

Clinical Pearls ■ Treatment tips for tinea pedis and yeast infections ■ Stopping the bleeding ■ Vitamin D3 and type 1 diabetes

65

Case Files ■ Providing health care for veterans who were exposed to Agent Orange during the Vietnam War

“We’ve opened a portal to a perpendicular dimension!”

© The New Yorker Collection 2016 from cartoonbank.com. All Rights Reserved.

92

“We’ve opened a portal to a perpendicular dimension!”

DEPARTMENTS cont’d

HOW TO CONTACT US THE CLINIC AL ADVIS OR • NOVE

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MBER 2016

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IEW ED FOR UM FOR NUR SE PRAC TITIO NER

NEWSLIN

E

■ Prediabe tes ■ Preeclam care psia screenin g ■ NSAIDs and heart failu re

FEATURE

SUBSCRIPTION CHANGES? For all questions regarding subscriptions (including a change of address or how to start or stop a subscription), please contact Customer Service at: custserv@haymarketmedia.com

LEGAL AD VISOR

Outdated vacc leads to a laws ine protocol uit

• Send it by e-mail to editor@ClinicalAdvisor.com ER 11

• Mail it to The Clinical Advisor, 275 7th Avenue, 10th Floor, New York, NY 10001

NOV EMB

ER 2016

| www.Clin icalA

dvisor.com

IN PEDIAT

NUTRITIO In celiac disease, the lining of small inte the stine is damaged by a reaction to gluten.

N

RIC

■ Feature

BIOFILMS INFECTIO AND N PAGE

19, NUMB

TOC_CA1116.indd 10

TO SUBMIT A CLINICAL QUESTION FOR PUBLICATION: • ClinicalAdvisor.com/AdvisorForum

inte

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46

VOLU ME

TO CONTACT THE EDITOR: • editor@ClinicalAdvisor.com • Call 646.638.6078

Child obe sity

rvention Discussing wei with children ght issues and parents

S

ADVANCE S

■ Dermatolo gic

BLISTERS Look-Alikes EROSIONSAND PAGE 77

10/26/16 11:55 AM

EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com Web Exclusives

The Waiting Room

ClinicalAdvisor.com/News

Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom

Zika virus in amniotic fluid may help predict prenatal diagnosis Researchers examined prenatal evolution and perinatal outcomes in neonates with developmental abnormalities associated with Zika virus infections.

Jillian Knowles, MMS, PA-C Using activity trackers to monitor transfusion-dependent patients Activity trackers can track a patient’s heart rate and may help transfusion-dependent patients estimate hemoglobin levels.

Treating alcohol use disorders in patients with alcoholic liver disease Total alcohol abstinence is the cornerstone of treatment for patients with alcohol use disorders and alcoholic liver disease.

Jillian Knowles, MMS, PA-C Should clinicians treat STIs before culture results are available?

Treating patients at high risk of a sexually transmitted infection before the culture results are available could lead to overtreatment.

Epidemiologic factors increase risk of missed HIV diagnosis The results of a national, cross-sectional study showed that 37% of participants could have been diagnosed with HIV at an earlier stage.

Jim Anderson, MPAS, PA-C, DFAAPA Athletic training: a path to becoming a physician assistant Many physician assistants come to the profession after working as certified athletic trainers on sports teams or in physical therapy clinics.

Multimedia ClinicalAdvisor.com/Multimedia Early allergen introduction such as eggs and peanuts may prevent allergies A recent study published in JAMA suggests that introducing foods such as eggs and peanuts to babies between 4 and 6 months and 4 and 11 months, respectively, will decrease their risk of allergies later in life.

Watch it here: ClinicalAdvisor.com/AllergyPreventionVideo FDA approves first artificial pancreas for T1D The FDA approved the first automated insulin delivery system for adult patients with type 1 diabetes. The

MAKING CONTACT

Follow us on Twitter @ClinicalAdvisor

MiniMed 670G automatically monitors glucose levels every 5 minutes and delivers insulin when needed.

Watch it here: ClinicalAdvisor.com/FDAInsulinVideo Early initiation of ART among serodiscordant couples An analysis published in the New England Journal of Medicine revealed that early initiation of antiretroviral therapy in sexual partners achieved a 96% reduction in the incidence of HIV infection. The study also included more than 5 years of follow-up to assess the durability of the therapy.

Watch it here: ClinicalAdvisor.com/ARTTherapyVideo

Like us on Facebook facebook.com/TheClinicalAdvisor

Visit us on the web ClinicalAdvisor.com

Go mobile with us mobile.ClinicalAdvisor.com

12 THE CLINICAL ADVISOR • NOVEMBER 2016 • www.ClinicalAdvisor.com

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Advisor 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 ClinicalAdvisor.com/AdvisorDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

Ortho Dx

In partnership with

TheJopa.org

Journal of Orthopedics for Physician Assistants

Leg pain after a soccer kick A 20-year-old woman presents with 2 weeks of rightsided leg pain after a soccer injury. She strained the leg during a kick, and swelling and pain developed shortly thereafter. The patient is having difficulty walking and reports significant weakness with hip flexion and knee extension.

WHAT IS THE BEST TREATMENT OPTION?

• • • •

She should not participate in sports for 6 – 12 weeks She should not participate in sports for 4 – 6 months Tissue biopsy Surgical repair

● See the full case at ClinicalAdvisor.com/OrthoDx_Nov16

Derm Dx A waxy, yellowish plaque since birth A 3-month-old male presents with a scalp lesion since birth. The child is normal developmentally, and his parents deny any history of genodermatoses or similar growths. Examination of the affected area reveals a 3-cm flesh-colored plaque with a yellowish hue and waxy surface texture.

CAN YOU DIAGNOSE THIS CONDITION?

• • • •

Linear epithelial nevus Nevus sebaceous Syringocystadenoma papilliferum Congenital syphilis

● See the full case at ClinicalAdvisor.com/DermDx_Nov16

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2016 13

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Newsline N O V E M B E R 2 016

Preeclampsia screening advised

by USPSTF page 18

Statins and advanced chronic kidney disease page 20

Contraception use linked to depression page 23

STEPWISE DIABETES prevention effectively reduces diabetes incidence by one-third among patients with prediabetes, according to a study published in Diabetes Care.

The randomized controlled trial included 578 overweight or obese Asian Indian adults with impaired glucose tolerance, isolated impaired fasting glucose, or a combination of both. Participants were randomized to standard lifestyle advice or a 6-month, culturally tailored, U.S. Diabetes Prevention Program–based lifestyle curriculum plus stepwise addition of metformin (500 mg, twice daily) for those at the highest risk of conversion to diabetes at ≥4 months of follow-up.

The researchers measured diabetes incidence biannually across the study groups. They found that 34.9% of those receiving standard lifestyle advice developed diabetes, compared with 25.7% from the intervention group (relative risk reduction [RRR], 32%).

The RRR was stronger among patients who were older than age 50 years, male, or obese. RRRs also varied by prediabetes type (isolated impaired fasting glucose, 12%; isolated impaired glucose tolerance, 31%; combination, 36%). Overall, 72.0% of participants required metformin in addition to lifestyle intervention.

However, this rate varied by prediabetes type (isolated impaired glucose tolerance, 51.3%; isolated

© THINKSTOCK

Stepwise diabetes prevention effective in prediabetes care Adding metformin in a stepwise manner to lifestyle education is effective for prediabetes care.

impaired fasting glucose, 76.5%; combination, 83.0%).

The program appeared to be less effective among patients with isolated impaired fasting glucose, and a higher proportion of these individuals required metformin therapy. “[E]xpert recommendations of adding metformin in a stepwise manner to lifestyle education is an effective method for preventing or delaying diabetes in adults with prediabetes, even in a resourcechallenged setting like a [low or middle income country],” the study authors concluded.

NSAID use linked to increased risk of hospitalization for heart failure SOME NONSTEROIDAL anti-inflammatory drugs (NSAIDs) are associated with an increased risk of hospital admission for heart failure, according to data published in BMJ. The study included adults who were older than 18 years of age and who had begun NSAID treatment between 2000 and 2010. Investigators identified 92,163 heart failure hospitalizations and 8,246,403 controls. They measured the association between the risk of hospitalization and the use of 27 individual NSAIDs, including 24 traditional NSAIDs and 4 COX 2 inhibitors.

The study authors found that current use of any NSAID within the preceding 14 days was associated with a 19% increased

risk of hospital admission compared with prior history of NSAID use (adjusted odds ratio [OR], 1.19).

Risk of hospital admission was increased for 7 traditional NSAIDs, including diclofenac, ibuprofen, indomethacin, ketorolac, naproxen, nimesulide, and piroxicam, and 2 COX inhibitors (etoricoxib and prioxicam).

Heart failure risk doubled at very high doses, defined as more than 2 daily doses, for diclofenac, etoricoxib, indomethacin, piroxicam, and rofecoxib. Medium doses, defined as 0.9– to 1.2– daily dose equivalents, of indomethacin and etoricoxib increased heart failure risk. The researchers did not observe an increased risk of heart failure with celecoxib at commonly used doses.

14 THE CLINICAL ADVISOR • NOVEMBER 2016 • www.ClinicalAdvisor.com

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some serotypes following the third dose of Prevnar 13®, compared with responses among infants who received antipyretics only as needed for treatment. Reduced antibody responses were not observed after the fourth dose of Prevnar 13® when acetaminophen was administered prophylactically.

Prior Vaccination With PPSV23 Prior receipt of Pneumovax® 23 (23 valent pneumococcal vaccine polyvalent, PPSV23) within 1 year results in diminished immune responses to Prevnar 13® compared to PPSV23 naïve individuals.

“Ugh, stop it, Dad—everyone knows you’re not making that happen!”

© The New Yorker Collection 2016 from cartoonbank.com. All Rights Reserved.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Available data on Prevnar 13® administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.

A developmental toxicity study has been performed in female rabbits administered Prevnar 13® prior to mating and during gestation. Each dose was approximately 20 times the human dose. This study revealed no evidence of harm to the fetus due to Prevnar 13®.

Data (Animal): In a developmental toxicity study of female rabbits, no adverse effects on female fertility and pre-weaning development were observed. There were no vaccine-related fetal malformations or variations.

Lactation Risk Summary Data are not available to assess the effects of Prevnar 13® on the breastfed infant or on milk production/excretion. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Prevnar 13® and any potential adverse effects on the breastfed child from Prevnar 13® or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

Pediatric Use Safety and effectiveness of Prevnar 13® in children below the age of 6 weeks have not been established.

Geriatric Use Of the total number of Prevnar 13® recipients aged 50 years and older in clinical studies (N=47,907), 94.5% (45,291 of 47,907) were 65 years and older and 30.3% (14,498 of 47,907) were 75 years and older.

High-Risk Populations Individuals with the diseases or conditions listed below are at increased risk of pneumococcal disease. Immunogenicity and safety data in these populations are limited.

Infants Born Prematurely Immune responses elicited by Prevnar 13® administered on a US schedule to preterm infants have not been studied. When preterm infants (<37 weeks gestational age, N=100) were administered 4 doses of Prevnar 13® on a non-US schedule, the serotype-specific IgG antibody responses after the third and fourth dose were lower compared to responses among term infants (≥37 weeks gestational age, N=100) for some serotypes; the effectiveness of Prevnar 13® in preterm infants cannot be established from this study.

Children With Sickle Cell Disease In an open-label, single-arm, descriptive study, 2 doses of Prevnar 13® were administered 6 months apart to children ≥6 to <18 years of age with sickle cell disease who previously received PPSV23 at least 6 months prior to enrollment. Children with a prior history of pneumococcal conjugate vaccination were excluded. For all vaccine serotypes, anti-pneumococcal opsonophagocytic activity (OPA) geometric mean antibody titers (GMTs) were higher after the first dose compared to pre-vaccination (N=95-131); OPA GMTs following the first and second dose were comparable.

The effectiveness of Prevnar 13® in this specific population has not been established.

Individuals With Hematopoietic Stem Cell Transplant In an open-label, single-arm, descriptive study, 4 doses of Prevnar 13® were administered to subjects ≥2 years of age (range 2 to 71 years) who had received an allogeneic hematopoietic stem cell transplant 3 to 6 months prior to enrollment. The first three doses of Prevnar 13® were administered one month apart, followed by a fourth dose of Prevnar 13® six months after the third dose. Sera were obtained approximately one month after each vaccination. Immune responses (IgG GMCs) after the first dose of Prevnar 13® were numerically higher for all serotypes compared with baseline. In addition, after each subsequent dose of Prevnar 13®, IgG GMCs for all serotypes were numerically higher than responses after the previous dose. The effectiveness of Prevnar 13® in this specific population has not been established.

Individuals With HIV Infection In an open-label, single-arm, descriptive study, 3 doses of Prevnar 13® were administered 6 months apart to HIV-infected adults ≥18 years of age, with CD4 counts ≥200 cells/µL and serum HIV RNA titer <50,000 copies/mL. All subjects had been vaccinated previously with PPSV23 at least 6 months prior to enrollment. For all vaccine serotypes anti-pneumococcal OPA GMTs were numerically higher after the first dose compared to pre-vaccination (N=227-253) and they were generally comparable following the first, second and third doses. In an open-label, single-arm, descriptive study, 3 doses of Prevnar 13® were administered 1 month apart to HIV-infected subjects ≥6 years of age with CD4 counts ≥200 cells/μL, and serum HIV RNA titer <50,000 copies/mL. Subjects were pneumococcal vaccine-naive. For all vaccine serotypes anti-pneumococcal OPA GMTs were numerically higher after the first dose compared to pre-vaccination (N=197-257); OPA GMTs following the first, second and third dose were generally comparable. The effectiveness of Prevnar 13® in these specific populations have not been established.

PATIENT COUNSELING INFORMATION Potential Benefits and Risks Prior to administration of this vaccine, the healthcare professional should inform the individual, parent, guardian, or other responsible adult of the potential benefits and risks of immunization with Prevnar 13®, the importance of completing the immunization series for their child(ren) unless contraindicated, and that any suspected adverse reactions should be reported to their healthcare professional.

Provide the Vaccine Information Statements, which are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines).

This product’s label may have been updated. For current Prescribing Information and further product information, please visit www.pfizerpro.com/products or call Pfizer Medical Information toll-free at 1-800-438-1985.

Manufactured by

Wyeth Pharmaceuticals Inc. A subsidiary of Pfizer Inc, Philadelphia, PA 19101

US Govt. License No. 3 Based on LAB-0469 14.0 (September 2016) CPT Code 90670 United States Patent Number: 5,614,382.

p17_Prevnar_CA1116.indd 17

“Your entire family has the flu, and they won’t be coming for Christmas!”

10/24/16 1:21 PM

Newsline Preeclampsia screening recommended by USPSTF PREGNANT WOMEN should be screened for preeclampsia with blood pressure measurements taken throughout their pregnancy, according to a draft recommendation statement published by the U.S. Preventive Services Task Force (USPSTF).

The task force gave a B grade to the recommendation, noting that obtaining blood pressure measurements could result in earlier diagnosis of the condition. The task force added that testing protein in the urine with a dipstick test has a low diagnostic accuracy for proteinuria detection in pregnancy.

Risk factors for preeclampsia include a history of eclampsia or preeclampsia, previous adverse pregnancy outcome, maternal comorbid conditions, or multifetal gestation, as well as nulliparity, obesity, African American race,

Blood pressure measurements are advised during each prenatal care visit throughout a woman’s pregnancy.

low socioeconomic status, and older maternal age.

The task force noted that blood pressure measurements should be obtained during each prenatal care visit throughout the pregnancy, and if a patient has a high blood pressure reading, the reading should be confirmed with additional measurements.

The revised criteria for the diagnosis of preeclampsia include high blood pressure ≥140 mm Hg or ≥90 mm Hg diastolic pressure on 2 occasions, at least 4 hours apart, after 20 weeks of gestation, and either proteinuria, thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, or cerebral visual symptoms.

Treatment options for diagnosed preeclampsia include close fetal and maternal monitoring, antihypertension medications, and magnesium sulfate. Potential harms of treating preeclampsia include preterm delivery, neonatal complications, cesarean delivery, and side effects from magnesium sulfate. To prevent preeclampsia in women who have an increased risk, the USPSTF recommends the use of low-dose aspirin after 12 weeks of gestation.

PATIENTS WITH chronic hepatitis C virus (HCV) infection without cirrhosis have a high rate of sustained viral response at 12 weeks with use of 3-week triple direct-acting antiviral therapy, according to a study in the Lancet Gastroenterology & Hepatology.

Researchers examined the antiviral efficacy and safety of 3 weeks of response-guided therapy with an NS3 protease inhibitor and dual NS5A inhibitor–NS5B nucleotide analogue. Patients with chronic HCV genotype 1b infection without cirrhosis were randomly assigned to 1 of

3 treatment groups (sofosbuvir, ledipasvir, and asunaprevir; sofosbuvir, daclatasvir, and simeprevir; or sofosbuvir, daclatasvir, and asunaprevir) until 6 patients in each group achieved an ultrarapid virologic response (plasma HCV RNA <500 IU/mL by day 2).

Patients who had an ultrarapid virologic response received 3 weeks of therapy, and those who did not achieve an ultrarapid response were switched to sofosbuvir and ledipasvir for either 8 weeks or 12 weeks. The primary end point was the proportion of patients who had a sustained virologic

Three-week triple HCV therapy led to sustained response at 12 weeks.

response at 12 weeks (SVR12) after treatment completion.

A total of 26 patients were included in the analysis—12 received sofosbuvir, ledipasvir, and asunaprevir; 6 received sofosbuvir, daclatasvir, and simeprevir; and 8 received sofosbuvir, daclatasvir, and asunaprevir. Six patients in each group (69%) achieved an ultrarapid virologic response. All patients who had an ultrarapid virologic response and were given 3 weeks of triple therapy achieved SVR12. The most common adverse events were fatigue (4 patients) and headache (3 patients).

IMAGES: © THINKSTOCK

Reducing hepatitis C therapy duration may be effective

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Newsline TOPICAL TIMOLOL maleate may be a well-tolerated and effective alternative to oral propranolol for infantile hemangiomas, especially thin, superficial hemangiomas, according to research published in Pediatrics.

The findings are based on a multicenter, retrospective cohort study of 731 patients who were treated with topical timolol at 9 centers. Katherine Püttgen, MD, from the Johns Hopkins School of Medicine in Baltimore, and colleagues analyzed infantile hemangiomas that were suitable for timolol, according to the treating clinician, as well as clinical details of the cases including photographs. The primary outcome measures were efficacy as assessed with use of visual analog scales for color and for size, extent, and volume based on a review of digital

photographs that were taken as standard of care.

The researchers found that 80.1% of infantile hemangiomas were localized, and 55.3% were superficial. The risk of disfigurement was the most frequent indication for therapy (74.3%).

Significant predictors of response included duration of therapy, initial thinness, and hemangioma subtype. The best response, according to the investigators, was for superficial infantile hemangiomas that were <1 mm thick.

Fifty-three (7.3%) cases required subsequent therapy with a systemic β-blocker. Adverse events were mild, occurring in 25 (3.4%) patients, and no cardiovascular side effects were reported.

“Young infants with infantile hemangiomas, particularly infants aged <3 months, have a high

© THINKSTOCK

Timolol effective treatment for infantile hemangiomas

Topical timolol maleate may help control infantile hemangiomas.

risk of accelerated hemangioma growth that can potentially result in permanent and disfiguring scarring,” stated the study authors. “In preselected patients with smaller and relatively superficial infantile hemangiomas, topical timolol maleate seems to be a safe and effective therapy to help control infantile hemangioma growth and accelerate involution.”

A MONG PATIENTS with advanced chronic kidney disease, relative reductions in major vascular events observed with statin therapy became smaller as estimated glomerular filtration rate (eGFR) declined, according to data published in the Lancet Diabetes & Endocrinology.

Statin therapy is commonly used among patients with mild or moderate chronic kidney disease, but the effects of this treatment are unknown among patients with an eGFR <30 mL/min per 1.73 m 2. Therefore, the Cholesterol Treatment Trialists’ Collaboration

The benefits of statin therapy are reduced as eGFR declines.

conducted a meta-analysis from 28 trials that included data from 183,419 individual participants to examine the effects of statin-based therapy in this patient population.

The researchers analyzed the effect of statin-based therapy on major vascular events, including nonfatal myocardial infarction or coronary death, stroke, or coronary revascularization in patients with chronic kidney disease. Participants were subdivided based on eGFR at baseline, and the investigators estimated treatment effects with rate ratio (RR) per mmol/L reduction in LDL cholesterol.

Participants receiving statinbased therapy had a reduced risk of a first major vascular event by 21% per mmol/L reduction in LDL cholesterol (RR, 0.79).

In addition, the investigators observed smaller relative effects on vascular events as eGFR declined.

The RR for eGFR ≥60 mL/ min per 1.73 m2 was 0.78, 0.76 for eGFR 45 to <60 mL/min per 1.73 m2, 0.85 for eGFR 30 to <60 mL/min per 1.73 m2, 0.85 for eGFR <30 mL/min per 1.73 m2 without dialysis, and 0.94 for patients on dialysis.

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Statins less effective in advanced chronic kidney disease

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Newsline Bipolar disorder treatment more effective in earlier stages PSYCHOLOGICAL and pharmacological treatments in the early stages of bipolar disorder are more effective than treatment in the later stages, according to a comprehensive literature review published in the International Journal of Bipolar Disorders.

Steven Marwaha, PhD, MSc, from the Unit of Mental Health and Wellbeing, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom, and colleagues searched for relevant literature using databases including Medline, Embase, Psychinfo, PsycArticle, and Web of Science.

They identif ied 8 primary papers and 2 meta-analyses that included a total of 8942 patients.

Five studies examined comparisons between first and multiple episodes, and the other studies

Treatment for bipolar disorder becomes less effective in later stages of the illness.

compared fewer vs more episode categories.

The results across the studies showed that treatment in earlier illness stages resulted in better outcomes in terms of response, relapse rate, time to recurrence, symptomatic recovery, remission, psychosocial functioning,

and employment. The association was observed for pharmacological and psychological treatments.

The researchers noted that there is a risk of selection, performance, and attrition bias in most studies. In addition, they pointed out that first hospital admission was unlikely to equate to a patient’s first episode, due to the varying durations of untreated illness. In 2 studies, when confounders were controlled, the effects of earlier treatment were attenuated and rendered nonsignificant.

“This review suggests that the progression to later stages of illness is associated with treatments becoming less effective and [this] chimes with the requirement for more complex treatment regimens for many people who have well-established bipolar disorder,” the study authors wrote.

A TOTAL OF 7,776 physician assistants (PAs) were newly certified in the United States in 2015, with New York, Pennsylvania, Florida, California, and Texas leading the way, according to results from an annual survey conducted by the National Commission on Certification of Physician Assistants (NCCPA).

PAs who passed the Physician Assistant National Certifying Examination (PANCE) in 2015 participated in the 2015 Statistical Profile of Recently Certified Physician Assistants. All participants responded to at least part

of the survey between January 1, 2015, and December 31, 2015.

The median age of recently certified PAs was 27 in 2015; 2,110 (27.1%) were men, and 5,666 (72.9%) were women. Overall, 67.2% of certified PAs are women.

In addition, 21.8% of newly certified PAs said that they could communicate with patients in a language other than English, a percentage that has increased steadily over the past 3 years.

Among other f indings, 798 (16.6%) of recently certified PAs plan to seek additional education or clinical training within the

About 73% of newly certified PAs are women, and a hospital setting is the most common practice setting for new PAs.

next 3 years (excluding on-thejob training or required continuing medical education [CME]).

Furthermore, 80.3% of PAs who have accepted a position said that that they did not face any challenges when searching for a job.

A hospital setting is the leading practice setting among recently certified PAs (50.4%), while 37.7% of PAs work in a hospital setting.

Survey results also showed that 26.9% of recently certified PAs with a clinical position work in primary care (family medicine/ general practice, general internal medicine, and general pediatrics).

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PA certification continues to increase, per NCCPA survey

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THERAPIST-LED cognitive behavioral therapy (CBT), lisdexamfetamine, second-generation antidepressants (SGAs), and topiramate may reduce binge eating frequency and related psychopathology, according to a study published in the Annals of Internal Medicine.

In addition, lisdexamfetamine and topiramate may reduce weight in adults with bingeeating disorder.

The meta-analysis included 9 waitlist-controlled psychological trials and 25 placebo-controlled trials that evaluated pharmacologic (n=19) or combination (n=6) treatment.

Researchers found that therapist-led CBT decreased bingeeating frequency and increased binge-eating abstinence (relative risk, 4.95).

Lisdexamfetamine was also associated with decreased bingeeating frequency and increased binge-eating abstinence (relative risk, 2.61), along with secondgeneration antidepressants (relative risk, 1.67).

“Our findings provide strong support for therapist-led CBT, lisdexamfetamine, and SGAs (as a group) in helping patients with BED [binge-eating disorder] reduce binge-eating frequency and achieve abstinence; with less confidence, they suggest similar benefits from topiramate and other forms of CBT,” the study authors wrote.

Hormonal contraception use associated with initial diagnosis of depression USE OF HORMONAL contraceptives is associated with antidepressant use and a first diagnosis of depression, particularly in adolescents, according to a study in JAMA Psychiatry.

Women aged 15 to 34 years living in Denmark were followed up from January 1, 2000, to December 2013. The women had no prior diagnosis of depression or other psychiatric illness.

Data were analyzed from January 1, 2015, to April 1, 2016. A total of 1,061,997 women with a mean age of 24.4 were included in the analysis. The types of contraception were progestogen-only pills, vaginal ring, transdermal patch, and levonorgestrel intrauterine system. The two outcome measures for incident depression were a redeemed prescription of an

Adolescents have the highest rates of a first diagnosis of depression.

antidepressant, as recorded in the National Prescription Register, and a first discharge diagnosis of depression for the Psychiatric Central Research Register.

Compared with nonusers, users of combined oral contraceptives were 1.2 times more likely to have a first use of antidepressants.

Women using progestin-only pills were 1.3 times more likely to have a first use of antidepressants, transdermal patch 2.0 times more likely, vaginal ring 1.6 times more likely, implant 2.1 times more likely, and levonorgestrel intrauterine system 1.4 times more likely. Analytics restricted to adolescents (aged 15 to 19 years) showed notably higher rates of first use of antidepressants and first diagnosis of depression compared with women aged 20 to 34 years.

FDA requires black box warning on HCV drugs THE FDA HAS ISSUED a warning regarding the risk of reactivating hepatitis B virus (HBV) among patients with a prior history of HBV who are receiving treatment with direct-acting antiviral (DAA) medicines for hepatitis C virus (HCV).

The FDA noted that some patients treated with DAA medicines experienced HBV reactivation, which resulted in serious liver problems or death within 4 to 8 weeks. The agency will now require a Boxed Warning to be included on drug labels for DAA medications, patient information leaflets, and medication guides to help clinicians screen and monitor HBV in patients receiving these medications.

Twenty-four cases of HBV reactivation were identified in co-infected patients treated with DAAs between November 2013 and July 2016. Two patients died, and one required a liver transplant.

The FDA states that “healthcare professionals should screen all patients for evidence of current or prior HBV infection before starting treatment with DAAs, and monitor patients using blood tests for HBV flare-ups or reactivation during treatment and post-treatment follow-up.”

In addition, the agency advises patients to tell a healthcare professional about any history of HBV infection or other liver problems before receiving treatment for HCV. ■

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Treatment for binge-eating disorder

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FEATURE: LESLIE ANNE PEEK, MSN, APRN, NP-C

Interventions in childhood obesity Effective use of research-based interventions and recommendations for overweight and obese children begin with a conversation with the family.

© PHOTO ILLUSTRATION BY BOBBY FARRELL

T

Caption in here like so and sometimes extends to two lines like this.

he growing epidemic of childhood overweight and obesity poses serious health concerns to our nation as well as to countries around the world. Since 1980, the figures on these conditions have more than tripled; in the United States from 2011 to 2012, 16.9% of children and adolescents aged 2 through 19 years were obese and 31.8% were either overweight or obese.1,2 It is expected that 70% of adolescents who are obese will become overweight or obese adults, and this figure rises to 80% if one or both parents are obese.3,4 These children are at risk for the development of conditions once thought to be diseases of adulthood: cardiovascular disease, diabetes, insulin resistance, fatty liver, high cholesterol, hypertension, and sleep apnea.5 The effects of childhood obesity reach far beyond physical health. Studies demonstrate a link between obesity and mental health issues; academic performance and psychological function have been observed to be poorer and rates of absenteeism higher in overweight and obese children than in their normal-weight counterparts.6 In 2007, Expert Committee recommendations (ECRs) were released that included a universal assessment of body mass index (BMI) at every well-child visit or at least yearly starting at age 2.5 In 2011, the Institute of Medicine published a report highlighting the consensus of the Centers for Disease Control and Prevention (CDC) and the American Association of Pediatrics (AAP) that BMI should be calculated at every

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well-child visit.7 Healthy People 2020, a collection of science-based nationwide health improvement goals, includes reduction of childhood obesity as a leading health indicator (LHI).8 The LHIs, a subset of high-priority goals, include the following goal: “Reduce the proportion of children and adolescents age 2–19 who are considered obese from 16.9% to 14.5%.”8 The U.S. Preventive Services Task Force (USPSTF) recommends an annual BMI assessment for all children aged 6 years and older.9 Although the USPSTF recommendation differs from that of the Expert Committee in regard to age at initiation of screening (6 vs 2 years), the inclusion of a yearly BMI assessment in both recommendations underscores its importance in screening for overweight and obesity. Nonetheless, overweight and obesity in children are underdiagnosed with respect to the current recommendations.10-15 If practitioners fail to diagnose overweight and obesity in children consistently, appropriate prevention and treatment cannot be initiated.

As this epidemic continues to proliferate, primary care providers, specifically nurse practitioners and physician assistants, are in a pivotal position to make a difference.

This article explores what can be done during office visits to help children avoid overweight and obesity, and ultimately the negative outcomes associated with these conditions; it discusses (1) the history and use of BMI as a diagnostic tool, especially in children; (2) current research findings and various intervention methods supported by the literature; and (3) the 2007 ECRs. To help practitioners put the latest research-based interventions and recommendations into use, a provider toolkit is included.

Body mass index

BMI is a measurement based on a person’s height (in meters) and weight (in kilograms). It is calculated as body weight (in kilograms) divided by the square of body height (in meters). Obtaining a patient’s BMI during an office visit is inexpensive, quick, and easy. The BMI provides an indirect measurement of body fatness, and its correlation with other anthropomorphic measurements, such as those obtained with dual-energy X-ray absorptiometry and underwater weighing, has been validated.16,17 Comparing the BMI with national reference data is the best possible method to define and identify overweight and obesity in children and adolescents.18 It is essential to rely on standardized methods, such as BMI, to identify overweight/obesity because informal methods such as visualization are often unreliable. A recent systematic review demonstrated that many parents of overweight and

Body mass index-for-age percentiles: Boys, 2 to 20 years 95th Percentile

A 10-year-old boy with a BMI of 23 would be in the obese category (≥ 95th percentile).

85th Percentile

A 10-year-old boy with a BMI of 21 would be in the overweight category (85th – < 95th percentile).

5th Percentile

kg/m2

A 10-year-old boy with a BMI of 13 would be in the underweight category (< 5th percentile).

A 10-year-old boy with a BMI of 18 would be in the healthy weight category (5th – < 85th percentile).

kg/m2

Age (years)

From the Centers for Disease Control and Prevention.23 Photo URL: http://www.cdc.gov/ healthyweight/images/growthchart_example1.gif. Accessed October 5, 2016.

FIGURE 1. Body mass index (BMI)-for-age percentiles: Boys, 2 to 20 years.

obese children and adolescents do not recognize them as such.19 To compound this issue, even highly trained healthcare professionals underrecognize overweight and obesity when relying on subjective, informal assessments.20,21 In one study, 80 healthcare providers were asked to categorize 33 children varying in body habitus as underweight, normal weight, overweight, or obese on the basis of their pictures.

The healthcare providers correctly identified only 40% of the children as overweight or obese, although 60% actually met the criteria for above-normal weight when BMI was used.20 This finding demonstrates that subjective assessments are not adequate to identify children who require a diagnosis and possible intervention.

With BMI proven as a reliable indicator of body fatness, the CDC and AAP recommend yearly BMI screening for overweight or obesity starting at the age of 2 years.16 A systematic review of 96 articles in 2013 found consistent evidence to support the use of annual BMI screening as

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BMI screening is only one part of identifying overweight or obese children. Further testing and evaluation for risk factors are essential. an important tool for the primary care provider to address childhood overweight and obesity.22 In adults, BMI values use set cutoff points, or threshold values, that are familiar to most clinicians. For instance, a BMI above 25 kg/m 2 is considered overweight, and a BMI above 30 kg/m2 represents obesity. However, the amount of body fat in children changes according to age and gender.

Consequently, BMI measurements for children and adolescents are interpreted with percentiles based on growth charts derived from population statistics.16 When considering the use of BMI screening for overweight and obesity in children and adolescents, practitioners need to be familiar with the use of percentiles from BMI charts to draw appropriate conclusions about risk categories (ie, underweight, normal weight, overweight, and obese.) The most current growth charts were last updated in 2000 and are available on the CDC website.23 An example is shown in Figure 1.

To use these charts correctly, providers must have the child’s age and calculate the BMI; for the BMI, height in inches and weight in kilograms are also needed. Automatic BMI calculators are often included in electronic medical records.

When BMI percentile categories are determined, (1) the appropriate growth chart must be used, (2) age is plotted on the x-axis, and (3) BMI (kg/m2) is plotted on the y-axis. The intersection will correlate with the BMI percentile ranges distributed across the growth chart (Figure 1). Providers should have on hand available tools and technology, such as BMI calculators, current growth charts, and/or electronic medical record–facilitated BMI tracking tools to simplify calculation and increase compliance (Table).

It should be noted that BMI screening is only one part of identifying overweight or obesity in children. Further testing and evaluation for risk factors, including genetics, family history, fitness level, and fat distribution, are essential to formulate a diagnosis. The CDC and AAP emphasize this point and stress that the primary goal of consistent, yearly BMI screening is to identify trends and subsequent changes in trends.5,16 Ultimately, the goal is to identify BMI changes early because intervention efforts in the early stages have been shown to be more successful.14 Current research: Are we assessing BMI at each visit?

Despite the consensus of the CDC, American Medical Association (AMA), USPSTF, and AAP regarding annual BMI assessments, practitioners do not consistently follow the

recommendations.10,12,20-22,24-28 Reported ranges on the use of BMI percentile assessments show widespread variation of 5% to 66.8%.26,27 In 2006, a survey of 99 family nurse practitioners showed that although 73% were aware of the ECRs, more than half reported that they never or rarely recorded a BMI annually or used a change in BMI to identify excess weight gain.24 This study was done before the updated ECRs were released in 2007.

Despite clear recommendations, studies continue to show poor use of the BMI percentile as a primary assessment strategy.25,28 Sharifi and colleagues, in a retrospective analysis of 126,000 well-child visits, investigated whether release of the 2007 ECRs had had an effect on practitioners’ assessment habits for childhood overweight and obesity by comparing a group from 2006 with a group from 2008.10 Even after the release of the 2007 ECRs, a large majority of children in this TABLE. Resources for primary care providers assessing children and adolescents for overweight and obesity Resource

URL

BMI general information

http://www.cdc.gov/healthyweight/ assessing/bmi

Adult BMI calculator

http://www.cdc.gov/healthyweight/ assessing/bmi/adult_bmi/english_bmi_ calculator/bmi_calculator.html

Child/adolescent BMI calculator

https://nccd.cdc.gov/dnpabmi/ calculator.aspx

BMI growth chart for boys, 2-20 years

https://www.cdc.gov/growthcharts/ data/set1clinical/cj41c023.pdf

BMI growth chart for girls, 2-20 years

https://www.cdc.gov/growthcharts/ data/set1clinical/cj41c024.pdf

Childhood Obesity Action Network guide for providers for implementing Expert Committee recommendations

http://www.ohsu.edu/xd/health/ services/doernbecher/patients-families/ healthy-lifestyles/upload/COAN ImplementationGuide62607FINAL.pdf

U.S. Department of Agriculture, Center for Nutrition Policy and Promotion: MyPlate (formerly MyPyramid) for recommended servings

http://origin.www.cnpp.usda.gov/ MyPlate.htm

BMI, body mass index.

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Weight can be a very difficult subject for clinicians to address with children or adolescents and their parents, especially if the parents are also overweight. study aged 2 to 17 years with a BMI in the 85th percentile or higher lacked diagnostic codes for overweight or obesity and did not have the recommended laboratory orders for an assessment of obesity-related comorbidities. Of interest, the number of diagnostic codes for children aged 2 to 5 years was significantly lower than the number for older children, suggesting that providers have less concern for weight-related issues in the preschool population. This finding is worrisome because obesity in these young children is associated with an increased incidence of obesity in adulthood as well as the development of comorbid conditions.3,5 One notable repercussion of inconsistent BMI assessment is the inability to translate potential overweight and obesity in children into diagnostic categories. The International Classification of Diseases, Ninth Revision (ICD-9) codes are not reflective of the actual prevalence of overweight and obesity.13-15,29 In a nationally representative sample of outpatient preventive visits from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey from 2005 to 2007, only 18% of patients in a BMI percentile of 95% or higher had a documented diagnosis of obesity.13 Using the same national surveys, Walsh and colleagues looked at 48,145 office visits for children aged 2 to 18 years from 2005 to 2009.30 Among the 19.5% of children who were obese by BMI standards, only 7% had the appropriate ICD-9 diagnostic code. Providers are not adequately diagnosing overweight and obesity, which hinders management and the initiation of appropriate treatment and interventions.13-15 An appropriate first step in tackling childhood overweight and obesity is to obtain an enhanced, timely diagnosis in the primary care clinic.

Barriers to implementation of recommendations

Aside from the evidence demonstrating underuse of the recommended BMI assessment, researchers have explored barriers to implementation of the 2007 ECRs. Frequently cited barriers include time constraints, futility of treatment efforts, lack of knowledge regarding current recommendations, reluctance to discuss weight-related issues, lack of patient and parental motivation, and lack of access to BMI charts.12,27,31,32 Interestingly, a survey showed that time constraints did not affect a provider’s ability to compute or document BMI; rather, providers were concerned about their ability to counsel patients identified as overweight or obese.32 Setting and environmental factors, such as training,

office staff support, and access to professional journals and continuing medical education, could improve the implementation of and adherence to practice recommendations.12 Knowledge of the expert recommendations did correlate with a higher incidence of BMI screening, and therefore, efforts to increase practitioners’ awareness of the recommendations appear promising.5,11,12,21,27,33-37 Weight can be a very difficult subject for clinicians to address with children or adolescents and their parents. A qualitative survey of communication barriers between maternal child health nurses and parents of overweight children revealed several themes: (1) It was difficult to initiate a discussion of weight issues; (2) growth charts were an essential tool to start conversations about overweight or obesity; (3) denial, defensiveness, and excuses were common reactions among parents; and (4) weight-related conversations were especially difficult if the parents were also overweight.38 Although this study involved maternal and child health nurses, it is likely that these barriers would also apply to other practitioners (ie, primary care providers) treating pediatric patients. Of particular interest was that the use of growth charts was helpful when a crucial conversation with patients and parents was initiated, which indicates that BMI charts can be valuable as a conversation starter.

Other studies have looked more specifically at these communication barriers and found that the technique of motivational interviewing may be an effective counseling strategy for overweight and obese children and their parents.39-41 Motivational interviewing is a patient-focused, and in this case parent-focused, method of communication that has shown promise as a counseling technique for a broad range of behavioral issues, including overweight and obesity.42 The goal of motivational interviewing is to focus on helping the patient develop internal motivation to change rather than on providing information and factual data. The role of the provider is to encourage and support the patient’s and/or parent’s commitment to change unhealthful behaviors while remaining empathetic and nonjudgmental. Specific patientcentered communication recommendations are included in the ECRs and underscore this important component of addressing the childhood obesity epidemic.

Awareness of these barriers will be helpful to primary care providers addressing the issue of overweight and obesity with children and adolescents. In an effort to focus on the interventions that can be made in the primary care setting,

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Prevention strategies include limiting consumption of sugar-sweetened beverages, consuming fruits and vegetables, and limiting television viewing. knowledge of the ECRs is a pivotal first step in addressing the epidemic. It is imperative to focus on the tangible recommendations provided in the ECRs and the toolkit/resources included here. With the elimination of several noted barriers, the essential first step of diagnosis is facilitated.

The Expert Committee recommendations

In 2005, the AMA, along with the Health Resources & Service Administration and CDC, convened an expert committee to revise outdated recommendations based on the latest available evidence-based findings and expert opinion.2 This committee comprised 15 professional organizations, scientists, and clinical experts, and their report is referred to as the Expert Committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report.5 This report includes the latest recommendations and current standards endorsed by the AAP and CDC. The report summarizes a shift from the simple identification of obvious obesity to universal assessment, universal preventive health messages, and early intervention.5 The universal assessment uses BMI calculation as the main starting point and recommends that this be done at each well-child visit and/or at least yearly. Once the BMI is established, the medical, behavioral, and attitude risks are specific to the current BMI, and the prevention and intervention recommendations are delineated.

Social and environmental components are considered in the prevention and intervention plans.

POLL POSITION

Which of the following statements do you most agree with? n = 253

■ I regularly provide diet/ nutrition and exercise counseling for all children I see.

■ I usually provide diet/nutrition and exercise counseling only to children who are overweight or obese.

■ A greater collaborative effort is needed to improve practice behaviors regarding childhood obesity prevention.

36.36% 54.15% 9.49%

For more polls, visit ClinicalAdvisor.com/Polls.

Stepped approach

The ECRs use a stepped approach to provide detailed assessment and treatment strategies for childhood overweight and obesity. With recommendations based on high-quality evidence whenever possible and expert opinion when needed, the report is inclusive of a wide spectrum of information on childhood overweight and obesity for any provider seeing patients aged 2 to 19 years. The report is divided into prevention, assessment, and treatment recommendations. The following sections discuss the specific recommendations. The steps of the recommendations are summarized in Figure 2.43 Prevention strategies

Prevention strategies are critical to addressing the childhood obesity epidemic. The report emphasizes the importance of educating families about consistent early efforts so that the recommendations are initiated in early childhood. This message is based on the belief that prevention efforts are easier to implement than the weight management and weight loss measures necessary once overweight or obesity occurs. The evidence supports the following prevention strategies: (1) limiting the consumption of sugar-sweetened beverages; (2) consuming a diet in line with the quantities of fruits and vegetables recommended by the U.S. Department of Agriculture (Table); (3) limiting television and screen time to less than 2 hours per day; (4) eating breakfast daily; (5) limiting dining out, particularly in fast food establishments; (6) encouraging family meals; (7) limiting portion size; and (8) involving the entire family in lifestyle changes. Various educational programs address these prevention strategies based on the 5-2-1-0 Campaign by the Maine Youth Overweight Collaborative, which is an easy way to educate families: 5 servings of fruits and vegetables, less than 2 hours of television time, 1 hour of physical activity, and 0 servings of sugar-sweetened beverages.34 The ECRs also include the following prevention recommendations based on available data and expertise: (1) eating a diet high in fiber, with calcium and balanced in macronutrients; (2) encouraging only breastfeeding until 6 months of age and then breastfeeding along with solid foods through 12 months of age; (3) moderate to vigorous physical activity for 60 minutes per day; and (4) limiting the consumption of energy-dense foods (ie, processed foods, fast food, nuts, trail mix). The report includes additional Continues on page 41

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Prevention and assessment recommendations provide clear and concise talking points when discussing weight issues with children and parents. information about implementing strategies for prevention, such as patient-centered communication and the roles of the family, provider’s office, school, and community. It is important that these prevention strategies be communicated to all children and adolescents at every well-child appointment regardless of their weight or BMI.

present, the fasting glucose, alanine transaminase (ALT), and aspartate transaminase (AST) levels should be measured every 2 years in patients aged 10 years or older. For patients with a BMI in the 95th percentile or higher who are older than 10 years, the ECRs include a lipid panel as well as measurement of the fasting glucose, ALT, and AST levels regardless of risk factors (Figure 2).

Assessment strategies

Assessment strategies are anchored in the annual well-child visit and start with the premise that weight, height, and BMI for age should be calculated annually. In addition, it is stressed that the BMI percentile should be plotted on current, standardized growth charts annually. The BMI percentile should be used to make an appropriate weight category diagnosis as follows: below 5th percentile, underweight; 5th through 84th percentiles, healthy weight; 85th through 94th percentiles, overweight; 95th through 98th percentiles, obesity; 99th percentile and above, severe obesity.

The use of annual measurements allows important trending analysis to identify concerning changes in a timely manner.

Recommendations also include a yearly qualitative assessment of dietary and behavioral patterns to reflect the prevention strategies noted above.

The ECRs recommend certain medical and behavioral risk assessments for children whose BMI is at or above the 85th percentile. Specifically, medical risks include future or persistent obesity, future or current obesity-related medical conditions, and current obesity-related medical conditions.

Parental obesity is also a strong risk factor for childhood obesity and should lead to enhanced efforts to establish healthful behaviors.

Weight-related problems should be screened via a thorough review of systems and physical examination to include the following: sleep; the respiratory, gastrointestinal, cardiovascular, endocrine, and nervous systems; and the skin.

Psychiatric and orthopedic evaluations should also be conducted. A family history of cardiovascular disease or type 2 diabetes would be considered a medical risk.

Specific laboratory testing is delineated in the ECRs and is based on BMI percentile category in conjunction with risk factors. The goal of laboratory testing is to identify nonalcoholic fatty liver disease, abnormal cholesterol levels, and type 2 diabetes mellitus.

For patients with a BMI in the 85th through 94th percentiles, lipid panel testing is recommended. If risk factors are

Patient-centered communication

Prevention and assessment recommendations provide clear and concise talking points for providers when they are discussing weight-related issues with children and parents.

However, as discussed above, it is imperative to be aware of a family’s cultural values and beliefs to provide culturally competent care. For example, families may differ in their beliefs about what is an attractive or healthy weight. Also, physical activity and lifestyle habits may be influenced by religion, environment, or culture. To gain trust and develop a positive relationship with patients and their parents, you must become familiar with their values and circumstances.

Knowledge of the motivational interviewing principles should be integrated with a culturally competent care model in which the provider identifies the family’s cultural beliefs and values.

The ECRs include specific patient-centered communication techniques, based on motivational interviewing, that can be incorporated in a provider’s dialogue with patients and families during a discussion of weight issues. The communication recommendations include the following: (1) nondirective questioning, (2) reflective listening, (3 comparison of values and current health practices, and (4) importance/ confidence rulers. Nondirective questioning helps the clinician avoid a directive style approach and allows parents or patients to explain their position on the issue.

An example of a nondirective question is, “What concerns, if any, do you have about your child’s weight?” Reflective listening occurs when the provider summarizes the patient’s or parent’s response without judgment. It helps the patient or parent to understand and resolve ambivalence by hearing his or her thoughts verbalized. The provider can help identify conflicting values and current health practices and may offer an opportunity to discuss alternative health behaviors. Lastly, using importance and confidence rulers allows parents or patients to come up with their own solutions. The following dialogue illustrates this technique: “On

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INTERVENTIONS IN CHILDHOOD OBESITY

PREVENTION TARGETS: Talking points for EVERY well-child visit • Reduce consumption of sugar-sweetened beverages.

• Encourage consumption of fruits and vegetables (>5 servings per day).

• Limit screen time to <2 h daily.

• Eat breakfast daily.

• Limit eating out, especially fast food.

• Encourage family meals.

MEDICAL RISKS

• Limit portion size.

• Use 5-2-1-0 messages (5 fruits/vegetables, 2 h of screen time, 1 h of physical activity, 0 sugar-sweetened beverages).

• Encourage only breastfeeding for first 6 mo.

Continue breastfeeding through 12 mo.

• Aim for 60 min of moderate to vigorous physical activity every day.

• Family history of CAD or DM type 2 • Parental obesity • HTN • Other comorbidities

WELL-CHILD EXAM Ages 2–18 y 1. Measure HT, WT, BMI. 2. Plot BMI on current CDC growth chart.

3. Classify WT, compare with past values, assess trend/velocity.

• Reinforce healthy behaviors.

• Review Prevention Targets (see box above).

• Review 5-2-1-0 messages.

Re-evaluate annually.

GOAL: Maintain normal growth velocity.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CAD, coronary artery disease; CDC, Centers for Disease Control and Prevention; DM, diabetes mellitus; HT, height; HTN, hypertension; PT, physical therapy; WT, weight.

5. UNIVERSAL Discuss Prevention Targets (see box above).

BMI 85th to <95th percentile: OVERWEIGHT

BMI ≥95th percentile: OBESE

Screen for Medical Risks (see box above).

• Screen for Medical Risks (see box above).

• Assess age.

No risk factors LAB: Fasting lipid panel

Risk factors

Age <10 y

LAB: Fasting lipid panel, all ages; glucose, ALT, AST every 2 y, if ≥10 y old

STAGE 1: PREVENTION PLUS • Arrange family visits with primary care provider.

• Customize time intervals to individual patient.

• Assess readiness to change.

• Assess diet, physical activity, and screen habits.

• Develop specific goal assignments for ALL Prevention Targets (see box above).

• Follow up every 3 to 6 mo.

GOAL: Decrease BMI and BMI velocity.

LAB: Fasting lipid panel

Goal not met

BMI 5th to <85th percentile: HEALTHY WEIGHT

4. Assess diet, physical activity, medical risk (including family history).

Age ≥10 y LAB: Fasting lipid panel, glucose, ALT, AST every 2 y if ≥10 y old

STAGE 2: STRUCTURED WEIGHT MANAGEMENT • Increased support and structure, individual and family visits with primary care provider • Daily planned diet, with balanced macronutrients • Additional reduction in screen time to <1 h • Planned, supervised activity for 1 h daily • Monitoring through logs, supervision • Possible dietician, counseling, PT, trainer

GOAL: Goal not met Decrease BMI and BMI velocity.

Referral

From Barlow SE5 and National Institute for Children's Health Quality.43

FIGURE 2. Expert Committee recommendations for clinicians for the prevention and treatment of overweight and obesity in children aged 2 to 18 years.

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Preventive health services, such as the well-child visit, provide an optimal opportunity for early detection of overweight and obesity in children. a scale of 0 through 10, how important is it for you to sit down for a family meal together? On a scale of 0 through 10, how confident are you that you could have a family dinner four nights per week?”

With these communication strategies and examples, providers can encourage internal motivation among patients and families. Goal setting, monitoring for identified behavior changes, and the use of positive reinforcement become the role of the provider as patients and their families direct their own behavior changes.

are intensified to a degree ideally managed by a specialist.

A comprehensive, multidisciplinary approach is essential.

Tertiary care interventions in stage 4 include pharmacologic management, highly restrictive diets, and possibly weight control surgery. It is important for primary care providers to be familiar with available resources in their community should any patients require this level of intervention.

A provider toolkit is included. This toolkit summarizes prevention and assessment approaches through stage 2 in the treatment algorithm (Figure 2).

Treatment strategies

Conclusion

Treatment strategies are outlined in detail in the ECRs and are based on a staged approach. Stage 1 is the prevention plus tier and is the first step in the treatment algorithm. Essentially, this stage focuses on the basic healthy dietary and physical activity habits that are highlighted in the prevention strategies.

Again, the focus here is consuming more than 5 servings of fruits and vegetables daily, minimizing the consumption of sugar-sweetened beverages, limiting television viewing time to less than 2 hours daily, eating at home more often, eating as a family unit, eating breakfast daily, and increasing physical activity to 60 minutes daily. These patients should be seen at more frequent intervals to closely monitor their progress, make appropriate adjustments, reinforce education, and encourage motivation.

Stage 2, structured weight management, should be instituted when the interventions in stage 1 fail to stabilize or reverse the BMI values as desired. In this stage, the same targeted behaviors of stage 1 are used along with additional support services and a more structured approach, including planned diets and structured meal plans. Patients also should be advised to restrict television viewing to less than 1 hour daily and set physical activity requirements for 60 minutes per day.

Behaviors should be monitored through daily logs, and the addition of clinical dietician referrals, family counseling sessions, and/or physical therapy sessions should be considered.

Ideally, patients at this stage should be seen monthly, and group sessions may be effective.

If a patient’s response to stage 2 interventions is not adequate, a transition to stage 3, comprehensive multidisciplinary intervention, may be required. Stage 3 and stage 4 are generally considered beyond the scope of primary care. Full details are available within the ECRs but are not included in this article because targeted behaviors and interventions

Preventive health services, such as the well-child visit, provide an optimal opportunity to detect overweight and obesity early and provide education and counseling. Nurse practitioners and physician assistants are involved in immunization, well-child visits, screening examinations, and parental education, and the addition of a BMI assessment is simple and easy to do. Well-child visits are recommended annually for children aged 2 through 19 years.44 With such frequent visits, this is an important time to set the stage for discussions regarding BMI, physical activity, diet, and behaviors—four components that are often cited as top contributors to the childhood obesity epidemic.2 Obesity prevention efforts should be instituted at the beginning of the relationship and continued at every well-child visit. Furthermore, it is critical to enhance providers’ knowledge of this epidemic and the ECRs. Although the problem of childhood overweight and obesity seems overwhelming, the educational tool proposed here will effectively pare down the issue to items that can be addressed by the primary care practitioner. Despite the fact that many factors are involved that go far beyond the scope of a clinic visit, we can make a difference at every well-child visit by consistently following the ECRs and identifying at-risk children. We owe it to our patients and our communities, and ultimately our nation’s health depends on it. ■ Leslie Anne Peek, MSN, APRN, NP-C, is a family nurse practitioner for Northern Nevada Medical Group in Reno, Nevada.

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INTERVENTIONS IN CHILDHOOD OBESITY

2. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity and

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22. Vine M, Hargreaves MB, Briefel RR, Orfield C. Expanding the role

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10. Sharifi M, Rifas-Shiman SL, Marshall R, et al. Evaluating the implementa-

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11. Hessler K, Siegrist M. Nurse practitioner attitudes and treatment

26. Mabry IR, Clark SJ, Kemper A, et al. Variation in establishing a diagnosis

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differ? J Am Acad Nurse Pract. 2012;24:97-106.

27. Harkins PJ, Lundgren JD, Spresser CD, Hampl SE. Childhood obe-

12. Klein JD, Sesselberg TS, Johnson MS, et al. Adoption of body mass

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2012;8:155-161.

[published erratum appears in Pediatrics. 2010;125:1305]. Pediatrics.

28. Huang TT, Borowski LA, Liu B, et al. Pediatricians’ and family physicians’

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weight-related care of children in the U.S. Am J Prev Med. 2011;41:24-32.

13. Patel AI, Madsen KA, Maselli JH, Cabana MD, Stafford RS, Hersh AL.

29. Cook S, Weitzman M, Auinger P, Barlow SE. Screening and counseling

Underdiagnosis of pediatric obesity during outpatient preventive care

associated with obesity diagnosis in a national survey of ambulatory pedi-

visits. Acad Pediatr. 2010;10:405-409.

atric visits. Pediatrics. 2005;116:112-116.

14. Benson L, Baer HJ, Kaelber DC. Trends in the diagnosis of over-

30. Walsh CO, Milliren CE, Feldman HA, Taveras EM. Sensitivity and speci-

weight and obesity in children and adolescents: 1999-2007. Pediatrics.

ficity of obesity diagnosis in pediatric ambulatory care in the United States.

2009;123:e153-e158.

Clin Pediatr. 2013;52:829-835.

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31. Flower KB, Perrin EM, Viadro CI, Ammerman AS. Using body mass index to identify overweight children: barriers and facilitators in primary care. Ambul Pediatr. 2007;7:38-44.

32. Yarborough BJH, DeBar LL, Wu P, et al. Responding to pediatric providers’ perceived barriers to adolescent weight management. Clin Pediatr.

2012;51:1063-1070.

33. Young PC, DeBry S, Jackson WD, et al. Improving the prevention, early recognition, and treatment of pediatric obesity by primary care physicians.

Clin Pediatr. 2010;49:964-969.

34. Stahl CE, Necheles JW, Mayefsky JH, et al. 5-4-3-2-1 go! Coordinating pediatric resident education and community health promotion to address the obesity epidemic in children and youth. Clin Pediatr.

2011;50:215-224.

35. Perrin EM, Vann JCJ, Lazorick S, et al. Bolstering confidence in obesity prevention and treatment counseling for resident and community pediatricians. Patient Educ Couns. 2008;73:179-185.

“Oh, no—Karen baked a cake so dense that not even light can escape.”

36. Pomietto M, Docter AD, Van Borkulo N, et al. Small steps to health: building sustainable partnerships in pediatric obesity care. Pediatrics.

2009;123(Suppl 5):S308-S316.

37. Haemer M, Cluett S, Hassink SG, et al. Building capacity for childhood obesity prevention and treatment in the medical community: call to action.

Pediatrics. 2011;128(Suppl 2):S71-S77.

38. Edvardsson K, Edvardsson D, Hörnsten Å. Raising issues about children’s overweight—maternal and child health nurses’ experiences. J Adv Nurs. 2009;65:2542-2551.

39. Small L, Anderson D, Sidora-Arcoleo K, Gance-Cleveland B. Pediatric nurse practitioners’ assessment and management of childhood overweight/obesity: results from 1999 and 2005 cohort surveys. J Pediatr Health Care. 2009;23:231-241.

40. Soderlund L, Malmsten J, Bendtsen P, Nilsen P. Applying motivational interviewing (MI) in counselling obese and overweight children and par© The New Yorker Collection 2016 from cartoonbank.com. All Rights Reserved.

ents in Swedish child healthcare. Health Educ J. 2010;69:390-400.

41. Taylor RW, Brown D, Dawson AM, et al. Motivational interviewing for screening and feedback and encouraging lifestyle changes to reduce relative weight in 4-8 year old children: design of the MInT study. BMC Public Health. 2010;10:271.

42. Miller WR. Motivational interviewing in service to health promotion.

Am J Health Promot. 2004;18:1-12.

43. National Institute for Children’s Health Quality. Implementation guide for Expert Committee recommendations on the assessment, prevention, and treatment of child and adolescent overweight and obesity. http://obesity.nichq.org/resources/expert committee recommendation implementation guide. Published 2007. Accessed October 5, 2016.

44. American Association of Pediatrics. Recommendations for preventive pediatric health care. https://www.aap.org/en-us/Documents/periodicity_ schedule.pdf. Updated October 2015. Accessed October 5, 2016.

45. Collins ME. Body figure perceptions and preferences among preadolescent children. Int J Eat Disord. 1991;10:199-208.

“If it’s a series of patterned clicks, I’m not here.”

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FEATURE: RONALD HOFFMAN, MD, CNS

The role of biofilms in chronic infections Bacteria in contact with living tissues form layers that resist penetration by the immune system or antibiotics, but promising treatments abound.

© SCIENCE SOURCE

W

Scanning electron micrograph of a Staphylococcus biofilm.

hat are some of the most challenging clinical problems you see in everyday practice? Do they include chronic sinusitis refractory to multiple antibiotics? Recurrent, difficult-to-treat urinary tract infections? Poorly healing ulcers resistant to topical antibiotics and successive debridement?

Seemingly ineradicable bacterial vaginosis and Candida vaginitis? Or, alternatively, chronic progressive periodontal disease with not just local dental but also systemic manifestations, such as heightened risk for cardiovascular disease?

When antibiotics fail, we put the blame on bacterial resistance. There is much substantiation for the idea that selective pressure on microbes pushes their adaptive mechanisms forward, resulting in the development of “superbugs.”

Drug development efforts continually seek to expand our arsenal of new, ever more powerful antibiotics. The traditional approach to infections involves the “culture and sensitivity.” But a marked disconnect has arisen between in vitro results and clinical responses. Why? A new understanding has emerged of how pathogens persist and thrive within human hosts.

In contrast to what we are used to seeing with traditional microscopes, bacteria and fungi in contact with living tissues or inert surfaces form complex communities: biofilms. Multiple species comprising thousands or millions of organisms may coexist in polysaccharide matrices elaborated by the microorganisms themselves; these form nearly impregnable slime layers that resist penetration by antibiotics or humoral defenses

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THE ROLE OF BIOFILMS IN CHRONIC INFECTIONS

Examples of biofilm

A common example of a biofilm is the “scum” that accumulates on our tooth surfaces between brushings. Run your fingernail over a front incisor, and you will harvest a slimy, whitish accretion that constitutes an oral biofilm. If left to accumulate, the biofilm will produce dental plaque and tartar, resulting in tooth decay and periodontal disease.

Tenacious biofilms can contaminate household appliances such as coffee makers, ice makers, and humidifiers if they are not frequently cleaned. Even disinfectants do not seem to daunt biofilms, as evinced by the slime that accumulates on swimming pool walls despite aggressive chlorination and the use of chemical retardants.

In medicine, biofilms often clog catheters and foul medical devices, where they form dense layers that cling to artificial surfaces. It has been reported that most if not all implant infections can be attributed to biofilms, including infections in vascular stents, artificial heart valves, dental prostheses, joint replacements, breast implants, cardiac pacemakers, cerebrospinal shunts, urinary catheters, biliary stents, intrauterine devices, peritoneal dialysis catheters, and contact lenses.

Biofilms and infections

Biofilms have been demonstrated to be implicated in a wide array of chronic infections, including sinusitis, otitis media, chronic obstructive pulmonary disease (COPD), endocarditis, decubitus and diabetic ulcers, prostatitis, conjunctivitis, superficial skin infections, airway infections in cystic fibrosis, vulvovaginitis, urinary tract infections, and periodontitis.

It has been estimated that biofilms complicate the majority of bacterial infections in humans.1 It has been reported that the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) for biofilm bacteria are 10 to 1000 times higher than the corresponding values for isolated, planktonic bacteria.2 Therefore, it is much more difficult to obtain sufficiently high antibiotic concentrations to eradicate biofilm pathogens without risking renal or hepatic toxicity.

Biofilm infections should be suspected in the following settings3: 1. Chronic respiratory infections in patients with cystic fibrosis (often caused by Pseudomonas aeruginosa) 2. Clinical signs of infection or inflammation that are nonresponsive or only temporarily responsive to antibiotic administration (even in the absence of positive cultures)

3. Poorly healing wounds 4. Presence of implantable devices, in-dwelling catheters, or orthopedic prosthetic devices Biofilms may elude detection via traditional culture and sensitivity methods. To diagnose and characterize biofilm infections properly, specialized techniques may be required: tissue biopsy, removal of the implicated device, precision microscopy, sonication of tissue or device specimens, immunochemistry, polymerase chain reaction (PCR) detection, or, in the case of certain pathogens, antibody response.

Treating biofilm infections

Combating biofilm infections requires a concerted multidisciplinary approach4 comprising the following steps5: 1. Removal of the affected foreign body (or draining of abscesses or debridement) 2. Proper selection of biofilm-active and well-penetrating antibiotics to which the infecting bacteria are sensitive 3. Topical or systemic administration of antibiotics in high doses and often in combination 4. Administration of newly identified agents that retard the formation of or promote the dispersal of biofilms Identification of new treatment agents that act against biofilms is the target of much ongoing research because in many cases, even the highest doses of combinations of conventional or novel antibiotics given for prolonged periods may result in treatment failures.

One promising avenue of research seeks to identify “antiquorum sensing” agents. These compounds interdict the

© JAMES CAVALLINI / SCIENCE SOURCE

elaborated by immune system cells. The result may be infections that are difficult to eradicate.

Color-enhanced light micrograph showing Pseudomonas aeruginosa (pyocyanic bacillus), a pathogenic bacterium.

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THE ROLE OF BIOFILMS IN CHRONIC INFECTIONS

Biofilms have been implicated in a wide array of chronic infections, including sinusitis, otitis media, COPD, endocarditis, and others.

© THINKSTOCK

intra-organism signaling that prompts individual microbes to form aggregates. Once a quorum is reached, the bacteria or fungi change their gene expression, close ranks, and elaborate mucopolysaccharides that comprise the biofilm matrix.

Candidate anti-quorum sensing agents include furanones (modeled after red algae, which produce this substance on their surface to retard microbial colonization); the antibiotic azithromycin; and ebselen, an inhibitor of cyclic dimeric GMP (c-di-GMP), a bacterial signaling agent.

While we await the development and mainstreaming of innovative pharmacologic strategies for combating quorum sensing, some studies have confirmed the anti-quorum sensing potential of natural agents. Chinese ginseng5 and garlic6 possess documented anti-quorum sensing properties.

Ginseng offers an additional mode of action against biofilms via its ability to promote bacterial motility while retarding bacterial swarming.7 Another strategy to combat biofilms currently being researched is to interfere with the formation of amyloidlike fibers that contribute to bacterial aggregation. While research is under way to identify candidate agents, the Food and Drug Administration (FDA) has yet to approve any. On the botanical side, it is of interest that parthenolides, which are natural derivatives of the feverfew plant, invoke this mechanism to disrupt preexisting biofilms. Parthenolides have also been found to prevent the formation of bacterial biofilms.8

Parthenolides, natural derivatives of the feverfew plant, disrupt preexisting biofilms and may prevent formation of bacterial biofilms.

Lactoferrin, a component of the innate defense against pathogens, is another natural substance that is under consideration for attenuating biofilms.9 Lactoferrin is a natural iron sequestrant. By analogy, the metal and mineral chelator disodium EDTA (ethylenediaminetetraacetic acid) has also been found to exert anti-biofilm effects.10 Natural enzymes have been proposed as a way of “digesting” the mucopolysaccharide matrix that comprises a biofilm.

A screening of proteases and polysaccharidases revealed specificities for certain biofilm constituents.11 Xylitol

Among the most intriguing and readily available agents available for retarding the formation of biofilms is the 5-carbon polyol sugar xylitol. Xylitol has long been incorporated in chewing gum, toothpastes, and mouthwashes, and it has been used as a low-calorie sugar substitute. Along with a related polyol sweetener erythritol, xylitol has been reported to have inhibitory effects on growth and adherence in some oral bacteria.12 Much of the interest in xylitol stems from its use in dentistry for prophylaxis against decay. The administration of xylitol in chewing gum and oral pastilles to schoolchildren in Finland has been the mainstay of a successful public health program for stemming that country’s epidemic of pediatric dental caries. Early intervention via swabbing the teeth and gums in infancy has likewise proved effective in protecting teeth.13 Xylitol appears to exert specific activity against Streptococcus mutans biofilms, implicated in dental caries and periodontal disease.14 It is thought that xylitol exerts its anti-cariogenic effects by causing S mutans organisms to auto-destruct via a “Trojan horse” mechanism: the uptake of xylitol through the microbial fructose phosphotransferase system and formation of a toxic metabolite, xylitol-5-phosphate, in the cells.

Subsequent accumulation of xylitol-5-phosphate interferes with carbohydrate metabolism and inhibits bacterial growth.

Other species of cariogenic bacteria are said to be susceptible to the biofilm-preventing actions of xylitol; moreover, the application of xylitol reduces acid production by oral pathogens, a key mechanism of dental enamel erosion and periodontal tissue invasion.15 The apparent success of xylitol in attenuating dental biofilms has led to an exploration of its potential application in chronic, refractory infections of the respiratory tract and

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Biofilms may elude detection via traditional culture and sensitivity methods. Specialized techniques such as tissue biopsy may be required. in persistent wounds. In a recent study of 20 volunteers, a 10-day course of xylitol irrigation resulted in a greater reduction of the symptoms of chronic rhinosinusitis than did saline irrigation.16 Finnish researchers demonstrated an antiadherence effect of 5% xylitol on pathogens implicated in otitis media.17 They theorized that nasal inhalation of a xylitol solution might confer protection against bacterial colonization of the middle ear given the anatomical communication of the nasal passages with the eustachian tubes.

The topical application of xylitol in combination with lactoferrin has been explored as a means of facilitating wound healing. Researchers recently demonstrated the superiority of a wound dressing containing lactoferrin/xylitol hydrogel in combination with silver over a commercially available hydrogel wound dressing in reducing wound biofilms.18 An interesting corollary to the wound-healing capabilities of xylitol has been proposed in atopic dermatitis or eczema.

Because a common feature of chronic refractory dermatitis is colonization with epidermal Staphylococcus aureus, it has been theorized that biofilm formation may play a role in the persistence of this skin condition; difficulty in eradicating dermatitis or eczema, even with repeated antibiotic administration, may be due to the persistence of S aureus biofilms. Researchers who applied emollient creams containing xylitol combined with farnesol (an acrylic sesquiterpene alcohol derived from the oil of plants, such as citronella oil) achieved the eradication of superficial staph biofilms after just 7 days.19 Some researchers have proposed that acne is a biofilm disorder, and future strategies against acne may involve the use not only of topical and systemic antibiotics but also surface agents in the hope of creating an unfavorable environment for the acne biofilm.20

sweetener, it has a minimal caloric effect. If a dog ingests xylitol, profound hypoglycemia and even liver failure can result.

The Pet Poison Helpline has reported more than 1500 calls for xylitol poisoning during the last 5 years. Symptoms of xylitol ingestion in animals may include the following: • Vomiting • Weakness • Incoordination or difficulty walking • Lethargy • Tremors • Seizures • Coma It is therefore imperative to store sweet-tasting products that contain xylitol securely out of the reach of inquisitive pets.

Human toothpastes containing xylitol should not be used for pets. If accidental ingestion by a pet is suspected, prompt referral to a veterinarian for supportive care is mandatory.21 Current strategies

Ultimately, the challenge of biofilm infections is likely to be addressed in the future via the deployment of high-tech pharmaceutical breakthroughs, perhaps alongside innovative strategies borrowed from nature. Meanwhile, as we await definitive solutions, the prevention and treatment of biofilm disorders must remain improvisational, perhaps involving the deft application of antimicrobials together with novel inhibitory or antiadherence substances. Because of the urgency of reducing the toll of serious infections now proving difficult to eradicate with antibiotics alone, intense research efforts will continue to focus on unraveling the mysteries of this elusive foe. ■ Ronald Hoffman, MD, CNS, is the founder and medical director of the Hoffman Center in New York City.

Cautions regarding xylitol

Xylitol is safe for humans. It has been approved internationally for use in oral care products and pharmaceuticals and as a sugar substitute for decades. Xylitol, like most sugar alcohols, may have a laxative effect when taken in large amounts. This is because, until the digestive system adapts, xylitol may not be fully digested and has an osmotic effect on the gastrointestinal tract.

The safety profile of xylitol for nonprimate species differs from that for humans in that xylitol can trigger the release of insulin from the pancreas. Because xylitol is a nonnutritive

References 1. Paredes J, Onso-Arce M, Schmidt C, et al. Smart central venous port for early detection of bacterial biofilm-related infections. Biomed Microdevices.

2014;16:365-374.

2. Monroe D. Looking for chinks in the armor of bacterial biofilms. PLoS Biol. 2007;5:e307.

3. Høiby N, Bjarnsholt T, Moser C, et al. ESCMID guideline for the diagnosis and treatment of biofilm infections. Clin Microbiol Infect. 2015;21(Suppl 1):S1-S25.

4. Wu H, Moser C, Wang H-Z, Høiby N, Song Z-J. Strategies for combating bacterial biofilm infections. Int J Oral Sci. 2015;7:1-7.

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THE ROLE OF BIOFILMS IN CHRONIC INFECTIONS

5. Song Z, Kong KF, Wu H, et al. Panax ginseng has anti-infective activity against opportunistic pathogen Pseudomonas aeruginosa by inhibiting quorum sensing. Phytomedicine. 2010;17:1040-1046.

6. Bjarnsholt T, Jensen PØ, Rasmussen TB, et al. Garlic blocks quorum sensing and promotes rapid clearing of pulmonary Pseudomonas aeruginosa infections. Microbiology. 2005;151(Pt 12):3873-3880.

7. Wu H, Lee B, Yang L, et al. Effects of ginseng on Pseudomonas aeruginosa motility and biofilm formation. FEMS Immunol Med Microbiol.

2011;62:49-56.

8. Romero D, Sanabria-Valentin E, Vlamakis H, Kolter R. Biofilm inhibitors that target amyloid proteins. Chem Biol. 2013;20:102-110.

9. Singh PK, Parsek MR, Greenberg EP, Welsh MJ. A component of innate immunity prevents bacterial biofilm development. Nature.

2002;417:552-555.

10. Banin E, Brady KM, Greenberg EP. Chelator-induced dispersal and killing of Pseudomonas aeruginosa cells in a biofilm. Appl Environ Microbiol.

2006;72:2064-2069.

11. Lequette Y, Boels G, Clarisse M, Faille C. Using enzymes to remove biofilms of bacterial isolates sampled in the food industry. Biofouling. 2010;26:421-431.

“Bad news, captain. The ship’s computer has been sharing all our personal data with the Romulans.”

12. Söderling EM, Hietala-Lenkkeri AM. Xylitol and erythritol decrease adherence of polysaccharide-producing oral streptococci. Curr Microbiol.

2010;60:25-29.

13. Mäkinen KK, Järvinen KL, Anttila CH, Luntamo LM, Vahlberg T. Topical xylitol administration by parents for the promotion of oral health in infants: a caries prevention experiment at a Finnish Public Health Centre.

Int Dent J. 2013;63:210-224.

14. Arunakul M, Thaweboon B, Thaweboon S, Asvanund Y, Charoenchaikorn K. Efficacy of xylitol and fluoride mouthrinses on salivary mutans streptococci.

Asian Pac J Trop Biomed. 2011;1:488-490.

“Of course, we just call them ‘necks.”

15. Badet C, Furiga A, Thébaud N. Effect of xylitol on an in vitro model of oral biofilm. Oral Health Prev Dent. 2008;6:337-341.

16. Weissman JD, Fernandez F, Hwang PH. Xylitol nasal irrigation in 2011;121:2468-2472.

17. Kontiokari T, Uhari M, Koskela MJ. Antiadhesive effects of xylitol on otopathogenic bacteria. J Antimicrob Chemother. 1998;41:563-565.

18. Ammons MC, Ward LS, James GA. Anti-biofilm efficacy of a lactoferrin/xylitol wound hydrogel used in combination with silver wound dressings. Int Wound J. 2011;8:268-273.

19. Nusbaum A, Kirsner R, Charles CA. Biofilms in dermatology. Skin Therapy Lett. 2012;17:1-5.

20. Burkhart CN, Burkhart CG. Microbiology’s principle of biofilms as a major factor in the pathogenesis of acne vulgaris. Int J Dermatol. 2003;42:925-927.

21. Xylitol toxicity in dogs. VCA Animal Hospitals website. http://www. vcahospitals.com/main/pet-health-information/article/animal-health/ xylitol-toxicity-in-dogs/4340.

All electronic documents accessed September 12, 2016.

© The New Yorker Collection 2016 from cartoonbank.com. All Rights Reserved.

the management of chronic rhinosinusitis: a pilot study. Laryngoscope.

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CME FEATURED COURSE

■ EDUCATIONAL OBJECTIVES Upon completion of this educational activity, participants will be better able to: • Describe current evidence about the prevention and management of pediatric allergic diseases • Employ strategies for weight gain in the premature neonate • Evaluate the latest developments in infant formulas • Assess the use of prebiotic and probiotic supplementation in infants • Propose practical nutritional interventions to families to improve infant nutrition ■ COMPLETE THE POST-TEST: Page 63

Release Date: February 25, 2016 Expiration Date: June 30, 2017 Estimated Time to Complete: 1.50 hours Accredited Provider: This educational activity is provided by Haymarket Medical Education.

Commercial Supporter: This activity is supported by an educational grant from Nestlé Nutrition Institute.

Program Description: The goal of this enduring continuing medical education (CME) activity is to provide clinicians with a concise overview and important take-home messages of selected presentations from the Advances in Neonatal and Pediatric Nutrition 2015 Conference. The live conference, accredited and hosted by the University of California San Diego, School of Medicine, brought together pediatric clinicians to learn about various topics relating to pediatric nutrition.

This enduring e-conference report aims to improve clinicians’ knowledge, competence, and performance related to: primary prevention of allergic diseases through nutritional interventions; managing food allergies in infancy and childhood; diet and autism; weight gain for the premature neonate; fortification of the preterm infant; updates on infant formulas; and shifts in the intestinal microbiota: therapeutic opportunities for prebiotics and probiotics.

Intended Audience: Pediatricians, pediatric nurse practitioners, pediatric physician assistants, primary care physicians, NPs, PAs, dieticians, and other healthcare professionals involved in the care of children Conflict of Interest Disclosure Policy: In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards for Commercial Support, Haymarket Medical Education (HME) requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. HME resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational programs. All relevant financial relationships shall be disclosed to participants prior to the start of the activity.

Furthermore, HME seeks to verify that all scientific research referred to, reported, or used in a continuing medical education (CME) activity conforms to the generally accepted standards of experimental design, data collection, and analysis. HME is committed to providing its learners with high-quality CME activities that promote improvements in healthcare and not those of a commercial interest.

Faculty Jae H. Kim, MD, PhD Associate Clinical Professor of Clinical Pediatrics Director, Neonatal-Perinatal Medicine Fellowship Program Nutrition Director, SPIN Program Divisions of Neonatology and Pediatric Gastroenterology, Hepatology and Nutrition UC San Diego Medical Center/Rady Children’s Hospital of San Diego San Diego, CA

Mead Johnson, Medela, Nestle Nutrition, and Nutricia; has received research funds from Ferring Pharmaceuticals and InfaCare Pharmaceuticals; and is a share holder in PediaSolutions.

Planners’ and Managers’ Disclosures: The HME staff involved in the planning and content review of this activity have no relevant financial relationships to disclose.

Accreditation Statement: Haymarket Medical Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Designation Statement: Haymarket Medical Education designates this enduring material for a maximum of 1.50 AMA PRA Category 1 Credits TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Accreditation Statement: AMA PRA Category 1 Credits TM meet the requirements of the Commission on Dietetic Registration (CDR).

Designation Statement: Registered dietitians (RDs/dietetic technicians, registered [DTRs]) will be able to receive 1.50 CPEUs for participating in this activity.

Disclosure of Unlabeled Use: This educational activity may contain discussion of approved and/or investigational uses of agents that are not indicated by the FDA. Nestlé Nutrition Institute and HME do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Nestlé Nutrition Institute and HME. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. 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.

If you have any questions relating to the accreditation of this activity, please contact cmequestions@haymarketmedical.com.

Instructions: There are no fees for participating in and receiving CME credit for this activity. During the period February 25, 2016 through June 30, 2017, participants must: 1) read the learning objectives and faculty disclosures; 2) complete the pre-assessment test; 3) study the educational activity; 4) complete the post-test and submit it online.

A statement of credit will be issued only upon receipt of the above elements and a post-test score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/Nov16feature.

Faculty Dislosure: Dr. Kim discloses that he is in receipt of intellectual property rights/patent holder for a newborn heart rate monitor; is a consultant for Medela; is on the speakers’ bureau for Abbott Nutrition,

Provided by

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CME

FEATURED COURSE:

JAE H. KIM, MD, PHD

Nutritional insights: Advances in pediatric nutrition Best practices for managing nutrition in neonatal and pediatric patients— including food allergies, allergic disorders, and supplementation—are reviewed.

Symptoms of celiac disease include those involving the GI system, fatigue, and weight loss.

V

arious nutrition topics may arise throughout the course of managing younger patients, from the perinatal through to the pediatric period. Several of the most exciting areas in nutrition over the past few years—including current evidence on preventing and managing pediatric allergies, recommending infant formulas, and utilizing practical nutritional interventions—are highlighted in this enduring e-conference report from the Advances in Neonatal and Pediatric Nutrition meeting.

© SCOTT BODELL / PHOTOTAKE

Preventing allergy: What infants eat makes a difference

The prevalence of food allergy has increased globally in recent years, and more than half of infants with atopic dermatitis (AD)—generally the first manifestation of atopy—develop other allergic disease by the time they are 3 years old. Given this situation, primary allergy prevention (avoiding onset of immunoglobulin E [IgE] sensitization) has become increasingly important, noted David M. Fleischer, MD, associate professor of pediatrics, University of Colorado Denver School of Medicine. The timing of introduction of complementary allergenic foods and the role of hydrolyzed formulas in high-risk infants who are not exclusively breastfed are particularly relevant to this goal.

A new look at delayed introduction of highly allergenic foods. In past years, the American Academy of Pediatrics (AAP) and other professional groups recommended delaying the introduction of highly allergenic foods, such as egg, peanut, tree nuts, and fish, for 1 to 3 years depending on the www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2016 53

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nts rmula

drolysate eHF-­‐W, eHF-­‐

AC d examinaEon

formulas in associated ffect on nce of AD in lasEng unEl

ma and allergic

mmunol.

Physician-diagnosed AD (adj. %)%] Physician-­‐diagnosed Eczema [adj.

food. Since 2000, however, thinking has shifted because of observational studies showing that early introduction of allergenic foods may actually prevent food allergy. And in 2015, a randomized controlled trial found that early introduction of peanut significantly decreased the frequency of development of peanut allergy among high-risk children.1 Investigators divided 640, 4- to 11-month-old infants with severe AD, egg allergy, or both into 2 groups: those with a positive skin-prick test for peanut allergy in 1 group and those without a positive test in the other. Infants in each of these groups then were divided into another 2 groups: those assigned to eating peanuts (in the form of Bamba, a peanut butter snack) or to not eating peanuts until they were 60 months (5 years) old. At the end of the 5-year study period, of the infants who did not have a positive skin-prick test for peanut allergy, 13.7% in the avoidance group had peanut allergy compared with 1.9% in the Bamba-consuming group.

Of the infants with a positive skin-prick test, only 10.6% of those consuming peanuts had developed peanut allergy vs 35.3% of those who had consumed no peanut.

Other studies also have suggested that early introduction of a variety of highly allergenic foods may reduce the risk an Infant N Interven.on Study: ofutri.on food allergy, while delayed introduction may increase this risk or of asthma or AD. Based on numerous study results, 10-­‐Ytheear Results AAP and the American Academy of Allergy, Asthma & 45 40

CMF eHF-­‐W pHF-­‐W eHF-­‐C

35 30 25 20 15

10 9 8 7 6 0

0

1

2

3

4

5 6 7 8 9 10

Age(years) (years) Age Adjusted cumulative incidence of parent-reported, physician-diagnosed AD.

Adjusted cumulaEve incidence of parent-­‐

AD = atopic dermatitis; GINI = German Infant Nutrition Intervention Study; CMF = reported physician-­‐diagnosed eczema in per-­‐ pHF-W = partially cow’s milk formula; eHF-W = extensively hydrolyzed formula–whey; hydrolyzed formula–whey; eHF-C = extensively hydrolyzed formula–casein. protocol (PP) populaEon. Von Berg A, et al. J Allergy Clin Immunol. 2013;131:1565-1573.

FIGURE 1. Hydrolyzed formulas and AD prevention: 10-year GINI study results

Immunology (AAAAI) have determined that no convincing evidence exists for delaying introduction of specific highly allergenic foods. Parents should offer them at 4 to 6 months of age, just as they do other complementary foods, except in children with severe food allergy or stubborn, moderate to severe AD—who would benefit from evaluation by an allergist.

When hydrolyzed formula makes sense. Because of a demonstrated association between early exclusive breastfeeding and protection against atopic symptoms, along with other evidence, the AAAAI recommends exclusive breastfeeding for 4 to 6 months to prevent allergic disease. When exclusive breastfeeding is insufficient or not possible, the AAAAI recommends that infants at high risk for developing allergy be given a hydrolyzed formula, which appears to delay or prevent AD compared with intact cow’s milk formula (CMF). This recommendation is based on results of the landmark German Infant Nutrition Intervention (GINI) study as well as subsequent research. GINI randomly assigned 945 high-risk infants to formula supplementation with CMF, partially hydrolyzed whey formula (pHF-W), extensively hydrolyzed whey formula (eHF-W), or extensively hydrolyzed casein formula (eHF-C) for 4 months. In the first 4 months, pHF-W and eHF-C were associated with preventing AD, an effect that was still evident in a follow-up study 10 years later (see Figure 1).2 No effect was seen on asthma and allergic rhinitis or allergic sensitization, however. Though some evidence suggests that an eHF may be a bit more beneficial than a pHF in preventing allergy, the evidence is not strong enough to offset the far greater costs of eHFs. Choosing feeds to help premature infants grow as they should

How to optimize available preterm infant formulas and products intended to supplement or augment breast milk was the focus of Jacqueline Keller, MS, RD—the neonatal intensive care unit (NICU) principal dietitian at the University of San Diego Medical Center. Noting that “we know that human milk is the recommended basis of nutrition for the premature infant, but we cannot achieve our growth goals with human milk alone,” she presented a strategy for increasing the nutrient delivery of breast milk in the hospitalized premature infant that was based on a 2014 publication of current evidence and expert opinion, and is expressed as amounts per kilogram of body weight per day and per 100 kcal of energy intake (see Table 1).3 The goal of this strategy is to achieve and maintain the rate of intrauterine growth and body composition of a healthy fetus of the same gestational age in utero.

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TABLE 1. A UCSD strategy to increase nutrient delivery of breast milk for the hospitalized premature infant Breast milk

20 cal/oz

22 cal/oz

24 cal/oz

26 cal/oz

28 cal/oz*

Premature infant

MBM or DBM† († When <1500 g or to bridge the gap until MBM is available)

50 mL MBM or DBM + 5 mL liquid human milk fortifier (HMF)

25 mL of MBM or DBM + 5 mL liquid HMF

25 mL of MBM or DBM + 5 mL of HMF + 5 mL of hydrolyzed 40 cal/oz liquid formula concentrate

25 mL* of MBM or DBM + 5 mL of HMF + 10 mL* of hydrolyzed 40 cal/oz liquid formula concentrate

UCSD = University of California—San Diego; MBM = maternal breast milk; DBM = donor breast milk. *An alternate recipe option per registered dietician review due to higher potential renal solute load: 17 mL of MBM + 5 mL of liquid HMF (EHMF or SHMF) + 5 mL of Nutramigen® liquid concentrate = 28 cal/oz.

Dietitian acknowledges that some recipes include off-label use of products at the discretion of the medical team.

Term liquid formula concentrates can be used to increase the caloric density of MBM for term infants. Example: 60 mL of MBM + 15 mL of 40 cal/oz infant formula liquid concentrate = 24 cal/oz MBM. Protein can be increased in MBM with the addition of Abbott Liquid Protein Fortifier: Add 3 mL of liquid protein to every 42 mL of MBM = 20 cal/oz MBM with ~3 g protein per 100 calories.

When breast milk is not available, clinicians have a variety of nutrient-dense ready-to-feed premature formulas from which to choose. They need to keep in mind that professional bodies, including the US Food and Drug Administration (FDA) and the AAP, recommend avoiding the use of powders in the NICU because they are not commercially sterile.

However, unlike in past years, many liquid products now are available, and most hospital formularies have such products.

The clinicians’ challenge is to work with “the cards that are available,” Ms. Keller said.

In planning nutrition for the premature infant after discharge, practitioners must consider birth history, medical course and any surgery, adjusted age and growth pattern near discharge, the mother’s breast milk supply, any history of formula intolerance or family preference, and practical matters such as family resources and insurance coverage. One basic strategy if the mother’s breast milk supply is anticipated to meet more than 75% of the infant’s daily feeding volume goal is to provide 1 oz of 30 kcal/oz premature formula 3 to 4 times a day after providing breast milk (see Figure 2).

For babies whose mothers can be expected to meet about 50% of the infant’s daily feeding volume goal, the supplemental premature post-discharge formula should be prepared to 24 kcal/oz, with needed adjustments to caloric density based on the babies’ rates of weight gain and how they are growing. When the anticipated breast milk supply is expected to meet less than 30% of the needed daily volume, 22 kcal/oz of premature post-discharge formula should be provided.

Ms. Keller also urged listeners to become more aware of some of the regulatory guidelines that influence the composition of the products that are available and their manufacture. The Infant Formula Act of 1980 gave the FDA authority over quality control for infant formula, and in 1985, acting on AAP recommendations, it issued

minimum required concentrations of 29 nutrients. In 2014, the FDA updated regulations to set standards for manufacturers of nonexempt infant formula (products intended for healthy, term infants), including testing for Salmonella and Cronobacter sakazakii as well as testing the final product for nutrient content before it enters the market and at the end of the product’s shelf life. Ms. Keller noted that nonexempt formula is subject to more detailed standards than exempt infant formulas (those used in the NICU).

Finding better strategies for optimal weight gain in premature neonates

Because postnatal growth is a major determinant of shortand long-term outcomes in extremely premature infants, If the MBM supply is anticipated to meet >75% of the infant’s daily feeding volume goal: Provide 1 oz of 30 kcal/oz premature formula 3 to 4 times per day after breastfeeding, or with expressed breast milk when bottle feeding.

Guidelines include: • Do not exceed 4 oz per day of the 30 kcal/oz premature formula • Do not provide all 3 to 4 oz of 30 kcal/oz premature formula at one feeding • Do not force the baby to finish all of the 30 kcal/oz formula. He/she may accept different amounts at different times of the day

Example: A 2.2-kg infant receiving 160 mL/kg of this feeding strategy, which includes 3 oz/day of Gerber Good Start Premature infant formula (30 kcal/oz) = ~120 kcal/kg, 2.7 g protein/kg, 98 mg Ca/kg, and 50 mg Phos/kg.

UCSD = University of California—San Diego; MBM = maternal breast milk.

FIGURE 2. A UCSD strategy to increase nutrient intakes of the premature infant after discharge

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the nutritional goal for these newborns is to reach a postnatal growth rate similar to that of the normal fetus of the same gestational age. Yet most of these infants gain less weight than do third-trimester fetuses, a deficit that results in extrauterine growth restriction (weight for gestational age below the 10th percentile). And as Jackie Wessel, MEd, RDN—a neonatal nutritionist at Cincinnati Children’s Medical Center—pointed out, optimal growth in extremely premature infants presents something of a dilemma: The goal is to improve growth so as to preserve neurodevelopment while minimizing too rapid a weight gain, which is associated with development of insulin resistance and metabolic syndrome later in life. It appears that the key is to diminish typical postnatal growth restriction in these infants; this will decrease the need for catch-up growth and reduce the risk of developing cardiovascular risk factors.

Tools for monitoring growth. Achieving growth goals is complicated by a lack of prescriptive growth charts. In 2013, Fenton and Kim revised the 2003 Fenton Preterm Growth

Curves equal the WHO Growth Standard at 50 weeks.

Sources: Intrauterine section—Germany (Voight 2010), United States (Olsen 2010), Australia (Roberts 1999), Canada (Kramer 2001), Scotland (Bonellie 2008), and Italy (Bertino 2010). Post term section—the World Health Organization Growth Standard, 2006. www.ucalgary.ca/fenton

Tanis FR, Jae KH. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatrics. 2013;13:59.

FIGURE 3. Fenton preterm growth chart for boys

Chart to conform with new World Health Organization growth standards, resulting in sex-specific actual-age growth charts based on recommended growth goals for preterm infants (see Figure 3).

The goal, Ms. Wessel said, is for the baby to have “continuing weight gain along the percentile or z score from birth.”

For extremely premature infants whose weights are below the third percentile, in the uncalibrated areas below the percentile curves on growth charts, calculating z scores—the standard deviation above or below the mean—may be the best way to monitor growth since z scores more accurately describe growth for babies under the third percentile. The revised Fenton charts and related information, including how to procure z score calculators, can be found at http:// www.ucalgary.ca/fenton/2013chart.

What the studies show. Research has shown how providing extremely premature infants with nutrients soon after birth is positively associated with growth during the first month of life.4 Further, it appears that enhanced first-week protein and energy intakes are associated with increased mental development at 18 months, with higher protein in the first week also tied to growth in length.5 Also notable, 1 study found that extremely premature infants can tolerate early aggressive intake of amino acids and fat emulsions (eg, Intralipid), which significantly increases positive nitrogen balance and caloric intake without increasing the risk of adverse side effects.6 These and similar study affirmations of early and cautiously aggressive nutrition are important, Ms. Wessel pointed out, because about 18% of extremely premature infants are below the 10th percentile for weight at birth, and even more—75%—fall below that percentile by discharge. When an NICU infant loses weight and drops a percentile, it is difficult to reclaim that loss, and the subnormal growth often persists into childhood.

Current nutritional strategies. “Many of our centers nowadays give protein right away, many in the first IVs,” Ms. Wessel observed. This is in the form of an amino acid–containing IV kept in the unit. Then total parental nutrition is written the next full day. It also must be kept in mind, Ms. Wessel stressed, that evaluation of neonatal nutritional adequacy in the premature infant is not determined by weight gain alone.

Linear and proportional growth, as well as body composition (adequate lean body mass and limited fat mass), are also important. Tools for measuring body composition include the Olsen 2015 body mass index (BMI) curves for preterm infants, which report percentiles and z scores, and whole body densitometry, which measures fat and fat-free mass. A new technique relies on air displacement plethysmography, but this method has not yet been validated in preterm infants.

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Diet and autism: Is there a connection?

Much remains to be learned about the cause of autism spectrum disorders (ASD), but it appears to encompass a combination of genetic, immunologic, and environmental elements, according to Alessio Fasano, MD, chief, division of pediatric gastroenterology and nutrition, Massachusetts General Hospital for Children. Many studies have established that certain gene mutations, especially on chromosomes 7 and 16, are linked to ASD, while other research has found associations with immune-system abnormalities. Observers are paying increased attention to ASD environmental risk factors—primarily nutrition—because the prevalence of this condition has exploded in too short a period to be accounted for by genetic mutations.

One theory is that we “did not evolve to deal with grains containing gluten” (wheat, rye, and barley), instead evolving by eating fruits, nuts, vegetables, and tubers, Dr. Fasano said.

For this evolutionary reason, we don’t have the enzymes to completely digest gluten. This poses a particular problem for children with ASD because of their enhanced gut permeability (when these children are put on a gluten-free, casein-free diet, the permeability goes back to that of other children), so the undigested gluten stays in the gut for hours, stimulating the immune system to mount a response. The molecule zonulin controls the spaces between the cells of the intestinal lining, modulating gut permeability; when these spaces open up too much (what is called a leaky gut), larger protein molecules such as gliadin (a protein in wheat) get into the bloodstream and incite an immunologic reaction. And to complicate matters in children with ASD who already tend to have a leaky gut, it appears that gliadin activates zonulin production, leading to increased intestinal permeability (see Figure 4). (Interestingly, the genes that code zonulin are on chromosome 16—the very chromosome that “is packed with other genes that are related to autism,” Dr. Fasano noted.)

And what does this series of events have to do with ASD? One theory is that because some of the undigested gluten peptides are structurally similar to the endorphins that control our behavior, these peptides traverse the blood-brain barrier, entering the brain and causing changes in behavior by interacting with endorphin receptors. Another possibility is that in autistic children, immune cells are programmed to leave the gut and go to the brain, where they produce inflammation associated with behavioral symptoms typical of ASD. It also appears that an individual’s microbiome (the bacteria in the human body) is a determinant of the inflammatory effects of gluten.

Yet a meta-analysis of gluten- and casein-free diets in ASD did not find that such regimens are a magic bullet for treating

this condition.7 (Casein, found in dairy products, is another immune-activating and inflammatory protein.) Of 6 studies, 3 found that these diets were not effective, while the other 3 found only 3 significant treatment effects: overall autistic traits, social isolation, and overall ability to communicate and interact.

No differences could be analyzed for 10 outcomes because of poor data. The meta-analysis authors concluded that current evidence for the efficacy of this diet is poor and that largescale, good quality, randomized controlled trials are needed.

Gluten-free diets: Separating the wheat from the chaff

The market for gluten-free foods in this country is booming. In 2014, retail sales totaled almost $2.6 million and are expected to reach $6.1 billion by 2017. Dr. Fasano reported that while it is generally known that someone with celiac disease should follow a gluten-free diet, many who have adopted this regimen cite other reasons, for example a belief that gluten-free food is healthier, will help them lose weight, or will resolve their gastrointestinal (GI) and extraGI symptoms. Though this suggests that a “fad factor” may well be part of gluten-free foods’ popularity, we now know that celiac disease is not the only health concern associated with gluten consumption—there actually are 3: • Celiac disease. In this heritable autoimmune condition, patients cannot tolerate gluten because their body responds to it by mounting T cells in the GI mucosa, leading to damage of the villi and preventing the proper absorption of nutrients. Symptoms include those involving the GI system, fatigue, weight loss, bone and joint pain, and migraine.

• Wheat allergy. As with other food allergies, wheat allergy incites the immune system to release antibodies (eg, IgE), which causes other cells to release inflammatory substances such as histamine, resulting in a variety of symptoms, from mild skin reactions to anaphylaxis.

Unlike celiac disease, however, wheat allergy does not cause severe intestinal damage.

• Gluten sensitivity. In this condition, the body mounts a stress response—often GI symptoms—but neither autoimmune nor allergic mechanisms are involved. (Gluten sensitivity probably is mediated by innate immunity, however.) Symptoms can be similar to those of celiac disease, with the most common being abdominal pain.

Other symptoms include AD or rash; headache; “foggy mind”; fatigue; diarrhea; depression; anemia; numbness of the legs, arms, or fingers; and joint pain (see Table 2).8 The only way to diagnose gluten sensitivity is to rule out both the allergic and autoimmune mechanisms that characterize

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Dysbiosis causes zonulin release and consequent leaky gut

Dysbiosis causes Dysbiosis causes zonulin release zonulin releaseand and consequent consequentleaky leaky gut

Activated inflammatory Activated Activated cells cause local infl ammatory inflammatory inflammation cells cellscause causelocal local responsible for infl ammation inflammation responsible the GI symptoms responsible for for the symptoms the GI GI p by ysymptoms a experienced experienced p by ya experienced subgroup of asubgroup subgroupofof ASD children ASD children ASD

Non-self antigens, Non-self antigens, including includinggluten, gluten,casein, casein, Non-self antigens,and andmicroorganisms microorganisms including gluten, casein, bioproducts gain access bioproducts Antigen Antigen presenting presenting into the the lamina and microorganisms into laminapropria propria cells(APC) (APC) present cells present non-self the bioproducts gain access the non-self Antigen presenting antigens to other to other into the lamina propria cells (APC)antigens presentcells immune immune cells the non-self antigens to other FIGURE 4. Possible gastrointestinal dysfunctions in ASD immune cells

wheat allergy and celiac disease, respectively. To illustrate how difficult it can be to diagnose gluten sensitivity, how debilitating its symptoms can be, and the potential benefits of a gluten-free diet, Dr. Fasano presented the case of a 19-year-old woman whose problems began with a 6-month history of recurrent abdominal pain and heartburn. Suspecting gastroesophageal reflux disease (GERD), her physician prescribed a proton pump inhibitor, which failed to relieve her symptoms. Not only did the patient’s GERD symptoms persist, but she also developed headaches, dizziness, numbness in her fingers, paresthesia, and gradual reduction of muscle strength in her legs that became so severe she was confined to a wheelchair. After neurologic conditions, including multiple sclerosis, were ruled out, the patient’s physicians also considered, and also ruled out, Lyme disease, Epstein-Barr virus, pernicious anemia, and lupus. The patient also was screened for celiac disease and tested negative. She nonetheless decided to follow a gluten-free diet, and within 3 weeks her GI symptoms resolved. Further, within 2 months her neurologic symptoms also improved. Six months after beginning the diet she could walk with a cane, and 12 months later she had completely regained her ability to walk.

How good is donor milk for preterm babies?

Debbie O’Connor, PhD, RD, professor, University of Toronto, Canada, focused on the efficacy and safety of donor

Activated inflammatory Activated inflammatory cells cells migrate to themigrate brain to the brain Activated where they where cause they local cause local inflammation infl ammation responsible inflammatory cells migrate responsible forsymptoms behavioral for behavioral to the brain where symptoms typicalthey typical ofinflammation ASD of ASD cause local responsible for behavioral symptoms typical of ASD

ASD = autism spectrum disorder; GI = gastrointestinal.

Adapted from Fasano A. Scientific American, Inc. 2009;60:38.

human milk compared with preterm formula as a supplement for premature infants. A mother’s own milk is, of course, the best food for all infants. As Dr. O’Connor noted, however, mothers may not be able to provide sufficient milk for a variety of reasons, perhaps because of illness, stress, or difficulty pumping or because they have given birth at the beginning of their third trimester when the mammary secretory cells are quite immature and “it takes a while to get things going.”

But it’s important to realize that the donor milk available from milk banks differs from the milk a baby gets directly from his or her mother. Donor milk is frozen then thawed, and is pooled and pasteurized. At the donor milk bank with which Dr. O’Connor is affiliated, milk is mixed from 3 different mothers and, in addition to pasteurization, undergoes 5 container changes and several freeze/thaw cycles, which affect both nutrients and bioactive components. For example, pasteurization destroys bile cell–dependent lipase (important for the digestion of fat), though the minerals in human milk are not affected at all, and the cytokines that are important in the prevention of necrotizing enterocolitis (NEC)—a potentially fatal condition for which infants who weigh <1500 g are at risk—are only slightly affected.

A Cochrane meta-analysis of 9 trials involving more than 1000 preterm or low-birth-weight (LBW) infants tackled the

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TABLE 2. Gluten intolerance: More than celiac disease Celiac disease (CD)

Gluten sensitivity (GS)

Wheat allergy (WA)

Time interval between gluten exposure and onset of symptoms

Weeks-Years

Hours-Days

Minutes-Hours

Pathogenesis

Autoimmunity (innate + adaptive immunity)

Immunity? (Innate immunity?)

Allergic immune response

Human leukocyte antigen (HLA)

HLA-DQ2/-DQ8–restricted (~97% positive cases)

Not HLA-DQ2/-DQ8–restricted (50% DQ2/DQ8 positive cases)

Not HLA-DQ2/DQ8–restricted (35%-40% positive cases, as in the general population)

Auto-antibodies

Almost always present

Always absent

Always absent

Enteropathy

Almost always present

Always absent (slight increase in IEL)

Always absent (eosinophils in the lamina propria)

Symptoms

Both intestinal and extra-intestinal (not distinguishable from GS and WA with GI symptoms)

Both intestinal and extra-intestinal (not distinguishable from CD and WA with GI symptoms)

Both intestinal and extra-intestinal (not distinguishable from CD and GS when presenting with GI symptoms)

Complications

Comorbidities

Absence of comorbidities and longterm complications (long follow-up studies needed to confirm it)

Absence of comorbidities

Long-term complications

Short-term complications (including anaphylaxis)

GI = gastrointestinal; IEL = intraepithelial lymphocytes.

question of whether it is better to provide preterm formula with its optimal levels of nutrients or donor breast milk.9 Four trials compared standard-term formula with donor breast milk, and 5 compared nutrient-enriched preterm formula with donor breast milk. In the most important finding, NEC was 2.77 times more likely to develop in babies fed formula than in those given donor milk. Donor milk also provided a slight advantage with regard to feeding tolerance (but only a few studies examined it). On the minus side, unlike with term and preterm formula, donor milk was not associated with sufficient weight, length, and head circumference growth for optimal neurodevelopment. The authors noted, however, that because only 2 of the studies used the nutrient-fortified donor breast milk that is now so common, the applicability of their findings is limited. And a trial in 363 very LBW infants that did compare fortified donor breast milk with preterm formula found that fortification did not lessen the protective effects of donor milk as a supplement against NEC. Also, growth was similar in infants fed the fortified donor milk and those fed formula.10 As for donor milk for the term baby of normal weight, Dr. O’Connor said that the research in this area is “pretty thin.” Given that pasteurization and freezer storage reduces the nutrient content of donor milk, more work is required to ensure that donor milk as an exclusive form of nutrition can meet the needs of a healthy, term infant.

Avoidance: The best (only!) way to manage food allergy

In introducing his talk on managing food allergies, Dr. Fleischer reviewed the categorization of food allergies into 2 types: a) those mediated by IgE, which typically are characterized by hives, swelling, or another reaction (the most serious, anaphylaxis) often within 15 to 30 minutes after ingestion, and b) non-IgE mediated, where symptoms typically are delayed and rarely are life-threatening. Mixed immune-mediated disorders—IgE and non-IgE—also exist, as do cell-mediated food allergies. All these immune system-related disorders are distinguished from food intolerance (most often to lactose), which is not mediated by the immune system.

To address a suspected food allergy, the clinician needs to identify the foods to which the child is allergic by setting up an elimination diet with the fewest number of foods to be avoided. Once a specific food allergy is diagnosed, avoidance of that food can be implemented. Dr. Fleischer recommends that the family of a child with a food allergy meet with a nutritionist to review likely sources of accidental exposure, learn how to read labels (a far less challenging task than it used to be), and figure out what foods to substitute for any nutrients being eliminated. Families also need to develop a “food allergy action plan” that encompasses knowing what to do in case of accidental exposure (treatment with epinephrine,

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an antihistamine, or both), how to recognize early signs and symptoms of an allergic reaction, and having epinephrine available and knowing how and when to use it—namely, soon after exposure (see Table 3).11 In a follow-up visit after an allergic reaction, the clinician should: a) review the child’s response to treatment, the circumstances leading to the reaction, and the advisability of having the child wear a medical ID bracelet (or another form of food-allergic identification), and b) make any necessary changes to the action plan. Providing emotional support also is important. Long-term management considerations should include monitoring if the child has been exposed to the offending food without having a reaction, making periodic reviews of his/her diet, and determining whether the child has developed allergies to other foods or has developed another allergic disease, such as asthma. Depending on the findings, results of routine TABLE 3. Food allergy patient/provider checklist Did we: – Verify that the family and/or child had auto-injectable epinephrine at the visit? o Ask if the child is carrying auto-injectable epinephrine. o Verify the auto-injectable device is intact. o Double-check the expiration date on the auto-injectable device. o Double-check the dose of the auto-injectable device and the patient’s weight.

– Demonstrate appropriate use of the auto-injectable epinephrine device?

– Ask the child’s caregiver to demonstrate appropriate use of the autoinjectable epinephrine device?

– Explain to the family their responsibility for always carrying autoinjectable epinephrine?

– Have the child demonstrate how to use an auto-injectable epinephrine device (if developmentally appropriate)?

– Ask the child to describe symptoms of anaphylaxis that would require the use of auto-injectable epinephrine? o The previous 2 questions are more important if: ◾ The child has had more than 1 previous systemic allergic reaction. ◾ The child has experienced severe life-threatening anaphylaxis. ◾ Anaphylaxis is triggered by peanut or a tree nut. ◾ The child had a severe reaction from a very small amount of ingested allergen. ◾ The child has persistent asthma.

• If the child has asthma, specifically discuss the importance of control of asthma symptoms in order to reduce the likelihood of severe or fatal anaphylaxis.

– Review a food allergy action plan?

– Provide an updated food allergy action plan if it has been more than 1 year?

– Verify and/or recommend a medical ID bracelet?

– Provide avoidance handouts?

– Refill prescriptions?

Bird JA, et al. J Allergy Clin Immunol Pract. 2015;3:1-11.

physical exams, impact of the allergy on quality of life, and any other relevant physical and psychological considerations, the clinician may want to consider skin or other testing or referral to an allergist, gastroenterologist, or psychosocial clinician.

Dr. Fleischer also tackled “peanut allergy misconceptions”— such as the belief that a child with peanut allergy is at high risk of a reaction to public exposure of peanut by, for example, smelling peanut butter or being near peanut dust and that his environment must be “peanut-free.” In these and similar situations, Dr. Fleischer said, “No protein is being released,” so the child is not at risk of an allergic reaction. Nonetheless, the preschool peanut-allergic child probably should eat at a peanut-free table, given that children of this age may pick up anything that looks appealing and put it in their mouths.

“But once they turn 4 or 5 years old” and know what they can’t eat, Dr. Fleischer noted, “it’s more helpful to have those kids sit with their friends than be isolated at a table where they’re known as the food-allergic child.”

Though immunotherapy for allergy is available in 3 forms— oral, sublingual, and epicutaneous—this type of treatment has not been approved by the FDA. Further, Dr. Fleischer believes that immunotherapy currently should be used only in clinical trials because “we don’t have long-term data and really know which patients are going to respond best and to which therapy.”

How “good bugs” promote good health

The medical community has become increasingly aware of the importance of balanced intestinal bacteria for healthy intestinal and immunologic development as well as for overall health. Kelly A. Tappenden, PhD, RD—a human nutrition, endowed professor at the University of Illinois—explored this subject by addressing what research has shown about how we can use probiotics (“good bugs”) and prebiotics (undigestible food elements that promote probiotics’ growth) to prevent or ease health problems in children.

How intestinal bacteria affect infant development.

“Contact with microbes begins in utero and proceeds in a stepwise manner during birth and early infancy,” Dr. Tappenden pointed out, noting the various functions of intestinal microbiota—especially to protect against pathogenic bacteria and aid in the development of immune and digestive/metabolic functions as well as neuronal development.12 Children’s microflora change in response to modifications in diet, antibiotics, and other events, which can result in an excess of harmful species or an absence of beneficial species, leading to dysfunctions such as intestinal inflammation. This “dysbiosis” is also associated with certain conditions such

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as celiac disease, inflammatory bowel disease (IBD), atopy, irritable bowel syndrome (IBS), NEC, and cystic fibrosis.

Microbiota—breast milk vs formula. In breastfed infants, Bifidobacteria, one of the most beneficial of the intestinal bacteria, rapidly increase after birth, quickly predominating in these babies’ flora. Formula-fed infants, on the other hand, have far lower levels of Bifidobacteria and other beneficial bacteria. Because of this difference, probiotic- and prebioticsupplemented formulas are available to promote in formula-fed infants intestinal microbiota similar to that of breastfed infants.

Support for probiotic and prebiotic use. Probiotics are living microorganisms found in foods and supplements as well as in the body. When consumed in sufficient quantities, probiotics exert health benefits, primarily by keeping the gut healthy. While specific probiotics have been found to have varying positive effects on preventing or easing a variety of conditions in children, the strongest evidence for their benefit is for diarrhea. Indeed, many trials have shown that probiotics can prevent the onset of antibiotic-associated diarrhea, with the 2 most effective strains being Lactobacillus rhamnosus GG (LGG) and Streptococcus boulardii. Also well established is the benefit of LGG and S boulardii in the treatment of acute watery diarrhea (primarily rotaviral), by reducing its duration, and Lactobacillus in acute infectious diarrhea. Evidence also indicates that specific strains of probiotics can be useful in preventing or managing AD associated with cow’s milk allergy, IBS, and nonalcoholic fatty liver disease; decreasing crying time in infants with colic; and preventing NEC in premature infants (see Table 4).

Prebiotics are plant fibers that nourish good bacteria already in the intestines, promoting their growth. In a randomized trial in 134 formula-fed infants, those who received a prebiotic-supplemented formula were significantly less likely than those who received a placebo-supplemented formula to have symptoms of allergy—whether AD, recurrent wheezing, or allergic urticaria—during the first 2 years of life. The infants who received the prebiotic-supplemented formula also had fewer episodes of upper respiratory tract infections and fever and needed fewer antibiotic prescriptions.13 Studies have also found that the prebiotic oligofructose reduces the likelihood of having a relapse of Clostridium difficile–associated diarrhea and that the prebiotic galactooligosaccharide alleviates symptoms of IBS. When the neonate is preterm/tiny, mother’s milk needs fortification

Though the superiority of mother’s milk to any other infant feed is universally accepted, it now seems clear that even this

optimum food requires fortification when the infant is of a very LBW. Research in 105 preterm infants “that really got people talking,” according to Dr. O’Connor, showed that LBW infants rarely achieve nutrient intakes that meet current recommended dietary intakes, inevitably accumulating significant nutrient deficits in the first few weeks of life (see Figure 5). These deficits, which can be directly related to later growth retardation, will not be replaced when current recommended daily intakes alone are fed.14 A Cochrane review supported the view that fortified human milk can make up for such nutrient deficits by promoting growth in preterm infants. The meta-analysis found that multicomponent fortifiers were associated with short-term increases in weight gain as well as in linear and head growth.

TABLE 4. When probiotics may help Strong evidence supporting probiotic use Clinical condition

Organism

Diarrhea Infectious adult – treatment

Saccharomyces (S) boulardii, LGG

Infectious child – treatment

LGG, Lactobacillus (L) reuteri

Prevention of antibioticassociated diarrhea

S boulardii, LGG, L casei, L bulgaricus, Streptococcus thermophilus

Inflammatory bowel disease Pouchitis – preventing and maintaining remission Immune response

VSL#3a LGG, L acidophilus, L plantarum, Bifidobacterium (B) lactis, L johnsonii, VSL#3a

Atopic dermatitis associated with cow’s milk allergy Treatment

LGG, B lactis

Moderate evidence supporting probiotic use Diarrhea Prevention of infection

S boulardii, LGG

Treatment of recurrent C difficile– associated diarrhea

S boulardii, LGG

Prevention of recurrent C difficile– associated diarrhea

S boulardii, LGG

Necrotizing enterocolitis

B infantis, Streptococcus thermophilus, B bifidum

Irritable bowel syndrome

B infantis

LGG = Lactobacillus (L) rhamnosus GG. a The probiotic VSL#3 is a mixture of 8 different species of bacteria, namely Streptococcus salivarius subsp. thermophilus, L casei, L plantarum, L acidophilus, L delbrueckii subsp. bulgaricus, B longum, B infantis, and B breve.

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Some of the included studies also saw an improvement in bone mineralization, but no long-term outcomes were measured.15 And a more recent study in more than 1000 infants born at 23 to 27 weeks’ gestation also found that early provision of nutrients is an important determinant of postnatal growth.4 Dr. O’Connor briefly reviewed the types of milk fortifiers that are available. She talked about the old-fashioned but still widely used powders as well as the popular Prolacta, a liquid fortifier. Fortifiers can be bovine- (most common), soy-, or human milk–based, and many NICUs compound in the hospital

pharmacy a mixture of liquid preterm formula with various commercial protein powders and minerals. NICUs vary greatly in their strategies for fortifying milk. But whatever the NICU’s policy, Dr. O’Connor recommends that, before discharge, the baby be put on the feeding regimen planned for home to make sure the infant “is growing okay” before leaving the hospital. ■ References 1. Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372:803-813.

2. Von Berg A, Filipiak-Pittroff B, Krämer U, et al. Allergies in high-risk schoolchildren after early intervention with cow’s milk protein hydroly-

Energy (kcals/kg) Intake

150

*

100

(GINI) study. J Allergy Clin Immunol. 2013;131:1565-1573.

50

3. Koletzko B, Poindexter B, Uauy R. Recommended nutrient intake levels

0

for stable, fully enterally fed very low birth weight infants. World Rev Nutr

-50

Diet. 2014;110:297-299.

-100

Cumulative deficit

sates: 10-year results from the German Infant Nutritional Intervention

4. Martin CR, Brown YE, Ehrenkranz RA, et al. Nutritional practices and

-150 -200

growth velocity in the first month of life in extremely premature infants.

-250

Pediatrics. 2009;124:649-657.

5. Stephens BE, Walden RV, Gargus RA, et al. First-week protein and

-300

*

-350 -400 -450 -500

≤30 weeks ≥31 weeks * P<.001

extremely low birth weight infants. Pediatrics. 2009;123:1337-1343.

6. Ibrahim HM, Jeroudi MA, Baier RJ, et al. Aggressive early total parental nutrition in low-birth-weight infants. J Perinatol. 2004;24:482-486.

-550 1

2

energy intakes are associated with 18-month developmental outcomes in

3

4

5

6

7. Millward C, Ferriter M, Calver S, et al. Gluten- and casein-free diets for autistic

7

spectrum disorder. Cochrane Database Syst Rev. 2008;16(2):CD003498.

Postnatal age (days)

8. Catassi C, Bai JC, Bonaz B, et al. Non-celiac gluten sensitivity: the new 6

Intake

frontier of gluten related disorders. Nutrients. 2013;5:3839-3853.

Protein (g/kg)

9. Quigley M, McGuire W. Formula versus donor breast milk for feed-

4

*

2

2014;4:CD002971.

0

10. Unger S, Gibbins S, Zupancic J, O’Connor DL. DoMINO: Donor milk

Cumulative deficit

-2

for improved neurodevelopmental outcomes. BMC Pediatr. 2014;14:123.

-4

11. Bird JA, Lack G, Perry TT. Clinical management of food allergy. J Allergy

-6

Clin Immunol Pract. 2015;3:1-11.

-8

12. Buccigrossi V, Nicastro E, Guarino A. Functions of intestinal microflora

-10 -12 -14 -16

ing preterm or low birth weight infants. Cochrane Database Syst Rev.

*

≤30 weeks ≥31 weeks * P<.001

in children. Curr Opin Gastroenterol. 2013;29:31-38.

13. Arslanoglu S, Moro GE, Schmitt J, et al. Early dietary intervention with a mixture of prebiotic oligosaccharides reduces the incidence of allergic manifestations and infections during the first two years of life. J Nutr.

-18

2008;138:1091-1095.

1

2

3

4

5

6

7

Postnatal age (days) Embleton ND, et al. Pediatrics. 2001;107(2):270-273.

FIGURE 5. Nutrient intake/deficits in preterm infants in the first week of life

14. Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics. 2001;107:270-273.

15. Kuschel CA, Harding JE. Multicomponent fortified human milk for promoting growth in preterm infants. Cochrane Database Syst Rev. 2004;(1):CD000343.

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POST-TEST Expiration date: June 30, 2017

Credit Designation: Haymarket Medical Education designates this enduring material for a maximum of 1.50 AMA PRA Category 1 Credits TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Registered dietitians (RDs/dietetic technicians, registered (DTRs) will be able to receive 1.50 CPEUs for participating in this activity.

A statement of credit will be issued only upon receipt of a completed pre-assessment test, activity evaluation form, and post-test with a score of 70% or better. All components must be completed and submitted online at ClinicalAdvisor.com/Nov16feature.

CREDITS: 1.50

|

Nutritional insights: Advances in pediatric nutrition

1. Early consumption of peanuts in infancy is associated with which of the following? a. No difference in likelihood of peanut allergy compared with delayed consumption of peanuts b. A more severe peanut allergy than with delayed consumption of peanuts c. Less likelihood of peanut allergy d. More likelihood of peanut allergy 2. In planning nutrition for the premature infant after discharge, which of the following is not a factor that needs to be considered? a. The mother’s breast milk supply b. The mode of delivery (Cesarean or vaginal birth) c. Adjusted age and growth pattern near discharge d. Family resources and insurance coverage 3. Studies show that provision of enhanced protein and energy intake early in life is associated with increased mental development at 18 months, studies show. When were these extra nutrients provided in this research? a. During the first week of life b. During the first month of life c. During the first 2 months of life d. During the first 6 weeks of life 4. Which of the following statements most accurately describes the findings of a meta-analysis of gluten- and casein-free diets in autism spectrum disorders (ASD)? a. Current evidence for efficacy of this diet is poor. b. This diet has many significant treatment effects. c. This diet has no significant treatment effects. d. This diet is associated with an increase in ASD symptoms.

5. Which of the following statements does not accurately describe gluten sensitivity? a. Gluten sensitivity is a diagnosis of exclusion. b. Gluten sensitivity produces symptoms that develop hours to days after exposure.

c. Gluten sensitivity is an autoimmune disease. d. The symptoms of gluten sensitivity can be similar to those of celiac disease.

6. Which of the following statements best describes the differences between donor milk available from milk banks and the milk a baby gets directly from his/her mother? a. There are no differences between donor milk and mother’s milk. b. Processing of donor milk affects only some nutrients. c. Processing of donor milk affects both nutrients and bioactive components of human milk. d. Processing of donor milk affects only the minerals in human milk.

7. What is the most important first step in addressing a suspected food allergy? a. Set up an elimination diet to determine if the child is allergic to a particular food. b. Have the parent/caregiver make an appointment with an allergist for the child. c. Have the child avoid all highly allergenic foods. d. Conduct skin testing or other allergy tests.

8. For which of the following conditions have probiotics been found to be most helpful? a. Atopic dermatitis b. Diarrhea c. Inflammatory bowel disease d. Colic 9. What is the ideal food for the premature infant in the neonatal intensive care unit (NICU)? a. Human milk, exclusively b. Human milk combined with multicomponent milk fortifiers c. A ready-to-feed premature formula, exclusively d. Human milk combined with powdered milk fortifiers

TO TAKE THE POST-TEST please go to: ClinicalAdvisor.com/Nov16feature

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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.

CLINICAL PEARLS TREATMENT TIPS FOR TINEA PEDIS AND YEAST INFECTIONS I enjoyed the pearl about using an alcohol sanitizer for yeast in skinfolds [Advisor Forum, October 2016, p. 45]. If the area is red, Selsun blue as a body wash will not sting, and drying with a hair dryer works well.—SUSAN SMITH, PhD, FNP, Albuquerque, N. Mex. (217-1) I also encounter many patients who get yeast infections in skinfolds. I have the patients apply a solid antiperspirant/ deodorant in the skinfold, once the skin is healed from the yeast rash. It works very well in preventing further yeast infections.—URSULA FULLER, FNP, BC, Osceola, Mo. (217-2) When treating tinea pedis, I often prescribe econazole cream (or any generic azole cream); apply BID until clear, Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 275 7th Avenue, 10th Floor, New York, NY 10001.You may contact us by e-mail at editor@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.

may repeat as needed, dispense 80 grams or 160 grams (if the patient has large feet), and it may be refilled 11 times.

Patients with a chronic disease for which we have no cure do better if you give them enough treatment so they do not keep running out. A-15 gram tube of clotrimazole cream is barely enough to cover 2 large feet for more than a week.

Also, once the tinea pedis on the soles is clear, I recommend that patients spray some type of antifungal spray BID or at least daily to their 10 toes/between the webspaces.

The spray helps to keep the webspaces dry and reduces the maceration/breakdown that often occurs. If the soles of the feet are getting itchy/scaly and it looks like the tinea pedis has recurred, then start up again with the econazole cream BID until clear.—CHRISTY FLORY, RN, MS, NP, Annapolis, Md. (217-3)

STOPPING THE BLEEDING As a midlevel practitioner providing wound care in a variety of rural areas, I have rediscovered the old adage that “All bleeding stops, eventually.” When bleeding is spewing in a pulsating manner or just gently puddling in a wound bed, pressure is the key to making it stop. Don’t take a quick peek every few seconds. Hold firm pressure for a few minutes before easing back the gauze for evidence of further bleeding. Failure to do so can dislodge the clot that is attempting to form.—LISA JOHNSON, APRN, CNS, Okmulgee, Okla. (217-4)

OUR CONSULTANTS

Philip R. Cohen, MD,

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.

Abimbola Farinde, PhD, PharmD,

is a professor at Columbia Southern University in Orange Beach, Ala.

Laura A. Foster, CRNP, FNP,

Abby A. Jacobson, MS, PA-C,

practices family medicine with Palmetto Primary Care Physicians in Charleston, S.C.

is an assistant professor at Thomas Jefferson University and a dermatology PA at Family Dermatology of Reading, Pa.

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VITAMIN D3 AND TYPE 1 DIABETES To reduce the incidence of type 1 diabetes, we should give 2000 IU of vitamin D3 to our newborns until age 1. A study in the Netherlands of more than 100,000 children and 31 years of follow-up showed that vitamin D3 at 2000 IU reduced the incidence of type 1 diabetes by 88%. No untoward side effects were found. I tell this to all parents of newborns. Vitamin D is an important immunoregulator that reduces inflammatory cytokines and obviously antibodies.

It also reduced influenza A by 42% in a study in Japan for preschool children.—PAUL BATTLE, PA-C, Denver (217-5)

CASE FILES PROVIDING CARE FOR VETERANS EXPOSED TO AGENT ORANGE Contributed by Sherril Sego, FNP-C, DNP (See photo at bottom of this page for more information about Dr. Sego.)

The marriage of two herbicides chemically known as 2, 4, 5-T and 2, 4-D yielded the product that became known as Agent Orange because of the orange striping on the barrels used for shipping it. Agent Orange was a potent defoliant that was used primarily during the Vietnam War in what the military code-named “Operation Ranch Hand.” The project officially began in 1961 and continued through 1971.

During the period of its use in Southeast Asia, an estimated 20,000,000 gallons of Agent Orange were sprayed over Vietnam and parts of Laos and Cambodia.

In the decades that followed, an ever-growing body of evidence has linked exposure to Agent Orange with a number of serious and potentially fatal diseases. The Veterans Benefits Administration (VBA) first officially recognized one

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.

of those health conditions as type 2 diabetes in 2002. Since then, many more conditions have been added to the list.

About 9 million military personnel served on active duty during the Vietnam era. At least 2.6 million were potentially exposed to Agent Orange based on their location of service and assigned duties. Since 2002, the VBA estimates that more than 650,000 veterans have been granted benefits because of their Agent Orange exposure. It was not until a 1991 law was passed acknowledging the nature of this chemical agent that Vietnam veterans were recognized as being at risk for health issues as a result of their exposure.

Since then, the U.S. government has spent more than $21 billion on compensation for Vietnam era veterans.

Further studies have resulted in the discovery of potential health problems in children of these veterans. The VA recognizes a limited number of birth defects in children of Vietnam veterans, including spina bifida and 18 other health conditions that occur in children of female veterans.

Healthcare providers should, in the course of gathering thorough health and social histories from patients, determine their veteran status and years and areas of service. While no primary care provider is likely to be able to positively conclude a correlation of current illness with historic Agent Orange exposure, direction should be offered to the patient regarding where to find more information about this issue.

Every veteran should know that: • Agent Orange was an herbicide and defoliant used in Vietnam that may potentially cause serious disease later in life.

• Vietnam era veterans may wish to participate in an Agent Orange Registry health exam. This exam is free and does not require enrollment in VA health care.

• The VA recognizes and offers support for the children of all veterans affected by Agent Orange who have birth defects. (217-6) n

Claire O’Connell, MPH, PA-C,

Katherine Pereira, DNP, FNP,

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

is assistant professor, Duke University School of Nursing, Durham, N.C.

Sherril Sego, FNP-C, DNP,

is an independent consultant in Kansas City, Mo.

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Dermatology Clinic CASE #1

Bilateral periorbital yellow-brown plaques MATTHEW M. WALLACE, BSC, AND JULIA R. NUNLEY, MD

A 62-year-old man with well-controlled rosacea, a monoclonal gammopathy of undetermined significance, and chronic lymphocytic leukemia (CLL; stable on no current therapy) was seen for a full-body skin check. Results of his examination were unremarkable except for the presence of periorbital, yellow-brown plaques with violaceous borders involving the upper and lower eyelids, bilaterally.

There was induration, but no warmth or tenderness, of the periorbital plaques.

What is your diagnosis? Turn to page 72

CASE #2

Six tan patches on a healthy teen MELINDA LIU, BA, AND MAURA HOLCOMB, MD

A healthy 16-year-old girl presents with six tan patches on her trunk and upper arms, freckles in her axillae, and a reddish discoloration under the tip of her thumbnail. The tan patches have been present since birth but have enlarged over the past 4 years. She reports paroxysmal pain and cold sensitivity involving the discolored portion of her thumb.

Examination reveals six tan-brown macules with smooth borders ranging from 16 to 20 mm, axillary freckling, and a tender red-blue nodule under the thumbnail.

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Dermatology Clinic CASE #1

Necrobiotic xanthogranuloma

A subtype of adult orbital xanthogranulomatous disease, necrobiotic xanthogranuloma (NXG) is an uncommon chronic granulomatous condition with cutaneous, ocular, and visceral manifestations.1-4 First described by Kossard and Winkelmann5 in 1980, NXG is a relatively new entity; approximately 150 cases have been documented in the medical literature.

The name is based on the histologic presence of necrobiosis described in eight patients with similar periorbital xanthomatous nodules and plaques.5 Classically, cutaneous NXG presents as yellow-orange-brown papules, indurated nodules, or plaques.1,3,5-7 Secondary features include telangiectasias, violaceous borders, atrophy, ulceration, and scarring.1,3,4,8 NXG most commonly develops within the periorbital region, affecting up to 85% of patients; the trunk and extremities are affected in up to 65% of patients.4,9 Periorbital lesions can be unilateral or bilateral, and can affect upper and/or lower eyelids.3 Approximately 90% of patients have involvement of multiple cutaneous sites.10 Extracutaneous involvement is observed in up to 18% of patients.10 Reported extracutaneous sites include the oral cavity,11 orbit,1,12 mastoid,8 parotid gland,13 lacrimal gland,14 brain,15 facial nerve,8 respiratory tract (larynx, trachea, bronchi, and lung),6,9,16-18 heart,6,19 pericardium,18 liver,1 spleen,6 kidney, 20 penis,8 vulva, 21 ovary,6 skeletal muscle,22 and bone.23 Although lesions are classically asymptomatic, a minority of patients complain of pruritus, tenderness, and/or dysesthesia.6 Ophthalmologic manifestations include episcleritis, uveitis, iritis, keratitis, cellulitis, and proptosis.9 Half of all patients with NXG have ocular symptoms, most commonly burning, dry, and painful eyes.6 Rarely, patients report diplopia or blurry vision.6 The mean age of onset is the fifth decade, with a range from the first to eighth decade, of life.6,9,10 Originally believed to have an equal sex-related ratio,6,9 a recent systematic review revealed a predominance in girls and women of 3:2.10 The presence of NXG is highly associated with the presence of an underlying immunoproliferative disorder; 90% of patients with NXG have a monoclonal gammopathy.9,10 A monoclonal gammopathy of undetermined significance

is present in up to half of all patients, and approximately 17% have multiple myeloma.9,10 Less commonly associated malignancies include non-Hodgkin lymphoma, Hodgkin lymphoma, and chronic lymphocytic leukemia.10,24,25 Hematologic disorders are diagnosed, on average, 2.4 years after the onset of NXG.8 Routine follow-up is necessary to monitor for the development of possible immunoproliferative disorders.2,4,8 Given the potential for visceral involvement and an underlying malignancy, diagnostic screening tests may be extensive. It is reasonable to obtain a complete blood cell count, comprehensive metabolic panel, lipid panel, erythrocyte sedimentation rate (ESR), C-reactive protein level, complement levels, and urine/serum protein electrophoresis or immunofixation.4 A systematic review of 118 patients with NXG demonstrated an elevated ESR in 75% and leukopenia in 54% of patients.1 Another review of 141 patients reported a low serum complement component 4 level and the presence of cryoglobulinemia in 77% and 32% of patients, respectively.10 In those with a monoclonal gammopathy, 95% had immunoglobulin (Ig) G involvement (71% IgGκ and 28% IgGλ); the remaining subjects had either IgA or IgM involvement.1,10 Interestingly, despite the yellowish hue, patients with NXG typically have low to normal lipid levels.26

Necrobiotic xanthogranuloma most commonly develops within the periorbital region, affecting up to 85% of patients.

Depending on clinical suspicion, additional studies, including a bone marrow biopsy, periorbital imaging, or echocardiogram, may be justified.4,17,27 Although laboratory findings are supportive for the diagnosis, physical examination and biopsy are paramount. In addition to the characteristic cutaneous lesions (vide supra), further evaluation may reveal abnormal eye findings, hepatomegaly, splenomegaly, and lymphadenopathy.6 Histopathology results of the suspected lesions should be obtained for confirmation; Mehregan and Winkelmann6 advocate for three biopsies from three different lesions to support the diagnosis.

Several histopathologic findings are characteristic for NXG. Dermal granulomatous inflammation and central necrosis extending into the subcutaneous tissue with sparing of the epidermis is typically seen.1,6 By definition, there are extensive

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areas of necrobiosis, or physiologic cell death with collagen degradation, with cholesterol clefts scattered throughout the area.1,4,10,28 Touton giant cells—multinucleated giant cells with an eosinophilic core and a ring of nuclei extending along the periphery surrounded by a foamy rim of cytoplasm—are typically seen.1,4,10 They are found in areas of high lipid content throughout the xanthogranulomatous lesion.1,4,10 Palisading foamy histiocytes and large foreign-body-type multinucleated giant cells may accompany Touton giant cells in the granulomatous milieu.1,4,10 Lymphocytes, plasma cells, and lymphoid nodules, occasionally with germinal centers, may also be present.1,4,6,10 Supportive immunohistochemical (IHC) findings include positive CD68 and CD163 staining results of the foamy histiocytes and Touton giant cells, confirming monocyte origin.7-10 Negative CD1 and PS100 IH staining results confirm NXG to be a type of non-Langerhans cell histiocytosis.

Disorders that resemble NXG must be considered in the differential diagnosis, including the other adult orbital xanthogranulomatous diseases: adult-onset xanthogranuloma, Erdheim-Chester disease, and adult-onset asthma with periocular xanthogranuloma; hyperlipemic xanthoma and diffuse plane normolipemic xanthoma should also be considered.3 Of these, NXG, hyperlipemic xanthoma, and diffuse plane normolipemic xanthoma are all associated with a monoclonal gammopathy, cholesterol accumulation, and low complement levels with cutaneous and visceral manifestations.10,29 Other cutaneous conditions should also be considered, including xanthelasma, xanthoma disseminatum, juvenile xanthogranuloma, granuloma annulare, foreign body granuloma, subcutaneous rheumatoid nodules, amyloidosis, and atypical sarcoidosis.6,9,10,28 Although the etiology of NXG remains elusive, several proposed hypotheses regarding its pathogenesis exist, all based on unknown triggers. Some postulate that the necrobiotic changes result from immune complex-mediated inflammatory necrosis with a subsequent foreign-body giant cell reaction.28 Others suggest lipid accumulation, along with the giant cell inflammatory reaction, are due to an elevation in macrophage colony-stimulating factor and complement reactions.26 Activation of fibroblasts and dermal macrophages by preexisting monoclonal immunoglobulins has also been proposed.30 An IgG monoclonal gammopathy could incite macrophage activation via their Fc receptors, resulting in xanthogranuloma formation.31 Alternatively, monoclonal immunoglobulins could induce lipid uptake by binding lipoprotein receptors on macrophages.7 Szalat and colleagues29 theorize that heightened cholesterol influx and decreased cholesterol efflux within the macrophage is a fundamental factor.

To date, there is no consensus regarding the most reliable and efficacious treatment regimen for NXG. Various therapeutic modalities have been utilized, with varying success. Given the rarity of the condition, treatment selection relies solely on outcomes reported from individual case series and reports.

The review by Spicknall and Mehregan1 provides a summary of reported treatments and subsequent outcomes. Alkylating medications (chlorambucil, cyclophosphamide, and melphalan), with or without systemic corticosteroids, were the most frequently used agents.1 Of these, melphalan had the best response rate and is the most frequently used agent.1 NXG typically does not respond to topical corticosteroids, although

Given the rarity of NXG, treatment selection relies on outcomes reported from individual case series and reports. intralesional and systemic corticosteroids have provided intermittent success.1 Favorable outcomes have also been reported with azathioprine, thalidomide, and interferon alfa.1 Treatment with methotrexate, dapsone, clofazimine, psoralen and ultraviolet A light, plasmapheresis, and radiation therapy have been used to little or no avail.1 Lesion excision can be curative, although recurrence after surgical intervention is common.1,24 Laser therapy is variably successful.1 Histologic examination of biopsies from the patient in our case revealed the characteristic findings consistent with the diagnosis of NXG, occurring in the setting of both a monoclonal gammopathy and underlying chronic lymphocytic leukemia. Because his disease was confined to the periorbital regions, he was referred to the ophthalmology department; he has had partial response to multiple injections of intralesional triamcinolone.

Matthew M. Wallace, BSc, is a medical student and Julia R. Nunley, MD, is a professor of dermatology and program director of dermatology at the Medical College of Virginia Hospitals of Virginia Commonwealth University in Richmond.

References 1. Spicknall KE, Mehregan DA. Necrobiotic xanthogranuloma. Int J Dermatol. 2009;48(1):1-10.

2. Rose A, Robinson M, Kamino H, Latkowski JA. Necrobiotic xanthogranuloma. Dermatol Online J. 2012;18(12):30.

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Dermatology Clinic 3. Kerstetter J, Wang J. Adult orbital xanthogranulomatous disease: a

22. Yasukawa K, Kato N, Hamasaka A, Hata H. Necrobiotic xanthogranu-

review with emphasis on etiology, systemic associations, diagnostic tools,

loma: isolated skeletal muscle involvement and unusual changes. J Am Acad

and treatment. Dermatol Clin. 2015;33(3):457-463.

Dermatol. 2005;52(4):729-731.

4. Wanat KA, Kim B, Rosenbach M. Multisystem diseases affecting the skin

23. Burdick AE, Sanchez J, Elgart GW. Necrobiotic xanthogranuloma asso-

and eye. Clin Dermatol. 2016;34(2):214-241.

ciated with a benign monoclonal gammopathy. Cutis. 2003;72(1):47-50.

5. Kossard S, Winkelmann RK. Necrobiotic xanthogranuloma with para-

24. Vieira V, Del Pozo J, Martinez W, et al. Necrobiotic xanthogranuloma

proteinemia. J Am Acad Dermatol. 1980;3(3):257-270.

associated with lymphoplasmacytic lymphoma. Palliative treatment with

6. Mehregan DA, Winkelmann RK. Necrobiotic xanthogranuloma. Arch

carbon dioxide laser. Eur J Dermatol. 2005;15(3):182-185.

Dermatol. 1992;128(1):94-100.

25. Balagula Y, Straus DJ, Pulitzer MP, Lacouture ME. Necrobiotic xantho-

7. Fernández-Herrera J, Pedraz J. Necrobiotic xanthogranuloma. Semin

granuloma associated with immunoglobulin M paraproteinemia in a patient

Cutan Med Surg. 2007;26(2):108-113.

with Waldenström macroglobulinemia. J Clin Oncol. 2011;29(11):e305-e307.

8. Wood AJ, Wagner MV, Abbott JJ, Gibson LE. Necrobiotic xanthogranu-

26. Matsuura F, Yamashita S, Hirano K, et al. Activation of monocytes in

loma: a review of 17 cases with emphasis on clinical and pathologic corre-

vivo causes intracellular accumulation of lipoprotein-derived lipids and

lation. Arch Dermatol. 2009;145(3):279-284.

marked hypocholesterolemia—a possible pathogenesis of necrobiotic xan-

9. Ugurlu S, Bartley GB, Gibson LE. Necrobiotic xanthogranuloma: long-

thogranuloma. Atherosclerosis. 1999;142(2):355-365.

term outcome of ocular and systemic involvement. Am J Ophthalmol.

27. Umbert I, Winkelmann RK. Necrobiotic xanthogranuloma with cardiac

2000;129(5):651-657.

involvement. Br J Dermatol. 1995;133(3):438-443.

10. Szalat R, Arnulf B, Karlin L, et al. Pathogenesis and treatment of xanthoma-

28. Bullock JD, Bartley GB, Campbell RJ, et al. Necrobiotic xanthogranu-

tosis associated with monoclonal gammopathy. Blood. 2011;118(14):3777-3784.

loma with paraproteinemia. Case report and a pathogenetic theory.

11. AlGain M, Szalat R, Vignon-Pennamen MD, et al. A rare case of disseminated

Ophthalmology. 1986;93(9):1233-1236.

skin and mucosal necrobiotic xanthogranuloma and xanthoma. J Eur Acad

29. Szalat R, Pirault J, Fermand JP, et al. Physiopathology of necrobiotic xantho-

Dermatol Venereol. 2016 Jan 25. doi: 10.1111/jdv.13577. [Epub ahead of print]

granuloma with monoclonal gammopathy. J Intern Med. 2014;276(3):269-284.

12. Mohsenin A, Sinard J, Huang JJ. Necrobiotic xanthogranuloma and

30. Hallermann C, Tittelbach J, Norgauer J, Ziemer M. Successful treat-

chronic lymphocytic leukemia of the conjunctiva masquerading as scleritis

ment of necrobiotic xanthogranuloma with intravenous immunoglobulin.

and uveitis. Clin Ophthalmol. 2012;6:2045-2047.

Arch Dermatol. 2010;146(9):957-960.

13. Zainal A, Razif MY, Makhashen M, et al. Necrobiotic xanthogranulomas

31. Langlois S, Brochot P, Reguiai Z, et al. Necrobiotic xanthogranuloma

of the parotid gland. J Laryngol Otol. 2010;124(5):569-571.

with multiple myeloma. Case report and pathogenic hypotheses. Joint Bone

14. Tucker NA, Discepola MJ, Blanco G, Burnier MN Jr. Necrobiotic xanthogran-

Spine. 2006;73(1):120-122.

uloma without dermatologic involvement. Can J Ophthalmol. 1997;32(6):396-399.

15. Shah KC, Poonnoose SI, George R, et al. Necrobiotic xanthogranuloma with cutaneous and cerebral manifestations. Case report and review of the literature. J Neurosurg. 2004;100(6):1111-1114.

CASE #2

Neurofibromatosis type 1

16. Fortson JS, Schroeter AL. Necrobiotic xanthogranuloma with IgA paraproteinemia and extracutaneous involvement. Am J Dermatopathol.

1990;12(6):579-584.

17. Winkelmann RK, Litzow MR, Umbert IJ, Lie JT. Giant cell granulomatous pulmonary and myocardial lesions in necrobiotic xanthogranuloma with paraproteinemia. Mayo Clin Proc. 1997;72(11):1028-1033.

18. Bara C, Barbarot S, Hamidou M, et al. Systemic necrobiotic xanthogranuloma with initial pericardial and pulmonary involvement [article in French]. Ann Dermatol Venereol. 2003;130(3):341-344.

19. Novak PM, Robbins TO, Winkelmann RK. Necrobiotic xanthogranuloma with myocardial lesions and nodular transformation of the liver. Hum Pathol. 1992;23(2):195-196.

20. Hunter L, Burry AF. Necrobiotic xanthogranuloma: a systemic disease with paraproteinemia. Pathology. 1985;17(3):533-536.

21. DeLuca IJ, Grossman ME. Vulvar necrobiotic xanthogranuloma. J Am Acad Dermatol. 2014;71(6):e247-e248.

Neurof ibromatosis type 1 (NF1, also known as von Recklinghausen disease) is the most common neurocutaneous disorder.1 It is an autosomal dominant condition with a nearly 100% penetrance and variable expressivity; it occurs due to a spontaneous mutation of the NF1 tumor suppressor gene on chromosome 17q11.2 in up to 50% of patients.1,2 NF1 encodes neurofibromin, a GTPase-activating protein that functions as a negative regulator of Ras signaling. This, in turn, stimulates the mitogen-activated protein kinase pathway, which promotes cell proliferation.1,3

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The most common clinical manifestation of NF1 is caféau-lait macules (CALs), which develop in more than 99% of patients.1 CALs are well circumscribed, uniformly light to dark brown macules 2 to 5 cm in diameter, with a smooth “coast of California” border that most commonly appear on the torso, buttocks, and legs.1-3 CALs typically present at birth, increase in number and size with the growth of the child, and darken with exposure to sun.3 Other cutaneous manifestations of NF1 include Crowe sign, cutaneous neurofibromas, plexiform neurofibromas, nevus anemicus, glomus tumors, and juvenile xanthogranulomas. Crowe sign refers to the numerous 1- to 4-mm brown macules that are commonly found in the intertriginous areas.1

The most common clinical manifestation of NF1 is café-au-lait macules, which develop in more than 99% of patients.

Dermal neurofibromas are benign hamartomatous tumors arising from the supporting connective tissue cells of peripheral nerves and present as dome-shaped or pedunculated, soft, rubbery papulonodules.1,2 Neurofibromas also demonstrate a characteristic “buttonhole” sign of invagination with pressure.1 Unlike cutaneous neurofibromas, which are undetectable before puberty, plexiform neurofibromas grow during early childhood, and approximately 10% undergo transformation into malignant peripheral nerve sheath tumors.1,2 Plexiform neurofibromas may present with hyperpigmentation, hypertrichosis, and thickening of the overlying skin.1 Nevus anemicus, also called hypoemic nevus, is a cutaneous anomaly typically located on the trunk, present in approximately 50% of patients with NF1.

It is characterized by pale, well-defined patches with minimal vascularization after rubbing.1,4,5 Glomus tumors are benign painful tumors on the fingertips and toes that arise from the glomus body, and they occur in approximately 30% of patients who have NF1.1,2 These lesions present with paroxysmal pain, intolerance to cold, localized tenderness, and an ill-defined area of reddish discoloration and swelling.1,2 Diagnosis of NF1 requires two of the seven criteria set by the National Institutes of Health (NIH), which include ≥6

Take-away points for neurofibromatosis type 1 Clinical presentation

Cutaneous manifestations include café-aulait macules, intertriginous macules (Crowe sign), cutaneous neurofibromas, plexiform neurofibromas, nevus anemicus, glomus tumors, juvenile xanthogranulomas

Differential diagnosis

• Other conditions with café-au-lait patches: McCune-Albright syndrome, Noonan syndrome • Conditions with pigmented macules: pigmentary mosaicism, Legius syndrome, LEOPARD syndrome, Peutz-Jeghers syndrome, mastocytoma, speckled lentiginous nevus, Becker nevus • Conditions causing tumors confused with neurofibromas: Bannayan-Riley-Ruvalcuba syndrome, multiple endocrine neoplasia type 2B, lipomatosis

Diagnosis

Meets 2 of 7 National Institutes of Health criteria: ≥6 café-au-lait spots >5 mm in prepubertal and >15 mm in postpubertal patients; ≥ 2 neurofibromas or ≥1 plexiform neurofibromas; freckling in the axillae or groin; optic glioma; ≥2 Lisch nodules; sphenoid dysplasia or cortical thinning of long bones; and a first-degree relative with neurofibromatosis type 1

Management

• No treatment recommended for café-au-lait patches or neurofibromas • Seek expert advice before removal of plexiform neurofibromas • Refer to appropriate specialties for extracutaneous manifestations; patient will require close collaboration of providers of different fields

LEOPARD: lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and deafness

CALs >5 mm in prepubertal and >15 mm in postpubertal patients; ≥2 neurofibromas or ≥1 plexiform neurofibromas; freckling in the axillae or groin; optic glioma; ≥2 Lisch nodules; sphenoid dysplasia or cortical thinning of long bones; and a first-degree relative with NF1.1 Commercially available testing can identify pathogenic NF1 mutations in >95% of nonfounder patients meeting the NIH criteria, which may aid diagnosis of NF1 in young patients who do not yet meet clinical criteria, and may suggest an alternative diagnosis in patients who meet criteria but do not have an identifiable NF1 mutation.1

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Dermatology Clinic

Melinda Liu, BA, is a medical student and Maura Holcomb, MD, is a dermatology resident at Baylor College of Medicine in Houston.

“People pay me to put steps on their Fitbits.”

“Not guilty, Your Honor, the menu clearly says ‘Death by Chocolate’ ” © The New Yorker Collection 2016 from cartoonbank.com. All Rights Reserved.

The differential diagnoses include other conditions with CALs, including McCune-Albright syndrome, Noonan syndrome, DNA repair syndromes, conditions with pigmented macules that can be confused with neurofibromas, including LEOPARD (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and deafness) syndrome, neurocutaneous melanosis, PeutzJeghers syndrome, mastocytoma, speckled lentiginous nevus, and conditions causing tumors that can be confused with neurofibromas, including lipomatosis, Bannayan-RileyRuvalcaba syndrome, and fibromatoses.1,3,6 Treatment of NF1 requires close collaboration of clinicians of multiple specialties, including neurology, pediatrics, genetics, ophthalmology, neurosurgery, plastic surgery, orthopedics, soft tissue tumor surgery, psychiatry, dermatology, radiology, and pathology, in order to facilitate a uniform approach to diagnoses and management of the condition and its complications.6 With regard to the dermatologic manifestations, treatment is not recommended for CALs or neurofibromas.6 Neurofibromas, in particular, should not be exposed to excessive heat or use of emollients, and expert advice should be sought prior to the removal of plexiform neurofibromas.6 The patient in our case was diagnosed with NF1 based on clinical findings, referred to a neurofibromatosis specialist for a thorough evaluation of musculoskeletal, cardiovascular, and neurologic systems, referred to an ophthalmologist for slit-lamp examination, and scheduled for a medical genetics consultation. ■

References 1. Chernoff KA, Schaffer JV. Cutaneous and ocular manifestations of neurocutaneous syndromes. Clin Dermatol. 2016;34(2):183-204.

2. Jouhilahti EM, Peltonen S, Heape AM, Peltonen J. The pathoetiology of neurofibromatosis 1. Am J Pathol. 2011;178(5):1932-1939.

3. Shah KN. The diagnostic and clinical significance of café-au-lait macules.

Pediatr Clin North Am. 2010;57(5):1131-1153.

4. Tadini G, Brena M, Pezzani L, et al. Anemic nevus in neurofibromatosis type 1. Dermatology. 2013;226(2):115-118.

5. Hernández-Martín A, García-Martínez FJ, Duat A, et al. Nevus anemicus: a distinctive cutaneous finding in neurofibromatosis type 1. Pediatr Dermatol. 2015;32(3):342-347.

6. Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet.

2007;44(2):81-88.

“Well, if I practiced all day, too.”

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Dermatologic Look-Alikes Blisters and erosions MELINDA LIU, BA, AND MAURA HOLCOMB, MD

CASE #1

CASE #2

A 60-year-old man with a history of Hashimoto thyroiditis and rheumatoid arthritis presents with a 3-month history of painful blisters and erosions, which initially presented in his oral mucosa and spread to his skin.

Two months ago, he was prescribed captopril for blood pressure control. Examination reveals erosions of his oropharyngeal mucosa and flaccid bullae on his scalp, face, neck, trunk, and groin. These bullae are positive for direct and indirect Nikolsky sign.

A 70-year-old man who recently began therapy with a diuretic and an angiotensin-converting enzyme inhibitor for hypertension presents with tense blisters on his skin. He had been prescribed a topical corticosteroid for intractable eczema 1 month earlier. Examination reveals tense blisters filled with serous fluid localized to the trunk and flexural aspects of the extremities. The oral cavity, face, and neck are free of lesions. Results of a test for a Nikolsky sign are negative.

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Dermatologic Look-Alikes CASE #1

Pemphigus vulgaris

Pemphigus vulgaris (PV) is an autoimmune bullous disease characterized clinically by flaccid blisters and erosions on the skin and mucous membranes, and histologically by acantholysis.1 Annual incidence rates range from 0.76 to 32 cases per million, and it is more frequently diagnosed in the fourth and fifth decades of life, especially in people of Jewish and Mediterranean ancestry.1-3 This condition is associated with a high mortality rate; however, the introduction of corticosteroids dramatically improved prognosis.3,4 It remains a life-threatening disease, largely due to complications of treatment.4 PV is also associated with other autoimmune diseases, including autoimmune thyroid diseases, myasthenia gravis, Sjögren syndrome, and rheumatoid arthritis.3 Triggering factors include medications and viral infections, but, in most cases, the trigger cannot be identified.3,5 PV is mediated by autoantibodies against desmosomes, which results in intraepidermal blisters, and it is the most common category of pemphigoid diseases.1,6 Clinically, PV classically presents with flaccid blisters that easily rupture, leaving painful erosions.7 Lesions initially present on the mucous membranes, especially the oral mucosa, and are followed by cutaneous involvement months later, most commonly on the scalp, face, neck, trunk, and groin.1,3,7 During active PV, both the direct and indirect Nikolsky signs are positive.1,7 The direct Nikolsky sign refers to exfoliation of the epidermis with slight rubbing of perilesional skin, and the indirect Nikolsky refers to that ability to laterally shift and enlarge the intact blister with pressure.1,7 The two major forms of PV are the mucosal dominant type and the mucocutaneous type.1 Diagnosis of PV is based on a combination of clinical and histopathologic features. Histologically, PV is characterized by the presence of acantholysis, which refers to the loss of keratinocyte adhesion, with formation of suprabasilar blisters.7 The residual basal keratinocytes at the base of the blister floor on the dermoepidermal junction zone result in the characteristic “tombstone effect.”1 Direct immunofluorescence shows intercellular immunoglobulin (Ig) G with or without C3 deposition on the cell surfaces of the keratinocytes in a honeycomb-like pattern.1,7 Indirect immunofluorescence shows a reticular pattern of desmoglein-3 IgG autoantibodies against epithelial

surfaces.1,7 Finally, an enzyme-linked immunosorbent assay (ELISA) result is positive for IgG or IgA autoantibodies against desmoglein-1 and desmoglein-3.1 ELISA is highly sensitive and specific for these PV autoantibodies; however, it is not a routine test and is indicated in difficult cases.7 The differential diagnosis for PV includes bullous pemphigoid (BP); however, this condition is characterized by tense blisters that typically do not involve the mucous membranes.8 The differential diagnosis may also include pemphigus foliaceus (PF); however, unlike PV, PF rarely involves the mucous membranes. Another condition that should be considered is dermatitis herpetiformis; however, it usually presents with pruritic papules and vesicles symmetrically distributed on the extensor surfaces instead of bullae.9 Erythema multiforme is another condition that is in the differential for PV, although it is characterized by a papule, vesicle, or a bulla surrounded by Take-away points for pemphigus vulgaris Clinical presentation

• Characterized by flaccid bullae and painful erosions involving the mucous membranes, scalp, face, neck, trunk, and groin • During active PV, both the direct Nikolsky sign (exfoliation of the epidermis with slight rubbing of perilesional skin) and indirect Nikolsky sign (ability to laterally shift and enlarge the intact blister with pressure) are positive • The two most common forms of PV are the mucosal dominant type and the mucocutaneous type

Differential diagnosis Bullous pemphigoid, pemphigus foliaceus, dermatitis herpetiformis, erythema multiforme Diagnosis

• Diagnosed through a combination of clinical, histopathologic, and immunohistochemical features • On histology, it is characterized by acantholysis and the “tombstone effect,” caused by the residual basal keratinocytes at the dermoepidermal junction zone • Immunohistochemical studies are positive for IgG or IgA autoantibodies against desmoglein-1 and desmoglein-3

Management

• Primary goal is to heal active lesions, decrease impairment in function, and maintain remission • Gold standard of therapy: oral glucocorticoids; however, they are associated with many side effects • First-line steroid-sparing agents: azathioprine and mycophenolate • Second-line steroid-sparing agents: high-dose intravenous immunoglobulin and rituximab

Ig: immunoglobulin; PV: pemphigus vulgaris.

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a purpuric macule or plaque resulting in a target sign.10 Also, test results for a direct Nikolsky sign are negative.10 The primary objective in treatment of PV is to heal the lesions, to decrease the associated impairment in function, and to maintain remission.1,2,6 Glucocorticoids alone or in combination with a steroid-sparing immunosuppressive agent are the gold standard of treatment.1,2,6 As a result of the introduction of oral glucocorticoids in PV therapy, its mortality rate has dropped from 75% to <10%.2 Unfortunately, it is associated with many side effects, including metabolic syndrome, cataracts, and loss in bone density.2 Azathioprine and mycophenolate mofetil are the first-line steroid-sparing agents.1,6 Other interventions that may be effective include high-dose intravenous immunoglobulin (IVIG) and rituximab, though the optimal dose of rituximab is unknown and its efficacy and safety need to be evaluated against oral glucocorticoids.6 The patient in our case was successfully treated with a course of oral corticosteroids with IVIG. The patient was then transitioned to azathioprine and the corticosteroid dose was reduced, with the goal of eliminating the need for corticosteroids completely. He is also on concomitant calcium and vitamin D supplements and bisphosphonates.

CASE #2

Bullous pemphigoid

Bullous pemphigoid (BP) is an autoimmune bullous disease mediated by autoantibodies directed against hemidesmosomes and characterized by tense, pruritic bullae.11,12 Annual incidence ranges from six to 14 cases per million, and it increases sharply with age; peak manifestation is at 70 years, making it the only autoimmune disease in which incidence increases with age.12,13 Patients typically have a chronic course with recurrences and a poor prognosis, mostly due to side effects of treatment, the advanced age of the patient, and other associated medical conditions.12 The most common associated diseases include neurologic and cardiovascular diseases and malignancies.12,14 Triggering factors include medications, especially diuretics, analgesics, captopril, and antibiotics; physical agents, including radiation therapy; surgical procedures and burns; and herpes virus infections.12,15 However, a triggering factor can only be

identified in approximately 15% of cases.4 Possible causes of BP include an imbalance between autoreactive T helper (Th) cells and T regulatory cells, Toll-like receptor activation, and Th17/ interleukin 17 pathway overactivation.11 Autoantibodies against the structural components of the hemidesmosome (BP180 and BP230) induce complement activation, recruitment of inflammatory cells, and the release of proteolytic enzymes.11 Clinically, BP presents with large, pruritic, tense serous or hemorrhagic blisters localized to the trunk and flexural aspects of the extremities.13,16 These lesions appear on erythematous, urticarial, eczematous lesions or apparently normal skin, the blisters evolve into eroded or crusted areas, and the lesions heal without scarring.16 Typically, BP does not involve the oral cavity, face, or neck.17 Lesions are preceded by intractable pruritic eczema-like or urticarial eruption, called the nonbullous phase, that lasts weeks to months.11 Diagnosis of BP is based on a combination of clinical, histopathologic, and immunologic criteria.18 Histologically, BP is characterized by subepidermal blisters with an eosinophilic infiltration.13 Direct immunofluorescence (DIF) demonstrating deposition of both IgG and C3 along the basement membrane is the gold standard for BP diagnosis.18 The salt-split DIF technique showing IgG/C3 deposit at the blister roof can be used to distinguish between BP and other bullous conditions.13 Another technique helpful for BP diagnosis is indirect immunofluorescence, which is positive for anti-bullous pemphigoid antigen 1and 2 at the basement membrane on monkey esophagus (monkey esophagus is a standard substrate for indirect immunofluorescence in BP).19 Finally, positive enzyme-linked immunosorbent assay (ELISA) results for autoantibodies against BP180 and BP230 are also indicative for BP.18 The differential diagnosis includes acquired epidermolysis bullosa (AEB) and bullous systemic lupus erythematosus (SLE). AEB commonly presents with tense vesicles and bullae located primarily on the extensor surfaces of the extremities and on the mucous membranes, unlike BP.10 Bullous SLE presents with large, tense, widespread and symmetrically distributed bullae typically on the upper part of the trunk, proximal upper extremities, neck, and face.13,20 However, both AEB and bullous SLE only demonstrate IgG deposits on the base of the blister.20 BP in the nonbullous phase may resemble chronic prurigo, eczema, and urticaria; however, it is very difficult to treat and will eventually progress to the classic bullae of BP.16 Treatment goals for BP are to alleviate the symptoms, shorten the duration of each flare, and maintain remission.11,20 Historically, the mainstay of BP treatment involved systemic

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Dermatologic Look-Alikes Take-away points for bullous pemphigoid Clinical presentation

• Characterized by large, tense, serous or hemorrhagic bullae localized to the trunk and flexural aspects of the extremities; rarely affects the oral cavity, face, and neck • Bullae often preceded the nonbullous phase, which lasts weeks to months and is characterized by an intractable pruritic eczema-like or urticarial eruption

2. Atzmony L, Hodak E, Gdalevich M, et al. Treatment of pemphigus vulgaris and pemphigus foliaceus: a systematic review and meta-analysis. Am J Clin Dermatol. 2014;15(6):503-515.

3. Alpsoy E, Akman-Karakas A, Uzun S. Geographic variations in epidemiology of two autoimmune bullous diseases: pemphigus and bullous pemphigoid. Arch Dermatol Res. 2015;307(4):291-298.

4. Cirillo N, Cozzani E, Carrozzo M, Grando SA. Urban legends: pemphigus vulgaris. Oral Dis. 2012;18(5):442-458.

5. Ruocco E, Ruocco V, Lo Schiavo A, et al. Viruses and pemphigus: an

Differential diagnosis

• Bullous phase: pemphigus vulgaris, acquired epidermolysis bullosa, bullous systemic lupus erythematosus • Nonbullous phase: chronic prurigo, eczema, urticaria

intriguing never-ending story. Dermatology. 2014;229(4):310-315.

6. Zhao CY, Murrell DF. Pemphigus vulgaris: an evidence-based treatment update. Drugs. 2015;75(3):271-284.

7. Panelius J, Meri S. Complement system in dermatological diseases—fire under the skin. Front Med (Lausanne). 2015;2:3.

Diagnosis

Management

• Diagnosed through a combination of clinical, histopathologic, and immunohistochemical features • On histology, characterized by subepidermal blisters • Direct immunofluorescence demonstrating immunoglobulin G and C3 deposit along the basement membrane is the gold standard • Immunohistochemical studies are positive for autoantibodies against BP180 and BP230 • Primary goal is alleviate symptoms, shorten duration of the flare, and maintain remission • First-line therapy: topical clobetasol • First-line steroid-sparing therapy: azathioprine • Other potentially useful treatments: mycophenolate mofetil, methotrexate, intravenous immunoglobulin, and cyclophosphamide

8. Arbache ST, Nogueira TG, Delgado L, et al. Immunofluorescence testing in the diagnosis of autoimmune blistering diseases: overview of 10-year experience. An Bras Dermatol. 2014;89(6):885-889.

9. Plotnikova N, Miller JL. Dermatitis herpetiformis. Skin Therapy Lett.

2013;18(3):1-3.

10. Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol. 2012;51(8):889-902.

11. Ruocco E, Wolf R, Caccavale S, et al. Bullous pemphigoid: associations and management guidelines: facts and controversies. Clin Dermatol. 2013;31(4):400-412.

12. Alpsoy E, Akman-Karakas A, Uzun S. Geographic variations in epidemiology of two autoimmune bullous diseases: pemphigus and bullous pemphigoid. Arch Dermatol Res. 2015;307(4):291-298.

13. Baum S, Sakka N, Artsi O, et al. Diagnosis and classification of autoimmune blistering diseases. Autoimmun Rev. 2014;13(4-5):482-489.

corticosteroids.11,18 However, recent literature indicates that topical clobetasol propionate is equally effective and superior to oral prednisolone with regard to overall survival, disease control, and adverse event profile in patients with extensive BP.18 Thus, topical clobetasol is now the first-line treatment for active BP.18 The first-line immunosuppressive and steroidsparing therapy is azathioprine.18 Other therapies that may be useful include mycophenolate mofetil, methotrexate, intravenous immunoglobulin, and cyclophosphamide.11 The patient in our case is currently managed with topical clobetasol. ■

14. Lo Schiavo A, Ruocco E, Brancaccio G, et al. Bullous pemphigoid: etiology, pathogenesis, and inducing factors: facts and controversies. Clin Dermatol. 2013;31(4):391-399.

15. Stavropoulos PG, Soura E, Antoniou C. Drug-induced pemphigoid: a review of the literature. J Eur Acad Dermatol Venereol. 2014;28(9):1133-1140.

16. Cozzani E, Gasparini G, Burlando M, et al. Atypical presentations of bullous pemphigoid: clinical and immunopathological aspects. Autoimmun Rev. 2015;14(5):438-445.

17. Kershenovich R, Hodak E, Mimouni D. Diagnosis and classification of pemphigus and bullous pemphigoid. Autoimmun Rev. 2014;13(4-5):477-481.

18. Zhao CY, Murrell DF. Advances in understanding and managing bullous pemphigoid [published online ahead of print Nov. 20, 2015]. F1000Res. doi:

Melinda Liu, BA, is a medical student and Maura Holcomb, MD, is a dermatology resident at Baylor College of Medicine in Houston.

10.12688/f1000research.6896.1 19. Nishie W. Update on the pathogenesis of bullous pemphigoid: an autoantibody-mediated blistering disease targeting collagen XVII. J Dermatol Sci.

References

2014;73(3):179-186.

1. Gregoriou S, Efthymiou O, Stefanaki C, Rigopoulos D. Management of

20. Reis-Filho EG, Silva Tde A, Aguirre LH, Reis CM. Bullous pemphigoid in

pemphigus vulgaris: challenges and solutions. Clin Cosmet Investig Dermatol.

a 3-month-old infant: case report and literature review of this dermatosis

2015;8:521-527.

in childhood. An Bras Dermatol. 2013;88(6):961-965.

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Conference Roundup American Thyroid Association 86th Annual Meeting Denver

SERUM TSH LEVELS IN PREGNANCY LINKED TO PREMATURITY IN OFFSPRING Serum thyrotropin (TSH) concentrations above the trimester-specific ranges in pregnancy appear to be associated with a 52% increased risk of prematurity in offspring, according to new data.

Researchers assessed potential associations between elevated maternal TSH levels during pregnancy using trimester-specific reference ranges as recommended by the American Thyroid Association guidelines in 2011.

The investigators looked at adverse obstetric or perinatal outcomes. Adverse obstetric outcomes included fetal loss, preterm labor, placental abruption, preeclampsia/eclampsia, cesarean section, gestational hypertension, and gestational diabetes. They also assessed adverse perinatal outcomes, which included prematurity, respiratory distress syndrome, admission to neonatal intensive care unit, and low birth weight.

“We found that offspring of mothers with elevated TSH levels above the trimester-specific reference ranges in pregnancy had a 1.52 times higher risk of prematurity,” said investigator Sun Y. Lee, MD, of Boston University School of Medicine. “The findings of our study are clinically relevant as they add to the existing evidence potentially advocating for thyroid function testing in pregnant women, with a simple treatment of levothyroxine if needed.”

Dr Lee noted that there is conflicting evidence regarding the effects of maternal subclinical hypothyroidism on adverse pregnancy outcomes. Subsequently, she said there is ongoing debate regarding universal screening, which would largely identify those with subclinical

Elevated serum TSH concentration did not predict fetal loss, preterm labor, placental abruption, preeclampsia, eclampsia, or gestational hypertension.

hypothyroidism, as compared with a casefinding approach. She noted a case-finding approach would largely only identify those with overt and more symptomatic hypothyroidism and so only those women would be referred for thyroid function testing during their pregnancy.

The researchers performed a retrospective cohort study of women aged at least 18 years with a singleton gestation. All the women were seen for prenatal care at Boston Medical Center between January 2007 and May 2014.

The infant data were obtained from electronic medical records. The investigators excluded any women with thyroid disease or thyroid medication or lithium use.

Maternal demographics, pertinent medical and obstetric history, and serum TSH levels from the first prenatal visit were used to predict adverse obstetric and perinatal outcomes. The investigators used trimester-specific ranges to define normal TSH values (first trimester, 0.1– 2.5mIU/L; second trimester, 0.–3mIU/L; third trimester, 0.3–3mIU/L.). Low birth weight was defined as 2500 g or less and prematurity was defined as gestational age at birth of less than 37 weeks.

The analysis included 6100 pregnant women (mean age, 29.4 years) with trimester-specific TSH values during pregnancy. The group was diverse: 17% of the women were white, 60% were black, and 14% were Latino. The mean gestational age at birth was 38.5 weeks.

The investigators found that 3844 of the women (63%) had TSH measured in the first trimester. Among these women, 383 (6.3%) had elevated trimester-specific TSH values, with a median of 3.33 mIU/L (range, 2.51–22.38 mIU/L). Dr Lee said elevated serum TSH levels in any trimester of pregnancy were associated

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with increased risks of prematurity compared with normal serum TSH values, after the researchers adjusted for potential confounders.

The investigators found that elevated serum TSH concentration did not predict fetal loss, preterm labor, or placental abruption. It also did not predict preeclampsia/eclampsia, cesarean section, gestational hypertension, and gestational diabetes. The same was true for neonatal respiratory distress syndrome, neonatal admission to intensive care unit, or low birth weight. In this cohort, there were no neonatal deaths.

“Our findings add to the evidence on potentially adverse effects of maternal subclinical hypothyroidism. More research with prospective data and information regarding presence of thyroid autoimmunity is needed to inform the debate,” said Dr Lee.

© DAVID GEE 2 / ALAMY STOCK PHOTO

CONGENITAL HYPOTHYROIDISM MAY BE UNDIAGNOSED IN A SIGNIFICANT NUMBER OF INFANTS The management of congenital hypothyroidism may be suboptimal in newborns, according to researchers.

Between 2006 and 2015 in Utah, the American Academy of Pediatrics (AAP) guidelines regarding screening for and treatment of congenital hypothyroidism in newborns were not always met, the investigators noted. This resulted in increased long-term disability due to the delayed diagnosis and inadequate treatment of the condition.

The researchers analyzed all the thyroid-stimulating hormone (TSH) values from two-thirds of all babies born in Utah between 2006 and 2015. The goal was to develop a normal range of TSH values in infants and children.

A Guthrie test is used to detect congenital hypothyroidism, which is inadequately treated in about half of children with the disorder.

“We were surprised to find that 50% of infants with congenital hypothyroidism had a delayed diagnosis of congenital hypothyroidism and 50% of children with congenital hypothyroidism were inadequately treated. A child with untreated congenital hypothyroidism will permanently lose up to half of an IQ point per day during the first month of life,” said study investigator Joel Ehrenkranz, MD, director of diabetes and endocrinology at Intermountain Healthcare in Murray, Utah.

The AAP recommends measuring TSH in all newborns so that infants with congenital hypothyroidism are diagnosed by 14 days of life, noted Dr Ehrenkranz. The association also recommends initiating immediate treatment with the goal of serum TSH lower than 5 mIU/L within 1 month of starting thyroxine replacement. The goal of the study conducted by Dr Ehrenkranz and colleagues was to assess whether the diagnosis and treatment of infants with congenital hypothyroidism in Utah corresponded to AAP guidelines.

The team obtained TSH measurements between 2006 and 2015 in 4394 children younger than 2. TSH was measured using a third generation chemiluminescent immunoassay.

The researchers found that the number of TSH measurements per infant varied from 1 to 18. An infant’s first TSH measurement was designated the initial TSH and those thereafter were designed subsequent TSH measurements.

The study showed that 82 of the 4394 (1.9%) infants referred for TSH measurement had an initial TSH of 20 mIU/L or greater.1 In addition, 43 infants (1.0%) were found to have an initial TSH of 20 mIU/L or greater by day 14 of life.1 The researchers found that delayed diagnosis of congenital hypothyroidism occurred in 39 of 82 (48%) infants referred for TSH immunoassay. In addition, 42 of 82 (51%) infants with congenital hypothyroidism were inadequately treated based on TSH greater than 5 mIU/L 1 month or more after the initial TSH of 20 mIU/L or greater. The study also showed that 39 infants had a delayed diagnosis of congenital hypothyroidism, defined as an initial TSH of 20 mIU/L or greater in an infant older than 14 days.

© ISM / PHOTOTAKE

Conference Roundup

ATA SONOGRAPHIC PATTERN RISK ASSESSMENT GUIDELINES VALIDATED A new prospective study has validated the newly adopted American Thyroid Association (ATA) sonographic pattern risk assessment for selection of thyroid nodules undergoing ultrasound-guided fine needle aspiration (FNA) based on Bethesda cytology and surgical pathology results. In addition, the study validates that cytological indeterminate nodules

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© JAMES CAVALLINI / SCIENCE SOURCE

with an ATA high-risk sonographic pattern have a high likelihood of being malignant.

Investigators examined the ATA sonographic pattern risk assessment (high, intermediate, low, and very low) of 211 thyroid nodules. All the nodules were selected for ultrasound-guided FNA, with evaluation of the results based on the Bethesda System for Reporting Thyroid Cytopathology. The researchers also looked separately at the surgical pathology results for the subset undergoing surgical excision.

“I was pleasantly surprised because it confirmed the risk estimates that the ATA had proposed in the recent guidelines published in January. So, we prospectively validated those recommendations,” said study investigator David Steward, MD, professor of otolaryngology–head and neck surgery at the University of Cincinnati in Ohio. He noted that traditionally nodules were biopsied based on their size. Although nodule size is still incorporated into the equation, clinicians now take into account sonographic assessment of the nodule.

The study included 199 patients (157 women and 42 men).

The 211 thyroid nodules averaged 2.4 cm in size (range, 1–7 cm). The investigators used the ATA ultrasound pattern risk assessment and the nodules were classified as high risk (4%), intermediate risk (31%), low risk (38%), or very low risk (26%) of malignancy.

The researchers found that the size of the nodules selected for ultrasound-guided FNA was inversely correlated with sonographic risk assessment. Specifically, they found that lower-risk nodules were larger on average, consistent with the ATA guidelines recommendation to only biopsy nodules with sonographically low- or very low-risk patterns if they are large.

In addition, results showed that the malignancy rates determined from cytology or permanent pathology varied significantly by ATA sonographic risk. For high-risk and intermediate-risk nodules, the rates were 100% and 17%, respectively. The rates were 12% for low-risk and 1% for very low-risk nodules. These are similar to the ATA estimated risks of 70% to 90% for high, 10% to 20% for intermediate, 5% to 10% for low, and less than 3% for very low risk.

The study also demonstrated that the distribution of Bethesda cytology classification varied significantly by ATA ultrasound pattern risk assessment. The high-risk nodules were 77% malignant or suspicious for malignancy and 22% atypical. For intermediate-risk nodules, 6% were malignant or suspicious for malignancy, 30% were atypical, 8% were follicular or Hürthle neoplasm, 47% were benign, and 9% were nondiagnostic. For the low-risk nodules, 1% were

Ultrasound showing a nodular tumor in the thyroid gland.

malignant or suspicious for malignancy, 25% were atypical or a follicular lesion of undetermined significance, 5% were follicular or Hürthle neoplasms, 61% were benign, and 8% were nondiagnostic. For the very low-risk nodules, 30% were deemed atypical or follicular lesions of undetermined significance and 70% were benign.

The researchers found that the malignancy rates of atypical cytological indeterminate nodules surgically excised also varied significantly by ATA sonographic risk. Rates were 100% and 21% for high- and intermediate-risk nodules, respectively, and 17% and 12% for low- and very low-risk nodules, respectively.

“It is not the first study to show the high positive predictive value of a high-risk sonographic pattern in cytological atypical indeterminate nodules, but it prospectively confirms the ATA guidelines recommendations,” said Dr Steward.

“It is important to have this knowledge that the sonographic pattern of the nodule will accurately stratify risk of malignancy from high to intermediate, low, and very low categories as suggested by the ATA guidelines so that physicians can inform patients of the likelihood of their nodule being benign or malignant based on the ultrasound and make an informed decision about whether to undergo needle biopsy,” he noted. “Further, if the biopsy is performed and comes back indeterminate for malignancy the sonographic risk assessment can help decision-making regarding possibly proceeding with surgery.” ■ These articles originally appeared on EndocrinologyAdvisor.com

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Stat Consult

A quick review of common conditions, using the best global evidence

Who is most affected

Celiac disease

• women more common than men (2.3:1) Incidence/prevalence

• annual incidence — 0.9 to 12.9 per 100,000 worldwide — 6.5 per 100,000 in 2008 in USA • prevalence 8.1 to 204 per 100,000 Likely risk factors

BY ALAN DRABKIN, MD

Dr. Drabkin is a senior clinical writer for DynaMed (www.ebscohost. com/dynamed), a database of comprehensive updated summaries covering more than 3,200 clinical topics, and assistant clinical professor of population medicine at Harvard Medical School..

• family history of CD • Down syndrome • HLA haplotype DR3-DQ2 Possible risk factors

• cesarean section • Turner syndrome • Williams syndrome Factors not associated with increased risk: in children

• breastfeeding duration, age, concurrent infection or gastroenteritis at time of gluten introduction • pertussis, Haemophilus influenzae type b, and measles/mumps/rubella vaccines

© BIOPHOTO ASSOCIATES / SCIENCE SOURCE

Associated conditions

In celiac disease, the surface pattern of the jejunal mucosa becomes flattened.

• Malignancy — lymphoma — small bowel and stomach cancer — non-Hodgkin lymphoma • Dermatologic — dermatitis herpetiformis — xerosis — keratosis pilaris • Immunologic — IgA deficiency — common variable immune deficiency • Rheumatologic — Sjogren syndrome — rheumatoid arthritis • Gastrointestinal — esophagitis — microscopic colitis Continues on page 89

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Stat Consult — irritable bowel syndrome • Endocrine — diabetes mellitus type 1 — thyroid disease in children • Neurologic — epilepsy • Kidney disease — IgA nephropathy • Liver disease — non-alcoholic fatty liver disease, PBCs, autoimmune cholangitis, elevated liver transaminases Causes

• autoimmune disorder with 2 primary components — genetic predisposition (presence of HLA-DQ2 or HLA-DQ8 haplotypes) — environmental trigger (ingestion of gluten-a storage protein found in wheat, barley, and rye)

— histologic changes in small intestinal mucosa include ■ partial to complete villous atrophy ■ crypt lengthening with increase in lamina propria ■ increase in intraepithelial lymphocytes • may need gluten challenge testing (if patients already on gluten-free diet, which can lead to normal serology and histology) Differential diagnosis

• other causes of villous atrophy include — tropical sprue — collagenous sprue — autoimmune enteropathy — AIDS enteropathy • allergic enterocolitis (milk protein allergy, soy allergy, rice allergy) • infectious gastroenteritis • microscopic colitis • lymphoma

History

• Chief concern — gastrointestinal symptoms may include chronic diarrhea, chronic constipation, abdominal pain, nausea vomiting, distended abdomen, and flatulence — abdominal complaints most common clinical presentation among children • Review of systems — extraintestinal signs and symptoms may include ■ Failure to thrive, stunted growth, delayed puberty ■ chronic anemia, osteopenia/osteoporosis, dental enamel defects, irritability, chronic fatigue, neuropathy, arthritis/arthralgia, amenorrhea, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) Physical

• Skin — dermatitis herpetiformis • HEENT — aphthous stomatitis — teeth discolored or enamel defects • Abdomen — abdominal distention, bloating with pain or cramping • Neuro — peripheral neuropathy Making the diagnosis

• confirm diagnosis if both — positive CD-specific serology

Testing overview

• testing recommended in patients with — suspected malabsorption — symptoms, signs, or laboratory evidence consistent with CD especially if first-degree relative with CD or type 1 diabetes — unexplained elevated alpha-1 antitrypsin (AAT) levels — children and adolescents with unexplained gastrointestinal symptoms, failure to thrive, delayed puberty, amenorrhea, iron deficiency anemia, or chronic fatigue • consider screening asymptomatic patients for — first-degree relatives of patients with confirmed CD — children and adolescents with increased risk ■ diagnosis of type 1 diabetes; family history of CD; growth failure, failure to thrive, or weight loss; diarrhea, flatulence, abdominal pain, or signs of malabsorption; frequent unexplained hypoglycemia; deterioration in glycemic control • serology testing recommended early in evaluation process (gluten still included in diet) — IgA anti-tissue transglutaminase antibody (tTG) is preferred single serologic test in patients >2 years old — if high risk of CD and possible IgA deficiency, measure total IgA or add immunoglobulin G (IgG)-based testing (for example, IgG deamidated gliadin peptides [DGPs]) — in children <2 years old, include IgA tTG test, and IgA- and IgG-DGPs — if IgA tTG >10 times upper limit of normal, consider

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Stat Consult • •

•

•

testing endomysial antibody and HLA-DQ serotyping to diagnose CD without endoscopy and biopsy HLA-DQ2 or DQ8 genotyping may rule out CD if other testing indeterminate upper endoscopy with small-bowel biopsy recommended to confirm diagnosis in patients with suspected CD; obtain multiple biopsies of duodenum including 1-2 of bulb and ≥ 4 of distal duodenum consider gluten challenge test if unable to establish diagnosis in patient on gluten-free diet — if symptoms develop and patient unable to tolerate in 2 weeks, proceed to biopsy — perform serology testing after 6 weeks consider testing for nutritional deficiencies (hemoglobin, iron, folate, vitamin B12, calcium, and vitamin D)

• Dietary supplements — select B vitamins may be associated with reduced anxiety and depressed moods in adults on strict gluten-free diet — L-carnitine might reduce fatigue in adults • Immunosuppressants — often considered necessary, but mostly anecdotal experience • Autologous hematopoietic stem cell transplantation — limited evidence in refractory CD Consultation and referral

• ACG 2013 recommends referral to registered dietitian experienced in CD for full nutritional assessment and gluten-free diet education • referral to support group and membership in a local celiac society may promote compliance with gluten-free diet

Treatment

Complications

• lifelong gluten-free diet recommended with avoidance of proteins from wheat, barley, and rye — all initial serology testing and biopsies should be performed before starting gluten restriction — avoid gluten in foods and medications; refer to registered dietitian experienced in CD — gluten-free diet may reduce symptoms in patients with positive endomysial antibodies and mild enteropathy — amount of gluten that causes symptoms varies among patients with CD — strict adherence to gluten-free diet for >5 years might reduce risk for non-Hodgkin lymphoma — oats and wheat starch-based gluten-free products in diet appear safe • treat nutritional deficiencies including iron, folate, vitamin B12, and vitamin D • in patients with newly diagnosed CD who also have anxiety and depression, adding psychological support when starting gluten-free diet associated with lower rates of depression after 6 months • consider medications in refractory CD (anecdotal use) such as — pancreatic enzyme — corticosteroids — immunosuppressants • monitor for new or residual symptoms, gluten-free diet adherence, and complications • follow-up for children to confirm normal growth and development; (consider BMD testing for osteoporosis) • introduce oats (kilned [regular] and unkilned) into diet and monitor for adverse reaction

• nutritional — iron deficiency anemia — vitamin D deficiency — malabsorption of micronutrients including fat-soluble vitamins, iron, and possibly vitamin B12 and folic acid • reproductive — reduced fertility in women for 2 years before diagnosis — recurrent spontaneous abortions, intrauterine growth restriction, preterm birth, and stillbirth • developmental complications — growth failure/short stature — failure to thrive — delayed puberty and menarche • low bone mineral density Prognosis

• increased all-cause mortality and non-Hodgkin lymphoma • increased risk of — end-stage renal disease — lymphoproliferative malignancy Prevention

• Timing of gluten introduction — delayed introduction of gluten-containing foods to >age 6 months may increase risk of CD compared to introduction at age 4 to 6 months — timing of gluten introduction in at-risk infants does not appear to affect risk of CD at age 3 to 5 years • Breastfeeding — inconsistent evidence regarding breastfeeding and reduced risk of CD ■

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LEGAL ADVISOR CASE

Outdated vaccine protocol

ANN W. LATNER, JD

Ms P was a nurse practitioner (NP) who was employed by a busy pediatricians’ office. There were two physicians and three NPs in the practice. Ms P was the newest and had only started in mid-2008. She primarily handled well-child visits and was responsible for making sure that a patient’s immunizations were up-to-date. The practice used a well-child template with boxes to check regarding immunizations and a section for notes. Ms P’s notes were regularly reviewed and signed by one of the pediatricians.

Mrs M was the mother of three patients who visited the pediatricians’ practice. She had 5-year-old twins and an infant son named Joe. In March 2009, when Joe was aged 4 and a half months, Mrs M brought him to the practice for a well-baby visit. At that visit, the infant was given the pneumococcal conjugate vaccine Prevnar 7, which provided him with protection against seven serotypes of pneumococcus.

In February 2010, the Food and Drug Administration (FDA) approved the use of Prevnar 13, which provides protection against an additional six serotypes of pneumococcus than

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A child deals with the consequences of a lesser vaccine, because a medical practice did not update its immunization policies.

The pediatric practice did not keep up-to-date regarding immunization procedures to ensure compliance with FDA and AAP policies.

Prevnar 7. The American Academy of Pediatrics (AAP) recommended that children who had already received the Prevnar 7 vaccine should also be vaccinated with Prevnar 13. However, the pediatricians’ practice where Ms P worked did not update its well-child template to reflect this.

Mrs M brought Joe back to the physicians’ office three times between May 2010 and November 2011 for the child’s 18-month, 24-month, and 36-month well-child visits. Ms P performed the check-ups, filled out the well-child templates, and submitted them to the physicians for review.

All three times, the pediatricians signed off on the evaluations with no questions asked.

In February 2012, Joe, then aged 3 years and 3 months, became very ill and was taken to the emergency department of the local hospital with symptoms of fever, cough, vomiting, and Continues on page 94

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.

92 THE CLINICAL ADVISOR • NOVEMBER 2016 • www.ClinicalAdvisor.com

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LEGAL ADVISOR increasing lethargy. At the hospital, he was diagnosed with pneumococcal meningitis. He was treated with ceftriaxone and vancomycin. However, the infection progressed to encephalitis, subdural empyema, obstructive hydrocephalus, septic shock, and respiratory failure. Joe developed disseminated intravascular coagulation with multi-organ failure.

He was hospitalized in the intensive care unit for six weeks.

During the child’s hospitalization, it was discovered that the pneumococcal strain was serotype 6A, which would have been covered by the Prevnar 13 vaccine. The treating physician at the hospital asked Mrs M whether Joe had received the Prevnar 13 vaccine. Mrs M called the pediatricians’ office and spoke to a medical assistant who looked at the chart and told Mrs M that the child had not received the vaccine, nor had his twin siblings. The children were promptly vaccinated, but Joe was left with permanent seizure disorder, vision impairment, bilateral profound hearing loss, and left hemiparesis.

The case illustrates what can happen when a medical practice has no process in place to update immunization policies.

On the advice of a friend, a distraught Mrs M sought the counsel of a plaintiff’s attorney. The attorney had the child’s medical records, including the well-child notes, reviewed by an expert. The expert told the attorney that the pediatric practice should have been giving children the Prevnar 13 vaccine by the time Joe had his 18-month visit, and certainly by the time he had his 24-month visit. The attorney told Mrs M that he would take the case, and he filed a lawsuit against the pediatric practice.

At trial, several experts testified about the Prevnar 13 vaccine. An infectious disease expert said that Prevnar 7 vaccination protected against the seven serotypes of pneumococcus that caused 80% of pneumococcal disease in infants.

However, when asked about the standard of care, the expert stated that Prevnar 13 should have been administered to Joe at his 24-month or 36-month well-child visit. All the other experts testified that the Prevnar 13 vaccine would likely have protected Joe from meningitis had it been given to him.

They noted that the vaccine was approved by the FDA in February 2010, and that the vaccine was readily available by the May 2010 well-child visit, when Joe was 18 months old.

Ms P was called to testify about the three well-child visits, and she was forced to admit that she was unaware of the

updated vaccine at the time of the visits and that she was following the template provided by the office, which only listed Prevnar 7.

The case went to the jury, and after several hours of deliberation, they returned a verdict for the plaintiff.

Legal background

In this particular case, Ms P was not sued personally. Instead, it was the practice, and the physicians, who were actually sued. While nurse practitioners do get sued personally, they are sued far less often than physicians. This is due to several reasons, but one major one is the common notion that physicians have “deep pockets” and are thus better candidates for a lawsuit.

Protecting yourself

This case was based on facts which took place between March 2009 and February 2012, a period of time during which the FDA approved the use of pneumococcal conjugate vaccine Prevnar 13. Prior to February 2010, only the Prevnar 7 vaccine was available, which provided less protection than Prevnar 13.

The case illustrates what can happen when a medical practice has no process in place to update immunization policies; it was primarily a result of system failure. The pediatric practice did not have a written office policy assigning a specific person the responsibility for updating immunization procedures to ensure compliance with FDA and AAP recommendations. Thus, when the new vaccine came out, the practice was still using printed well-child forms that had not been updated to reflect the new recommendations.

Whichever NP was conducting the well-child appointment would only see Prevnar 7 as a choice; therefore, the practice failed in keeping immunization tracking up to date.

How could this have been avoided? The practice should have assigned someone to routinely check and update the practice’s immunization policy with up-to-date immunizations. Ms P should have been following FDA updates via professional publications or the FDA website, particularly those that affect her client base—children. And finally, the physicians should not have been blindly signing off on wellchild forms without reviewing immunization information and making sure that it was up-to-date.

In today’s Internet-savvy world, it is inexcusable to be uninformed about FDA-approved immunizations. ■ Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

94 THE CLINICAL ADVISOR • NOVEMBER 2016 • www.ClinicalAdvisor.com

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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 an independent consultant in Kansas City, Mo.

Vitamin K

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Vitamin K, discovered by Danish scientist Henrik Dam in 1929, is well known for its effects on the clotting cascade in blood.1 Also known as phylloquinone, vitamin K is important because it has been found to be involved in many metabolic processes in the body. As recently as 1974, researchers were able to isolate vitamin K’s role in blood coagulation in human beings.2 For such a prominent vitamin, however, its processes, impact, and methods of metabolism in humans remain poorly understood.

Kale is a good source of vitamin K.

Background Vitamin K is widely known as an antidote or antagonist of warfarin-induced bleeding. It is a key component in the body’s manufacture of prothrombin in the clotting cascade.

It has also been a long-standing practice to give newborns an immediate injection of supplemental vitamin K to prevent potentially lethal hemorrhage. This is done because newborns have only 30% to 60% of recommended levels of vitamin K, making them more susceptible to bleeding.3

Science In addition to its role in hemostasis, vitamin K plays a pivotal role in the metabolism of calcium in the human body. In a cascade similar to that in hemostasis, phylloquinone is converted in the intestinal tract, the endothelium, and in other organs from the plant form, vitamin K1, into the more active form, K 2, with subgroups of K4 (menaquinone-4) and K7

(menaquinone-7).4 These forms serve as essential coenzymes that facilitate the incorporation of calcium into hydroxyapatite crystals in the bone, thereby playing a key role in bone structure maintenance.5 A meta-analysis of studies researching vitamin K intake and the incidence of osteoporosis in postmenopausal women reviewed data from trials involving nearly 7000 participants.6 Overall results of pooled data revealed a relative risk reduction of 0.50 in favor of vitamin K supplementation.6 In a study of more than 240 women with known osteoporosis, researchers randomly assigned the participants to either no change in management or diet (control group) or daily supplemental vitamin K2.7 At the end of the study, participants were examined for new compression fractures and lumbar bone mineral density. The control group, as expected, showed increased fractures and continued loss of lumbar bone density. Some fractures also occurred in the supplemented group; however, there were significantly fewer fractures than in the control group and the supplemented group had a much smaller loss of lumbar bone mineral density.7

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2016 95

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ALTERNATIVE MEDS UPDATE The role of vitamin K in bone maintenance is significant, but perhaps the more exciting possibility for vitamin K supplementation is the potential for reversal of atherosclerosis. The mechanism of action of vitamin K and calcium deposition in soft tissues involves the known action of a calcium inhibitory protein that requires vitamin K to function.8 This is seen especially in the arterial endothelium. Increased vitamin K intake has been shown to reduce arterial calcium deposition in humans and, in some animal studies, has been shown to reverse existing plaque.8 In a pivotal population study, researchers enrolled nearly 8000 men and women aged 55 years and older into a 10-year trial evaluating the relationship between reported dietary intake of vitamin K and aortic calcification.9 All-cause mortality and incident cardiovascular events showed a strong inverse relationship with vitamin K, specifically K4 intake, and especially in higher risk level participants.

Safety, interactions, side effects Vitamin K has long been used as an antidote for warfarin overdose. This is important because, for those taking warfarin, a dietary habit such as enjoying fresh green leafy vegetables, can push a stable international normalized ratio into the danger zone. There is, however, increasing evidence that the K4 form and some other forms of vitamin K do not interact in the clotting cascade in the same way that K1 does and that some of the increased calcium maldistribution seen in those on long-term warfarin therapy can be mitigated by small daily doses of vitamin K. Other interactions tend to be those that cause vitamin deficiency by interfering with normal gut absorption. Broad-spectrum antibiotics reduce absorption by as much as 74%.10

the most common form. The cost is relatively modest, at about $20 per month’s supply.

Summary

Vitamin K may reduce the risk of bone fractures in osteoporosis.

Foods are the preferred source of vitamin K; however, supplements are widely available in many subtypes.

How supplied, dose, cost

As a healthcare provider, it is not a simple task to decide whether to recommend vitamin K supplementation to patients. The decision must involve eliciting a detailed personal and family history to determine risk factors for osteoporosis and atherosclerosis as well as performing a comprehensive dietary evaluation. In addition, as with many supplements, patients must understand that if they are told to take supplemental vitamin K, it is likely to be a life-long therapy. ■ References 1. Dam H. The antihemorrhagic vitamin of the chick: Occurrence and chemical nature. Nature. 1935;135:652-653.

2. Stenflo J, Fernlund P, Egan W, Roepstorff P. Vitamin-Kdependent modifications of glutamic acid residues in prothrombin. Proc Natl Acad Sci U.S.A. 1974;71:2730-2733.

3. American Academy of Pediatrics Committee on Fetus and Newborn. Controversies concerning vitamin K and the newborn. Pediatrics. 2003;112:191-192.

4. Shearer MJ, Newman P. Metabolism and cell biology of vitamin K. Thromb Haemost. 2008;100:530-547.

5. Bügel S. Vitamin K and bone health in adult humans.

Vitam Horm. 2008;78:393-416.

6. Huang ZB, Wan SL, Lu YJ, Ning L, Liu C, Fan SW. Does vitamin K2 play a role in the prevention and treatment of osteoporosis for postmenopausal women: a meta-analysis of randomized controlled trials. Osteoporosis Int. 2015;26:1175-1186.

7. Shiraki M, Shiraki Y, Aoki C, Miura M. Vitamin K 2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis. J Bone Miner Res. 2000;15:515-521.

8. O’Keefe JH, Bergman N, Carrera-Bastos P, FontesVillalba M, DiNicolantonio JJ, Cordain L. Nutritional strategies for skeletal and cardiovascular health: hard bones, soft arteries, rather than vice versa. Open Heart.

2016;3:e000325.

9. Geleijnse JM, Vermeer C, Grobbee DE, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam study. J Nutr. 2004;134:3100-3105.

10. Conly J, Stein K. Reduction of vitamin K 2 concentrations in human liver associated with the use of broad spectrum antimicrobials. Clin Invest Med. 1994;17:531-539.

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Foods are the preferred source of vitamin K; however, supplements are widely available, although in a confusing array of subtypes. In a medical setting, vitamin K is usually administered as an injection, but for consumers purchasing over-the-counter supplemental vitamin K, capsules or tablets are 96 THE CLINICAL ADVISOR • NOVEMBER 2016 • www.ClinicalAdvisor.com

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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2016 97

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COMMENTARY Katherine F. O’Donnell, DNP, APRN, FNP-BC, is a family NP, Department of General Surgery, University of Texas Health Science Center, in San Antonio.

Recertifying from inactive status Fifteen years ago, a nurse practitioner (NP) contacted me because she was looking for a preceptor for her clinical hours. She was not a traditional student, but rather an NP whose certification had lapsed, placing her on “inactive” status. In Texas, where I practice, the Texas board of nursing defines inactive status as an individual “for whom more than 4 years have lapsed since completion of the advanced practice educational program or who have not practiced in the advanced practice role during the previous 4 years” (Texas board of nursing rule 22 T). Returning to active status requires completion of a refresher course or extensive orientation. This includes didactic and/or clinical experiences

For the APN who is recertifying, it is important to establish relationships with other APNs at the local and national level.

encompassing advanced assessment, diagnosis and treatment, pharmacotherapeutics, ordering and interpretation of diagnostic tests, and performing procedures safely and competently.

The orientation requires a minimum of 400 supervised clinical hours.

My colleague had tried to find a preceptor in the local NP program but was unsuccessful because she was not enrolled as a student. After months of phone calls, emails, and networking, she contacted me, and I agreed to be her preceptor. In addition to the supervised clinical hours, she also took advanced pharmacology and studied for the national certification exam, which she took at the completion of the preceptorship. This process took 2 years, and she is now a practicing NP. The journey to recertification for the inactive advanced practice nurse (APN) can be lengthy and frustrating, especially when looking for someone to provide supervised, clinical hours. Finding a preceptor can be challenging, particularly in communities where NP programs exist. The recertifying practitioner may be in direct competition with traditional NP students for preceptor hours. Some programs require students to have preceptor agreements prior to starting an NP program. In addition to completion of required clinical hours, most states now require passing a national certification exam as part of the consensus model for regulation of APNs (Hartigan C. AACN Adv Crit Care. 2011;22[1]:50-67). The

consensus model of APN regulation was developed in 2007 and requires licensure, accreditation, certification, and education (LACE) as the model for all APNs in the United States (Stanley J. JNP. 2009;5[2]:99-104). Thus far, 17 states have fully implemented the consensus model.

For the APN who is recertifying, it is important to establish relationships with other APNs at the local and national level. Membership in professional organizations provides education, opportunities for networking, and socialization with other APNs. Attending regular meetings and conferences may provide opportunities for meeting potential preceptors and employers.

Contacting local NP programs may be another way to connect with APNs willing to provide the necessary hours. Recertifying APNs may need to work with multiple providers to acquire enough hours. Flexibility is key.

Recently, I was approached at a local meeting by an APN who needed a preceptor to complete clinical hours to return to active status. Along with my colleagues, I was able to help her find several APNs who were willing to help, and she was able to complete the required hours.

Through networking, professional organizations, and identifying potential preceptors, it is possible to help the inactive APN return to the workforce. I challenge all of my colleagues to step up and assist our fellow APNs to re-join their profession as active, practicing clinicians. ■

98 THE CLINICAL ADVISOR • NOVEMBER 2016 • www.ClinicalAdvisor.com

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