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BACK-TO-SCHOOL ISSUE
Contemporary
PEDIATRICS
Expert Clinical Advice for Today’s Pediatrician AUGUST 2019 VOL. 36 | NO. 08
THE ONLY AVAILABLE FDA-APPROVED
THE ONLY AVAILABLE PRESCRIPTION
FDA-APPROVED PRESCRIPTION TREATMENT INDICATED FOR PINWORM
TREATMENT INDICATED FOR PINWORM
ELIGIBLE PATIENTS Eligible pa
tients, sa
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RM prescriptio
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PAY AS
†
LITTLE AS $
5*
MAY PAY AS LITTLE AS $5 If you have
EMVERM
any questio
at 1-877-264
Bin: 610524
ns, please
-2440. Plea
Savings Ca
call us (8:0
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0 AM-8:00 PM
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s and eligibili , Monday-Friday)
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RxGrp: 507
77194 RxPCN:
ID: Loyalty
Issuer: (80
840)
†
Subject to eligibility. Individual out-of-pocket costs may vary. *Up to a max
imum benefit
of $80.
Not valid for patients covered under Medicare, Medicaid, or other
federal or state programs. Please see full terms, conditions, and eligibility
criteria at EmvermSavings.com.
FDA, US Food and Drug Administration.
SELECT IMPORTANT SAFETY INFORMATION
Contraindication: EMVERM is contraindicated in persons with a known
hypersensitivity to the drug or its excipients (mebendazole, microcrystalline
cellulose, corn starch, anhydrous lactose, sodium starch glycolate,
magnesium stearate, stearic acid, sodium lauryl sulfate, sodium saccharin,
and FD&C Yellow #6).
Please see Brief Summary on
pages 3-4. For Full Prescribing
Information, visit EmvermHCP.com.
1
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EMVERM PROVIDES A 95% CURE RATE AGAINST PINWORM1
THE ONLY AVAILABLE FDA-APPROVED PRESCRIPTION TREATMENT INDICATED FOR PINWORM
PRESCRIBE WITH CONFIDENCE
ₔ;OL((7Red Book recommends mebendazole as one of the drugs of choice
LEARN MORE AT
for pinworm infection2 EmvermTreatment.com
ₔMebendazole has been prescribed by physicians for more than 40 years3
EMVERM DOSING FOR PINWORM
ₔ7H[PLU[ZZOV\SKILprescribed 2 tablets. EMVERM can often cure pinworm symptoms in a single dose. However,
a second course of treatment may be necessary after 3 weeks to prevent reinfection and to kill any worms that hatched
HM[LY[OLÄYZ[[YLH[TLU[1,4
– Dosing is the same for adults and children1
■ One 100 mg tablet, for one day
– Chewable, kid-friendly tablet can also be swallowed whole or crushed and mixed with food1
AAP, American Academy of Pediatrics.
SELECT IMPORTANT SAFETY INFORMATION (continued)
Warnings and Precautions:
ₔ9PZRVMJVU]\SZPVUZ!*VU]\SZPVUZPUPUMHU[ZILSV^[OLHNLVM`LHYOH]LILLUYLWVY[LK
ₔ/LTH[VSVNPJL�LJ[Z!5L\[YVWLUPHHUKHNYHU\SVJ`[VZPZOH]LILLUYLWVY[LKPUWH[PLU[ZYLJLP]PUNTLILUKHaVSLH[OPNOLYKVZLZ
and for prolonged duration. Monitor blood counts in these patients
ₔ4L[YVUPKHaVSLHUKZLYPV\ZZRPUYLHJ[PVUZ!:[L]LUZ1VOUZVUZ`UKYVTL[V_PJLWPKLYTHSULJYVS`ZPZ:1:;,5OH]LILLUYLWVY[LK
^P[O[OLJVUJVTP[HU[\ZLVMTLILUKHaVSLHUKTL[YVUPKHaVSL
Please see Brief Summary on pages 3-4. For Full Prescribing Information, visit EmvermHCP.com.
References: 1. EMVERM [prescribing information]. 2. American Academy of Pediatrics. Red Book: 2018–2021 Report of the Committee on Infectious Diseases. 31st ed.
Itasca, IL: American Academy of Pediatrics; 2018:634-635, 994. 3. Friedman AJ, Ali SM, Albonico M. [published online December 24, 2012.] J Trop Med. 2012;2012:590463.
4. Treatment. Centers for Disease Control and Prevention website. https://www.cdc.gov/parasites/pinworm/treatment.html.
Updated August 30, 2016. Accessed April 29, 2019.
© 2019 Amneal Pharmaceuticals LLC
All rights reserved. Printed in USA
2 PP-HCP-MEB-US-0064 06/2019
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EMVERM® (mebendazole) 100 mg Chewable Tablets The safety of mebendazole was evaluated in 6276 subjects who participated in 39 clinical trials
BRIEF SUMMARY: Complete information about EMVERM® can be found in the Full Prescribing Information. for treatment of single or mixed parasitic infections of the gastrointestinal tract. In these trials, the
formulations, dosages and duration of mebendazole treatment varied. Adverse reactions reported in
INDICATIONS AND USAGE
mebendazole-treated subjects from the 39 clinical trials are shown in Table 2.
EMVERM® is indicated for the treatment of patients two years of age and older with gastrointestinal
infections caused by Ancylostoma duodenale (hookworm), Ascaris lumbricoides (roundworm), Enterobius Table 2: Adverse Reactions Reported in Mebendazole-treated Subjects from 39 Clinical Trials*
vermicularis (pinworm), Necator americanus (hookworm), and Trichuris trichiura (whipworm). Adverse Reaction(s)
DOSAGE AND ADMINISTRATION Gastrointestinal Disorders
The recommended dosage for EMVERM® is described in Table 1 below. The same dosage schedule Anorexia, Abdominal Pain, Diarrhea, Flatulence, Nausea, and Vomiting
applies to adults and pediatric patients two years of age and older. The tablet may be chewed, swallowed, Skin and Subcutaneous Tissue Disorders
or crushed and mixed with food. Rash
Table 1: Dosage of EMVERM in Adult and Pediatric Patients (two years of age and older) *Includes mebendazole formulations, dosages and treatment duration other than EMVERM® 100 mg tablet
Pinworm Whipworm Roundworm Postmarketing Experience
(enterobiasis) (trichuriasis) (ascariasis) Hookworm The following adverse reactions have been identified in adult and pediatric patients postmarketing with
Dose 1 tablet, once 1 tablet morning 1 tablet morning 1 tablet morning mebendazole formulations and dosages other than the EMVERM® 100 mg chewable tablet. Because these
and evening for 3 and evening for 3 and evening for 3 reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
consecutive days consecutive days consecutive days estimate their frequency or establish a causal relationship to drug exposure.
Table 3: Adverse Reactions Identified During Postmarketing Experience with Mebendazole*
If the patient is not cured three weeks after treatment, a second course of treatment is advised. No special
procedures, such as fasting or purging, are required. Adverse Reaction(s)
Blood and Lymphatic System Disorders Agranulocytosis, Neutropenia
CONTRAINDICATIONS
Immune System Disorders Hypersensitivity including anaphylactic reactions
EMVERM® is contraindicated in persons with a known hypersensitivity to the drug or its excipients
Nervous System Disorders Convulsions, Dizziness
(mebendazole, microcrystalline cellulose, corn starch, anhydrous lactose, sodium starch glycolate,
Hepatobiliary Disorders Hepatitis, Abnormal liver tests
magnesium stearate, stearic acid, sodium lauryl sulfate, sodium saccharin, and FD&C Yellow #6).
Renal and Urinary Disorders Glomerulonephritis
WARNINGS AND PRECAUTIONS Skin and Subcutaneous Tissue Disorders TEN, SJS, Exanthema, Angioedema, Urticaria, Alopecia
Risk of Convulsions
Although EMVERM® is approved for use in children two years of age and older, convulsions have been *Includes mebendazole formulations, dosages and treatment duration other than EMVERM® 100 mg
reported in infants below the age of 1 year during post-marketing experience with mebendazole, including chewable tablets
EMVERM®. DRUG INTERACTIONS
Hematologic Effects Concomitant use of mebendazole, including EMVERM®, and metronidazole should be avoided.
Agranulocytosis and neutropenia have been reported with mebendazole use at higher doses and for USE IN SPECIFIC POPULATIONS
more prolonged durations than is recommended for the treatment of soil-transmitted helminth infections. Pregnancy
Monitor blood counts if EMVERM® is used at higher doses or for prolonged duration. Risk Summary
Metronidazole Drug Interaction and Serious Skin Reactions The available published literature on mebendazole use in pregnant women has not reported a clear
Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) have been reported with the concomitant association between mebendazole and a potential risk of major birth defects or miscarriages [see Data].
use of mebendazole and metronidazole. Avoid concomitant use of mebendazole, including EMVERM® and There are risks to the mother and fetus associated with untreated helminthic infection during pregnancy
metronidazole. [see Clinical Considerations].
ADVERSE REACTIONS In animal reproduction studies, adverse developmental effects (i.e., skeletal malformations, soft
Clinical Studies tissue malformations, decreased pup weight, embryolethality) were observed when mebendazole was
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in administered to pregnant rats during the period of organogenesis at single oral doses as low as
the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and 10 mg/kg (approximately 0.5-fold the total daily maximum recommended human dose [MRHD]). Maternal
may not reflect the rates observed in practice. toxicity was present at the highest of these doses [see Data].
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The estimated background risk of major birth defects and miscarriage for the indicated populations is clear determination of the risk of EMVERM® to a breastfed infant; therefore, developmental and health
unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the benefits of breastfeeding should be considered along with the mother’s clinical need for EMVERM® and any
U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically potential adverse effects on the breastfed infant from EMVERM® or from the underlying maternal condition.
recognized pregnancies is 2–4% and 15–20%, respectively. Pediatric Use
Clinical Considerations The safety and effectiveness of EMVERM® 100 mg chewable tablets has not been established in pediatric
Disease-Associated Maternal and/or Embryo/Fetal Risks patients less than two years of age. Convulsions have been reported with mebendazole use in children
Untreated soil transmitted helminth infections in pregnancy are associated with adverse outcomes less than one year of age.
including maternal iron deficiency anemia, low birth weight, neonatal and maternal death. Geriatric Use
Data Clinical studies of mebendazole did not include sufficient numbers of subjects aged 65 and older to
Human Data determine whether they respond differently from younger subjects.
Several published studies, including prospective pregnancy registries, case-control, retrospective cohort, OVERDOSAGE
and randomized controlled studies, have reported no association between mebendazole use and a In patients treated at dosages substantially higher than recommended or for prolonged periods of time, the
potential risk of major birth defects or miscarriage. Overall, these studies did not identify a specific pattern following adverse reactions have been reported: alopecia, reversible transaminase elevations, hepatitis,
or frequency of major birth defects with mebendazole use. However, these studies cannot definitely agranulocytosis, neutropenia, and glomerulonephritis.
establish the absence of any mebendazole-associated risk because of methodological limitations,
Symptoms and signs
including recall bias, confounding factors and, in some cases, small sample size or exclusion of first
In the event of accidental overdose, gastrointestinal signs/symptoms may occur.
trimester mebendazole exposures.
Treatment
Animal Data
There is no specific antidote
Embryo-fetal developmental toxicity studies in rats revealed no adverse effects on dams or their progeny
at doses up to 2.5 mg/kg/day on gestation days 6–15 (the period of organogenesis). Dosing at CLINICAL STUDIES
≥10 mg/kg/day resulted in a lowered body weight gain and a decreased pregnancy rate. Maternal Efficacy rates derived from various studies are shown in Table 4 below:
toxicity, including body weight loss in one animal and maternal death in 11 of 20 animals, was seen Table 4: Mean Cure Rates and Egg Reductions from Clinical Studies
at 40 mg/kg/day. At 10 mg/kg/day, increased embryo-fetal resorption (100% were resorbed at 40 mg/
kg/day), decreased pup weight and increased incidence of malformations (primarily skeletal) were Pinworm Whipworm Roundworm
observed. Mebendazole was also embryotoxic and teratogenic in pregnant rats at single oral doses during (enterobiasis) (trichuriasis) (ascariasis) Hookworm
organogenesis as low as 10 mg/kg (approximately 0.5-fold the total daily MRHD, based on mg/m2). Cure rates mean 95% 68% 98% 98%
In embryo-fetal developmental toxicity studies in mice dosed on gestation days 6–15, doses of
Egg reduction — 93% 99% 99%
10 mg/kg/day and higher resulted in decreased body weight gain at 10 and 40 mg/kg/day and a
mean
higher mortality rate at 40 mg/kg/day. At doses of 10 mg/kg/day (approximately 0.2-fold the total daily
MRHD, based on mg/m2) and higher, embryo-fetal resorption increased (100% at 40 mg/kg) and fetal
PATIENT COUNSELING INFORMATION
malformations, including skeletal, cranial, and soft tissue anomalies, were present. Dosing of hamsters and
Advise the patient to read the FDA-approved patient labeling (Patient Information).
rabbits did not result in embryotoxicity or teratogenicity at doses up to 40 mg/kg/day (1.6 to 3.9-fold the
total daily MRHD, based on mg/m2). Advise patients that:
In a peri- and post-natal toxicity study in rats, mebendazole did not adversely affect dams or their progeny • Taking EMVERM® and metronidazole together may cause serious skin reactions and should be avoided.
at 20 mg/kg/day. At 40 mg/kg (1.9-fold the total daily MRHD, based on mg/m2), a reduction of the number • EMVERM® can be taken with or without food.
of live pups was observed and there was no survival at weaning. No abnormalities were found on gross You are encouraged to report negative side effects of prescription drugs to the FDA. Visit
and radiographic examination of pups at birth. www.fda.gov/medwatch, or call 1-800-FDA-1088. To report SUSPECTED ADVERSE REACTIONS
Lactation contact Impax Laboratories, Inc. at 1-877-994-6729.
Risk Summary Please see Full Prescribing Information including Patient Information at www.emvermhcp.com.
Limited data from case reports demonstrate that a small amount of mebendazole is present in human milk
Distributed By: Impax Specialty Pharma
following oral administration. There are no reports of effects on the breastfed infant, and the limited reports
Hayward, CA 94544
on the effects on milk production are inconsistent. The limited clinical data during lactation precludes a
07/2017 PP-XPI-MEB-US-0008
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BACK-TO-SCHOOL ISSUE
Contemporary
PEDIATRICS
Expert
Expe
Expert
rt C
Clinical
lini
linica
call Ad
Advi
Advice
vice
ce ffor
or T
Today’s
Today
oday
oday’s
sPPediatrician
edia
ediatr
tric
icia
ian
n AUGUST 2019 VOL. 36 | NO. 08
Navigating Thyroid disorders
Manifestations,
Autism
evaluation, management
Pharmacologist’s Notebook
Epinephrine
autoinjectors
Primary care’s pathway to
the medical home 6 pitfalls in
managing ADHD
HEALTH AN
ARE
D LIFE
TR A N
SITI
Recognize and Refer
NG C ONS
LIF
E -LO Dx clues from a
RTIVE TOOLS
pediatric allergist
SUPPO
LA
NG
UA
GE
G
ED CARE
IN
ENTER DE
EN
A MILY- C LA
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DSM YS
SC
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EILL ANCE
TAL SURV
LOPMEN CO
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DEV SQ M
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ContemporaryPediatrics.com
A
DI
Contemporary editorial
advisory board
Gary L Freed, MD, MPH Andrew J Schuman, MD
table of contents Percy and Mary Murphy Professor
of Pediatrics, Professor of Health
Clinical Assistant Professor
of Pediatrics, Geisel School of
Management and Policy, Associate Medicine at Dartmouth, Lebanon,
PHARMACOLOGIST’S NOTEBOOK Chair, Department of Pediatrics, New Hampshire
6 Epinephrine autoinjectors Director of Faculty Programs, Office
for anaphylaxis of Health Equity and Inclusion, Steven M Selbst, MD
University of Michigan, Ann Arbor, Professor of Pediatrics, Sidney
11 Journal Club Michigan Kimmel Medical College at Thomas
14 Puzzler Jefferson University, Philadelphia,
Harlan R Gephart, MD Pennsylvania, and Attending
CLINICAL FEATURE Clinical Professor of Pediatrics Physician, Pediatric Emergency
21 Building a medical home Emeritus, University of Washington Medicine, Nemours/Alfred I duPont
for children with autism School of Medicine, Seattle, Hospital for Children, Wilmington,
Washington Delaware
PEER-REVIEWED FEATURES
27 Elopement and wandering W Christopher Golden, MD Scott A Shipman, MD, MPH
with ASD: Practical tips Assistant Professor of Pediatrics Director of Primary Care Affairs,
for PCPs (Neonatology), Pediatric Clerkship Director of Clinical Innovations,
Director, Johns Hopkins University Association of American Medical
33 Thyroid disorders: School of Medicine, Medical Colleges, Washington, DC
Manifestations, evaluation, Director, Newborn Nursery, Johns
and management in children Hopkins Hospital, Baltimore,
and adolescents Maryland
contributing editors
Michael G Burke, MD Section Editor for Journal
CLINICAL FEATURE
Donna Hallas, PHD, CPNP, Club, Chairman, Department of Pediatrics, Saint Agnes
43 6 pitfalls to avoid in PCPNP-BC, PMHS, FAANP Hospital, Baltimore, Maryland
managing ADHD Clinical Professor, New York
University Meyers College of Bernard A Cohen, MD Section Editor for Dermcase,
52 Dermcase Professor of Pediatrics and Dermatology, Johns Hopkins
Nursing, and Director, Pediatric
RECOGNIZE & REFER Nurse Practitioner Program, New University School of Medicine, Baltimore, Maryland
53 Diagnostic clues from a York, New York
Carlton K K Lee, PharmD, MPH, FASHP, FPPAG
pediatric allergist Section Editor for The Clinical Pharmacologist’s
IN ADDITION Michael S Jellinek, MD Notebook, Clinical Pharmacy Specialist in Pediatrics,
Professor Emeritus of Psychiatry Department of Pharmacy, Johns Hopkins Hospital,
51 Advertising Index
and of Pediatrics, Harvard Medical Associate Professor of Pediatrics, Johns Hopkins
School, Boston, Massachusetts University School of Medicine, Baltimore, Maryland.
THE EDITORS ARE PLEASED TO ANNOUNCE the availability of our new parent company’s continuing education activities. We’ve
picked this one especially for our Contemporary Pediatrics’ readers. Go to: bit.ly/2vrsvN3
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2 C O N T E M P O R A RY P E D I AT R I C S . C O M | AU G U S T 2 019
Dr. Lee’s Clinical
pharmacologist’s notebook
Epinephrine autoinjectors
CARLTON LEE, PHARMD,
MPH, FASHP, FPPAG,
for anaphylaxis
section editor for The Epinephrine is essential for treating anaphylaxis in children, and
Clinical Pharmacologist’s
Notebook, is a clinical autoinjectors are the preferred method for administering epinephrine
pharmacy specialist in
Pediatrics, Department of in an anaphylactic emergency. There is no one-size-fits-all approach to
Pharmacy, Johns Hopkins
Hospital, and associate the optimal dose for all children, so here is expert advice about how
professor of Pediatrics,
Johns Hopkins University
to choose what’s best for your patient.
School of Medicine, cy medical services (EMS) arrival, patients
LISA M HUTCHINS, PHARMD, BCPPS;
Baltimore, Maryland.
KEITH KLEINMAN, MD were more likely to have normal vital signs
than those who did not receive epinephrine.5
A
naphylaxis is a severe systemic aller- Prompt epinephrine administration for ana-
gic reaction that may be life threat- phylaxis is associated with a reduced rate
ening if not quickly recognized and of hospitalization, severe shock, hypoxic-
treated. Anaphylaxis most often re- ischemic encephalopathy, and death. 2 This
sults from immunoglobulin (Ig)E-mediated highlights the need for proper access to and
DR HUTCHINS is a pediatric mast cell degranulation leading a combina- prescribing of epinephrine for pediatric pa-
emergency medicine
tion of respiratory and circulatory compro- tients in the out-of-hospital setting, particu-
clinical pharmacy
specialist, Johns Hopkins mise, coupled with dermatologic, gastroin- larly in light of prior reports that patients are
Hospital, Baltimore, testinal, and neurologic symptoms.1 Whereas not effectively prepared for episodes of ana-
Maryland. the prevalence of anaphylaxis varies by loca- phylaxis after a first encounter, mostly due to
tion worldwide, it is estimated that 0.05% to inadequate prescribing of epinephrine.6
2% of people in the United States will experi-
ence anaphylaxis within their lifetime.1 Epinephrine product selection
The most frequently identified out-of- The preferred formulation of epinephrine for
hospital causes of anaphylaxis are insect anaphylaxis is an autoinjector formulation3
stings and food allergies. 2 In children, an because autoinjectors provide a premeasured
DR KLEINMAN is pediatric allergic reaction to food is the most com- packaged dose that requires no measurement
chief resident and mon reason for anaphylaxis.2-4 Incidence of or manipulation for dose accuracy. There are
pediatric emergency anaphylaxis among children is increasing, several of these epinephrine autoinjectors
medicine fellow, Johns
which highlights the need for appropriate (EAIs) on the market and deciding on the op-
Hopkins Hospital,
Baltimore. The authors and affordable access to epinephrine. 5 Pre- timal formulation for the patient presents its
and section editor have scribing intramuscular (IM) epinephrine for own challenges.
nothing to disclose in self-administration in the community setting For example, some of the products once
regard to affiliations with
is recommended for any patient who presents activated provide verbal instructions to guide
or financial interests in
any organizations that with an anaphylactic reaction.1-3 the patient or caregiver in administration,
may have an interest in Recently, it was found that when epineph- which may be helpful in an emergency. Other
any part of this article. rine was administered to pediatric patients products have instructions printed directly
in the prehospital setting prior to emergen- on the autoinjector itself, preventing the user
6 C O N T E M P O R A RY P E D I AT R I C S . C O M | AU G U S T 2 019
pharmacologist’s notebook
from having to keep track of both the
medication and the instructions sep- NOTE FROM DR LEE The diverse product line of epinephrine autoinjectors (EAIs)
arately. Some formulations also have used for anaphylaxis requires patients, caretakers, and healthcare providers to
a training device available so the pa- be educated on the correct method for dose administration. With the prevalence
tient and caregiver can practice and of drug shortages and back orders, the need for reeducation to an alternative
see what the product feels like in their available dosage form is likely.
hands before actual use. For details —CARLTON LEE, PHARMD, MPH, FASHP, FPPAG
on administration and features of the
available autoinjectors and other epi-
nephrine products on the market, see tion. In children weighing less than able dose for the autoinjectors is 0.1
the Figure below. 7.5 kg, the recommended dose is 0.01 mg, which was added to the market
Dose selection of autoinjectors is mg/kg, which cannot be supplied by in November 2017 for the treatment of
another problem because the premea- any of the currently available autoin- anaphylaxis in children between 7.5
sured doses do not allow for manipula- jector products. The smallest avail- kg and 15 kg.7 In addition to the novel
EPINEPHRINE AUTOINJECTORS
FIGURE AND RELATIVE COSTS
EPINEPHRINE PRODUCT
FORMAT, Concentration,
Relative Cost a DIRECTIONS FOR USE HIGHLIGHTS LIMITATIONS
Patient at any weight range
Adyphren Amp II vial Remove cap from vial. All supplies included for Patient-specific
and syringe kit10 Swab top of vial with alcohol swab and drawing up weight-based dose needs to be
1 mg/mL let dry. dose for any size patient. drawn up at the time
Attach needle to syringe and pull syringe of need.
$
back to desired volume to be pulled up. No training device
Remove cap from needle and inject air available.
from syringe into vial.
Withdraw dose from vial.
Insert needle into middle of outer thigh at
a 90° angle.
EpinephrineSNAP–V Push plunger of syringe to inject entire
vial and syringe kit11 dose.
1 mg/mL Remove needle and dispose of in sharps
$$ container.
Patient weight 7.5 kg to
pharmacologist’s notebook TABLE CONTINUED EPINEPHRINE AUTOINJECTORS AND RELATIVE COSTS EPINEPHRINE PRODUCT FORMAT, Concentration, Relative Cost a DIRECTIONS FOR USE HIGHLIGHTS LIMITATIONS Patient weight 15 kg to
0 lbs., 14 oz., and made for EVERY INCH RECOMMEND AQUAPHOR FOR BABY’S SKINCARE NEEDS Data on file. Beiersdorf Inc. ©2017
pharmacologist’s notebook
CONTINUED FROM PAGE 8
TABLE CONTINUED EPINEPHRINE AUTOINJECTORS AND RELATIVE COSTS
EPINEPHRINE PRODUCT
FORMAT, Concentration,
Relative Cost a DIRECTIONS FOR USE HIGHLIGHTS LIMITATIONS
Generic autoinjector Varied Training devices may be Not all products
0.15 mg/0.15 mL OR available. equivalent to brand
0.15 mg/0.3 mL autoinjectors, so
substitutions are
$$
not automatically
allowed at the
pharmacy level.
Symjepi prefilled Pull cap off to expose needle without Instructions written on No training device
syringe15 touching plunger. syringe. available.
0.15 mg/0.3 mL Slowly insert needle into middle of outer Manual dexterity
$$ thigh. required to push
After needle is in thigh, push plunger all plunger.
the way down until it clicks. Exposed needle
Hold for 2 sec. may cause anxiety
Remove syringe and massage area for prior to injection.
10 sec. Safety concerns
Slide the safety guard up until it clicks to with exposed
cover the needle. needle before and
after injection.
Patient weight ≥30 kg (FDA approved). Patient weight ≥25 kg (AAP recommendation).
Adrenaclick Remove gray end caps from both ends. Training device available. Package insert with
autoinjector13 Hold autoinjector with the red end down. Needle does not automatically instructions to hold
0.3 mg/0.3 mL Inject into the middle of the outer thigh. retract. for 10 sec, which is
Instructions for use written on longer than other
$$ Hold in place for 10 sec.
autoinjector. products.
Check the red end; if needle is exposed,
dose was administered.
Insert autoinjector back into carrying case,
red (needle) end first and replace cap.
Auvi-Q autoinjector12 Pull red safety guard firmly down to Training device available. Cost
0.3 mg/0.3 mL remove from device. Electronic voice instruction
Place black end of device to middle of outer system gives directions for
$$$$$
thigh and push firmly until you hear a click use when activated.
and hiss.
Hold for 2 sec.
Needle retracts automatically for safety TABLE CONTINUED
after use. ON PAGE 42
such, the prescription of outpatient proach to prescribing epinephrine. when prescribing a vial with a syringe
epinephrine, the only treatment For children weighing less than 7.5 kg, and needle. In addition, the costs of
known to be lifesaving in this condi- risks of prescribing an inappropri- EAIs has recently been highlighted
tion, is more important now than ever ately high dose of epinephrine when due to a large spike in patient out-of-
before. Selection of an epinephrine prescribing an autoinjector must be pocket costs and increased charges
product must take into account the balanced with risks of delay in ad- by the drug manufacturers without a
product and patient-specific factors. ministration and potential errors in major change to the products.
There is not a one-size-fits-all ap- dosing in an emergency situation CONTINUED ON PAGE 42
10 C O N T E M P O R A RY P E D I AT R I C S . C O M | AU G U S T 2 019Dr. Burke’s
journal club BY MARIAN FREEDMAN
KEY TAKES ON MUST-READ STUDIES
himself a good writer, Michael always and Missy began
IN MEMORIAM sought out my opinion when he had doubts traveling more,
Editor’s Note: This month’s edition about what he had written, respected any sometimes to faraway
features the last Journal Club that changes I suggested, and lavishly praised places, and while
Dr. Michael Burke wrote with his the abstracts I wrote. In short, he was my Michael reported
colleague and friend, Marian ideal professional partner. on these adventures
Freedman, for Contemporary Over time, we began exchanging in glowing terms, I
Pediatrics. Here follows Ms. information about our personal lives, loved how he continued
Freedman’s own memories of that including recommendations on travel to appreciate life’s small pleasures. In
collaboration and also tributes from companies, books, and even a massive one of his last e-mails, for example,
some of Dr. Burke’s many friends, snow shovel (the Big Scoop), which he he commented on how nice it was to
colleagues, and admirers. purchased from Amazon after I raved spend a quiet weekend morning writing
about it. Mostly we wrote about our his commentaries while sitting in his
For more than 20 years, Michael and families—he was a devoted father to screened-in porch—“my favorite place in
I prepared the monthly Journal Club 3 daughters—and, as the years passed, so the house and maybe in the whole world,”
together; he selected the studies, I wrote did the Burke family milestones, including as he put it—and he often ended his
the summaries, and he prepared the college graduations and, most recently, communications with a simple
commentaries. Month after month, year a wedding. Michael obviously adored “Life is good.”
after year, we exchanged e-mails about his wife, Missy, whom he found a way to Sadly, life is not as good without you in
these matters, meeting in person only mention in most of his e-mails. it, Michael. I will miss you.
once in all that time. Although he was Once they had an empty nest, Michael —Marian Freedman, Contributing Editor
PUBLISHED IN THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
Sunscreen ingredients are
absorbed systemically
A
pplying sunscreen as often as African American. Participants were ticipant) and assessed them for each
manufacturers recommend divided into 4 groups of 6 individu- of the 4 active ingredients: avoben-
results in plasma concentrations als, with each group assigned to use zone, oxybenzone, octocrylene, and
of sunscreen’s 4 active ingredients 1 of 4 commercially available sun- ecamsule.
that exceed the threshold for safety screens—2 different sprays, a lotion, All 4 products were associated with
concerns established by the US Food or a cream. They applied the prod- concentrations greater than 0.5 ng/
and Drug Administration (FDA), ucts 4 times a day for 4 days, covering mL—the FDA’s safety cutoff—that
according to a recent study. The body areas generally left uncovered were reached after 4 applications
clinical significance of these findings by swimsuits, but not exposed to di- on the first day of the trial. For avo-
has not been established, however. rect sunlight. Investigators collected benzone, maximum plasma con-
Investigators enrolled in the trial multiple blood samples on each of centrations for the 2 different sprays,
24 healthy volunteers aged from 18 to the 4 application days and 3 subse- lotion, and cream were 4.0 ng/mL,
60 years, 14 of whom were black or quent days (30 samples for each par- 3.4 ng/mL, 4.3 ng/mL, and 1.8 ng/mL,
Michael G Burke, MD is Chairman, Department of Pediatrics, Saint Agnes Hospital, Baltimore, Maryland.
AU G U S T 2 019 | C O N T E M P O R A RY P E D I AT R I C S . C O M 11journal club
respectively. For the 3 products con- ecamsule plasma concentration ex- considers below consideration for
taining oxybenzone (the cream did ceeding 0.5 ng/mL on day 1. systemic effect (0.5 ng/mL). However, the
not include it), plasma concentra- Adverse events, which resolved in all authors are quick to note that the clinical
tions exceeded 20 ng/mL on day 7, participants, included rash—most com- relevance of systemic absorption of
and all participants who received mon—milia, and pruritis (Matta MK, et these compounds is not yet known and
formulations containing oybenzone al. JAMA. 2019;321[21]:2082-2091). suggest that these findings may induce
had plasma concentrations exceed- the FDA to ask the manufacturers for
ing 0.5 ng/mL within 2 hours after a THOUGHTS FROM The FDA published further studies. In the meantime, they
DR. BURKE
single application on day 1. All 4 prod- this highly publicized said, “These results do not indicate that
ucts resulted in octocrylene plasma report as a preliminary study to individuals should refrain from the use of
concentrations exceeding 0.5 ng/mL, determine if sunscreens should be sunscreen.” So, as summer continues,
starting from day 1 and lasting tested for carcinogenicity and recommend sun protection, including
through day 7. Only the cream con- embryofetal toxicity. All the active liberal use of sunscreen, but keep an eye
tained ecamsule, and 5 of 6 partici- ingredients generated blood levels out for revised recommendations or
pants in the cream group had an higher than the threshold the FDA product changes based on further study.
PUBLISHED IN PEDIATRICS IN MEMORIAM CONTINUED
Twenty years ago, Mike had an idea.
Using an asthma self-management We created the Reach Out And Read
tool improves outcomes (ROAR) program, the first hospital-
based pediatric literacy program in
Children with asthma who use a web- and the physician’s office (via e-mail the state of Maryland. Nearly 30,000
new and gently used books were
and mobile–web-based self-manage- or text) for early signs of asthma con-
distributed to children in the Peds
ment tool show high and sustained trol deterioration, and real-time rec-
clinic at St. Agnes Hospital. This gentle
self-monitoring and improved asthma ommendations. The e-AT also records
soul modeled a holistic approach to
outcomes, a study in asthmatic children and promotes adherence by generating
healthcare long before its time.
showed. The 2- to 17-year-old partici- a congratulatory message and a $10 gift
—Kathy Smith
pants, whose persistent asthma was be- certificate every time 4 assessments
Assistant Secretary of State
ing managed at a pediatric ambulatory are completed. State of Maryland
clinic, were matched with controls dur- Of the 327 children and parents en-
ing the 1-year study period. Investiga- rolled in the trial of e-AT, 65% had main- Many of us will remember [Dr. Burke]
tors compared outcomes in these week- tained adherence at 12 months. Com- as a gentle. soft-spoken leader who
ly users of an electronic-AsthmaTracker pared with baseline, participants had was a kind-heartd pediatrician, caring
(e-AT) with their own baselines as well significantly increased quality of life, and supportive to the Pediatric staff.
as with outcomes in the controls—asth- asthma control, and had fewer reduced, —Christine Vias-Plummer
matics who were receiving usual care at interrupted, and missed school and Former Child Life Specialist,
the study’s participating clinics. workdays at all quarterly assessments. St. Agnes Hospital
The e-AT is based on the asthma con- Compared with 1 year before the inter- Dr. Burke was a kind, generous,
trol test, modified for weekly assess- vention, they had fewer emergency de- compassionate man who cared deeply
ment, and coupled with decision sup- partment (ED) and hospital admissions and was passionate in his desire to
port for proactive care. It features au- and less oral corticosteroid (OCS) use. improve the lives of all children. I feel
tomated reminders to continue self- Compared with controls, partici- lucky to have worked with him.
monitoring, graphing of real-time pants also had reduced ED and hos- —Barbara L. Burns, C-TAGME
results, alerts for patients, parents, pital admissions and OCS use. Par- University of Maryland
School of Medicine
12 C O N T E M P O R A RY P E D I AT R I C S . C O M | AU G U S T 2 019journal club
IN MEMORIAM CONTINUED
ents remained satisfied with the e-AT Dr. Burke was and remains a true hero to
Those of us who knew and treasured
throughout the trial (Nkoy FL, et al. the innumerable people he touched during
Michael know there is no way to fully
Pediatrics. 2019;143[6]:e20181711). his life—as well as a leader and friend.
sum up what an incredible clinician,
—Lesley S. Hanes, MD, MSC
teacher, and human being he was. US Food and Drug Administration
THOUGHTS FROM The authors report that —Tina L. Cheng, MD, MPH
DR. BURKE
more than 8 million Johns Hopkins University
School of Medicine I hope the family and those who loved him
children in the United States have asthma
find peace in their hearts as they know how
and that 54% of them had an asthma What struck me [about Mike] was many people he helped around the world
exacerbation in 2016. Data from 2008 how kind and thoughtful he was. with his knowledge and care for patients.
showed that asthma was responsible for —William T. Zempsky, MD, MPH —Esteban Pérez, MD
10 million missed school days and 14 million Connecticut Children’s Medical Center From online
missed parent workdays that year. Imagine
Michael Burke’s humble and soft-
the impact if this program (with a 32% to Few are those who stepped into my life to
spoken manner belied his tremendous
59% reduction in ED visits and change it for the better. Dr Burke was one.
impact on the field of Pediatrics and
hospitalizations and a 26% to 35% reduction [He] was a soft-spoken giant who embraced
the world beyond. He inspired all of us
in the need for oral steroid use) was me with his genuine passion for teaching
who were fortunate to work with him
implemented across the country. This and mentorship. He led by example.
by modeling kindness, compassion,
innovative approach is worth a careful look. —Fatima Ismail, MBBS
service, and joy.
You can check out the e-AT at https:// United Arab Emirates
—Evelyn Cohen Reis, MD
asthmatracker.utah.edu/public/index.php. UPMC Children’s Hospital of Pittsburgh CONTINUED ON PAGE 49
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© 2019 REBIScan, Inc. 1. JAMA Ophthalmol. 2014;132(7):B14-B20. doi10.100/jamaophthalmol2014.424 the guidance of a licensed healthcare practitioner.puzzler PATIENT CASES TO TEST YOUR DX IQ
Sudden neutropenia and
emesis in an SGA infant
ABID HAQUE, BS; OLIVIA WARE, BA; BARBARA HARRISON, MS, CGC; SWATI JAIN GOEL, MD
A 24-year-old G2P1001 African American female at 38.2 weeks of gestation
THE
CASE was induced for labor for a fetus with prenatally diagnosed intrauterine growth
restriction (IUGR). She subsequently delivered via normal spontaneous delivery
complicated by presence of heavily meconium-stained amniotic fluid with no signs of
meconium aspiration. The infant cried immediately at birth with Apgar scores of 9/9, with
deductions for color at 1 and 5 minutes.
On initial examination, the infant er than 20 individuals worldwide. She can male with a learning disability
was notably small for gestational age was not anemic, had no other chron- and is also the father of the mother’s
(SGA) and below the 10th percen- ic diseases such as hypertension, and first child. He has hemoglobin AA. Of
tile (-3 SD) for weight (2047g), height was well nourished with adequate note, this mother reported that she
(43.2 cm), and head circumference weight gain during pregnancy. The also was “very small” at birth.
(30 cm). See Figure 1. No dysmor- maternal blood type was A-positive;
phic features were noted, and her AB screen was negative; Group B Hospital course
newborn physical examination was strep (GBS) was negative; rubella im- Although rooming with the mother is
otherwise normal. She was full term mune. The remainder of prenatal labs the optimal environment for infants,
based on her Dubowitz assessment were found to be negative/within nor- those who are SGA need to be moni-
(Dubowitz score = 38). mal limits. tored closely to ensure adequate feed-
The mother has another daughter ing, absence of hypoglycemia, and
Maternal and familial (aged 5 years; gestational age at birth, ability to maintain thermal stabil-
history 38.3 weeks) also found to have sym- ity. This infant initially latched well
Maternal prenatal labs were all with- metric IUGR/SGA at birth with au- at the breast, was normoglycemic
in normal limits with no tobacco, al- tism and developmental delay. The and normothermic, but shortly after
cohol, or illicit substance use reported maternal grandmother of the infant birth had had a significant episode
during the course of her pregnancy. died at age 31 years from kidney dis- of blood-tinged emesis (not deemed
The mother’s past medical history ease, and the siblings of the infant’s to be swallowed maternal blood) and
was significant for a learning disorder maternal great-grandmother also was transferred to the transitional
and a rare hemoglobinopathy called had passed away from kidney-related nursery for further evaluation.
hemoglobin Willamette, a variant of complications. The father of the in- Due to persistence of emesis and
the beta-globin gene that affects few- fant is a 22-year-old African Ameri- subsequent hypothermia, a sepsis
Want to read more of your colleagues’ puzzling cases?
Find the whole collection at ContemporaryPediatrics.com/pediatric-puzzler
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S FIGURE 1 Fetal growth chart obtained at time of birth. The infant met criteria for small for gestational age (SGA)
in 3/3 parameters (weight, height, head circumference) and thus qualified as symmetric intrauterine growth
restriction (IUGR).
screen was sent and the infant was 3 different formulas for some ongo- the infant was negative and the clini-
IMAGE CREDIT/AUTHOR SUPPLIED
started on empiric intravenous (IV) ing spitting and a concern for formula cal symptoms had improved, so the
antibiotics of ampicillin and genta- intolerance. The infant’s symptoms antibiotics were discontinued. She
micin. After acute obstruction was improved on ProSobee (soy formula) also required thermal support in an
ruled out, the infant was preferen- and she stooled normally with benign incubator and weaning protocol was
tially fed with breast milk, and when abdominal examination. initiated based on monitoring of her
that was not available was trialed with After 48 hours, the blood culture on ongoing weight gain and ability to
16 C O N T E M P O R A RY P E D I AT R I C S . C O M | AU G U S T 2 019puzzler
probable cause for her constellation TABLE 1
of clinical findings.
DIFFERENTIAL
Laboratory testing DIAGNOSIS FOR
and imaging IUGR AND EMESIS
At the time of her initial presentation,
blood was also sent for a CBC, com-
IN THE NEONATE
prehensive metabolic panel (CMP),
and blood culture, and the infant was Neonatal abstinence syndrome
scheduled for an abdominal x-ray TORCH infections
given her recurrent bouts of emesis. Sepsis
Her point-of-care glucose testing for Hemoglobinopathy (chromosomal)
24 hours remained stable and was Other chromosomal abnormality
subsequently discontinued. Her ab-
Abbreviations: IUGR, intrauterine growth restric-
dominal radiograph (Figure 2) re- tion; TORCH, toxoplasmosis, other, rubella, cyto-
vealed a normal-sized heart with megalovirus, herpes simplex virus.
S FIGURE 2 The patient’s heart mildly distended segments of bow-
is normal size. There are mildly el in the abdomen and an overall gas drawal can include a high-pitched cry,
distended segments of bowel in the pattern that did not appear to be ob- emesis, tremors, fever and/or sweat-
abdomen. Overall bowel gas pattern structed. Her CMP levels were: so- ing, poor feeding, or diarrhea. This
does not appear obstructed at this dium, 134-137; potassium, 4.5-5.9; diagnosis was ruled out because of
time. chloride, 109; carbon dioxide (CO2), the combination of a negative urine
17-20; creatinine, 0.22-0.32; and cal- toxicology screen (for both mother and
cium, 9.9-11. Additional labs revealed baby) and noncontributory history; ie,
maintain normothermia. Because of a neutropenia that presented over the the patient’s mother denied any tobac-
her mother’s history of a rare hemo- course of her hospital stay. A periph- co, alcohol, illicit drugs, or prescrip-
globin variant, close monitoring of her eral blood smear was examined and tion drug use during this pregnancy.
complete blood count (CBC) was initi- found to be within normal limits. Fi- The second most likely differen-
ated. The results revealed the begin- nal blood cultures sent on 2 separate tial was a possible TORCH infection:
nings of a sudden neutropenia on day occasions showed no growth and infection from toxoplasmosis, other
of life 9—absolute neutrophil count urine cytomegalovirus (CMV) cul- (syphilis, parvovirus, varicella zoster
(ANC) of 1472—for which she received ture was negative. Pursuant to stan- virus [VZV], human immunodeficien-
another course of antibiotics and was dard nursery protocol, a newborn cy virus [HIV], Zika virus), rubella, cy-
placed on reverse isolation. Repeat metabolic screen was sent and came tomegalovirus (CMV), or herpes sim-
culture results remained negative but back positive for a hemoglobinopathy. plex virus (HSV). Of these, infection
despite initial improvement the neu- with CMV, rubella, or VZV can result
tropenia returned on day of life 16. Differential diagnosis in IUGR. However, the patient’s moth-
Hematology consult revealed nor- Given the host of symptoms and com- er was rubella immune, so congenital
mal peripheral smears and no defini- plex history that the patient present- rubella was not suspected. Fewer than
tive diagnosis for the neutropenia. As ed, there were multiple possible dif- 2% of women who contract VZV dur-
part of the obstetric evaluation of the ferentials (Table 1). ing their first 20 weeks of pregnancy
prenatally diagnosed growth restric- Exposure to drugs (prescribed or give birth to an infant with congenital
tion and complex family history, Ge- illicit) in utero can result in neonatal varicella syndrome. It is also prob-
IMAGE CREDIT/AUTHOR SUPPLIED
netics consultation with the mother abstinence syndrome (NAS) due to able, given the mother’s age, that she
had been ongoing. Results of the ma- withdrawal from illicit substances obtained the VZV vaccination as a
ternal genetic analysis were obtained used prenatally or withdrawal due to child or contracted it prior to becom-
during this infant’s hospitalization discontinuation of prescription medi- ing pregnant. Furthermore, cutaneous
and this ultimately enabled the final cations (typically narcotic therapy). scars in a dermatomal pattern can be
diagnosis on this infant providing a Signs and symptoms of this with- seen at birth or as a rash within the first
AU G U S T 2 019 | C O N T E M P O R A RY P E D I AT R I C S . C O M 17puzzler
TABLE 2 hemolysis or abnormal cells, particu- TABLE 3
ASYMMETRIC larly target RBCs, leaving a possible
other chromosomal abnormality as
SYMMETRIC IUGR
IUGR the most likely cause of the patient’s CHROMOSOMAL ABNORMALITIES
symptoms.
Placental insufficiency Trisomy 13 Turner syndrome
The infant had symmetrical IUGR,
Maternal hypertension Trisomy 18 Chromosomal
recurrent episodes of emesis, and
Trisomy 21 aneuploidy
Both chromic and gestational unexplained neutropenia in the con-
Preeclampsia text of an extremely complex family CONGENITAL MALFORMATIONS
Maternal vascular disease genetic history. Intrauterine growth
Chronic severe diabetes restriction is defined as a fetus with Gastroschisis Renal
Congenital abnormalities
Chronic pulmonary disease an estimated weight below the 10th (polyhydramnios)
heart disease
Abbreviation: IUGR, intrauterine growth restriction. percentile for gestational age.1 Over- Russell-Silver
all, IUGR affects about 5% of the gen- syndrome
10 days of life (not observed on this pa- eral obstetric population. However,
tient). Thus, VZV was not high on the the incidence varies depending on MATERNAL DRUG USE
list of suspected TORCH infections. If survey demographics (eg, geograph- Cigarette Anticoagulants
the IUGR was caused by a TORCH in- ic location, standard of growth curve smoking (warfarin and
fection, the most likely one would have used).2 It is most often idiopathic, but heparin)
Cocaine use
been CMV, but the viral culture came it can be grouped based on etiology: Antineoplastic
Other
agents
back negative. symmetric versus asymmetric.1,3 substance (methotrexate and
Lower on the differentials were Asymmetric growth restriction abuse cyclophosphamide)
sepsis and a possible inherited he- (Table 2) implies a fetus who is under- Anticonvulsants
(phenytoin and
moglobinopathy. There are a host nourished and is directing most of its valproate)
of hematologic disorders associated energy to maintaining growth of vital
with diminished fetal growth. Given organs at the expense of fat deposition. CONGENITAL INFECTIONS
that this patient’s mother has hemo- These infants will have preservation of
Toxoplasmosis Tuberculosis
globin Willamette (`51Pro→Arg)— limb length and head circumference
Syphilis HIV
an extremely rare hereditary hemo- but be of low birth weight. This type of
Varicella Rubella
globinopathy caused by structural growth restriction is usually the result
Malaria Cytomegalovirus
defects as a result of a mutation that of placental insufficiency.2
substitutes proline with arginine at Symmetric IUGR (Table 3), also Abbreviations: HIV, human immunodeficiency virus;
the 51st position in the ` chain—clini- called early-onset IUGR, implies a fe- IUGR, intrauterine growth restriction.
cians suspected it as a possible cause tus whose entire body is proportion-
for the host of symptoms the patient ally small. The period of insult for somy 18, Trisomy 21, and Turner syn-
displayed. A review of the research symmetrical IUGR is generally ear- drome.1,3 Other fetal risk factors for
showed that it does not produce clini- lier in gestation (first trimester) when symmetric IUGR include congenital
cal evidences of significant hema- compared with asymmetrical IUGR malformations such as gastroschisis,
tologic or chemical abnormalities, (third trimester), and the prognosis congenital heart disease, and renal
except for the presence of target red is poorer.4 Symmetric IUGR encom- abnormalities. Russell-Silver syn-
blood cells (RBCs). Most patients are passes a minority of cases (30%) and drome manifests as IUGR with post-
asymptomatic, but some can pres- is due to intrinsic factors such as chro- natal growth deficiency, limb and
ent with hemolytic anemia due to its mosomal anomalies and aneuploidy, facial asymmetry, clinodactyly, and
high reticulocyte index and RBCs. congenital infections in early preg- episodes of hypoglycemia.6
The mother was not diagnosed with nancy, congenital malformations, Maternal risk factors for symmet-
anemia during pregnancy, and the and multiple gestations.5 ric IUGR include prior IUGR, as is the
patient’s peripheral blood smear Common chromosomal abnor- case in this infant. Certain medica-
displayed normochromic and nor- malities of IUGR are considered fetal tions such as the anticonvulsants
mocytic RBCs with no evidence of risk factors, including Trisomy 13, Tri- phenytoin and valproic acid, antico-
18 C O N T E M P O R A RY P E D I AT R I C S . C O M | AU G U S T 2 019Should antibiotics be
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Viral conjunctivitis is the most common cause of infectious conjunctivitis, also known as pink eye.1
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misdiagnosis of type could lead to serious complications, spread of infection, unnecessary antibiotic
prescriptions, ocular allergies and toxicities associated with antibiotic use and antibiotic resistance.
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