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EgyptianPediatricsYahoo Group
http://health.groups.yahoo.com/group/
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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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
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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:
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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
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and/or objectives of this
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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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DOI: 10.1542/pir.2015-00442016;37;135Pediatrics in Review
Gregory M.T. GuilcherHematopoietic Stem Cell Transplantation in Children and Adolescents
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DOI: 10.1542/pir.2015-00442016;37;135Pediatrics in Review
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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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