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EgyptianPediatrics/

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ZikaVirus – Pediatricians BeAware

Every fewyears, a “new ” (not really) funny-

sounding infectious disease is in the news

and causing anxiety: rst it was SARS

(severe acute respiratory syndrome), then

avian u, swineu, dengue, MERS (Middle

East respiratory syndrome), chikungunya,

Ebola, and now in 2016 it ’s Zika virus.

Zika virus wasrst identiedin 1947at

the East African Virus Research Institute (now the Uganda Virus Research

Institute) in Entebbe, Uganda, as a cause of febrile illness in rhesus macaques.(1) Until 2007, Zika virus caused only rare cases of human disease in Africa and

Southeast Asia. However, in April 2007, an outbreak was reported on Yap Island

that subsequently spread to other Polynesian islands. This was followed in 2015

by an explosive and widespread outbreak in South and Central America that

is ongoing. Brazil seems to be particularly severely affected.

Zika virus is transmitted by Aedes mosquitoes, the same mosquito that transmits

Dengue and Chikungunya viruses. The Aedes mosquitoes that are known to transmit

or can potentially transmit Zika virus are present in 32 States (2). Although so far

no autochthonous cases of Zika virus transmitted by mosquitoes have been

diagnosed in the United States, one sexually transmitted case of Zika virus has

been identied in the United States during the current pandemic. (3)

The incubation period for Zika virus infection is 2 to 14 days. The disease

has a wide spectrum and only 1 in 5 infected patients becomes symptomatic.

Hospitalizations are uncommon and death is rare. Clinically, Zika virus infec-

tion presents similarly to many other viral infections, with fever (often low-

grade), vomiting, maculopapular rash, arthralgias, myalgias, retro-orbital pain,

and conjunctivitis.

Serologic diagnosis is not dependable because of potential cross-reactivity

with dengue and chikungunya viruses. Polymerase chain reaction that can detect

the RNA of Zika virus is available from the Centers for Disease Control and

Prevention (CDC) and some state health departments.

There is no commercially available test for Zika virus and no specic antiviral

treatment; management is primarily supportive. There is also no vaccine to

protect against Zika virus infection. Prevention is largely dependent on avoidance

of areas where there is active Zika virus transmission (Figure) as well as mosquito

control and measures to prevent mosquito bites.

Compared to previous “new ” emerging infections, Zika virus infection

has particular interest for pediatricians because of the major concern that

such infection may be responsible for microcephaly in infants born to infected

women. Although no causal relationship has been determined between Zika

virus infection during pregnancy and microcephaly in the newborn, the many-

fold increase in cases of microcephaly in the midst of a Zika virus epidemic

AUTHOR DISCLOSURE Dr Rathore has

disclosed nonancial relationships relevant to

this article. This commentary does not contain

a discussion of an unapproved/investigative

use of a commercial product/device.

Vol. 37 No. 4 A P R I L 2 0 1 6 133

Commentary

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offers compelling epidemiologic suggestion of a link. (4) A

total of 2,401 suspected cases of microcephaly have been

reported in Brazil during the period of outbreak. Of these,

134were conrmed as being related to Zika virus infection,

102 were considered not related, and 2,165 are still under

investigation. (5) Further careful research is needed to

determine if this temporal association is causative.

Because of this concern, the CDC recommends that

pregnant women avoid travel to areas of ongoing Zika virus

transmission. If travel is necessary, measures should be

taken to prevent mosquito bites. Pregnant women returningfrom areas of Zika virus activity should consider testing to

determine if they have become infected. (6)

This “new ” viral infection is another reminder that world

is becoming smaller, and infections once exotic and far off

can reach our shores quickly and sometimes stealthily. We

need to be vigilant in identifying potential emerging infec-

tion threats quickly. Building public health infrastructure in

under-resourced parts of the world benets not just local

populations but those of us in the resource-rich parts of the

world.

Mobeen H. Rathore, MD, CPE

Editorial Board member

University of Florida Center for HIV/AIDS Research,

Education and Service (UF CARES)

Jacksonville, FL

References1. Dick GWA, Kitchen SF, Haddow AJ. Zika virus. I. Isolations

and serological specicity. Trans R Soc Trop Med Hyg . 1952;

46(5):509–520

2. Fauci AS, Morens DM. Zika virus in the Americas – yet another

arbovirus threat. N England J Med . 2016;374(7):601–604

3. Oster AM, Brooks JT, Stryker JE, et al. Interim guidelines for

preventionof sexual transmission of Zika virus - United States,2016.

MMWR. 2016;65(5):120–121, DOI: http://dx.doi.org/10.15585/mmwr.mm6505e1

4. Oliveira Melo AS, Malinger G, Ximenes R, Szejnfeld PO, Alves

Sampaio S, Bispo de Filippis AM. Zika virus intrauterine infection

causes fetal brain abnormality and microcephaly: tip of the iceberg?

Ultrasound Obstet Gynecol . 2016;47(1):6–7

5. European Centre for Disease Prevention and Control. Epidemiological

Update: Outbreaks of Zika Virus and Complications Potentially Linked to

the Zika virus infection . 2015. Available at: http://ecdc.europa.eu/

en/press/news/_layouts/forms/News_DispForm.aspx?ID¼

1342&List ¼8db7286c-fe2d-476c-9133-18ff4cb1b568&Source¼http%3A

%2F%2Fecdc%2Eeuropa%2Eeu%2Fen%2Fpress%2Fepidemiological

%5Fupdates%2FPages%2Fepidemiological%5Fupdates%

2Easpx#sthash.oX5TQfDj.dpuf . Accessed February 5, 2016

6. Petersen EE, Staples JE, Meaney-Delman D, et al. Interim

guidelines for pregnant women during a Zika virus outbreak –

United States, 2016. MMWR Morb Mortal Wkly Rep. 2016;65

(2):30–33

Figure. Areas of reported Zika virus transmission.

Parent Resources from the AAP at HealthyChildren.org• https://www.healthychildren.org/English/ages-stages/prenatal/Pages/Zika-Virus.aspx

• Spanish: https://www.healthychildren.org/Spanish/ages-stages/paginas/Pages/Zika-Virus.aspx

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DOI: 10.1542/pir.2016-00032016;37;133Pediatrics in Review

Mobeen H. Rathore Pediatricians Be Aware−Zika Virus

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Hematopoietic Stem Cell Transplantation inChildren and Adolescents

Gregory M.T. Guilcher, MD*

*Section of Pediatric Oncology/BMT, Alberta Children ’ s Hospital; Departments of Oncology and Pediatrics, University of Calgary, Calgary, Alberta, Canada.

Educational Gap

Hematopoietic stem cell transplantation (HSCT) indications and practices

have changed signicantly over the last 20 years. Evolving hematopoietic

stem cell sources, less toxic conditioning regimens, and improving graft-

versus-host disease prophylaxis and therapy have broadened the

application of HSCT from malignant conditions to increasing numbers of

nonmalignant diseases.

Objectives After completing this article, the reader should be able to:

1. Understand general principles of allogeneic and autologous

hematopoietic stem cell transplantation (HSCT), including the variety of

hematopoietic stem cell sources.

2. Discuss the variability in intensity of current conditioning approaches,

which inuences the risks and applicability of HSCT.

3. Recognize that HSCT involves acute and chronic complications and the

importance of general clinicians and subspecialists in their

management.

4. Review the pathophysiology of graft-versus-host disease, its

presentation, and its prevention and management.

5. Identify the increasing number of nonmalignant indications for HSCT in

children such that children who might benet from this procedure are

considered for timely referral as appropriate.

CASE STUDY

A 1-year-old child is referred to your of ce for a developmental assessment due to

delayed speech and gross motor skills. You notice coarse facial features and on

physical examination document corneal clouding, hepatosplenomegaly, and

numerous skeletal deformities. You suspect a metabolic disorder and request

an urgent referral to a metabolic specialist. The specialist clinically diagnoses

Hurler syndrome (mucopolysaccharidosis IH) and conrms a-L-iduronidase

deciency with urinary glycosaminoglycan testing and subsequently by enzyme

AUTHOR DISCLOSURE Dr Guilcher has

disclosed nonancial relationships relevant to

this article. This commentary does contain a

discussion of an unapproved/investigative

use of a commercial product/device.

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deciency in broblasts. While genetic testing results are

pending, you discuss the case with the metabolic specialist

andagree that an urgentreferral to a pediatric hematopoietic

stem cell transplantation (HSCT) specialist is warranted

before genetic testing results are available. The best neuro-

logic outcomes are seen when HSCT is performed as soon

as possible, preferably before age 2 years. Having general

knowledge about HSCT planning and complications, you

help the family prepare for their meeting with the pediatric

HSCT specialist, allowing for a more productive consulta-

tion, and offer to share ongoing care of the child both before

HSCT and during subsequent follow-up.

NOMENCLATURE

HSCT is the procedure of infusing blood stem cells from a

donor into a recipient. When the donor and recipient are

different people, the procedure is termed an allogeneic

HSCT; if the donor and recipient is the same person, it is

an autologous HSCT. Syngeneic HSCT describes a donation

between identical twins.

Hematopoietic stem cells (HSCs) may be collected from

bone marrow, peripheral blood, or the umbilical cord/

placental unit of a newborn (UCB).

Human leukocyte antigens (HLAs) are tested at major

histocompatibility loci: Class I (A, B, and C) and Class II

(DR; DQ in some centers). At least 6 loci routinely are

analyzed for a UCB product and 8 to 10 loci for a live donor

product (ie, bone marrow or peripheral blood). The degreeof matching is expressed as the numerator of matched loci

over the denominator of loci tested. HLA matching may be

tested at low (antigenic), medium, or high (allelic) levels of

resolution.

Graft-versus-host disease (GVHD) is a serious and poten-

tially life-threatening complication of HSCT in which the

donor T cells cause an inammatory response in the recip-

ient tissues. This complication is described in detail later,

but the risk of its development has been historically reduced

by the best possible HLA matching at major loci as well as

the use of a related donor due to closer matching at untestedminor histocompatibility antigens. Newer approaches to

haploidentical HSCT (see denition later) and novel GVHD

prevention strategies, however, are reducing GVHD rates,

even in the setting of greater HLA disparity.

Allogeneic HSC donors are further characterized in

terms of the relationship between the donor and recipient

(Table 1). Fully matched related donations can come from a

minor or adult sibling or rarely a parent (often with a history

of consanguinity). Haploidentical HSCT involves donation

from a rst-degree relative (usually a mother) who shares 1

haplotype, typically matched at 5 to 8 of 10 HLA loci.

Unrelated HSC products may come from UCB donations

or a living adult donor (not minors).

Conditioning refers to the preparative chemotherapy,

immunotherapy, and/or radiotherapy given to a recipient

before stem cell infusion to facilitate engraftment of allo-

geneic donor HSCs and to prevent rejection. In this setting,

the HSCs are a primary component of the curative therapy;

in autologous HSCT, the conditioning is the actual therapy

and the HSCs are administered to rescue the hematopoietic

system. Myeloablative conditioning refers to intensive che-

motherapy and/or radiation doses suf cient to cause bone

marrow aplasia in the absence of HSC infusion. Reduced-intensity conditioning (RIC) describes nonmyeloablative or

less intensive conditioning regimens.

HSCs for UCB and autologous donation must be cryo-

preserved, whereas most allogeneic live donor products are

donated during the conditioning of the recipient. Allogeneic

products may also be manipulated to reduce plasma, red

blood cells, or T cells, depending on the donor-recipient

blood group matching/mismatching, the stem cell source,

the routine practices of the HSCT center, and the indication

for HSCT.

TRENDS IN PRACTICE

Internationally, more than 2,000 allogeneic HSCTs were

reported to have been performed in recipients younger than

age 20 years in 2012. (1) The use of UCB has increased over

the last 20 years, as have donations from unrelated live

donors. These trends are affected by improvements in

supportive care (including GVHD prevention and treat-

ment) as well as donor availability, with expanded live donor

and UCB registries.

TABLE 1. Nomenclature for HematopoieticStem Cell Donors

Matched Sibling Donor MSD

Mismatched Sibling Donor MMSD

Matched Familia l Donor (eg, parent) MFD

Mismatched Familial Donor MMFD

Matched Unrelated Donor MUD

Mismatched Unrelated Donor MMUD

Matched indicates all tested human leukocyte antigen (HLA) loci are the

same between donor and recipient.

Mismatched means at least 1 HLA locus differs between donor and

recipient (at either allelic or antigenic level of testing).



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RIC was developed for older recipients who were ineli-

gible for myeloablative conditioning due to comorbidities.

Its use has expanded to many nonmalignant indications for

children in whom a phenotype can be reversed with even

relatively low numbers of engrafted donor HSCs (mixed

donor chimerism) and there is a mix of hematopoietic cells

of donor and recipient origin. Several conditions, such as

severe combined immune deciency, hemophagocytic lym-

phohistiocytosis, and hemoglobinopathies, are known to be

cured with stable mixed-donor chimerisms as low as 20% to

30%. (2) Theappeal of RIC lies in reduced ratesof GVHD and

transplant-related mortality (TRM) in addition to fewer acute

and late toxicities due to lower doses of conditioning agents.

The increased use of RIC and haploidentical HSCT has

also inuenced the growing proportion of HSCT recipients

with nonmalignant diseases. This trend toward HSCT for

nonmalignant conditions is due to improved outcomes with

upfront non-HSCT childhood leukemia therapies as well as

advancements in the safety of HSCT. As the risks of mor-

bidity and mortality decrease, the potential application of

HSCT as a curative option for various nonmalignant dis-

eases broadens.

Expertise in haploidentical HSCT is increasing world-

wide, particularly in Europeand the United States. Its appeal

lies in the almost universal availability of a donor, particu-

larly for potential recipients whose HLA haplotypes are

underrepresented on existing volunteer registries. Risks

of GVHD and infection (due to T-cell depletion) as well

as required laboratory infrastructure complicate its applica-tion, but improved supportive care options have increased

the practice of haploidentical HSCT. Newer techniques such

as the use of cyclophosphamide after HSC infusion have

resulted in markedly improved rates of engraftment and

reduced rates of GVHD and infectious complications. (3)

PRINCIPLES OF HSCT

Allogeneic HSCT involves the replacement of the decient

recipient hematopoietic system with that of the donor. The

best possible HLA-matched donor is used, with a preferencefor matched sibling, followed by matched related donors.

HLA testing and matching is currently limited to 8 to 10

major histocompatibility loci for living donors, yet minor

histocompatibility (H) antigens also inuence the risk of

GVHD. Minor H antigens are potentially immunogenic

peptides genetically coded outside of the major histocom-

patibility complex (MHC). (4) The coding loci for H antigens

are scattered throughout the genome in contrast to the

MHC being coded on chromosome 6. As a result, a related

fully HLA-matched donor is almost always preferred to an

unrelated donor with the same number of matched loci.

Unrelated donors may be identied through international

live donor registries or accredited public UCB banks. Iden-

tifying an unrelated donor and proceeding with HSCT

usually takes 1 or more months, depending on the rarity

of the recipient HLA-typing, donor availability to proceed

with donation, and medical clearance of both donor and

recipient. This process is generally shorter for UCB prod-

ucts because the donation has already been made and the

product has been cryopreserved.

Allogeneic stem cells can be donated as 1 of 3 stem cell

sources:

• Bone marrow

• Peripheral blood stem cells

• Umbilical cord blood

Table 2 describes the method of donation as well as

advantages and disadvantages of each source of allogeneic

HSCs. Peripheral blood stem cells are less commonly used

in pediatric HSCT recipients due to higher risks of chronic

GVHD; they are typically only used for malignant indica-

tions or as part of a RIC protocol. Many considerations are

balanced in choosing a stem cell source: the recipient ’s

underlying condition, the degree of HLA matching, the

urgency of the HSCT, the risk to the donor (particularly

for minor sibling donors who cannot consent for them-

selves), donor preference for method of donation, donor

health status (which may preclude a method of donation),

ABO status of donor and recipient, and size discrepancy

between donor and recipient. The stem cell dose (ie, num-ber of donor HSCs) required for the HSCT recipient is

calculated based on recipient weight, which may not be

achievable based on the size of a prospective living donor.

Donations from living donors are almost always collected

within 2 days of infusion to ensure that the HSCT is not

subsequently cancelled due to a change in the recipient ’s

eligibility status and to avoid cell loss with cryopreservation.

UCB products contain a xed number of cryopreserved stem

cells. A given UCB unit may have suf cient stem cells for a

smaller recipient but may be inadequate for a larger patient.

Additional considerations include the age of the donor,the donor sex, and any pregnancies (if applicable). Younger

donors generally have more cellular bone marrows and

produce greater HSC yields. In addition, their donations

are associated with lower GVHD rates in recipients. Dona-

tions from females, particularly with increasing parity, are

associated with higher rates of GVHD. Male recipients with

female donors are at highest risk. (10)

Autologous stem cell collections are almost always from

peripheral blood, with bone marrow harvests usually

reserved for failed peripheral blood collections. Such



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collections are typically timed at the point of initial hema-

topoietic recovery following myelosuppressive chemotherapy,

in combination with granulocyte colony-stimulating factor

(G-CSF). “Steady-state” collections can also be performed

with G-CSF administration alone. The HSCs are then

cryopreserved to be used later to rescue the patient following

high doses of chemotherapy or radiation, allowing for more

rapid hematopoietic recovery.

HSCs are infused into the recipient after conditioning

chemotherapy and/or radiation (see next section). Such cells

TABLE 2. Review of Hematopoietic Stem Cell Sources

HSC STEM CELL

SOURCE METHOD OF COLLECTION ADVANTAGES DISADVANTAGES

Bone Marrow Donor undergoes anesthesia, is

placed prone, and marrowharvested bilaterally from iliac crests

High engraftment rates Pain after harvest for donor

Collection proceeds until donormaximum volume collected(10-20 mL/kg) or target HSCdose achieved (whichevercomes rst)

Lower rates of chronic GVHDcompared to peripheral blood (6)

Donor size limits volume of marrowthat can be harvested (transfusionof donor is discouraged)

Research underway regardingbenets of G-CSF administrationbefore donation to improve yield (5)

High volumes of product can causevolume overload for recipient

ABO incompatibility warrantsprocessing of sample to reducered blood cells and/or plasma(HSC loss occurs with eachprocessing step)

Peripheral Blood Donor receives G-CSF for 3-5 daysprior to donation

High engraftment rates G-CSF exposure to donor can causebone pain

Apheresis catheter placement fordonor (often a femoral venous lineunder anesthesia for pediatric donors)

Higher stem cel l y ields Ongoing concern over long-termrisks of G-CSF exposure to donorbone marrow (although datashow no clear evidence of harm)

Possibly lower relapse ratesfor malignant diseases (6)(7)

Higher rates of chronic GVHD (6)

1-2 days of donation on apheresismachine (typically 4-8 hr/day)

May allow for lower-intensityconditioning

Smaller donors unable to undergoapheresis without blood productexposure due to extracorporealblood volume (transfusion of donor is discouraged)

Collection proceeds until target HSCdose achieved (diminishing yieldwith ongoing time on circuit)

Donor may not mobilize stem cellsperipherally (more common inadult donors)

Umbilical CordBlood

Collected after clamping of umbilicalcord blood

Product can be procuredquickly for HSCT

Higher rates of nonengraftment(graft failure) (9)

Method of collection should notcompromise mother or neonataldonor in any way

HLA mismatching more permissive(ie, 4-6/6 match can be used)due to lower rates of GVHD

Cell dose per recipient weight islimited to existing cryopreservedproduct (xed) and may belowered, depending on viabilitybefore freezing and after thawing

Sample is processed and cryopreserved May be superior for metabolicdisorders (8)

May obviate the need for minorsibling donation if sibling UCBavailable

Higher rates of viral infections(delayed immune recovery) (9)

No donor risk Cannot access additional HSCs if nonengraftment or early relapsefor donor lymphocyte infusion

Medical history of donor generally

unknown

G-CSF ¼granulocyte colony-stimulating-factor, GVHD¼graft-versus-host disease, HLA¼human leukocyte antigen, HSC ¼hematopoietic stem cell,

HSCT ¼hematopoietic stem cell transplantation, UCB¼umbilical cord blood



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are infused into the venous system using a central vascular

access device but may also be infused into a peripheral

intravenous catheter. No lters can be placed on the tubing,

which could block the HSCs from entering the circulation.

Premedication is required for cryopreserved products to avoid

reaction to the preservative required for the cells to tolerate

freezing, and such premedication is also used for ABO

incompatibilities with bone marrow products. The HSCs

enter the marrow via adhesion molecule recognition and

start to grow and mature immediately. However, 2 to 3 weeks

generally is required for measurable neutrophil counts (or

engraftment) and for red blood cell and platelet transfusion

independence. The fastest rates of HSC engraftment are seen

with autologous rescues and with peripheral blood stem cell

products; UCB products are often the slowest to engraft. (9)

CONDITIONING FOR HSCT

Conditioning, or the preparative regimen, refers to the

combination of chemotherapy, immunotherapy, and/or

radiation therapy given to an HSCT recipient before the

HSC infusion. Such conditioning is usually administered

over 1 to 2 weeks before HSC infusion. Immune suppres-

sion, notably reduction or ablation of innate immune and T

cells, is necessary to prevent rejection of the HSCs in the

setting of allogeneic HSCT. Conditioning may also serve as

disease-directed therapy in allogeneic HSCT for malignant

disease. Serotherapy is a form of immunotherapy typically

involving antithymocyte globulin or alemtuzumab (mono-clonal antibody to CD52) that is intended to address host

immune cell depletion, although it is primarily adminis-

tered for in vivo GVHD prophylaxis. Total body irradiation

(TBI) is highly myelosuppressive but is associated with

many undesirable acute and late toxicities.

Myeloablative conditioning is standard for malignant

disease HSCT indications and has been used historically

for nonmalignant conditions as well. The goal of myeloa-

blation is to replace all cell lines of the hematopoietic sys-

tem (eg, lymphoid, myeloid) completely with donor HSCs.

Although most experts consider eradication of all recipient blood cells to be essential for a person with leukemia, as few

as 20% donor cells in the decient cell line can reverse the

abnormal phenotype in a nonmalignant condition. (2) The

ability to cure a nonmalignant disease in the setting of

mixed-chimerism following RIC has greatly increased the

safety and application of HSCT to a broader number of

nonmalignantdiseases. Graft failure after RIC often results in

autologous recovery of the recipient ’s original HSCs.

Autologous HSCT conditioning regimens are almost

exclusively composed of high-dose combinations of

chemotherapy with or without radiation therapy targeted

at the underlying disease (usually malignant). The goal is to

rescue the patient after otherwise intolerable doses of these

agents given to intensify therapy.

RISKS OF HSCT

HSCT is associated with numerous acute and long-term

toxicities. The conditioning, its intensity (myeloablative

versus RIC), preexisting comorbidities, prior chemotherapy

exposure, and the stem cell source all inuence the risks of

complications and TRM. Children and adolescents gener-

ally tolerate myeloablative conditioning better than adults,

but TRM rates are still typically 5% to 10%. RIC was initially

designed to offer HSCT to patients with comorbidities, so

TRM rates are inherently lower, as are rates of many

toxicities. HSCT adverse effects on growth, development,

and fertility are especially pertinent in children and adoles-

cents (Table 3). (11)(12) A detailed discussion of these late

effects is beyondthe scope of thisarticle, but comprehensive

follow-up by general pediatricians and a team with expertise

in HSCT late effects care and surveillance is recommended.

Surveillance guidelines have been published by the Chil-

dren’s Oncology Group and other research bodies. (11)(12)(13)

Infections/Immune Reconstitution

HSCT usually involves myelosuppression as well as func-

tional impairment of adaptive immunity. (14) As mentioned

previously, neutrophil engraftment typically occurs 2 to 3weeks after HSC infusion, which is an important milestone

for innate immune protection against bacteria and fungi.

Natural killer cell recovery usually is complete by 1 month

post-HSCT, offering additional protection against infection.

T-cell function is impaired by intent during periods of

prophylaxis or therapy for GVHD, and GVHD in itself is

a dysregulated immune state, with poor function and pro-

tection against infection. For those HSCT recipients who

can stop GVHD prophylaxis by 6 months post-HSCT,

lymphocyte class switching (producing immunoglobulin

[Ig]G after IgM production) can be seen between 6 and 8months after HSC infusion.

Children must be monitored for opportunistic infections

after HSCT. Bacteremia and sepsis are frequent, particularly

during the neutropenic phase before engraftment. Fungal

infections are also a concern during neutropenic phases or

corticosteroid therapy. Respiratory viruses such as respira-

tory syncytial virus and adenovirus can be devastating in an

immunocompromised host. Primary infection or reactiva-

tion with cytomegalovirus and Epstein-Barr virus (EBV)

warrant preemptive surveillance and intervention based



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on international guidelines and institutional practices. EBV

can be associated with posttransplant lymphoproliferative

disorder. Acyclovir prophylaxis for herpes simplex virus-1

(HSV-1) in seropositive recipients is generally administered

for up to 1 year post-HSCT and may also confer some

protection against varicella-zoster virus. (15)(16) BK virus

is a polyoma virus that is generally harmless in an immu-

nocompetent host. However, it can cause hemorrhagic

cystitis and renal dysfunction in HSCTrecipients if viremia

is present. Pneumocystis jiroveci prophylaxis is also indicated

until immune suppression has been withdrawn.

The Centers for Disease Control and Prevention, in

collaboration with several international HSCT organizations,

have established guidelines for infectious prophylaxis, and

international guidelines also exist for the management of

fever and neutropenia in pediatric HSCTrecipients. (16)(17)

Finally, children require reimmunization after HSCT, but

clinicians must exercise caution regarding the timing of live

vaccine administration. Recommendations for the timing of

immunizations for children who have undergone HSCTcan

be referenced and are updated regularly. (16)(18)

Mucositis

Almost all children who undergo myeloablative HSCT

experience mucositis. This painful inammation of the

gastrointestinal mucosa is due to direct toxicity from con-

ditioning agents and is compounded by a local inam-

matory state in the setting of neutropenia. It can occur

anywhere between the oral mucosa and rectum, and inten-

sive intervention with narcotic and adjuvant therapies is

often required, with resolution typically occurring after

neutrophil engraftment. As the intensity of the conditioning

is reduced, the severity of mucositis decreases. Nutritionsupport is commonly required while mucositis is present.

The risk of bacterial translocation across the lining of the

mucosa and secondary HSV-1 and fungal infections are a

concern.

Nutritional Support

Many children require nutritional supplementation post-

HSCT due to decreased intake, which may be related to

nausea, anorexia, malabsorption, or mucositis. Even when

many other complications abate, many children and ado-

lescents need support to ensure adequate hydration andcaloric intake. In addition, metabolic needs are often

increased due to a catabolic state, with extensive tissue

healing required postconditioning. HSCT centers often

have strong preferences regarding the safest and most

benecial methodof nutritional supplementation. Intractable

nausea and gut integrity, with potential compromise due to

mucositis or GVHD, should be considered when deliber-

ating about enteral feeding. In the absence of contraindi-

cations, enteral feeding has potential benets to the liver in

promoting biliary ow, which is important because the liver

TABLE 3. Late Effects of Pediatric HematopoieticStem Cell Transplantation (11)( 12)

Endocrine Growth disturbance ( including growthhormone deciency)

Hypothyroidism

Thyroid nodulesHypogonadismDelayed or precocious pubertyInfertilityObesity (including sarcopenic obesity)Osteopenia/osteoporosisAvascular necrosisMetabolic syndrome

Ophthalmologic CataractsXerophthalmia

Auditory Hearing loss

Neurologic Neurocognitive impairmentCerebrovascular disease

Pulmonary Pulmonary brosisBronchiolitis obliterans with or without

organizing pneumonia (usually chronicGVHD)

Cardiovascular Congestive heart failureConduction abnormalitiesValvular disease

Renal Chronic kidney diseaseHypertensionProteinuria

Gastrointestinal Hepatic siderosisFocal nodular hyperplasia of liverEsophageal stricturesGVHD of upper or lower tracts

Hepatic GVHD

Secondary malignancy Acute myelogenous leukemia (almostexclusive to autologous HSCT)

Posttransplant lymphoproliferativedisease (non-Hodgkin lymphoma)

Solid tumors (skin, brain, thyroid,musculoskeletal, oral cavity, breast,gynecologic)

Dental Disordered tooth eruptionIncreased risk of cariesXerostomia

Psychosocial Depressed moodAnxietyPosttraumatic stress disorder

Relationship dif cultiesVocational dif cultiesChronic fatigue

GVHD¼graft-versus-host disease, HSCT ¼hematopoietic stem cell

transplantation



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TABLE 5. Nonmalignant Disease Indications for Allogeneic PediatricHSCT

Primary Immune Deciencies

• Phenotype must be severe enough to justify HSCT

• Specic genetic mutation identication ideal (can support indication for HSCT as well as inuence conditioning)

Hemoglobinopathies

• Thalassemia major

∘ Matched sibling or unrelated live donor

∘ Unrelated UCB and haploidentical HSCT experimental

• Sickle cell disease (Hg SS, Sß0, or SC)

∘ Matched sibling donor

∘ Unrelated donor and haploidentical HSCT experimental

∘ Indications vary among centers, often some evidence of prior sickle cell complications required

Inherited Bone Marrow Failure Syndromes

• Severe aplastic anemia

• Fanconi anemia

• Shwachman-Bodian-Diamond syndrome

• Diamond-Blackfan anemia

• Dyskeratosis congenita

• Amegakaryocytic thrombocytopenia

Metabolic/Genetic Disorders (29)

• Infantile osteopetrosis

• Mucopolysaccharidoses

∘ Hurler syndrome (MPS IH), standard of care

∘ Optional indications (after frontline enzyme replacement therapy, if available)

n Hurler/Scheie (MPS IH/S)

n Scheie (MPS IS)

n Maroteaux-Lamy (MPS VI)

n Sly (MPS VII)

• Leukodystrophies

∘ Cerebral X-linked adrenoleukodystrophy

n Before advanced disease

∘ Metachromatic leukodystrophy, late onset

∘ Krabbe disease, generally early onset

• Miscellaneous disorders, optional indications

∘ Fucosidosis

∘ a-mannosidosis

Continued



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and subsequently stopped. For this reason, HSCTrecipients

are not expected to receive lifelong immune suppression, in

contrast to patients who receive solid organ transplantation.

INDICATIONS FOR HSCT

Historically, most allogeneic HSCT procedures in children

were for malignant diseases such as leukemias and lym-

phomas. With improving cure rates using chemotherapy for

such cancers, the proportion of nonmalignant disease indi-

cations for pediatric HSCT continues to increase.

Malignant Disease

Common malignant disease indications for allogeneic

HSCT in children are acute leukemias and some non-

Hodgkin and Hodgkin lymphomas. High-risk clinical/

biological features or relapse are usually present (Table4). Myelodysplastic syndrome, a preleukemic state with risk

of conversion to acute myeloid leukemia, is almost always

treated with HSCT in children. Chronic myelogenous leu-

kemia is often managed with tyrosine kinase inhibitors

alone, so fewer affected children and adolescents are rec-

ommended to undergo HSCT.

Autologous HSCT is performed routinely for children

with high-risk neuroblastoma and for relapsed lymphomas.

Many brain tumor treatment plans are incorporating high-

dose chemotherapy and autologous HSCT, particularly for

children younger than age 3 years, in an effort to spare ordelay radiation therapy to the developing brain. Current

research is exploring the use of autologous HSCT in chil-

dren and adolescents with solid tumors, such as Ewing

sarcoma, who have high-risk features.

Nonmalignant Disease

Allogeneic HSCT is increasingly performed for nonmalig-

nant disease indications as rates of TRM and GVHD are

reduced. These diseases confer lifelong risks of morbidity or

mortality and often require complex supportive care (Table 5).

Chronic transfusions for hemoglobinopathies are associ-

ated with signicant risks of iron overload and resultant

complications. For some of these conditions, the risks of

HSCT are affected substantially by the type of donor avail-

able, and the resulting recommendation for HSCT may be

affected. Primary immune deciencies such as severe com-

bined immune deciency, X-linked chronic granulomatous

disease, and Wiskott-Aldrich syndrome are examples of

nonmalignant diseases for which HSCT is commonly per-

formed. A large body of evidence supports the safety and

ef cacy of HSCT for severe aplastic anemia, with increasing

data to guide clinicians in decision-making for inherited

bone marrow failure syndromes. Thalassemia major has an

established track record for related and unrelated HSCT,

with a clear phenotype of lifelong transfusion dependence

and risk of iron overload.

Sickle cell disease (SCD) is increasingly recognized as adisease with limited life expectancy and variable quality of life

despitebest supportive care. As a result,interestis growingin

the application of HSCT to those with sickling syndromes.

Although a history of complications of SCD had been man-

dated in the past to justify HSCT, the safer HSCT techniques

have prompted increasing interest from patients, hematolo-

gists, and HSCT practitioners to intervene before organ

dysfunction occurs, notably neurologic and lung injury.

Some metabolic diseases such as mucopolysaccha-

ridoses are routine indications for HSCT, although the poten-

tial bene

ts are less clear for other metabolic diseases. (29)Table 5 summarizes some of the more standard indications,

with an acknowledgement that HSCT is performed in some

centers for life-threatening metabolic diseases with fewer

data regarding potential benet. (29) HSCTcan help prevent

neurologic progression in a metabolic disease due to

replacement of the decient enzyme by monocytes pro-

duced from the HSCs following engraftment. Because

HSCT generally only halts and does not reverse neurologic

progression and knowing that HSC-derived enzyme

replacement can take months to reach the central nervous

TABLE 5. (Continued )

∘ Aspartylglucosaminuria

∘ Farber

∘ Gaucher types 1 (non-neuronopathic) and 3 (Norrbottnian)

∘ Niemann-Pick type C-2

∘ Wolman syndrome

HSCT ¼hematopoietic stem cell transplantation, MPS¼mucopolysaccharidosis, UCB¼umbilical cord blood



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system (CNS) due to slow migration of donor-derived

monocytes into the CNS, early HSCT is critical for indicated

conditions. Generally other non-CNS manifestations of the

metabolic disorders are not reversed with HSCT. Discus-

sions about the appropriateness of HSCT should happen

relatively soon after making a diagnosis, and those who

manage such conditions routinely should be aware of

evolving indications for this group of diseases.

The practice of autologous HSCT for nonmalignant

conditions is relatively limited. Some encouraging results

for those with severe SLE suggest that some patients may

derive temporary benet in terms of corticosteroid-sparing

or reduced disease activity. (30) Repopulation of the bone

marrow and peripheral blood with fewer autoreactive

clones, in addition to the use of disease-modifying agents

such as cyclophosphamide as part of the conditioning, may

explain this period of improvement. Gene therapy trials for

hemoglobinopathies are incorporating autologous HSC col-

lection and ex vivo manipulation, with reinfusion following

conditioning designed to give the manipulated cells a survival

advantage. (31) The use of autologous HSCT for traumatic

brain injuries and cerebral palsy is an areaof intenseresearch,

but these indications are experimental at present.

CME quizand references for this articleare at http://pedsinreview.

aappublications.org/content/37/4/135 .

Summary • Hematopoietic stem cell transplantation (HSCT) refers to the

infusion of either allogeneic or autologous hematopoietic stem

cells.

•

Newer techniques to reduce the risk of complications areexpanding the applicability of HSCT.

• Nonmalignant disease indications for HSCT are increasing.

• Observational and cohort studies (level C evidence) indicate that

acute and long-term toxicities remain an important consideration

for patients, families, and clinicians in making a recommendation

for HSCT and warrant lifelong surveillance. (11)(12)(13)(21)

• Based on overwhelming evidence from observational studies

(level B evidence), graft-versus-host disease can be a signicant

cause of morbidity and mortality in allogeneic HSCT. (22)(24)

• General pediatricians and subspecialists should be aware of

evolving and newly established nonmalignant indications for

HSCT to make appropriate referrals (level D evidence). (28)(29)

(30)

Parent Resources from the AAP at HealthyChildren.org• https://www.healthychildren.org/English/health-issues/conditions/cancer/Pages/Cancer-Therapies.aspx

• Spanish: https://www.healthychildren.org/Spanish/health-issues/conditions/cancer/Paginas/Cancer-Therapies.aspx


http://pedsinreview.aappublications.org/content/37/4/135http://pedsinreview.aappublications.org/content/37/4/135https://www.healthychildren.org/English/health-issues/conditions/cancer/Pages/Cancer-Therapies.aspxhttps://www.healthychildren.org/Spanish/health-issues/conditions/cancer/Paginas/Cancer-Therapies.aspxhttp://pedsinreview.aappublications.org/http://pedsinreview.aappublications.org/http://pedsinreview.aappublications.org/http://pedsinreview.aappublications.org/https://www.healthychildren.org/Spanish/health-issues/conditions/cancer/Paginas/Cancer-Therapies.aspxhttps://www.healthychildren.org/English/health-issues/conditions/cancer/Pages/Cancer-Therapies.aspxhttp://pedsinreview.aappublications.org/content/37/4/135http://pedsinreview.aappublications.org/content/37/4/135

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PIR QuizThere are two ways to access the journal CME quizzes:

1. Individual CME quizzes are available via a handy blue CME link under the article title in the Table of Contents of any issue.

2. To access all CME articles, click “ Journal CME ” from Gateway ’ s orange main menu or go directly to: http://www.aappublications.

org/content/journal-cme.

REQUIREMENTS: Learnerscan take Pediatrics in

Review quizzes and claim

credit online only at:

http://pedsinreview.org.

To successfully complete

2016 Pediatrics in Review

articles for AMA PRA

Category 1 Credit TM,

learners must

demonstrate a minimum

performance level of 60%or higher on this

assessment, which

measures achievement of

the educational purpose

and/or objectives of this

activity. If you score less

than 60% on the

assessment, you will be

given additional

opportunities to answer

questions until an overall

60% or greater score is

achieved.

This journal-based CME

activity is available

through Dec. 31, 2018,

however, credit will be

recorded in the year in

which the learner

completes the quiz.

1. A 13-year-old girl with acute myeloblastic leukemia has relapsed 6 months after

completing her initial course of chemotherapy. You explain to the parents that the only

potential cure will be hematopoietic stem cell transplantation (HSCT). Which of the

following options is the best donor for this girl?

A. Allogenic transplant using a rst cousin who matches at 8/10 loci.

B. Allogenic transplant using a sibling who matches at 8/10 loci.

C. Allogenic transplant using an unrelated donor who matches at 8/10 loci.

D. Allogenic transplant using her mother who matches at 8/10 loci.

E. Autologous transplant.

2. Which of the following would be the best therapy for the child described in the previous

question?

A. Chemotherapy alone to attempt prolonged remission.

B. Myeloablative conditioning prior to transplant.C. Reduced-intensity conditioning prior to transplant.

D. Serotherapy prior to transplant.

E. Total body irradiation prior to transplant.

3. A 5-year-old boy underwent HSCT 12 days ago because of neuroblastoma. He is now

complaining of increasing abdominal pain. You note that he has icterus and mild

generalized edema. Laboratory studies reveal a total bilirubin of 4.5 mg/dL (76.9 mmol/L)

and conjugated bilirubin of 2 mg/dL (34.2 mmol/L) but only mild elevations in

transaminase values. The most likely cause of his symptoms is:

A. Cytomegalovirus.

B. Hepatitis A.

C. Hepatitis B.

D. Sepsis.

E. Sinusoidal obstructive syndrome.

4. A 7-year-old girl with homozygous sickle cell anemia underwent HSCT from an unrelated,

human leukocyte antigen-identical donor 7 months ago. She has been complaining of

fatigue for 2 weeks and now has developed a feeling of her mouth being dry. On physical

examination she has a widespread nonspecic erythematous rash over hertrunk and arms.

There is no cyanosis or jaundice. She has shotty anterior cervical nodes but no other

signicant adenopathy. The most likely cause of her symptoms is:

A. Acute graft-versus-host disease.

B. Chronic graft-versus-host disease.

C. Cytomegalovirus.

D. Epstein-Barr virus.

E. Human herpesvirus 6.

5. A 4-year-old girl presents with bruising and pallor. She is found to have pancytopenia. Abone marrow aspirate and biopsy are diagnostic of myelodysplastic syndrome. Which of

the following is themost appropriate treatment for this child’s myelodysplastic syndrome?

A. Begin chemotherapy and evaluate the response long term.

B. Begin prophylactic antibiotics to prevent sepsis.

C. Maintain the patient on transfusions until she becomes unresponsive to them.

D. Observe the child until the pancytopenia becomes severe.

E. Proceed to HSCT once an appropriate donor is identied.


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Gregory M.T. GuilcherHematopoietic Stem Cell Transplantation in Children and Adolescents

ServicesUpdated Information &

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Gregory M.T. GuilcherHematopoietic Stem Cell Transplantation in Children and Adolescents

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Physical Abuse of ChildrenJill C. Glick, MD,* Michele A. Lorand, MD,† Kristen R. Bilka, MMS, PA-C‡

*Department of Pediatrics, University of Chicago; Medical Director, Child Advocacy and Protective Services, University of Chicago Comer Children’ s Hospital,

Chicago, IL.†

Division of Child Protective Services, Department of Pediatrics; Medical Director, Chicago Children’ s Advocacy Center, John H. Stroger, Jr. Hospital of Cook

County, Chicago, IL.‡ Departmentof Pediatrics,University of Chicago; PhysicianAssistant,Child Advocacy andProtectiveServices,University of Chicago ComerChildren’ s Hospital,Chicago,IL.

EDITOR’S NOTE

This article stresses the importance of the “sentinel injury,” a physical injury that

is unusual for the age of the child and may herald more serious injuries, thereby

necessitating further evaluation.

Joseph A. Zenel, MD

Editor-in-Chief

Practice Gap

Before receiving a diagnosis of child abuse, 25% to 30% of abused infants

have “sentinel” injuries, such as facial bruising, noted by clinicians or

caregivers. (1)(2)(3)(4)(5)(6) Although easily overlooked and often considered

minor, such injuries are harbingers warning clinicians that pediatric patients

require further assessment. Appropriate intervention is critical, and the

clinician plays a major role in identifying children who present with signs

or symptoms concerning for child physical abuse by ensuring appropriate

and expeditious medical evaluations and reports to child protective services.

Objectives Aftercompleting this article, thereader shouldbe able to:

1. Identify which injured children require a child abuse evaluation.

2. Recognize subtle signs and nonspecic symptoms of major trauma in

infants.

3. Understand sentinel injuries and their signicance.

4. Know which laboratory and imaging studies to obtain when child

physical abuse is suspected.

5. Understand the legal obligation to report children with injuries that are

suspicious for physical abuse and develop a thoughtful approach to

informing parents of this legal obligation.

CASE PRESENTATION

A privatepractice pediatrician receives a phone call from a community emergency

department (ED) physician regarding one of her patients, a 4-month-old infant

being treated for bronchiolitis. TheED physician informs her that the baby ’s chest

AUTHOR DISCLOSURE Drs Glick and Lorand

and Ms Bilka have disclosed no nancial

relationships relevant to this article. This

commentary does not contain a discussion of

an unapproved/investigative use of a

commercial product/device.



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radiograph has revealed multiple posterior rib fractures in

different stages of healing, and physical examination shows

a cluster of small bruises on her cheek. The mother denies a

history of trauma and has no explanation for the ndings.

The ED physician is concerned that the baby has been

abused and his plan includes admitting the patient to the

hospital to obtain a head computed tomography (CT) scan,

skeletal survey, complete blood cell count, coagulation stud-

ies, electrolytes, and liver function tests. He also plans to

consult with the child abuse pediatrician and arrange for an

evaluation of the patient ’s siblings. Lastly, he tells the

primary pediatrician that he will explain the clinical ndings

to the family and le a report with the child welfare system.

The primary pediatrician thankshim for contacting her and,

recalling no signicant medical history, pulls the patient ’s

chart.

The baby ’s most recent visit was slightly more than 1

week ago for her routine 4-month health supervision

visit. She is a term infant who has no prior medical

complaints other than colic at 1 month of age that has

resolved. On recent physical examination, the baby ap-

peared well, with normal growth and development, and

the mother did not raise any concerns during the visit.

The primary pediatrician now notes that she documented

a small circular bruise on the baby ’s chest that the mother

stated occurred when a 3-year-old sibling hit the baby with a

toy. Having had a longstanding relationship with this

mother and family, she accepted this explanation for the

bruise.After reviewing the chart, she explores the current

literature and management of suspected child physical

abuse, including the American Academy of Pediatrics

clinical report on evaluation of suspected child physical

abuse. (7) She now understands that the bruise she noted

on examination was a sentinel injury that should have

prompted further evaluation. As a result of the case, her

practice group plans to review and implement guidelines

for the identication and evaluation of children present-

ing with signs or symptoms concerning for physical

abuse.

INTRODUCTION

Child physical abuse is a dif cult diagnosis to entertain

primarily because clinicians are hesitant to accept that

caretakers can injure children. The diagnosis is further

complicated by the reality that caretakers rarely disclose

maltreatment, preverbal or obtunded children cannot provide

a history, and signs and symptoms of physical abuse may be

subtle and confused with other common pediatric diagnoses.

Clinicians must appreciate that with few exceptions, almost

any injury can be either abusive or accidental.

Once considered a strictly social problem, child abuse is

now also recognized as a medical problem. A recent survey

by the Children’s Hospital Association revealed that more

than 90% of responding hospitals have child protection

teams, and more than 50% have at least 1 of the 324 board-

certied child abuse pediatricians in the United States on

staff. (8)

Recognition of the profound impact of childhood expe-

riences on adult health and well-being, beginning with

Feleitti’s landmark adverse childhood experiences study,

further solidies the need for clinicians to recognize

possible maltreatment and intervene. (9) Adverse child-

hood experiences have wide-ranging, cumulative, and

direct impacts on adult health, increasing the incidence

of chronic diseases and early death. (9)(10) The role of

the clinician is therefore not only limited to promoting

wellness but also to decreasing or eliminating long-term

health consequences resulting from childhood exposure to

trauma and violence.

EPIDEMIOLOGY

In 2014, over 3.5 million children were subjects of child

maltreatment reports. Of those, 702,000 children (20%)

were found to have evidence of maltreatment. (11) This

translates to an annual victimization rate of 9.4 children

per 1,000 in the United States and a prevalence rate of 1 in8 children by age 18 years. (12) Neglect is the most

common form of child maltreatment, constituting 75%

of indicated reports; 7% are attributable to physical abuse.

In 80% of child physical abuse cases, a biological parent is

the perpetrator. Children in their rst postnatal year have

the highest victimization rate (24.4 per 1,000), and chil-

dren younger than age 3 years have the highest fatality

rate, comprising over 70% of the nationally estimated

1,580 child maltreatment deaths in 2014. Child welfare

data and trends, however, are dubious because of a lack of

standardized terminology and differences in report andresponse types across states.

RISK FACTORS FOR CHILD PHYSICAL ABUSE

Risk factors for abuse are commonly categorized into

parental, child, and social characteristics. Identication of

risk factors aids in the assessment of abuse but more

importantly aids in the ability to counsel parents and

develop preventive strategies. Risk factors are not, in

and of themselves, diagnostic. Many families have risk



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factors and never abuse their children, while others have

no apparent risk factors and do abuse their children. Child

abuse does not discriminate; it affects children of all ages,

socioeconomic classes, and ethnic groups.

Parental/household risk factors include substance

abuse, mental illness, interpersonal violence (IPV), single

and/or teen parent, and a nonrelated adult in the home.

Among the social risk factors are social isolation, poverty,

lower levels of education, and large family size. Child-

related risk factors include prematurity, low birthweight,

intrauterine drug exposure, and developmental and phys-

ical disabilities. The most signicant risk factorfor abuse is

the age of the child, with infants and toddlers being at

greatest risk for serious and fatal child physical abuse.

A clear association exists between particular developmen-

tal stages and physically abusive injuries, such as excessive

crying and abusive head trauma or toilet training and

inicted scald burns. Awareness of these developmental

triggers should guide anticipatory guidance, with the poten-

tial for preventing an abusive injury.

IPV is a substantial risk factor for child abuse, and each

health supervision visit should include IPV screening.

Exposure to violence itself, even if the child is not physically

harmed, has signicant and long-lasting effects.

WHEN TO CONSIDER THE DIAGNOSIS OF CHILD

PHYSICAL ABUSE

Injuries are common in childhood. Although most child-hood injuries are accidental, the clinician must appreciate

that almostany injury canbe abusive. With theexception of

patterned marks, very few injuries are pathognomonic for

abuse. In the nonverbal child, injuries may be apparent or

covert; many children present with nonspecic symptoms

and a lack of history. Child physical abuse should be

entertained in any infant displaying signs or symptoms

potentially explained by trauma, such as irritability, lethargy,

vomiting, apnea, seizures, or coma.

Several studies of abused children have demonstrated

that antecedent sentinel injuries, such as bruises, intraorallesions, and skeletal trauma, were noted by medical pro-

fessionals or caregivers before a subsequent abusive act,

while children presenting with accidental injuries were not

found to have sentinel injuries. (1)(2)(3)(4)(5)(6) Because

infants are essentially nonmobile and nonweight-bearing,

they should never have bruising. Therefore, any injury in

an infant must be viewed as signicant and descriptive

language such as “minor” should not be used. Identifying

a sentinel injury with appropriate evaluation of the child may

be lifesaving.

As children become mobile, the incidence of expected

accidental trauma increases, and common childhood

injuries such as bruises over bony prominences and

toddler’s, clavicular, and skull fractures are seen. In

contrast to children with abusive injury, witnesses often

corroborate accidental injuries in ambulatory children,

caregivers seek timely care, they provide a consistent

history, and the mechanism described explains the injury

observed. Because the incidence of child physical abuse is

highest in children younger than age4 years, theclinician

must have a high index of suspicion and add abusive

trauma to the differential diagnosis of the ill-appearing

young child.

Determining which injured children require an evalua-

tion for child physical abuse should account for the age and

developmental ability of the child, the injury sustained, the

adequacy of the historical explanation provided, and

TABLE 1. Criteria for Consideration to Initiate aChild Physical Abuse Assessment

Age and Development

• Nonmobile infant with any injury

• Injury in nonverbal child

• Injury inconsistent with child’s ability

• Statement of harm from a verbal child

Injury

• Any injury in a nonmobile infant

• Uncommon in age group

• Occult nding

• Mechanism not plausible

• Multiple injuries, including involvement of multiple organs

• Injuries of differing ages

• Pattern of increasing frequency or severity of injury over time

• Patterned cutaneous lesions

• Bruises to torso, ear, or neck in child younger than age 4 years

• Burns to genitalia, stocking or glove distribution, branding, or pattern

History

•Chief complaintdoes notcontaincaregiver concern foran injuryand plausible history

• Caretaker response not commensurate to injury

• Unexplained delay in seeking care

• Lack of, inconsistent, or changing history

• Inconsistencies or discrepancies in histories provided byinvolved caretakers



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clinical ndings (Table 1). Fundamentally, when injuries

are not explained or historical data provided contain incon-

sistencies or insuf ciencies, a child abuse evaluation is

warranted. Any child younger than age 2 years who pre-

sents with a suspicious injury should have a skeletal

survey. Other studies should be obtained based upon

clinical concern and ndings. Negative studies do not rule

out child abuse.

HISTORY OF THE PRESENT ILLNESS AND CHILD

PHYSICAL ABUSE

A thorough history of present illness is the single most

useful piece of information to aid the clinician in making a

correct diagnosis. The detailed history should be obtained

in separate interviews with each caregiver, the child (if

possible), verbal siblings, and any other persons in the

household. Interviews should be conducted such that each

parent or caregiver can give a history in his or her own

words. He or she should be allowed to provide the entire

history without interruption, decreasing the chance that

the interviewer unintentionally redirects or suggests a

mechanism. Details about the mechanism of injury, the

events leading up to the injury, and whether the injury was

witnessed or unwitnessed should be elicited. For example,

in injuries related to falls, having parents recreate the

scene, describing the height of furniture, ooring, and

the position of the child before and after the fall, is

essential.A history of the onset and progression of symptoms

since the child last appeared well should be obtained.

Determining who was caring for the child and asking each

of the caretakers how the child appeared by focusing on

descriptions of activity and movement (particularly during

feeding, bathing, and diaper changing) can aid in deter-

mining when a child may have been injured. For infants

with intracranial injury, it may be dif cult to develop a

timeline of when the child was last well because the infant

may be thought of as “well-appearing” while asleep when

the child actually may be seriously injured. Important features of the history that should raise concern for an

abusive injury include: no history of trauma; a history of

trauma inconsistent with the severity, pattern, or timing of

the injury; injury inconsistent with the developmental

capabilities of the child; multiple or evolving histories;

discrepant histories from the same caregiver or between

caregivers; injury attributed to a sibling or pet; and a delay

in seeking medical care.

In addition to a detailed history of the incident, the

patient ’s birth, past medical, developmental, and dietary

histories should be obtained. A complete social history

identies risk factors for maltreatment, and a family med-

ical history focusing on illnesses such as bone disease or

bleeding tendencies allows for screening and identication

of possible underlying medical problems in the patient.

PHYSICAL EXAMINATION AND DIAGNOSTIC

EVALUATION

A thorough and well-documented physical examination of

any child with concerns for possible child abuse is imper-

ative. The clinician should be aware that children may suffer

more than one type of abuse; the physically abused child

may also be neglected or sexually abused. The child’s mental

status, affect, and level of activity should be noted. The child

must be undressed and all skin surfaces examined with

good lighting. The entire body must be evaluated, including

areas that may be overlooked, such as the pinnae, behind the

ears, the oral cavity including the teeth and frenula, the soles

and palms, the genitals, and the anus. Every cutaneous

injury should be described according to color, shape, size,

and location. Photographic documentation or drawings

should be completed and placed in the medical record.

The presence or absence of swelling and the ability to move

limbs should be noted. Paradoxical comfort (a baby who is

more comfortable when not being held but cries when

picked up) may be observed in infants with occult injuries

such as rib fractures. An assessment of the child’s nutri-

tional status, including completion of a growth chart, iscrucial because neglect, malnutrition, and failure to thrive

may be comorbidities with physical abuse.

The diagnostic evaluation of suspected physical abuse

should always be driven by the history, physical examination,

and differential diagnosis. Clinicians must consider the pos-

sibility that multiple types of traumamay coexist andrecognize

that injuries maybe occult. Anynonverbal and nonambulatory

child with an injury should have a standard child abuse

evaluation (Table 2) no matter how “minor” the injury. The

most prudent approach is to rule out skeletal trauma in all

children younger than 2 years of age with a standard skeletalsurvey and assess for occult central and/or internal injuries

by choosing appropriate imaging and laboratory studies

(Table 3).

ABUSIVE HEAD TRAUMA

Abusive head trauma (AHT) has the highest mortality of

all forms of child physical abuse, with an estimated

fatality rate greater than 20%. Survivors have irreversible

sequelae of brain injury, ranging from minor behavioral



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issues and neurodevelopmental delays to signicant neu-

rodevelopmental delays, seizures, blindness, and paraly-

sis. (13) The incidence of AHT is 15 to 30 cases per

100,000 infants annually in the United States. AHT

occurs most often in children younger than age 2 years

and crying is the most commonly identied trigger.

Recognizing that the phrase “shaken baby syndrome”

implies a specic mechanism, in 2009 the American

TABLE 2. Protocol for the Evaluation of Suspected Child Physical Abuse

History of Present Illness

• Interview primary caretakers separately; note historian ’s ability to provide history

• Ask caretakers about age-appropriate developmental abilities of child. Observe child if possible

• Develop a timeline from when the child was last agreed upon to be in his or her usual state of good health and note the following:

B Onset of symptoms and progression

B The patient’s observed mental status and activity level. Ask specically about how the child appeared at time of hand off betweencaretakers

• Note if there were any witnesses, photos taken of child, or other corroborating information

Social History

• List all adults having access to the child, including age, relationship, and contact information

• List all children, including age and relationship; identify in which home they reside

• Note history of drug or alcohol abuse, intimate partner violence, mental illness, prior history of involvement with child protective services

Relevant Past Medical History

• Skeletal trauma: child or family history of bone disease, diet history

• Abusive head trauma (AHT) and cutaneous injuries: child or family history of bleeding diathesis, eg, prolonged bleeding after circumcision,umbilical cord removal, or surgery or as a result of past injuries

Physical Examination

• Examineclosely forpossibleintraoral injuriessuch as frenulum tears;explore all

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