Shigella Pediatrics

visual diagnosis
Chronic Diarrhea and Failure to

Thrive in a 5-Year-Old Girl
Mohammed Hasosah, MD,* Mohamed Satti, MD,
Amirshazad Hayat, MD*
Presentation
Figure 1. Endoscopic view showing edematous and friable

colonic mucosa with multiple ulcers (arrows).
Author Disclosure
Drs Hasosah, Satti, and Hayat have disclosed no financial
relationships relevant to this article. This commentary does
not contain a discussion of an unapproved/ investigative use
of a commercial product/device.
A 5-year-old girl presents to the clinic with a history of

chronic diarrhea and failure to thrive of 6 months
duration. She had a known history of hemophagocytic
lymphohistiocytosis diagnosed at age 2 months. Six
months later, she underwent allogeneic bone marrow
transplantation (BMT) (unrelated peripheral blood stem
cell). The mother describes the diarrhea as mucousy and
bloody. The diarrhea (8 loose bowel movements per day)
is associated with weight loss. She has a poor appetite but
no vomiting or abdominal distension. She has no rashes.
She was a product of full-term, normal pregnancy. Her
review of system ndings were unremarkable.
Physical examination reveals that her weight and
height are both below the fth percentile for age. Vital
signs are normal. She is listless and dehydrated. The rest
of physical examination ndings are normal.
The laboratory study ndings include a hemoglobin
level of 9.2 g/dL (92 g/L) (reference range, 12.2
15.3 g/dL [122153 g/L]) and normal white blood cell,
platelet, C-reactive protein, bilirubin, alkaline phosphatase, alanine transaminase and aspartate aminotransferase
values. The stool samples contains many white blood
cells, but her stool culture results are negative. Sigmoidoscopy reveals erythematous mucosa and multiple ulcers
(Figure 1). The histopathologic biopsy of the sigmoid reveals crypt apoptotic epithelial cells (Figure 2). A diagnosis is made based on clinical, endoscopic, and pathologic
ndings.
*Department of Pediatric Gastroenterology, King Saud Bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Jeddah, Kingdom of Saudi Arabia.
Department of Pathology, King Saud Bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Jeddah, Kingdom of Saudi Arabia.
Pediatrics in Review Vol.35 No.6 June 2014 e29
Downloaded from http://pedsinreview.aappublications.org/ at Health Internetwork on July 29, 2014
visual diagnosis
allogeneic hematopoietic cell transplantation involving multiple sites

and occurs in approximately 50% of
transplant recipients. (2)
Pathogenesis, Risk factors,

and Presentation
Chronic GVHD can affect most organs of the body, with skin and oral
manifestations being the most common. Eyes, gastrointestinal tract,
lungs, joints, and liver can be affected
as well. The pathogenesis of chronic
GVHD occurs when immune cells
transplanted from a nonidentical donor (the graft) recognize the transplant recipient (the host) as foreign,
thereby initiating an immune reaction
that causes disease in the transplant recipient. (2) The most important risk
factors for chronic GVHD include
prior history of acute GVHD, the
use of a nonT-celldepleted graft,
older age of donor and recipient,
malignant indication for transplantaFigure 2. Biopsy specimen of the sigmoid colon showing crypt distortion, focal surface tion, the use of total body irradiation
epithelial degeneration, crypt apoptotic epithelial cells (black arrow), focal cryptitis in a preparative regimen, previous sple(white arrow), and crypt dropout with mixed lymphoplasmacytic inflammatory infiltrate nectomy, immunosuppression other
in the lamina propria (double black arrow).
than cyclosporin-methotrexate, mismatched or unrelated peripheral blood
stem cell, cytomegalovirus seropositivity (donor and reDiagnosis
cipient), and chronic myeloid leukemia. (3)
The diagnosis of graft-versus-host disease (GVHD) is esGastrointestinal GVHD causes profuse diarrhea, intestitablished by clinical judgment, laboratory evaluation, and
nal bleeding, cramping, malabsorption, abdominal pain,
biopsy results. GVHD is conrmed in this child by the
and paralytic ileus. The diarrhea is greenish mucoid, watery,
combination of the following: (1) previous allogeneic
and secretory in nature. Upper gastrointestinal tract inBMT, (2) gut involvement (chronic bloody diarrhea),
volvement without enteric manifestation has been described
and (3) gastrointestinal biopsy ndings (crypt destrucin 13% of children. Common symptoms are anorexia, naution, single cell dropout, and cell apoptosis). In this case,
sea, vomiting, and dyspepsia. The endoscopic ndings are
the child has chronic GVHD because she developed
nonspecic, and there is a broad differential diagnosis, inGVHD more than 100 days after BMT.
cluding bacterial, fungal, viral, and parasitic infections.
In gastrointestinal GVHD, gastrointestinal biopsy specimens show diffuse edema and mucosal swelling followed
Discussion
by variable crypt cell apoptosis (eg, exploding crypts),
GVHD is divided into 2 types: acute GVHD and chronic
a mixed chronic and predominantly lymphoplasmacytic
GVHD. Acute GVHD describes a syndrome that consists
inltrate, and possibly crypt dropout. Fibrosis of the lamina
of dermatitis, enteritis, and hepatitis occurring within the
propria is also present.
rst 100 days after BMT. Chronic GVHD develops more
than 100 days after transplantation and is an autoimmuneDifferential Diagnosis
like syndrome that consists of impairment of multiple
The differential diagnosis of chronic bloody diarrhea and
organs or organ systems, involving skin, liver, lung, and intesfailure to thrive in a child who had allogeneic bone
tine. (1) Chronic GVHD remains a major complication of
e30 Pediatrics in Review Vol.35 No.6 June 2014
visual diagnosis
marrow transplantation must include GVHD. Other differential diagnoses include bacterial colitis, CMV colitis,
cryptosporidium colitis, aspergillus colitis, candida colitis
and ischemic colitis. Pseudomembranous colitis, secondary
to antibiotic therapy and chemotherapy or radiotherapyinduced colitis are other causes of chronic bloody diarrhea
and failure to thrive.
On ofce follow-up after hospital discharge, the patient was improving and her bloody diarrhea has resolved.
Her prednisolone dose and schedule were modied by
the transplant team based on her clinical course. Laboratory ndings, repeated sigmoidoscopy, and biopsy ndings were normal.
Summary
Management
The primary therapy for chronic GVHD includes prednisone combined with azathioprine, cyclosporin or tacrolimus,
and thalidomide, whereas secondary therapy for chronic
GVHD includes high-dose corticosteroids, tacrolimus,
mycophenolate mofetil, rapamycin, extracorporeal photopheresis, rituximab, thalidomide, acitretin, hydroxychloroquine, pentostatin, and psoralenUV A. (4)(5)
Patients with chronic GVHD are treated with prolonged immunosuppressive treatment for a mean of 2
to 3 years from the initial diagnosis, with 10% of those
surviving for at least 7 years still receiving immunosuppressive treatment at that time or beyond. (6) Glucocorticoids
with or without calcineurin inhibitors (ie, cyclosporine or
tacrolimus) remain the standard initial treatment, but signicant adverse effects and unsatisfactory outcomes, particularly for patients with high-risk features of chronic
GVHD, support the need for more effective and less toxic
therapies. (6)
However, the outcome of the disease is usually severe,
especially in cases of gastrointestinal involvement, and the
necessary intensive immunosuppressive treatment renders the host vulnerable to opportunistic infections.
For this reason, histologic conrmation of the diagnosis
is recommended to avoid inappropriate treatment of
patients.
Chronic GVHD usually develops 100 days after BMT

and is a serious and potentially life-threatening long-term
complication. Chronic GVHD can occur after previous
or ongoing acute GVHD or in patients without a history
of acute GVHD (eg, de novo disease) as illustrated by this
case. In evaluating a patient presenting with chronic
diarrhea more than 100 days after BMT, one must consider a serious underlying illness such as chronic GVHD
because it is a major cause of morbidity and mortality
of allogeneic stem cell transplantation. As indicated by
this case, chronic GVHD can cause diarrhea. Complete
evaluation of the diarrhea state should be part of the
initial investigation. In many cases, however, the diagnosis of GVHD is not straightforward, and gastrointestinal
biopsy and histologic conrmation is often necessary to
corroborate a clinical impression of chronic GVHD.
Suggested Reading
Ratanatharathorn V, Ayash L, Lazarus HM, Fu J, Uberti JP.
Chronic graft-versus-host disease: clinical manifestation and
therapy. Bone Marrow Transplant. 2001;28(2):121129
References
1. Ferrara JL, Deeg HJ. Graft-versus-host disease. N Engl J Med.
1991;324(10):667674
2. Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host

disease. Biol Blood Marrow Transplant. 2003;9(4):215233
3. Zecca M, Prete A, Rondelli R, et al; AIEOP-BMT Group. Italian
Patient Course
Because of her chronic bloody diarrhea, the patient was admitted to the hospital for evaluation and treatment of colitis. Empirical ampicillin and gentamicin therapy was
started for 48 hours but was discontinued after blood
and urine culture results were negative. No pathogens were
detected in stool cultures; also the result of a CMV-PP65
antigen test was negative. In our patient, bleeding, anemia,
and diarrhea were relieved by supportive management, including uid, blood products, and enteral nutrition. Gastrointestinal biopsy specimens excluded the above differential
diagnosis and conrmed chronic GVHD. Methylprednisolone, 2 mg/kg/d, was prescribed, which led to an excellent
outcome and reduced the diarrhea and bleeding.
Association for Pediatric Hematology and Oncology-Bone Marrow

Transplant. Chronic graft-versus-host disease in children: incidence,
risk factors, and impact on outcome. Blood. 2002;100(4):1192
1200
4. Wolff D, Gerbitz A, Ayuk F, et al. Consensus conference on
clinical practice in chronic graft-versus-host disease (GVHD): rstline and topical treatment of chronic GVHD. Biol Blood Marrow
Transplant. 2010;16(12):16111628
5. Wolff D, Schleuning M, von Harsdorf S, et al. Consensus
conference on clinical practice in chronic GVHD: second-line
treatment of chronic GVHD. Biol Blood Marrow Transplant.
2010;17:117
6. Vigorito AC, Campregher PV, Storer BE, et al; National
Institutes of Health. Evaluation of NIH consensus criteria for
classication of late acute and chronic GVHD. Blood. 2009;114(3):
702708
Pediatrics in Review Vol.35 No.6 June 2014 e31
Article
infectious diseases
Influenza and Parainfluenza Viral Infections

in Children
Thomas G. Fox, MD*
John C. Christenson, MD*
Author Disclosure
Drs Christenson and
Fox have disclosed no
financial relationships
relevant to this article.
This commentary does
Practice Gaps
1. Because influenza and parainfluenza viruses are responsible for significant morbidity
and mortality in young infants and children, especially those with chronic conditions,
clinicians must learn to recognize, treat, and prevent infections caused by these
viruses.
2. Disease caused by influenza virus can be prevented through the vaccination of all
persons 6 months or older. Special attention should be given to pregnant women and
persons with chronic medical conditions, such as asthma, congenital heart disease,
and neuromuscular disorders.
not contain
a discussion of an
Objectives
unapproved/
investigative use of
a commercial product/
device.
1.
2.
3.
4.
5.
After completing this article, readers should be able to:
Describe the epidemiology of influenza and parainfluenza virus infections.

Recognize the clinical features of influenza infections.
Select the most appropriate vaccines for the prevention of influenza.
Differentiate clinically between influenza and parainfluenza virus infections.
Order the most appropriate test for the diagnosis of respiratory viral infections.
Introduction
Inuenza and parainuenza viruses (PIVs) are among the most common respiratory pathogens that affect infants and children worldwide. Infections and their complications are responsible for a signicant number of hospitalizations and fatalities on a yearly basis. In
most temperate climate countries, seasonal patterns of disease are observed. In warmer climates, disease can be observed year round. The fear of an inuenza pandemic looms when
new strains are discovered. Recognition and prevention become pressing priorities. In recent
years, a greater emphasis in preventing inuenza through vaccination has emerged within the
United States. Many health care systems have mandatory vaccinations programs for health
care professionals. In addition, vaccination is now recommended for all persons 6 months or
older. Available antiviral agents are effective not only as therapy but also as preventive agents.
PIVs are the most common cause of laryngotracheitis or croup in children. In recent
years, these viruses have become recognized as important pathogens in the immunocompromised host. Unfortunately, an effective antiviral regimen or vaccine still eludes us. In
this review, we summarize the key aspects of what is known about inuenza and PIVs, including their clinical manifestations, treatment, and prevention.
Influenza Virus
Abbreviations
IIV:
LAIV:
LRI:
PCR:
PIV:
URI:
Historical Aspects
inactivated inuenza vaccine

live attenuated inuenza vaccine
lower respiratory tract infection
polymerase chain reaction
parainuenza virus
upper respiratory tract infection
The avian origin H1N1 inuenza pandemic of 19181919

(Spanish u) has been described as the single most fatal
event in human history, responsible for more than 50 million
deaths worldwide. (1) Subsequent pandemics occurred in
1957 (H2N2 Asian u) and 1968 (H3N2 Hong Kong
u). The emergence of swine-origin novel H1N1 inuenza
in March 2009 heralded the fourth inuenza pandemic in
*Department of Pediatrics, Ryan White Center for Pediatric Infectious Disease, Indiana University School of Medicine, Riley Hospital
for Children, Indianapolis, IN.
Pediatrics in Review Vol.35 No.6 June 2014 217
infectious diseases influenza & parainfluenza
the last 100 years. Inuenza epidemics can be traced back

at least 2000 years, and the rst true pandemic (intercontinental disease) occurred in 1580.
Influenza Biology
Inuenza viruses are classied as orthomyxoviruses and
contain a negative sense single-stranded RNA genome.
There are 3 major inuenza types: A, B, and C. The individual virus is spherically shaped and studded with 2
major proteins: hemagglutinin and neuraminidase. Differences in the hemagglutinin and neuraminidase antigens form the basis for the nomenclature of inuenza
A subtypes (eg, H1N1 vs H3N2). Inuenza strains are
further categorized according to type, location, and year
and are given a strain number (eg, A/California/7/2009
[H1N1]).
Hemagglutinins facilitate attachment of the virus to
the columnar epithelial cell in the respiratory tract. After
uptake of the virion by endocytosis, an inux of protons
through the virus M2 channel allows release of viral
RNA, which is then imported to the nucleus. The virus
hijacks the hosts cellular machinery to produce the proteins and genetic material needed for viral progeny. Neuraminidases function in the budding of the newly formed
virion to aid in its release from the host cell. (2)
Influenza Genetics and the Pandemic Threat

The genetic characteristics of inuenza viruses facilitate
the generation of novel strains with the potential to cause
human disease. The inuenza genome is composed of 8
RNA segments that can rearrange if more than one inuenza subtype infects the same host. The virus contains its
own RNA polymerase, which, in contrast to DNA polymerase, lacks proofreading functions. Consequently,
point mutations occur with regular frequency during genome replication. The accumulation of these point mutations is known as antigenic drift and is responsible
for the seasonal variation of inuenza A strains that cause
annual epidemics. Antigenic shift occurs when an inuenza A strain with a novel hemagglutinin (and sometimes
a novel neuraminidase) enters the human population. A
pandemic occurs if this newly generated strain causes disease in humans and can efciently spread from person to
person and throughout the world. To date, 17 unique
hemagglutinin antigens and 10 unique neuraminidase
antigens have been identied. (2) Many of these inuenza subtypes naturally infect the hundreds of bird species susceptible to inuenza. Birds can be infected by
multiple different strains simultaneously and serve as a genetic pool for the generation of new inuenza strains.
The human population has so far been susceptible to
a limited number of inuenza subtypes. Human infection

and effective human-to-human transmission has been
achieved by only 3 hemagglutinins and 2 neuraminidases
in 3 combinations: H1N1, H2N2, and H3N2. (3) Because of differences in preferred cellular binding sites, different inuenza strains preferentially infect birds and
humans. However, pigs (swine) are susceptible to infection from both avian and human strains. Swine can serve
as mixing vessels to produce novel strains that subsequently infect humans. In recent years, 2 inuenza A
strains of avian origin, H5N1 and H7N9, were responsible for several clusters of human disease in Asian countries, resulting in many hospitalizations and a high
fatality rate. (4)(5)
2009 Novel H1N1 Pandemic

In March 2009, a new strain of inuenza A was identied
that caused signicant disease in humans and could efciently spread from person to person, leading to the
fourth inuenza pandemic of the last 100 years. This virus
was a novel combination of 2 individual swine viruses,
hence the term swine-origin H1N1 or swine u. From
April 2009 to March 2010, novel H1N1 was responsible
for an estimated 60 million illnesses, 270,000 hospitalizations, and 12,270 deaths in the United States. (6) As seen
in previous pandemics, novel H1N1 disproportionately
affected young adults and children, as well as pregnant
and postpartum women. There were 317 conrmed pediatric deaths during the pandemic, signicantly higher
than prior years. The excess childhood deaths are probably explained by the increased attack rate in the young
rather than enhanced virulence in this age group. (7)
Epidemiology and Transmission

Epidemics of inuenza occur annually during the winter
months in temperate regions of the world, typically peaking in January or February in the Northern hemisphere.
There is no clear inuenza season in equatorial countries,
where inuenza can circulate year round. Children are
important vectors of disease because of higher attack rates
and more prolonged viral shedding compared with
adults. The peak incidence of infection occurs earlier in
the pediatric population. An increase in missed school
days in children sick with inuenza often precedes increased work absenteeism in adults.
Inuenza virus is transmitted primarily by large particle droplets, although contaminated surfaces can also
spread disease. The incubation period is 1 to 4 days
(mean, 2 days). Viral shedding correlates with fever intensity and begins 24 hours before symptom onset, peaks
at day 3, and resolves by day 7. (8) However, young
218 Pediatrics in Review Vol.35 No.6 June 2014
children and individuals with compromised immunity can

shed virus for extended periods. The severity of disease
may also correlate with duration of shedding.
Hospitalization rates for inuenza are highest in children younger than 2 years and adults older than 65 years.
Children with certain comorbidities are at increased risk
of hospitalization and inuenza complications. These
complications include hemoglobinopathies, diabetes
mellitus, neuromuscular disorders, chronic kidney disease,
and congenital heart disease. Children with underlying
pulmonary disease, such as asthma and cystic brosis, are
at risk for more severe disease.
Clinical Manifestations
Classic inuenza infection is characterized by the sudden
onset of fever, chills, and myalgias followed by prominent
upper respiratory tract symptoms, such as rhinorrhea,
cough, and sore throat. It is critical to recognize that
younger children are less likely to present with this ulike
syndrome. This is especially true in infants, who can present with fever and irritability with minimal respiratory
ndings. It is difcult in younger children to distinguish
clinically inuenza infection from infections due to other
respiratory viruses (eg, respiratory syncytial virus and PIV)
that circulate in communities during the same periods, and
the manifestations of disease can be identical. Table 1 provides a comparison of clinical features between inuenza
and PIVs. Upper respiratory tract infection (URI), laryngotracheitis (croup), bronchiolitis, and pneumonia are all
possible presentations of inuenza in the younger child.
Gastrointestinal symptoms are uncommon in adults but
can be the primary symptoms in children with inuenza.
Complications
Bacterial infection of the respiratory tract is the most
common complication of inuenza infection and includes
otitis media, sinusitis, and tracheitis. Pneumococcal pneumonia is a relatively common complication and should be
suspected in the child who develops fever and a lobar inltrate during the convalescent period. Less common than
Streptococcus pneumoniae, staphylococcal infection can complicate acute inuenza and lead to a diffuse necrotizing
pneumonia with a high mortality rate, especially if caused
by methicillin-resistant Staphylococcus aureus. Parapneumonic
effusions and empyemas are common complications.
Acute myositis can occur during convalescence but is
almost always benign. It occurs more commonly with inuenza B. The typical presentation is a child who has sudden onset of severe pain in the calves and refusal to walk.
The serum creatine kinase level is usually elevated. Severe
encephalopathy and encephalitis have been reported with
inuenza infection. Reye syndrome is a rare form of encephalopathy that has been associated with inuenza infection and salicylate (eg, aspirin) use.
Clinical Comparison of Influenza and Parainfluenza Viral

Infections
Table 1.
Clinical Condition
Influenza
Parainfluenza
Comments
Afebrile URI
DD
Febrile URI
Acute otitis media
Pneumonia
Laryngotracheobronchitis (croup)
DDD
DD
D
D
D
DDD
DD
DDD
Coryza and pharyngitis are common with PIV

infections.
Flulike illness
Bronchiolitis
Sepsis-like syndrome
Myositis
D
D
D
DDD
Rare
Rare
Myocarditis
Encephalopathy, aseptic meningitis,
Guillain-Barre syndrome
Rare
Rare
Rare
Rare
Croup by influenza virus is more severe: thicker

secretions, higher temperatures, more severe
airway obstruction, and more bacterial
superinfections.
PIV is third most common cause of bronchiolitis.
Mostly observed with influenza B virus. Myositis
associated with PIV infection tends to be milder
and of shorter duration.
Necrotizing encephalitis reported with influenza
virus.
PIVparainuenza virus; URIupper respiratory tract infection.
Laboratory Diagnosis
Laboratory testing is the mainstay in the diagnosis of inuenza infection. Clinical ndings alone are insufciently
sensitive or specic, especially in younger children who
less often have classic ndings. Accurate and rapid diagnosis of inuenza infection can allow prompt initiation of
antiviral therapy while simultaneously limiting antibiotic
use. A variety of testing modalities exist, and each has its
merits. Serologic (antibody) testing for inuenza infection is important in the epidemiologic study of disease
but does not play a role in clinical management. Similarly,
although laboratory culture of inuenza virus is essential
for vaccine development and antiviral resistance testing,
other methods have proven more clinically useful. (9)
Regardless of the diagnostic method used, proper
sampling is paramount. Nasopharyngeal specimens are
preferred over throat swabs. (9) The timing of specimen
collection will also affect the validity of the result. A sample obtained in a patient with an inuenza-like illness on
days 2 to 3 of symptoms (when inuenza virus shedding
is at its peak) will yield a more reliable result compared
with one obtained later in the disease course. (9)
Rapid Antigen Testing

Rapid antigen testing is the most commonly used
method in the laboratory diagnosis of inuenza infection
and plays a vital role in high-volume patient settings, such
as emergency departments, especially during epidemics of
disease. In fact, the rst case of 2009 pandemic inuenza
infection in the United States was diagnosed using a rapid
antigen test. These assays work by measuring the immunologic reaction between inuenza antigens from the patients secretions with a specic inuenza antibody. The
advantages of rapid antigen tests include quick results
(15 minutes), bedside or point-of-care testing, and distinguishing inuenza type A from B.
Rapid antigen testing can be part of treatment algorithms in the management of patients with suspected inuenza. (10) Rapid antigen tests for inuenza are highly
specic, allowing for efcient allocation of antivirals during peaks of activity. The major disadvantage of rapid
tests is their low and highly variable sensitivity, ranging
from 20% to 90%. (9) Therefore, a negative rapid test result in a patient presenting with sudden onset of high fever, myalgias, and cough during peak inuenza activity
could be falsely negative. One important aspect of rapid
inuenza testingand rapid viral tests in generalis that
the accuracy of the test result is directly correlated with
the prevalence of disease in the community. As stated
in the above example, during periods of peak viral activity, a negative rapid test result in a patient with an
inuenza-like illness could be falsely negative. If that same

patient presents during a period with minimal circulating
inuenza but has a positive rapid antigen test result, the
test result is likely to be falsely positive. However, inuenza
strains can cause infections in out-of-season times of the
year like in the case of an inuenza A (H3N2) variant that
initially circulated in the United States during the summer
months with outbreaks associated with contact with swine
at state and county fairs in the Midwest. (11)
Molecular Tests
Molecular methods of detection are replacing viral culture as the gold standard in the diagnosis of many viral
infections, including inuenza. Polymerase chain reaction
(PCR)based assays offer superior sensitivity and turnaround time compared with viral culture and are becoming
more widely available in many laboratories. The PCRbased tests for inuenza are often part of multiplex assays
that can concomitantly detect inuenza and other important viruses, aiding in the diagnosis of noninuenza respiratory infections. Most PCR-based inuenza assays can
distinguish inuenza types (A from B). Some tests reliably
determine specic subtype (eg, H1N1 vs H3N2), which
proved valuable in guiding antiviral therapy during the
2009 H1N1 pandemic. None of the currently available
rapid antigen tests can discriminate inuenza A subtypes.
Other Testing Choices

Direct and indirect uorescent antibody testing can be
performed on patient secretions and provide results
within a few hours. These tests are highly specic but
have variable sensitivities. The reliability of the results
can vary, depending on the skill of the performing technician. They are more expensive than rapid antigen tests.
Treatment
Inuenza infection is a benign self-limited disease in most
children and adults, regardless of whether treatment is
provided. However, inuenza infection can cause severe
disease and death in both high-risk patients and healthy
individuals. The administration of active antiviral therapy
early in the course of disease has been found to shorten
symptom duration and prevent the spread of virus. It may
also be benecial in hospitalized patients and in those
with severe disease, even if started later in the disease
course. Treatment should optimally be initiated within
48 hours of symptom onset.
The decision to provide antiviral therapy as treatment
or prophylaxis should be based on the duration of symptoms and the individuals risk of progression to severe disease. Hospitalized patients with suspected or conrmed
inuenza should receive therapy. Patients at high risk for

severe disease and complications should also be provided
therapy and prophylaxis (Tables 2 and 3). (10)
Candidates for Antiviral

Treatment
Table 2.
Antiviral treatment is recommended as soon as possible

for any person with confirmed or suspected influenza
in any of the following categories:
Is hospitalized
Has severe, complicated, or progressive illness
Is at higher risk for influenza complications
Persons at higher risk for influenza complications:
Children younger than 2 years
Adults 65 years or older
Persons with chronic pulmonary (including asthma and
cystic fibrosis), cardiovascular, renal, hepatic,
hematologic, metabolic disorders, or neurologic and
neurodevelopmental conditions (including cerebral
palsy, muscular dystrophy, or spinal cord injury)
Persons with immunosuppression
Women who are pregnant or post partum (within 2
weeks after delivery)
Persons younger than 19 years who are receiving longterm aspirin therapy
American Indians or Alaska Natives
Persons who are morbidly obese
Residents of nursing homes and other chronic care
facilities.
There are 2 classes of antivirals available for the treatment and chemoprophylaxis of inuenza: the adamantanes
and the neuraminidase inhibitors. The adamantanes include amantadine and rimantadine and work by interfering with the viral M2 ion channel to prevent the release
of viral RNA into the host cell after endocytosis. The
adamantanes do not have activity against inuenza B. Furthermore, because of widespread resistance among inuenza
A strains, their use in the treatment and chemoprophylaxis
of inuenza A is not recommended at this time. The
neuraminidase inhibitors have activity against both inuenza A and B, and although resistant strains of inuenza
A have been found, most circulating inuenza strains are
susceptible. Neuraminidase inhibitors block viral neuraminidase, which prevents the budding and release of viral progeny. Oral oseltamivir and inhaled zanamivir are 2
neuraminidase inhibitors currently available for clinical
use. Intravenous formulations of zanamivir and a third
agent, peramivir, are being investigated. Oseltamivir is
approved for the treatment of inuenza in children older
than 2 weeks and for chemoprophylaxis down to age 3
months. However, according to existing safety information, oseltamivir can be used to treat inuenza in both
term and preterm infants from birth. (12) Zanamivir is
approved for use in the treatment of children 7 years
and older and as prophylaxis in children 5 years and older.
Oral oseltamivir can cause gastrointestinal distress but in
general is well tolerated. Cough and bronchospasm have
been associated with the use of inhaled zanamivir. It
should be used with caution in patients with underlying
pulmonary dysfunction (eg, asthma). For antiviral indications and dosages, see Tables 2 and 3. (10)(12)
Prevention
Yearly vaccination is the main strategy of prevention
against inuenza. All persons 6 months and older should
be vaccinated. Inuenza is responsible for its greatest
morbidity in young infants, children younger than 5
years, and individuals 65 years and older. In addition,
persons with chronic medical conditions, such as asthma,
heart disease, cystic brosis, diabetes mellitus, neuromuscular disorders, cancer, and other immunodeciencies,
are at an increased of severe disease and death. In recent
years, a signicant number of infants and children have
died of the disease. Although many had underlying medical conditions, close to 50% of fatalities were in previously
healthy children. Unfortunately, only approximately 50%
of children with cognitive, neurologic, and seizure disorders received the vaccine. (13) Infants younger than 6
months are at risk for severe disease. Although vaccination
is not indicated in this age group, preliminary studies have
found that inuenza vaccines are safe and immunogenic in
infants as young as 6 to 12 weeks. (14) In an open-label
study, vaccination of inuenza-seronegative infants induced levels of antibody similar to levels in 6-month-olds.
Preexisting maternal antibodies appear to blunt the immune response in vaccinees. (15) One strategy that will
protect these young infants is the vaccination of mothers
during pregnancy because maternal antibodies in the infants
have been found to be protective up to 6 months. (16)(17)
The vaccination of mothers was more than 90% effective in
preventing inuenza-related hospitalizations of their infants.
(18) More mothers need to be vaccinated. When vaccination is not proactively recommended, only 16.1% of pregnant women receive the vaccine. (19) If vaccination is
recommended to the pregnant woman by a health care
practitioner, 70.5% will receive it. The vaccination of children in daycare has been found to reduce inuenza-related
morbidity among members of the household. (20)
Multiple vaccines are distributed within the United
States (Table 4). Most are inactivated products, but a live
Table 3.
Antiviral Agents for Treatment and Chemoprophylaxis of Influenza
Agent
Age Group
Treatment
Chemoprophylaxis
Oseltamivir
Adults
Children 12
months
15 kg
>1523 kg
>2340 kg
>40 kg
Infants 911
months
Term infants 38
months
Term infants 03
monthsa
75 mg twice daily
75 mg once daily
30 mg twice daily
45 mg twice daily
60 mg twice daily
75 mg twice daily
3.5 mg/kg per dose
twice daily
3 mg/kg/dose twice daily
30 mg once daily
45 mg once daily
60 mg once daily
75 mg once daily
3.5 mg/kg per dose once daily
Preterm infants
Dosing based on
postmenstrual ageb
Zanamivir
Adults
Children
3 mg/kg per dose twice daily
<38 weeks: 1.0 mg/kg per

dose twice daily.
3840 weeks: 1.5 mg/kg per
dose twice daily.
>40 weeks: 3 mg/kg per
dose twice daily
10 mg (two 5-mg inhalations)
twice daily
7 years: 10 mg (two 5-mg
inhalations) twice daily
3 mg/kg per dose once daily

Not recommended unless situation
is judged critical. Limited safety
and efficacy data. Consult pediatric
infectious disease specialist.
Not recommended unless situation is
judged critical. Limited safety and
efficacy data. Consult pediatric
infectious disease specialist.
10 mg (two 5-mg inhalations)

once daily
5 years: 10 mg (two 5-mg inhalations)
once daily
a
Approved by the Food and Drug Administration down to age 2 weeks. However, on the basis of existing safety information, oseltamivir can be used to treat
inuenza in both term and preterm infants from birth.
b
Postmenstrual age is gestational age plus chronological age.
attenuated intranasal vaccine (LAIV) and a recombinant

vaccine are available. The antigenic composition of the various vaccines is determined on a yearly basis based on
worldwide and national surveillance of current and past inuenza seasons. The composition of the 20132014 trivalent
inuenza vaccine is A/California/7/2009 (H1N1)like
virus, A/Victoria/361/2011 (H3N2), and B/Massachusetts/2/2012like virus. The quadrivalent vaccine
contains an additional inuenza B strain, B/Brisbane/
60/2008like virus, which will cover both the Victoria
and Yamagata lineages. This year, quadrivalent vaccines
that contain antigens for 2 strains each of inuenza A
and B are also available in addition to trivalent vaccines.
Healthy individuals 2 years or older can receive either
an inactivated inuenza vaccine (IIV) or LAIV. The
LAIV is licensed for healthy persons ages 2 to 49 years.
It is contraindicated in persons with underlying medical
and immunosuppressive conditions. Administration of the
vaccine to young infants has also led to wheezing. Although caution is merited, high-risk individuals with impaired immune systems do not appear to have signicant
adverse events or prolonged viral shedding after the inadvertent exposure to LAIV. Several studies have found
superior efcacy of LAIV compared with IIA. (21) In children 6 years or older and adolescents with asthma, the LAIV
provided a 32% increase in protection against cultureproven inuenza infections when compared with IIA.
(22) Viral shedding from the nasopharynx occurs after
vaccination, which peaks approximately 2 days after vaccination. Postvaccination symptoms, such as runny nose,
headache, and sore throat, do not correlate with viral shedding. Mean duration of shedding was approximately 2.8
days. Viral shedding can be observed with LAIV recipients
up to 6 to 8 days after vaccination. With this in mind, practitioners should exercise caution when deciding who
should receive this vaccine. Persons caring for persons with
Table 4.
Influenza Vaccines, 2013-2014
Vaccine Trade Name

(Manufacturer)
Inactivated, trivalent
Afluria (CSL Limited)
Fluarix (GlaxoSmithKline)
Flucelvax (Novartis Vaccines
and Diagnostics)
Flulaval (ID Biomedical
Corporation of Quebec)
Fluvirin (Novartis Vaccines
and Diagnostics)
Fluzone (Sanofi Pasteur)
Fluzone Intradermal
(Sanofi Pasteur)
Inactivated quadrivalent
Fluarix Quadrivalent
(GlaxoSmithKline)
Fluzone Quadrivalent
(Sanofi Pasteur)
Flulaval Quadrivalent (ID
Biomedical Corporation
of Quebec)
Inactivated, trivalent, high dose
Fluzone High-Dose
(Sanofi Pasteur)
Recombinant, trivalent
FluBlok (Protein Sciences)
Live attenuated, quadrivalent,
intranasal
FluMist Quadrivalent
(MedImmune)
Presentation and Route of

Administration
Mercury Content
mg /0.5 mL)
Age
Indications
9 yearsa
24.5
0
9 years
3 years
18 years
<25.0
3 years
0.5 mL single-dose prefilled

syringe, IM
0.5 mL, IM (5.0 mL multidose vial)
0.25 mL, single-dose prefilled
syringe, IM
syringe or single-dose vial, IM
0.1 mL prefilled microinjection
system, ID
1.0
4 years
25.0
0
635 months
36 months
25
0
6 months
1864 years

syringe, IM
0.25 mL, single-dose prefilled
syringe, IM
0.5 mL single-dose prefilled syringe
or single-dose vial, IM
3 years
635 months
36 months
0.5 mL single-dose prefilled syringe

or single-dose vial, IM
syringe, IM
syringe, IM
<25.0
3 years

syringe, IM
65 years
0.5 mL, single-dose vial, IM
1849 years
0.2 mL intranasal sprayer
249 yearsb
IDintradermal; IMintramuscular.
a
The Advisory Committee on Immunization Practices recommends that this vaccine not be given to infants and children ages 6 months through 8 years
because of an increased risk of febrile reactions. If no other inuenza vaccine is available for children ages 5 to 8 years, the vaccine could be used only after
discussing with parents or caregivers the risks and benets of vaccination.
b
Healthy, nonpregnant individuals.
Table modied from Centers for Disease Control and Prevention. (23)
immunosuppression need to practice caution to minimize

the spread of attenuated virus. If caring for severely immunosuppressed persons who require protective environment, the caregiver should not receive this vaccine. (23)
Injectable IIVs are used in individuals who are not
candidates for LAIV. Health care workers who work
with immunocompromised persons should receive this
vaccine. Vaccine effectiveness varies signicantly among

age groups and persons with various medical conditions.
Because of this variability, it is critical that more persons
receive their yearly vaccine. The higher the number of
vaccinated individuals, the better protected the at-risk
community is. This is critical in groups with a large number of infants younger than 6 months.
Antibodies against inuenza viruses are type specic.

Eighty percent to 95% of children 6 months or older develop protective antibody levels after 2 doses of vaccine.
(24) In children ages 6 to 35 months, 50% will develop
protective antibody levels, and in those ages 3 to 9 years,
75% will develop protective antibody levels. Vaccine efcacy varies according to season, patient age, type of vaccine,
and study design. Using culture-conrmed studies, vaccine
efcacy varies between 56% and 100%. Inuenza vaccines
have been found to be immunogenic and safe when given
simultaneously with other vaccines. All infants and children
younger than 9 years will require 2 doses of vaccine separated by 4 weeks if receiving the vaccine for the rst time.
Most inuenza vaccines have been derived from chicken
embryo tissue cultures. In persons with documented allergies to egg, the administration of vaccines may be considered to be contraindicated. However, recently, cell culture
and recombinant vaccines have become available, allowing
for the vaccination of patients with allergies to eggs. Patients with a history of anaphylaxis to egg products should
not be vaccinated with chick embryoderived vaccines (Table 5). Skin testing by an allergist-immunologist is no longer recommended for children with a history of urticaria
after the consumption of egg products. (12)(23) A recent
Influenza Vaccination: Egg

Allergy (12)(23)
Table 5.
Symptom
Treatment
If tolerates lightly cooked

eggs (scrambled eggs)
without reaction
Develops ONLY hives after
eating eggs or eggcontaining foods
Vaccinate with LAIV, TIIV,

or QIIV
After eating eggs or

egg-containing foods,
the child experiences
hypotension, respiratory
distress (wheezing or
throat swelling), nausea
or vomiting, and
reactions requiring
epinephrine and/or
medical attention
If 1821 years: administer

RIV3 OR TIIV or QIIV
(observe for reaction for
at least 30 minutes
after vaccination)a
If 1821 years: administer
RIV3 OR refer to
allergist-immunologist
LAIVlive attenuated inuenza vaccine (intranasal);

QIIVquadrivalent inactivated inuenza vaccine; RIV3recombinant
inuenza vaccine, trivalent; TIIVtrivalent inactivated inuenza
vaccine.
a
RIV3 is licensed for persons ages 1849 years.
retrospective medical record review study of egg-allergic

children concluded that patients without a history of anaphylaxis to egg can receive the inuenza vaccine without
the need for skin testing. (25) Current recommendations
of the Centers for Disease Control and Prevention and
the American Academy of Pediatrics recommend the use
of the newer recombinant vaccine for individuals ages 18
to 49 years with a history of anaphylaxis or hives to egg.
(12)(23) For individuals with a history of only hives, vaccination with an IIV can be performed safely.
For infants and children ages 6 to 36 months, a dose of
0.25 mL of the IIV is administered by the intramuscular
route. Past age 3 years, 0.5 mL is administered. The intranasal vaccine delivers a dose of 0.1 mL into each nostril.
Recently, an intradermal vaccine became available, resulting in a less painful injection. This vaccine was found
to be more immunogenic than vaccines administered via
the intramuscular route. There is currently limited experience with this vaccine in young children.
Large postlicensure population-based studies have failed
to demonstrate any increase in clinically important medically attended events in the 2 weeks after vaccination. Acute
respiratory infections, acute otitis media, and asthma episodes are less common in the weeks after vaccination. Fever,
malaise, pain at the site of injection, myalgias, and headaches have been reported after the receipt of inuenza vaccines. Wheezing and rhinorrhea have been reported after
LAIV. Febrile seizures can occur after vaccination. However, its risk appears to be related to a specic vaccine produced by CSL Biotherapies (Auria). Because of the risk,
this vaccine is not recommended for children younger than
9 years. In transplantation patients, vaccination did not alter
allograft function or cause rejection episodes. Oculorespiratory syndrome, an acute, self-limited reaction to IIVs that
consists of red eyes, cough, wheeze, chest tightness, difculty breathing, sore throat, or facial swelling, has been
reported 2 to 24 hours after vaccination. It resolves spontaneously within 48 hours. This syndrome may represent
a type of hypersensitivity reaction. Guillain-Barr syndrome
has been described after inuenza vaccination. The risk is
considered low. After vaccination, 1 additional GuillainBarr syndrome case per 1 million was observed.
Parainfluenza Virus
Biology and Epidemiology
PIVs are members of the Paramyxoviridae family. They
are RNA viruses with a viral envelope covered with glycoproteins, such as hemagglutinins-neuraminidases and
fusion proteins, that are responsible for the entry into respiratory epithelial cells, where they replicate exclusively.
Other members of this family include respiratory syncytial

virus, mumps, measles, and human metapneumovirus.
There are 4 antigenically distinct types of PIV (PIV-1,
-2, -3, and -4). There are also 2 antigenic subtypes
(PIV-4A and PIV-4B). Most of the disease caused by
PIV occurs in children younger than 5 years and is responsible for 6% to 11% of hospitalizations due to respiratory
infections. (26)(27) Most hospitalizations are in infants
younger than 1 year. Parainuenza viruses are responsible
for approximately 4% of all respiratory tract infections. (28)
Coinfections with other respiratory viruses are a common
occurrence, with percentages as high as 40%. (29) Coinfected children tend to have a longer duration of symptoms
and prolonged viral shedding. By age 5 years, all children
have been infected by all types of PIV. (30)(31)
PIVs are a frequent cause of childhood disease, such as
laryngotracheobronchitis (croup) and pneumonia. PIV-1
and -2 are the most common causes of croup, especially
during the fall season, whereas PIV-3 is mostly responsible for lower respiratory tract infections (LRIs), such as
bronchiolitis and pneumonia, occurring mostly in the
spring and summer months. The epidemiology of PIV4 has been less known, but it appears to be responsible
for URIs and LRIs in infants younger than 6 months.
In a recently published retrospective study, PIV-4 had
a year-round prevalence with clinical features similar to
those of PIV-3. (32) No patients with PIV-4 had croup.
PIV infections mostly involve the large airways of the
lower respiratory tract of children. Tropism for this region is inuenced by the large number of ciliated epithelial cells in the area. Many of the clinical features of PIV
infections are indistinguishable from those observed with
other viruses, such as inuenza virus (Table 1). PIV-1, -2,
and -3 are responsible for most pediatric disease, with
PIV-3 being responsible for 50% of all PIV infections.
(30)(31) In a study of children in China, PIV-3 was
the most common PIV isolated (61% of children), followed by PIV-1 (21% of children). PIV-4 was detected
in 10% of children with PIV infection. (33)
Clinical Aspects
The virus is transmitted through exposure to contaminated nasopharyngeal secretions by droplets or contact
with contaminated surfaces. The usual incubation period
is 2 to 4 days, with viral shedding that may last up to 1
week after onset of symptoms. Infected persons may shed
virus up to 1 week before onset of symptoms. The duration of shedding may be serotype specic, with PIV-3
lasting 3 to 4 weeks. Acute otitis media is frequently preceded by infections caused by PIV. PIVs are responsible
for 18% to 45% of all URIs. (34)(35) Coryza, rhinorrhea,
pharyngitis, and low-grade fever are common features of

URI caused by PIV. Cervical lymphadenopathy is generally absent.
In contrast to inuenza viruses, in most communities
PIVs circulate all year. Cases of croup observed in the
summertime are generally caused by PIVs. The clinical
presentation of croup is distinctive. A sudden onset of
a hoarse, barkinglike cough accompanied by laryngeal
obstruction, dyspnea, and inspiratory stridor is common.
Symptoms usually last 3 to 5 days. The presence of fever
and recurrence helps differentiate it from spasmodic
croup. In some young children, drooling, difculty swallowing, and decreased appetite can be observed. However, excessive drooling, severe respiratory distress, and
a child sitting quietly and still at the edge of a chair are
highly suggestive of epiglottitis, an infection usually associated with Haemophilus inuenzae type b, which now is
rare thanks to routine vaccination. Children with croup
generally do not require intubation. Children with croup
caused by inuenza virus tend to be more febrile, have
tenacious thick secretions, and have more severe laryngeal obstruction. Subglottic stenosis is a common complication of croup. Subglottic stenosis may lead to
prolonged intubation and/or symptoms of coughing
and respiratory distress. A steeple sign is frequently observed on an anteroposterior radiograph of the neck
and chest. The epiglottis appears normal on a lateral neck
radiograph. PIV-1 is isolated in most children with croup.
Laryngitis in children is frequently caused by a PIV.
All types of PIV, but especially PIV-1 and PIV-3,
cause bronchiolitis, which is indistinguishable from disease caused by respiratory syncytial virus and human
metapneumovirus. Five percent to 15% of bronchiolitis
cases are caused by PIV. (36)(37) Fever, tachypnea, retractions, expiratory wheezing, rales, and air trapping
are common features. Approximately 10% of outpatient
LRIs are caused by PIV-1, -2, and -3. Young infants, especially those born prematurely, can experience apnea in
the presence of an LRI. Most hospitalizations will occur
in the rst year of life. Conjunctivitis is observed in more
than 35% of infected children. The most severe LRI will
occur in chronically ill or immunocompromised children.
Patients with weakened immune systems, such as those
with T-cell deciencies or who have undergone hematopoietic stem cell transplantation, are at risk of more severe
disease, such as pneumonia. Pneumonia in this population can be life-threatening, with a fatality rate of approximately 30%. (38)(39) Patients undergoing HSCT have
the highest mortality, especially in the rst 100 days of
the transplantation, when lymphopenia is common. Prolonged viral shedding is a common feature of children
with primary immunodeciency. Reinfections are common but tend to be milder or asymptomatic in the otherwise immunocompetent host.
Diagnosis
With the exception of direct uorescent and PCR assays, there are no rapid diagnostic assays, especially
for point-of-care testing. Diagnosing PIV infection
can be important because it may obviate the use of antibacterial therapy. Most laboratories consider nasopharyngeal aspirates and washes to be the most optimal
specimens for the detection of respiratory viruses by reverse-transcription PCR and direct immunouorescence. However, nasopharyngeal ocked swabs are
easier to perform and are better tolerated by patients.
The sensitivity of both methods was excellent (100%)
for respiratory viruses other than adenovirus. (40)
PCR-based testing from bronchoalveolar lavage has
high sensitivity and specicity.
Treatment
There is no available licensed antiviral therapy for the
treatment of PIV infections. Aerosolized or systemic ribavirin with and without intravenous immunoglobulin has
been used as treatment in immunocompromised children
and adults with severe disease. (41) Most of the gathered
experience comes from uncontrolled trials or anecdotal
reports. However, on the basis of the favorable results
of these limited trials, this regimen should be considered
in the compromised child with lower respiratory tract disease. Management of these infections is supportive.
Attention to proper hydration so the child can mobilize secretions appears to be reasonable However, the use
of humidied inhaled air (cool mist) delivered in a tent or
hood has no demonstrable benet for the child with
croup. (42)(43) In patients with croup, the use of epinephrine and dexamethasone is associated with a reduction of symptoms. The use of nebulized budesonide and
intramuscular and oral dexamethasone has been found to
be benecial in patients with croup, resulting in shorter
hospital stays and fewer return visits. (44) In comparative
studies, they appear to be equally effective. (45)(46)
Nebulized epinephrine is associated with a reduction in
symptoms of croup. (47) Most practitioners will give this
agent in combination with a corticosteroid.
Prevention
There are no available vaccines. Handwashing is an effective way of preventing the transmission of respiratory viruses. Transmission appears to be related to contact with
infectious droplets.
Summary
On the basis of strong epidemiologic evidence,
influenza and parainfluenza viruses are responsible for
significant morbidity and mortality in young infants
and children and in persons with chronic medical
conditions. (1)(4)(26)(27)(35)
On the basis of research evidence, influenza vaccines
are effective in preventing disease in high-risk
individuals. (8)(17)(18)
On the basis of strong research evidence, influenza
vaccines are safe in young infants and children 6
months or older. (8)(15)
On the basis of research evidence, the use of
corticosteroids and epinephrine is beneficial in the
treatment of laryngotracheitis caused by
parainfluenza viruses. (44)(45)(46)(47)
Strong evidence supports the use of influenza vaccines
in pregnant mothers as a strategy to prevent disease in
infants younger than 6 months. (17)(18)(19)
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budesonide, and intramuscular, and oral dexamethasone for treatment of croup. Int J Pediatr Otorhinolaryngol. 2004;68(4):453456
47. Bjornson C, Russell K, Vandermeer B, Klassen TP, Johnson
DW. Nebulized epinephrine for croup in children. Cochrane Database
Syst Rev. 2013;(10)CD006619
PIR Quiz Requirements

To successfully complete 2014 Pediatrics in Review articles for AMA PRA Category 1 CreditTM, 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.
NOTE: Learners can take Pediatrics in Review quizzes and claim credit online only at: http://pedsinreview.org.
1. A previously healthy 5-year-old boy has a 3-day history of high temperatures, sore throat, coughing, and malaise.
He is diagnosed as having influenza A. Which of the following statements is correct about his condition?
A.
B.
C.
D.
E.
He is likely to benefit from oseltamivir.

Oseltamivir is not likely to be beneficial.
A prophylactic antibiotic would be beneficial.
A chest radiograph is always indicated.
Hospitalization is required.
2. Which of the following vaccine strategies would be most protective of an infant boy younger than 6 months?
A. Vaccination of the infant in the first 6 months of life.
B. Vaccination of the teachers of his siblings.
C. Use of oseltamivir chemoprophylaxis during influenza season.
D. Avoidance of state fairs.
E. Vaccination of mother during pregnancy, caregivers, and school-age siblings.
3. A healthy 5-year-old girl gets an upset stomach when she eats eggs. The parents deny hives or respiratory distress.
Which of the following statements would best describe her ability to receive the yearly influenza vaccine?
A. She has a serious egg allergy and should not receive the vaccine.
B. She can receive the live attenuated intranasal vaccine but not the inactivated type.
C. She does not have a significant egg allergy and can receive the vaccine safely.
D. Do not vaccinate. Use chemoprophylaxis instead.
E. Give vaccine preceded by injection of epinephrine.
4. A 2-year-old boy has a croup-like illness. Which of the following statements is FALSE?
A.
B.
C.
D.
E.
Parainfluenza types 1 and 2 are common causes of croup.

Previously healthy children should receive ribavirin as antiviral therapy.
Child may benefit from receiving dexamethasone and epinephrine.
Crouplike symptoms accompanied by high temperatures most likely represent an infection by influenza virus.
Subglottic stenosis is a known complication.
5. Influenza vaccines are effective in preventing disease in high-risk children. Which of the following statements
is/are CORRECT?
A. Patients with asthma can receive live-attenuated intranasal vaccine.
B. Recombinant influenza vaccine can be administered to a 5-year-old egg-allergic child.
C. Yearly influenza vaccination of household contacts will diminish risk of acquiring infection.
D. Intranasal quadrivalent vaccine is protective against 4 strains of influenza A.
E. B and D
Cystic Fibrosis CME Quiz Correction

In the May 2014 article Cystic Fibrosis (Paranjape SM and Mogayzel PJ. Pediatrics in Review. 2014:35(5):194. DOI: 10.1542/
pir.35-5194), there was an error in Question 2 of the CME quiz. The query sentence before the answer options should read:
The most likely explanation for the normal newborn screen finding is that: . . The correct answer option E remains
unchanged. The online versions of the article and quiz have been corrected. The journal regrets the error.
Noncontraceptive Use of Contraceptive Agents

Monique Collier Nickles and Elizabeth Alderman
Pediatrics in Review 2014;35;229
DOI: 10.1542/pir.35-6-229
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/content/35/6/229
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2014 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601.
Article
adolescent medicine
Noncontraceptive Use of Contraceptive

Agents
Monique Collier Nickles,
MD,* Elizabeth Alderman,
Educational Gap
According to 2006-2008 National Survey of Family Growth data, 33% of adolescents
ages 15 to 19 years using combined oral contraceptives do so solely for noncontraceptive
reasons, mostly to alleviate problems and symptoms associated with menstrual periods.
Consequently, it is necessary for physicians to become more knowledgeable of the known
health benefits and noncontraceptive uses of contraceptive agents to enhance their
treatment and care for adolescent patients. (1)
MD
Author Disclosure
Dr Collier Nickles has
disclosed no financial
relationships relevant to
this article. Dr Alderman
has disclosed no
contain a discussion of
an unapproved/
Objectives
1. Identify medical conditions treatable with hormonal contraception.

2. Identify noncontraceptive benefits of contraceptive agents for adolescents.
3. Recognize conditions and diseases for which menstrual regulation or suppression can
benefit adolescents, improve disease outcome, and enhance quality of life.
4. List the relative and absolute contraindications to the use of combined hormonal
contraceptives.
5. Describe different contraceptive methods available for use.
device.
Introduction
Recent data have revealed that more than 30% of adolescent girls use contraceptive agents
solely for noncontraceptive reasons, typically to alleviate symptoms associated with mention with the North
strual periods but also for acne and endometriosis. (1) Most noncontraceptive uses of these
American Society for
agents are off-label; however, they have been deemed appropriate secondary to research
Pediatric and Adolesand Cochrane review. This represents a change from historical trends in which contracepcent Gynecology
tive agents, specically, oral contraceptive pills, were typically used by adolescents primarily
(NASPAG)
for prevention of unintended pregnancy. In addition to this shift, another important
change during the past decade has been the introduction
of several new hormonal contraceptive agents. Not only
has direct advertising to the public through various media
Abbreviations
increased public awareness of these newer methods, but
CDC:
Centers for Disease Control and Prevention
marketing campaigns often highlight many of the nonconCHC:
combined hormonal contraceptive
traceptive health benets of these methods to increase use
COCP:
combined oral contraceptive pill
of the product. Because adolescents often are prescribed these
FDA:
Food and Drug Administration
newer contraceptive agents and are targets of such marketing
GnRH:
gonadotropin-releasing hormone
campaigns, it is imperative for pediatricians to become more
LNG-IUS: levonorgestrel intrauterine system
knowledgeable of their noncontraceptive indications and
NSAID: nonsteroidal anti-inammatory drug
health benets.
Written in collabora-
PCOS:
PMDD:
PMS:
SCD:
vWD:
vWF:
polycystic ovary syndrome

premenstrual dysphoric disorder
premenstrual syndrome
sickle cell disease
von Willebrand disease
von Willebrand factor
Menstrual Regulation
Many adolescent girls have irregular menstrual periods.
The most common cause of irregular menstruation is
anovulatory bleeding secondary to immaturity of the
hypothalamic-pituitary-ovarian axis. However, thyroid disorders,
*Department of Pediatrics, Lincoln Medical and Mental Health Center, Bronx, NY.
Department of Pediatrics, Division of Adolescent Medicine, Childrens Hospital at Montefiore and Albert Einstein College of
Medicine, Bronx, NY.
adolescent medicine noncontraceptive use of contraceptives
polycystic ovarian syndrome, and sexually transmitted infections are other common causes of irregular menstruation in
adolescents.
Normal menstrual periods in adolescents usually occur
every 21 to 45 days, with duration of ow between 3 and
7 days. Blood loss for each cycle is approximately 30 to
40 mL. Irregular menstruation is characterized by bleeding
infrequently (oligomenorrhea) or too frequently (polymenorrhea). Variable menstrual cycle duration and/or
menorrhagia (menstrual loss of >80 mL per cycle) or
scanty menstrual ow may also occur. The presence of
frequent, heavy menstruation often is the primary cause
of iron-deciency anemia in female adolescents, the incidence of which signicantly increases when blood losses
exceed 80 mL per cycle.
Combined hormonal contraceptives (CHCs), including
the combined oral contraceptive pill (COCP), the contraceptive transdermal patch, and the contraceptive vaginal
ring, can all be used to regulate menstruation. These agents
are composed of estrogen in the form of ethinyl estradiol
and various types of progestins, which are synthetic, orally
active, progesterone-like hormones that also have androgenic and estrogenic properties. CHCs regulate menses
by suppressing ovulation through inhibition of the
gonadotropin-releasing hormone (GnRH) axis. Estrogen
suppresses follicle-stimulating hormone and follicular
development, whereas progestin prevents the luteinizing
hormone surge in midcycle. Together, the hormones in
CHCs inhibit ovulation and proliferative changes in the
uterus, leading to endometrial thinning and atrophy with
continued use.
There are many different formulations of hormonal contraceptive agents (Table 1). Most contain varying amounts
of ethinyl estradiol, ranging from 10 to 35 mg with varying
progestins. Low-dose COCPs (3035 mg of ethinyl estradiol) are the most commonly used agents, given the lack
of bone density protection associated with use of extremely
low-dose COCPs (1020 mg of ethinyl estradiol). Most
COCPs consist of a 28-day pill pack with 21 days of active
hormonal pills followed by 7 days of placebo pills; however,
there are also formulations with a 28-day pill pack that consists of 24 days of active hormonal pills followed by 4 days of
placebo or iron pills, as well as formulations that consist of 21
days of active hormonal pills only, allowing the patient to
remain pill free during the week of vaginal bleeding. COCPs
can be categorized either as monophasic, which contain
a consistent amount of hormones within each pill, or
multiphasic, which vary the amount of progestin or estrogen.
Most adverse effects of CHCs are minor. Adverse effects associated with the estrogen component include
nausea, vomiting, headaches, breast tenderness, and
changes in body weight. Adverse effects associated with

progesterone include acne, weight gain, increased hair
growth, and depression. More serious complications of
the estrogen component of CHCs are deep venous
thrombosis and arterial disease, such as myocardial infarctions and stroke; however, these complications are rare,
especially within the adolescent age group. To decrease
likelihood of adverse effects and serious complications,
CHCs with lower doses of both estrogen (<50 mg of
ethinyl estradiol) and progestins (varying doses, depending on the type of progestin) have been developed.
Most adolescents can be prescribed any of the CHCs
safely; however, for adolescents with coexisting medical
conditions, physicians should refer to guidelines developed by the Centers for Disease Control and Prevention
(CDC), which outline the absolute and relative contraindications to contraceptive agent use (Table 2). (2) Using
these guidelines, a physician can determine whether
CHCs are appropriate given the patients medical condition and, if necessary, prescribe another form of contraception. Another consideration is potential drug interactions
with medications the patient is taking (Table 3). Physicians should always check for use of these medications
when prescribing CHCs because concomitant use may
be associated with decreased efcacy of either of these
medications.
Through articial control of the menstrual cycle,
CHCs induce monthly withdrawal bleeding, also known
as a pill period. For oral contraceptive pills, this is the
week when no pills or placebo pills are taken instead of
active hormonal pills. For the contraceptive patch and
the contraceptive ring, this is the patch-free or ring-free
week of administration. Because of the presence of a thinner, atrophied endometrium, both menstrual blood loss
and menstrual period duration are decreased. Thus, the
likelihood of iron-deciency anemia is reduced in current
users of CHCs.
Specic treatment protocols with CHCs can be used
to regulate irregular bleeding in urgent clinical situations.
In cases of menorrhagia without anemia, CHCs are typically dosed as they are for contraception: 1 pill daily or
use of 1 patch weekly or vaginal ring per menstrual cycle.
However, for acute episodes of menorrhagia with associated anemia, altered treatment is necessary. For such situations, high doses of COCPs (3 or 4 pills) help to stop
bleeding quickly to prevent worsening anemia. Once
bleeding has stopped, the high-dose COCP regimen
should be tapered to 1 pill daily. A commonly used tapering
regimen is to give 1 pill every 6 hours until the bleeding
stops, then 1 pill 3 times per day for 2 days, 1 pill twice
per day for 2 days, and lastly 1 pill daily until the anemia
Table 1.
Commonly Used Hormonal Contraceptive Agents
Type
Estrogen
Progestin
Brand Names
Monophasic
COCPs
20 mg of ethinyl estradiol
0.1 mg of levonorgestrel
Alessea
1 mg of norethinedrone acetate
3 mg of drospirenone
0.15 mg of desogestrel
0.3 mg of norgestrel
1.5 mg of norethinedrone acetate
3 mg of drospirenone
1 mg of norethinedrone
Loestrin Fe 1/20b
Yazc
Apri,d Ortho-Cepte
Lo/Ovral-28f
Loestrin Fe 1.5/30g
Yasminc, Ocellad
Ortho-Novum 1/35,e
Nortrel 1/35d
Sprintec,d Ortho-cyclen,e
Mononessah
Ovcon-35g
Loestrin 24Feg
Lo Loestrin Feg
Estrostep Feg
20
20
30
30
30
30
35
Triphasic
COCPs
POPs
Extendedcycle COCPs
Vaginal ring
Transdermal
patch
Implant
mg
mg
mg
mg
mg
mg
mg
of
of
of
of
of
of
of
ethinyl
ethinyl
ethinyl
ethinyl
ethinyl
ethinyl
ethinyl
estradiol
estradiol
estradiol
estradiol
estradiol
estradiol
estradiol
0.25 mg of norgestimate
10 g of ethinyl estradiol
20 mg/30 mg/35 mg of ethinyl
estradiol
0.4 mg of norethindrone
1 mg of norethindrone acetate
1 mg of norethindrone acetate
1 mg of norethinedrone acetate
30 mg/10 mg of ethinyl estradiol

2.7 mg of ethinyl estradiol, 15 mg of
ethinyl estradiol released per day
0.75 mg of ethinyl estradiol, 20 mg of
ethinyl estradiol released per day
Injectable
Intrauterine
systems
Ortho Tri-Cyclene
0.18 mg/0.215 mg/0.25 mg of

norgestimate
0.35 mg of norethinedrone
Micronor,e Nor-QDh
Seasoniqueb
11.7 mg of etonogestrel, 120 mg of
etonogestrel released per day
6 mg of norelgestromin, 150 mg of
norelgestromin released per day
68 mg of etonogestrel, variable
release rate
150 mg of depot
medroxyprogesterone acetate
52 mg of levonorgestrel, 20 mg of
levonorgestrel released per day
13.5 mg of levonorgestrel, 14 mg of
levonorgestrel released per day
Seasonaled
Nuvaringi
Ortho-Evrae
Nexplanoni
Depo-Proveraj
Mirenac
Skylac
COCPscombined oral contraceptive pills; POPsprogestin-only pills.

a
Wyeth Pharmaceuticals Inc.
b
Duramed Pharmaceuticals Inc.
c
Bayer HealthCare Pharmaceuticals.
d
Teva Pharmaceuticals USA.
e
Janssen Pharmaceuticals Inc.
f
Akrimax Pharmaceuticals.
g
Warner Chilcott Company Inc.
h
Actavis.
i
Merck & Co Inc.
j
Pzer Inc.
has resolved. Use of pills will be stopped to allow a withdrawal bleed when the patient is not anemic.
Another effective contraceptive used to treat menorrhagia in adolescents is a levonorgestrel intrauterine system (LNG-IUS). The CDCs US medical eligibility criteria
for contraceptive use clearly state that intrauterine systems are safe and appropriate for nulliparous adolescents
and older women. There are currently 2 LNG-IUSs on

the market: Mirena (LNG-IUS-52 mg) (Figure 1) and
Skyla(LNG-IUS-13.5 mg) (Figure 2). Both are T-shaped
polyethylene devices with a steroid reservoir around the
stem. Both contain the progestin levonorgestrel, which
is released at a daily steady rate (Table 1). Mirena is approved by the Food and Drug Administration (FDA) for
Centers for Disease Control and Prevention Medical Eligibility

Criteria for Combined Hormonal Contraceptive Use
Table 2.
No Restrictions to Use
(WHO Category 1)
Cautionary Use, Advantages

Usually Outweigh Risks (WHO
Category 2)
Age <40 years
Women >6 weeks post

partum
Thyroid disorders
Minor surgery without
immobilization
Epilepsy
Relative Contraindications to
Use (WHO Category 3)
Absolute Contraindications
to Use (WHO Category 4)
Smoking <35 years
Current or past history of

deep vein thrombosis or
pulmonary embolism with
low risk of recurrence
Women 36 weeks post

partum without risk factors
for venous
thromboembolism
Lactation >1 month post
partum
Major surgery without
prolonged immobilization
First-degree family history of
pulmonary embolism
Women 36 weeks post

partum with risk factors for
venous thromboembolism

pulmonary embolism
with high risk of
recurrence
Women <3 weeks post
partum
Lactation < 1 month

postpartum
Moderate hypertension (140
159/9099 mm Hg)
Severe hyperlipidemias
Varicose veins
Systemic lupus erythematosus

with negative
antiphospholipid antibody
Superficial thrombophlebitis
Postabortion
History of pregnancy-related
cholestasis
Viral hepatitis carrier
Gallbladder disease,
asymptomatic or treated by
cholecystectomy
Migraine without aura
History of cholestasis related

to past combined hormonal
contraceptive use
Current or medically treated
gallbladder disease
Nonmigrainous headaches
Severe dysmenorrhea
Heavy or irregular
menstrual bleeding
Family history of breast
cancer
Benign breast disease
Uterine fibroids
Pelvic inflammatory disease
HIV/AIDS
Antiretrovirals, nucleoside
reverse transcriptase
inhibitors
Sexually transmitted
infections
Inflammatory bowel disease

without risks for deep vein
thrombosis/pulmonary
embolism
Unexplained vaginal bleeding
Current use of medications

that decrease OCP efficacy
Inflammatory bowel disease
with risks for deep vein
thrombosis or pulmonary
embolism
History of breast cancer
without recurrence for >5
years
Surgery with prolonged

immobilization
Severe hypertension
(>160/100 mm Hg)
Hypercoagulability
disorders (factor V
Leiden, protein C
deficiency, etc)
Systemic lupus
erythematosus with
positive or unknown
antiphospholipid
antibody
Known thrombogenic
mutation
Liver disease (including
severe cirrhosis, tumors,
active viral hepatitis)
Migraine with aura
cerebrovascular event or
disease
ischemic heart disease
Cervical cancer
Current breast cancer
Undiagnosed breast mass

Uncomplicated valvular heart
disease
Uncomplicated solid organ
transplantation
Uncomplicated diabetes
mellitus
Antiretrovirals, nonnucleoside
reverse transcriptase
inhibitors
Obesity
Vascular disease
Complicated valvular heart
disease
Complicated solid organ
transplantation
Diabetes mellitus with
complications
Continued
Table 2.
(Continued)
No Restrictions to Use
(WHO Category 1)
Malaria, schistosomiasis,
tuberculosis
Thalassemia, irondeficiency anemia
Benign ovarian tumors
Endometriosis, endometrial
hyperplasia
Depressive disorders
Current use of most
antibiotics, antifungals,
or antiparasitics
Cautionary Use, Advantages

Usually Outweigh Risks (WHO
Category 2)
Rheumatoid arthritis
Relative Contraindications to
Use (WHO Category 3)
Absolute Contraindications
to Use (WHO Category 4)
Sickle cell disease
HIVhuman immunodeciency virus; OCPoral contraceptive pill; WHOWorld Health Organization.
menorrhagia, effective for 5 years, and indicated in women

of reproductive age who have had at least one child. Skyla,
which is FDA approved for women under 18 years old, is
a slightly smaller LNG-IUS effective for 3 years and indicated in both multiparous and nulliparous women of reproductive age, including adolescents under the age of 18. An
LNG-IUS requires clinician insertion and removal; however,
it is a highly effective form of contraception. Its low failure
rate is attributable to lack of patient responsibility for administration or compliance other than having it inserted by
a physician at onset of use, thereby creating a means of
forgettable contraception.
The mechanism of action of the LNG-IUS involves
thickening of cervical mucus and thinning of the endometrial
lining. Consequently, there is a signicant reduction in

menstrual blood loss over time, which often progresses
to amenorrhea. A study of young women with menorrhagia with low ferritin levels who had the Mirena LNG-IUS
inserted found that after 12 months of use, 95% had increased ferritin levels, suggesting that when menstrual
blood loss decreased, the iron stores returned to normal.
(3) In addition, 58% became amenorrheic, providing additional evidence that LNG-IUS signicantly reduces
menstrual blood loss. Although the LNG-IUS is an excellent, well-tolerated contraceptive agent, its greatest disadvantage is intermenstrual bleeding and spotting in
the rst months of use.
Common Medications
Which Adversely Interact with
CHCs
Menorrhagia in adolescents is most commonly secondary

to anovulation due to an immature hypothalamic-pituitaryovarian axis; however, there are many coagulopathies that
cause menorrhagia, such as von Willebrand disease (vWD)
and deciency of certain clotting factors. In fact, menorrhagia
with severe anemia is a common presentation of vWD.
Patients may also present with easy bruising, excessive
bleeding at the time of surgical or dental procedures,
or gastrointestinal or mucocutaneous bleeding.
In the normal clotting cascade, during menstruation,
denuded endometrial glands and stroma are shed into the
endometrial cavity, whereas intravascular brin-platelet
plugs form to allow for hemostasis. In patients with vWD,
through various mechanisms, abnormal von Willebrand
factor (vWF) or decreased vWF in plasma impairs microvascular thrombosis and coagulation, resulting in menorrhagia and irregular uterine bleeding.
Table 3.
CHCs Decrease Efficacy
Decrease Efficacy of CHCs
Lamotrigine
Griseofulvin
Rifampin
Rifabutin
Ritonavir
Oxcarbazepine
Phenytoin
Barbiturates
Carbamazepine
Topiramate
Felbamate
Primidone
St. Johns wort
Hematologic Chronic Illnessvon Willebrand

Disease and Deficiency of Clotting Factors
Figure 1. Mirena Intrauterine System (levonorgestrel in-
trauterine system, 52 mg). Reproduced with permission from

Bayer HealthCare Pharmaceuticals Inc.
The quality of life for patients with vWD and clotting factor deciencies, whether genetic or acquired, may be signicantly impaired by menorrhagia. Many miss school or work
and report a reduction in other daily activities during menstruation. Use of CHCs in patients with a subtype of vWD characterized by partial quantitative defects in vWF (usually type 1)
can suppress and regulate menses. Estrogen within the CHCs
causes an elevation of plasma vWF, which decreases the
frequency of menstrual blood loss and subsequent anemia.
Given the various consequences of menorrhagia in
these patients, physicians should consider proactively
starting CHC therapy when patients with vWF are Tanner stage 4 and perimenarchal to help manage menorrhagia from the start. This is especially useful if the patients
family members and/or siblings required transfusions
with their rst menstrual periods. If the patient is very
short or the physician wants to maximize the growth, at Tanner stage 4, the physician can track patients every 3 to 6
months and prescribe CHCs as height progresses. With this
kind of proactive approach, the patients rst menstrual periods do not need to be the cause of severe anemia.
In a retrospective study of girls 9 to 18 years with vWD
looking at treatment of menorrhagia with both low-dose
COCPs vs desmopressin for a 6-month to 4-year period,
Figure 2. Skyla Intrauterine System (levonorgestrel intrauter-
ine system, 13.5 mg). Reproduced with permission from Bayer

HealthCare Pharmaceuticals Inc.
patients had signicantly decreased menorrhagia with use

of oral contraceptive pills. (4) No serious adverse events
were reported with use. High-dose COCPs are not recommended secondary to the estrogen inuence on coagulation factors. This treatment could increase adverse events,
particularly thromboembolic events.
Treatment for Perimenstrual Symptoms and

Catemenial Conditions
Many patients may be affected by catamenial conditions,
menstrual symptoms, or medical conditions, which are
exacerbated at the time of menses. Contraceptive agents

can be useful in treatment of many of these conditions.
Dysmenorrhea
Dysmenorrhea, dened as painful menstruation, is the
most common gynecologic condition in adolescent girls,
affecting 60% to 93%. Historically, dysmenorrhea has
been one of the most common reasons contraceptive
agents are prescribed for noncontraceptive indications.
Although primary dysmenorrhea, dened as painful menses
not due to any pelvic disease, is much more common during
adolescence, dysmenorrhea secondary to pelvic disease
(secondary dysmenorrhea) may also affect adolescent
patients.
Although many adolescents experiencing dysmenorrhea do not seek medical care specically for their symptoms, diagnosis and alleviation of dysmenorrhea are critical
because the condition often is a cause of signicant disability.
Many adolescents miss school or work and also adjust
their daily social and physical activities because of the pain
experienced during menstrual periods.
The dening symptom of primary dysmenorrhea is
midline, crampy, lower abdominal pain. It usually begins
a couple days before or with onset of menses and lasts
for 8 to 72 hours. Usually, pain is most intense on the rst
and/or second day of menstrual ow. Secondary symptoms of primary dysmenorrhea are more variable and
may include breast tenderness, low back pain, diarrhea,
bloating, headaches, mood lability, nausea, vomiting,
and near-syncope. Symptoms associated with secondary
dysmenorrhea are more varied and linked to the pelvic
condition. The physical examination of a girl with dysmenorrhea is also variable and often dependent on the timeline
of the patients menstrual cycle. If the patient is close to or
experiencing menstruation, mild to moderate suprapubic
tenderness with normal bowel sounds may be present.
At other times within the menstrual cycle, the physical
examination ndings may be unremarkable. A pelvic examination with bimanual examination is not usually required; however, an external genital examination should
be performed on all girls regardless of sexual activity.
Sometimes, a rectoabdominal examination to rule out
a mass may be indicated to assess for a pelvic mass. Laboratory and radiologic workups are usually not necessary
when history and physical examination provide sufcient evidence that primary dysmenorrhea is likely the
inciting cause of pain.
Primary dysmenorrhea is caused by excess secretion of
prostaglandins and leukotrienes, resulting in contractions
of uterine muscle. Therefore, its treatment is linked to inhibition of these mediators. Nonsteroidal anti-inammatory
drugs (NSAIDs), cyclooxygenase inhibitors that reduce

the production of prostaglandins, are typically used as
rst-line treatment. If taken correctly before the onset
of menstrual pain and continued appropriately, this class
of medications relieves dysmenorrhea in up to 80% of
adolescents. For those adolescents who do not experience complete relief with NSAIDs, CHCs may be used
instead of or in conjunction with them. Hormones in
CHCs act by suppressing ovulation and diminishing
the endometrial lining of the uterus. Consequently, menstrual uid volume decreases along with the amount of
prostaglandins produced, which subsequently then reduces dysmenorrhea by decreasing uterine motility and
uterine cramping. For patients with persistent dysmenorrhea, despite the use of oral contraceptives and NSAIDs,
extended cycling of CHCs may be prescribed to decrease
the number of menstrual periods and thus the occurrence
of dysmenorrhea.
A Cochrane review of COCPs states that they may be
helpful for dysmenorrhea; however, interpretation of
the results is limited because of the variable quality of
the randomized controlled trials studied. (5) Although
this review reveals inconclusive data regarding COCP
use for dysmenorrhea, clinical practice and other studies
suggest that COCPs and other CHCs are effective treatment
modalities for the treatment of primary dysmenorrhea.
Other Catamenial Conditions

Headaches
Many women experience headaches during menstrual
periods. After dysmenorrhea, headaches are the most
frequent menstrual-related symptoms. Usually, the headaches occur immediately before the onset of menses and
possibly through the duration of menses. Numerous
studies have documented the association between the onset of headaches and hormonal uctuations, particularly
estrogen. Headaches are thought to be triggered by
the sharp decrease in estrogen levels immediately before
menstrual ow. Physicians often attempt to treat headaches with traditional cycling of CHCs; however, because
both estrogen and progestin levels decrease before a withdrawal bleed, women who use CHCs often are symptomatic during the hormone-free interval, but many have less
severe headaches than if they were not taking CHCs.
Extended and continuous placebo-free CHC regimens have been used to decrease the number of hormone
uctuations and subsequently reduce the headaches experienced by patients. Such menstrual regulation has
had tremendous quality-of-life implications for many
women with headaches and has been found to be
associated with improvement in work productivity and

involvement in activities. However, before initiating
use of CHCs to treat headaches, a practitioner must be
certain that the headache is not associated with an aura
because use of CHCs in patients with migraines with aura
are absolutely contraindicated as per CDC medical eligibility criteria guidelines for contraceptive use (Table 2).
In addition, because the estrogen component of the
CHCs may themselves cause headaches, patients should
be counseled that if there is worsening of headaches or
onset of new headaches after initiation of CHC use, they
must contact their physician to be evaluated.
Epilepsy
Many women with a medical history of epilepsy have severe seizures during menstruation. Catamenial epilepsy is
described as the cyclical increase in seizures around the
time of menses or at other phases of the menstrual cycle,
usually during perimenstrual or periovulatory periods in
normal ovulatory cycles and during the luteal phase in
anovulatory cycles. The mechanism of these cyclical
changes is thought to be secondary to the proconvulsant
effect of estrogen and the anticonvulsant effect of progesterone. The cause of exacerbation of seizures during
the middle of the menstrual cycle is likely linked to the
surge of estrogen occurring before ovulation, which is
unaccompanied by a comparable increase in progesterone. Contrasting this, it is a decit of progesterone,
which contributes to increased seizures during menstruation.
Although COCPs have usually been found to be ineffective to improve seizure control, depot medroxyprogesterone acetate has been reported to have positive effects
in decreasing the frequency of seizures in some women.
Depot medroxyprogesterone acetate is progesterone derivative, which is administered intramuscularly at 3month intervals at a dosage of 150 mg per injection.
Its mechanism of action is via inhibition of ovulation at
the hypothalamic level and via thickening and an increase
of cervical mucus. Depot medroxyprogesterone acetate
changes the endometrium so that it becomes more secretory and eventually atrophic. One major benet of depot
medroxyprogesterone acetate in these patients is that it
usually does not adversely interact with antiepileptic medications as many COCPs do. Many antiepileptic medications decrease efcacy of COCPs, and concomitant use of
COCPs with the antiepileptic medication lamotrigine can
decrease lamotrigines efcacy, thereby lowering a patients
seizure threshold (Table 3).
Although DMPA has many benets, some signicant
adverse effects are associated with the method. Irregular
bleeding and spotting usually occur during the rst 6 to 9
months of receiving depot medroxyprogesterone acetate.

Although heavy bleeding is rare, this is the most common
reason the method is discontinued. In addition, other potential adverse effects include weight gain, headaches, depression, alopecia, fatigue, and osteopenia.
The negative effect of depot medroxyprogesterone
acetate on bone mineral density has received signicant
attention, especially with regard to the adolescent population. Studies have found that depot medroxyprogesterone
acetate signicantly contributes to bone mineral density
loss. This is probably due to the relative estrogen deciency
patients experience with depot medroxyprogesterone
acetate. However, the changes are entirely reversible,
and after discontinuation, bone density not only recovers, it also increases. When prescribing depot medroxyprogesterone acetate to adolescents, physicians should
discuss the benets and risks, as well as inform the adolescent and family of possible risk of bone loss. While
patients are using depot medroxyprogesterone acetate,
supplements of vitamin D (400 IU) and calcium carbonate (1300 mg) may be prescribed, as well as estrogen
supplements if the patient is at high risk or has
osteopenia.
Premenstrual Syndrome
Premenstrual syndrome (PMS) is another common problem in menstruating women. It is characterized by a variety of symptoms, such as mood swings, mastalgia, food
cravings, fatigue, irritability, and depression. The prevalence of PMS increases as the adolescent matures from
menarche to more established ovulatory cycles. Symptoms
of PMS are likely caused by cyclic hormonal uctuations and hormonal-mediated uctuations in neurotransmitters. Premenstrual symptoms may occur in
more than 75% of menstruating women; however,
PMS occurs in only 20% to 40% of women. To establish the diagnosis of PMS, patients symptoms must be
consistent with PMS, be relieved shortly after the onset of menses, and be associated with some impairment
of daily activity.
Premenstrual dysphoric disorder (PMDD) is a severe
form of PMS, which affects 3% to 8% of menstruating
women. PMDD requires the presence of both affective
(mood or emotional) and somatic (physical) symptoms.
According to the Diagnostic and Statistical Manual of
Mental Disorders (Fifth Edition) criteria for PMDD,
women must have at least 5 symptoms, including a mood
problem, as well as substantial impairment in an activity
of daily living. (6) These symptoms should be prospectively captured with a symptom log, which can be reviewed with the physicians.
CHCs are likely to alleviate the physical symptoms associated with PMS but do not signicantly improve the
emotional symptoms of PMS. However, a newer COCP
with drospirenone and low estrogen (drospirenone, 3
mg, and ethinyl estradiol, 20 mg) has been approved
by the FDA for treating PMDD and has been found to
be more effective in treating these emotional symptoms
than other CHCs. Most COCPs are derived from 19nortestosterone; however, drospirenone is derived from
spironolactone rather than 19-nortestosterone. Thus,
drospirenone is an antimineralocorticoid progestin that
may inuence uid balance and consequently prevent
uid retention, weight gain, bloating, and an increase
in blood pressure seen in menstruating women. Serious
adverse effects of drospirenone include the possibility
of hyperkalemia in patients taking other drugs, which
can increase potassium, and an increased risk of thromboembolic events when compared with COCPs that contain
other types of progestin.
Other Chronic Medical Conditions

Sickle Cell Disease
Hormonal contraceptive agents also have noncontraceptive benets effects on patients with sickle cell disease
(SCD). Many physicians are very concerned and cautious
about potentially causing blockage of blood vessels and
a subsequent bone pain crisis or promoting a thromboembolic event. Despite these concerns, it is safe to prescribe
patients with SCD, who have not had a thromboembolic
event, most contraceptive agents. Progestin-only contraceptive agents are preferred, and as CDC medical eligibility criteria guidelines state, there are no restrictions on
use of progestin-only contraceptives and LNG-IUSs for
SCD. (2) However, for those patients who will not use
progestin only measures, the benets of CHCs or the
copper intrauterine device may outweigh the theoretical
or proven risks of using these methods.
Multiple studies have revealed that depot medroxyprogesterone acetate contributes to a decrease in the frequency, severity, and duration of painful crises in female
patients with SCD. The possible mechanism of action is progestin stabilizing the red blood cell membranes and making
cells less prone to sickling, which causes the pain crises.
A recent Cochrane review supports these studies. It reported that depot medroxyprogesterone acetate is a safe
contraceptive method in women with SCD, and that in
addition to providing effective contraception, depot
medroxyprogesterone acetate appears to reduce sickle
pain crises. (7) With regard to CHC use in patients with
SCD, many studies have not found an increase in pain
crises or other complications of SCD disease among

women who used CHCs.
Rheumatoid Arthritis
There is no conclusive evidence in regard to a protective
effect of contraceptives against rheumatoid arthritis;
however, clinical practice has indicated that contraceptives may positively inuence the severity and clinical
course of rheumatoid arthritis.
Menstrual Suppression
Many adolescent women require suppression or elimination of menstrual bleeding for a variety of reasons, ranging from personal preference to coexisting medical
conditions. Menstrual suppression offers signicant control over the menstrual cycle. Despite common belief,
there is no scientic or medical basis of the need for intermittent use of hormonal contraception that allows for
a monthly withdrawal bleed. Many patients taking CHCs
with a 4- or 7-day break to allow for withdrawal bleeding
(perceived period) often continue to have difculties with
other perimenstrual symptoms, such as dysmenorrhea,
menorrhagia, headaches, bloating, and emotional lability,
during the contraceptive-free interval. In addition, intermittent use of hormonal contraception has not been found
to be any safer than using hormonal contraception continuously. To date, there are no long-term negative health
consequences associated with menstrual suppression.
In a study conducted in the Netherlands that used
a telephone interview inquiring about womens attitudes
toward changes in menstrual bleeding caused by COCPs
and hormonal replacement therapy, adolescents aged
15 to 19 years indicated a desire for less painful and
shorter menstrual bleeding signicantly more often than
reproductive-age women. (8) All women preferred decreasing the frequency of bleeding to less than once
a month or completely eliminating menstrual periods
altogether. When asked specically about what bleeding
frequency they would prefer if manipulated by COCPs,
72% of the adolescents stated never or less than once
a month. Similar studies conducted in the United States
have revealed comparable reactions. (9) Younger women,
those already using birth control, low-income women,
and women with severe symptoms during menstruation
were those most receptive to suppression of menses.
A specic COCP (Seasonale, 150 mg of levonorgestrel
and 30 mg of ethinyl estradiol) was introduced in 2003
and offers greater menstrual suppression than traditional
COCPs. This COCP contains 84 days of active hormone
tablets followed by 7 inactive pills, creating an extended
cycle of 91 days and giving the user only 4 withdrawal

bleeds a year. Adverse effects, such as premenstrual symptoms, headaches, mood changes, and heavy or painful
monthly bleeding due to hormone withdrawal, are reduced. In addition, patients using this COCP rarely have
anemia secondary to infrequent withdrawal bleeding.
Studies have reported that extended-cycle COCPs are effective, safe, and well tolerated.
If desired, more practical, or less costly for the patient,
a physician can use any other 24- or 28-day formulations
of monophasic COCPs to extend the patients cycle. This
extended cycle is achieved in a similar manner by simply
advising the patient to take only the active hormone tablets within the pack continuously from pack to pack during an extended period, typically 3 months. When the
patient nishes the active hormonal pills within the third
pack, she can take the placebo pills to produce a withdrawal bleed.
Although COCPs are commonly used for extended or
continuous cycling, the transdermal contraceptive patch
is not an ideal choice for continuous cycling secondary
to increased estrogen levels. Systemic estrogen levels
are estimated to be 1.6 times higher in the transdermal
patch than with the standard low-dose COCP. Studies
have found that there is a possible increased risk of venous
thromboembolism in patch users; therefore, extending
cycling without a hormone-free interval is not recommended. On the other hand, extended and continuous
cycling schedules that use the vaginal ring have been
studied and found to be safe, tolerable, and effective. Results revealed an acceptable bleeding prole in most patients, reduction of pelvic pain, and a high continuation
rate. There was no increase of thromboembolic events or
increased endometrial hyperplasia. An adverse effect of
the continuous use of the vaginal ring was some breakthrough bleeding and spotting; however, this is a common adverse effect of both traditional and extended or
continuous cycling of many CHCs that adolescents
should be counseled to expect. If breakthrough bleeding
is bothersome to patients, they can be instructed to stop
use of the pill for 4 days to allow a withdrawal bleed and
then resume administration of the remaining pills. Bleeding and spotting tend to improve with continued use of
CHCs, and most patients are willing to tolerate this to
have fewer menstrual periods. A few of the conditions
treated with menstrual suppression are discussed below.
Patients With Physical and Mental Disabilities

Menstrual periods can be particularly difcult for both
patients and caregivers of patients with physical or mental
disabilities. Adolescents with such disabilities often have
a high frequency of reported painful, heavy, and prolonged bleeding and behavior problems during menses.
The disability can often make it challenging for patients
or caregivers to maintain good hygiene during menstruation. Many families seek assistance from medical professionals for menstrual-related symptoms and request
regulation and/or suppression to deliver more predictable and less frequent menstruation. Some families may
request hysterectomy or permanent sterilization for such
patients; however, this is often not a viable treatment for
ethical and medical reasons. Therefore, patients with signicant physical and/or mental disabilities may benet
from infrequent menstrual periods or induction of longterm amenorrhea by treatment with CHCs.
Long-term amenorrhea can be induced by extended
CHC regimens; however, similar results can also be achieved
with progestin-only medications. Depot medroxyprogesterone
acetate is an agent frequently requested by patients and caregivers for menstrual suppression. Depot medroxyprogesterone
acetate is an excellent agent for menstrual suppression because most patients usually achieve amenorrhea after the
third or fourth dose, and it has few drug interactions. Another benet of depot medroxyprogesterone acetate is that
patients are not burdened with daily pill administration or
weekly/monthly administration of the transdermal patch
or vaginal ring. Lastly, with use of this method, estrogen is
avoided, which could potentially be contraindicated in such
patients or contribute to negative perimenstrual symptoms.
Immobility is fairly common in patients with physical
and mental disabilities. Because of its negative effects on
bone development, using depot medroxyprogesterone
acetate presents a signicant risk to these patients. Moreover, CHCs should not be used in girls who are immobile
because of increased risk of deep vein thrombosis and
subsequent emboli. Instead, progestin-only pills may also
be used as an alternative to depot medroxyprogesterone
acetate in patients with lack of or limited mobility. Another excellent alternative method is an LNG-IUS, which
is progestin only and has a high rate of achieving amenorrhea with low risk to bone health. A limited number of
studies support LNG-IUS use in adolescents with physical and mental disabilities. This method can reduce menstrual bleeding without adverse effects on bone health
and only needs introduction or insertion every 5 years.
Breakthrough menstrual bleeding, which is common during
the rst few months after insertion of the LNG-IUS, can be
reduced by administering a 5- to 7-day course of NSAIDs to
patients. Although Nexplanon is another progestin only
form of contraception that one may consider using, it can
be associated with episodic vaginal bleeding, so it may not
be effective in achieving amenorrhea.
Patients With Malignant Tumors

Contraceptive agents benet adolescent girls with malignant tumors receiving chemotherapy. Many cancer patients must receive ablative or high-dose chemotherapy,
which destroy the bone marrow until recovery of blood
stem cells. Patients become pancytopenic, which results
in severe morbidity secondary to their vulnerability to multiple diseases and infections. Growth factors help with recovery of white and red blood cell lines; however,
thrombocytopenia is more difcult to treat because of
a lack of an existing comparable platelet growth factor.
These girls may subsequently experience bleeding from
multiple body sites, including the uterus, resulting in menorrhagia. Often, such patients will require immediate
blood products, such as platelets, packed red blood cells,
and/or high-dose estrogen, to stop bleeding. To prevent
these often emergency circumstances, pretreatment with
depot medroxyprogesterone acetate, CHCs, or GnRH agonists has been used successfully to induce amenorrhea in
such patients before the induction of the chemotherapeutic
regimen. Progestin-only contraceptive agents are preferred
over CHCs secondary to the potential adverse effects of estrogen on coagulation; however, given their higher rates of
obtaining amenorrhea, GnRH agonists are usually chosen
as rst-line treatment in such clinical situations.
Another clinical situation for which contraceptive agents
can be benecial is for girls with malignant tumors who
are amenorrheic after radiation, chemotherapy, or bilateral
oophorectomy. Lack of estrogen has consequences to bone
health and may cause other symptoms, such as vaginal dryness. Estrogen replacement may be achieved by using CHCs.
Treatment of Other Medical and Gynecologic

Conditions
Acne
Acne, a disorder of sebaceous glands of the skin, is another common condition that affects adolescents. It affects 40 million to 50 million people in the United
States annually. Morbidity associated with acne and adverse effects of treatment can lead to both physical and
emotional scars during a patients lifetime.
The pathogenesis of acne is multifactorial. There can be
an increased rate of sebum production, which results from
an excess production of androgens from either the ovary or
the adrenal glands. In addition, the sebaceous glands of
many patients, particularly adolescents, are hyperresponsive
to androgens. Consequently, the increased sensitivity to androgen results in secretion of excess amounts of sebum.
Testosterone levels in women using CHCs are reduced
signicantly through various mechanisms. Perhaps one of
the strongest mechanisms of reduction is via suppression

of ovulation. When ovulation does not occur, luteinizing
hormone levels are suppressed, and androgen synthesis
within the ovary and adrenal glands is signicantly decreased.
Androgen bioavailability also is reduced by CHCs because ethinyl estradiol increases the level of the sex hormone
binding globulin, the protein that binds free androgens,
which in turn increases binding of testosterone. Another
way acne occurs is when testosterone is converted in the hair
follicles and skin to dihydrotestosterone by the enzyme 5-areductase. CHCs prevent this conversion by blocking androgen receptors and inhibiting 5-a-reductase activity.
Androgen levels may be reduced by different degrees,
depending on the type of CHC used. As stated previously, CHCs are composed of estrogen and various types
of progestins. Progestins typically have progestational activity but also have varying levels of androgenic activity.
CHCs that contain third-generation progestins, such as
norgestimate, levonorgestrel, and drospirenone, have relatively greater afnity for progesterone receptors than for
androgen receptors compared with older agents. Thus,
theoretically, for treatment of acne, their ability to counteract the increased sebum production by the androgendependent sebaceous glands should be better than older
contraceptive agents. Because of this benet, many CHCs
with these specic types of progestins, such as the triphasic
(35 mg of ethinyl estradiol; 0.18 mg, 0.215 mg, and 0.25
mg of norgestimate; and 20 mg of ethinyl estradiol and
3 mg drospirenone) have been marketed, FDA approved, and used specically for the treatment of acne.
In addition, a triphasic COCP with varying degrees of
estrogen has also been FDA approved and used for acne.
Although a few studies have found increased levels of
sex hormonebinding globulin and decreased testosterone levels in women using COCPs with less androgenic
progestins, in the Cochrane review studying the use of
COCPs for treatment of acne, results revealed that all
COCPs reduced acne lesion counts, severity grades,
and self-assessed acne compared with placebo. (10) In
addition, it stated that the differences in the comparative
effectiveness of COCPs containing varying progestin
types and dosages were less clear and data was limited
for any particular comparison. (10) Thus, the review
provides evidence that all types of COCPs can be used
by physicians for acne treatment with similar efcacy.
Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a condition characterized by chronic anovulation and hyperandrogenism.
Clinical symptoms and signs of PCOS include irregular
menstrual cycles, infertility, hirsutism, and acne.
In addition to anovulation secondary to immaturity of

the hypothalamic-pituitary-ovarian axis and coagulation
disorders, PCOS is a fairly common cause for irregular
menstruation and acute episodes of menorrhagia in adolescent patients. The mechanism of PCOS involves increased androgen levels, which lead to anovulatory
menstrual cycles. Anovulatory cycles result in unopposed
estrogen exposure of the endometrium, which leads to
endometrial thickening. When the endometrium eventually
outgrows its blood supply, it begins to shed in an unpatterned way that is associated with irregular menstruation
and often acute episodes of menorrhagia.
CHCs treat PCOS by increasing cycle regularity by
delivering estrogen and progesterone in an orderly fashion, which restores synchrony to the endometrium. In
addition, as mentioned above, CHCs suppress ovarian,
adrenal, and peripheral androgen secretion through suppression of ovulation, increase of the levels of sex
hormonebinding globulin, and inhibition of testosterone
conversion. However, CHCs may not have any effects on
the metabolic issues, which occur in PCOS.
Structural Lesions
OVARIAN CYSTS. During development of the ovum
during the menstrual cycle, small cysts may form around
the egg while the egg is developing and moving. These
cysts usually self-resolve, but some can persist, grow
large, and/or become painful. It has become common
clinical practice to prescribe CHCs to induce regression
of ovarian cysts, but there is little evidence that supports
this practice. Results of a Cochrane review revealed that
COCPs did not cause ovarian cysts to regress faster: most
self-resolved in 2 to 3 months. (11)
Although CHCs are likely not helpful in promoting ovarian cyst regression, historically, women taking CHCs are less
likely to develop ovarian cysts compared with non-CHC
users. This is secondary to CHCs inhibition of ovulation,
thereby preventing eggs from being released and resulting
in a subsequent decrease in cyst formation. However, most
studies with these ndings were conducted with older
higher-steroid dose COCPs. Recent data with newer
lower-steroid doses do not show similar results because they
have been found to have little effect on cyst formation.
ENDOMETRIOSIS. Endometriosis is the presence of endometrial tissue in sites outside the uterine cavity, most
commonly the ovaries and peritoneum. The condition is
frequently found in women with painful periods, dyspareunia, pelvic pain, and infertility. The mechanism of endometriosis is unclear; however, the most commonly accepted
theory is that retrograde menstrual ow is involved with
development of the condition. In addition to this theory,

this condition is also thought to have a genetic component
because it is found to occur more frequently in rst-degree
relatives of women with endometriosis.
Clinically, pelvic pain secondary to endometriosis may
be associated with mild posterior uterine or cul-de-sac
tenderness. The diagnosis of endometriosis is denitively
made by visualizing the lesions on laparoscopy; however,
current guidelines suggest that a laparoscopy is not always
necessary before starting treatment. If the patient is experiencing signicant symptoms of pain suggestive of endometriosis, then the condition can be empirically treated
with COCPs. COCPs have been thought to down-regulate
cell proliferation and enhance apoptosis in the endometrium of patients with endometriosis. COCPs have a few
signicant advantages over other hormonal treatments:
they can be taken indenitely, they offer long-term symptom control, and they are generally more acceptable to
women than alternative hormonal treatments. The alternative (GnRH analogues) is limited to 6 months of use because of associated bone loss.
A recent Cochrane collaborative review supported the
use of COCPs as an alternative treatment for the painful
symptoms of endometriosis. (12) Other contraceptive
methods to consider are continuously cycled COCPs,
which have been reported to decrease menstruationrelated pain symptoms. In addition, LNG-IUS, has been
reported to effectively treat chronic pelvic pain associated
with endometriosis compared with GnRH. The advantages of LNG-IUS are that it does not provoke hypoestrogenism and requires only one medical intervention for
introduction of the device every 5 years.
UTERINE FIBROIDS. There is conicting evidence regarding the effect of CHCs on uterine broids. However, a few
studies have reported a reduced risk of development of uterine broids with COCP use. One study found that increased
duration of COCP use was associated with increased protection and 10 years of use resulted in a 30% risk reduction. (13)
Other Benefits of Contraceptive Agents

Reduction of Cancers
OVARIAN CANCER. CHCs have the added benet of
reducing the risk of ovarian cancer via suppression of ovulation. Lack of ovulation decreases direct pituitary hormone
effects on the ovarian epithelium, thereby decreasing injury
and subsequent repair of the ovary. The likelihood of ovarian cancer is signicantly decreased in women who have
taken COCPs. The protective effect increases with duration
of use of the COCPs and continues after discontinuing use
of the COCPs. Both the older higher-dose pills (50 mg
of estrogen) and the newer COCPs with lower estrogen

dosages (30 mg of estrogen) have been studied, and no
difference in protective effect exists between high- and
low-dose COCPs.
ENDOMETRIAL CANCER. CHCs also reduce the risk of
endometrial cancer. The probable mechanism is via reduction of endometrial cell mitotic activity by the action of progestins. In addition, CHCs can reduce the
risk of endometrial hyperplasia and endometrial cancer, resulting from unopposed estrogen exposure by regulating
the cycle and stabilizing the endometrium. Studies have
found that the amount of risk reduction depends on duration of use; however, this risk reduction can persist for
many years after discontinuation of COCP use. Depot medroxyprogesterone acetate has also been found to decrease
the risk of endometrial cancer for users.
COLON CANCERS. Colon cancer risk may also be reduced with CHC use. The mechanism of risk reduction
is related to bile acid production. Progestins and exogenous estrogen may reduce bile acid production, and because bile acids act as promoters of colon carcinogenesis,
CHCs can decrease their synthesis and subsequently decrease the risk of colorectal cancer. Previous studies have
reported a risk reduction with high-dose COCPs; however,
the evidence for use of low-dose COCPs is inconclusive.
Reduction of Risk for Pelvic Inflammatory

Disease
The risk of developing pelvic inammatory disease is signicantly decreased with use of CHCs and medroxyprogesterone
acetate. Both these agents create progestin-associated thickening of cervical mucus, which impedes ascent of pathogens
into the upper genital tract and uterine cavity. Multiple
studies have found a reduction of risk and severity in
patients that acquire pelvic inammatory disease during
COCP use. Those young women taking COCPs who develop pelvic inammatory disease have a 60% decreased
risk of hospitalization. (14) Among women with chlamydia, risk of pelvic inammatory disease was 80% less
than in those women not using the COCP; however, a similar association was not seen in women with gonorrhea.
Protection is limited to current users; a patients past use
of COCPs does not exert a protective effect.
Reduction of Benign Breast Disease

Fibrocystic change and broadenoma development are
signicantly reduced after 1 to 2 years of CHC use. Current CHCs users are at lowest risk, but there is a decreased
risk of benign breast disease with increasing duration of
use. The likely mechanism of action is inhibition of breast
cell proliferation that normally occurs in the follicular

phase of an ovulatory menstrual cycle. Because ovulation
is suppressed with CHCs, breast cell proliferation is also
decreased.
Summary
On the basis of strong research evidence, there
are many noncontraceptive advantages to use of
hormonal contraceptive agents in adolescent girls. (3)
(4)(5)(7)(10)(11)(12)(13)(14)
On the basis of research evidence and consensus, most
of these agents are safe with minor adverse effects.
(2)(3)(4)(5)(7)(10)(11)(12)(13)(14)
On the basis of research evidence and consensus,
through application of evidence-based approaches
and proper counseling, pediatricians can use various
contraceptive agents to treat several medical
conditions and to help alleviate many of the undesired
symptoms and complications associated with
menstrual periods. (2)(3)(4)(5)(7)(10)(11)(12)(13)
(14)
On the basis of research evidence and consensus, these
agents may be used in sexually active adolescents to
simultaneously help prevent unintended adolescent
pregnancies. (2)(3)(4)(5)(7)(10)(11)(12)(13)(14)
References
1. Jones RK. Beyond Birth Control: The Overlooked Benets of
Oral Contraceptive Pills. New York, NY: Guttmacher Institute;
2011
2. Centers for Disease Control and Prevention. U.S. medical
eligibility criteria for contraceptive use, 2010: adapted from the
World Health Organization medical eligibility criteria for contraceptive use, 4th edition. MMWR Recomm Rep. 2010;59(RR-4):
186. http://www.cdc.gov/reproductivehealth/UnintendedPregnancy/USMEC.htm. Accessed May 6, 2013.
3. Andersson JK, Rybo G. Levonorgestrel-releasing intrauterine
device in the treatment of menorrhagia.BJOG. 1990;97:690694
4. Amesse LS, Pfaff-Amesse T, Leonardi R, Uddin D, French JA II.
Oral contraceptives and DDAVP nasal spray: patterns of use in
managing vWD-associated menorrhagia: a single-institution study.
J Pediatr Hematol Oncol. 2005;27(7):357363
5. Wong CL, Farquhar C, Roberts H, Proctor M. Oral contraceptive pill for primary dysmenorrhoea. Cochrane Database Syst Rev.
2009; (4):CD002120.
6. Diagnostic and Statistical Manual of Mental Disorders. 5th ed.
Arlington, VA: American Psychiatric Association; 2013
7. Manchikanti Gomez A, Grimes DA, Lopez LM, Schulz KF.
Steroid hormones for contraception in women with sickle cell
disease. Cochrane Database Syst Rev. 2012;(2):CD006261
8. den Tonkelaar I, Oddens BJ. Preferred frequency and characteristics of menstrual bleeding in relation to reproductive status, oral
contraceptive use, and hormone replacement therapy use. Contraception. 1999;59(6):357362
9. Association of Reproductive Health Professionals. Menstruation and Menstrual Suppression Survey. http://www.arhp.org/
Publications-and-Resources/Studies-and-Surveys/Menstruationand-Menstrual-Suppression-Survey/Full-Report. Accessed May
6, 2013.
10. Arowojolu AO, Gallo MF, Lopez LM, Grimes DA. Combined
oral contraceptive pills for treatment of acne. Cochrane Database
Syst Rev. 2012;(7):CD004425
11. Grimes DA, Jones LB, Lopez LM, Schulz KF. Oral contraceptives for functional ovarian cysts. Cochrane Database Syst Rev.
2011;(9):CD006134
12. Davis LJ, Kennedy SS, Moore J, Prentice A. Modern combined

oral contraceptives for pain associated with endometriosis. Cochrane
Database Syst Rev. 2009;(3):CD001019
13. Ross RK, Pike MC, Vessey MP, Bull D, Yeates D, Casagrande
JT. Risk factors for uterine broids: reduced risk associated with
oral contraceptives. Br Med J (Clin Res Ed). 1986;293(6543):
359362
14. Wlner-Hanssen P, Svensson L, Mrdh PA, Westrm L.
Laparoscopic ndings and contraceptive use in women with signs
and symptoms suggestive of acute salpingitis. Obstet Gynecol. 1985;
66(2):233238
PIR Quiz Requiremetns

1. What are the effects of combined hormonal contraceptives on the risk of cancer?
A.
B.
C.
D.
E.
Increased risk of endometrial cancer.

Increased risk of ovarian cancer.
Increased risk of colon cancer.
No effect on either endometrial or ovarian cancer.
Decreased risk of endometrial, ovarian, and colon cancer.
2. Which of the following statements accurately describe characteristics of a levonorgestrel intrauterine system?
A. Newer products can be safely self-inserted by the patient.
B. These products provide safe and reliable contraception for 3 to 5 years.
C. These products reliably result in consistent, monthly menses.
D. These products should not be used in nulliparous adolescents.
E. These products are excellent for control of menorrhagia but are ineffective for contraception.
3. What is the primary mechanism of action of the combined oral contraceptive pill (COCP) in preventing pregnancy?
A.
B.
C.
D.
E.
Inhibition of ovulation and proliferative changes in the uterus.

Inhibition of implantation of the fertilized ovum.
Blocks the ability of sperm to penetrate and fertilize the egg.
Increased proliferative changes in the uterus, leading to bleeding and spontaneous abortion.
Direct spermicidal effect.
4. Which of the following is NOT a noncontraceptive benefit of COCPs?

A.
B.
C.
D.
E.
Treatment
Treatment
Treatment
Treatment
Treatment
of
of
of
of
of
menorrhagia.
dysmenorrhea.
premenstrual syndrome physical symptoms.
excessive menstrual bleeding in von Willebrand disease.
seizures.
5. Which of the following is true about the use of hormonal contraceptive agents in patients with sickle cell disease?
A. The use of these agents is contraindicated in sickle cell disease.
B. Progestin-only contraceptive agents are preferred.
C. These agents substantially increase the rate of sickle cell pain crises.
D. High-dose estrogen-progestin formulations are recommended.
E. Depot medroxyprogesterone acetate should not be used in patients with sickle cell SS disease.
Gastrointestinal Bleeding
Gary A. Neidich and Sarah R. Cole
Pediatrics in Review 2014;35;243
DOI: 10.1542/pir.35-6-243
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Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
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Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2014 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601.
Article
gastroenterology
Gastrointestinal Bleeding
Gary A. Neidich, MD*
Educational Gaps
Sarah R. Cole, MD*
Author Disclosure
Drs Neidich and Cole
have disclosed no
1. Pediatricians should be familiar with diseases that may present with gastrointestinal
bleeding in patients at varying ages.
2. Pediatricians should be aware of newer technologies for the identification and therapy
of gastrointestinal bleeding sources.
3. Pediatricians should be familiar with polyps that have and do not have an increased
risk of malignant transformation.
4. Pediatricians should be familiar with medications used in the treatment of children
with gastrointestinal bleeding.
not contain
a discussion of an
Objectives
unapproved/
device.
1. Formulate a diagnostic and management plan for children with gastrointestinal

bleeding.
2. Describe newer techniques and their limitations for the identification of bleeding,
including small intestinal capsule endoscopy and small intestinal enteroscopy.
3. Differentiate common and less common causes of gastrointestinal bleeding in children
of varying ages.
4. Identify types of polyps that may present in childhood and which of these have
malignant potential.
Introduction
An 11-year-old boy is seen in the emergency department after fainting at home. He has
a 2-day history of headache and dizziness. Epigastric pain has been present during the past 2
days. His pulse is 150 beats per minute, and his blood pressure is 90/50 mm Hg. An intravenous bolus of normal saline is administered; his hemoglobin level is 8.1 g/dl (81 g/L).
He passes a melanotic stool. He is admitted to the pediatric intensive care unit and prescribed intravenous esomeprazole. He receives a transfusion of packed red blood cells,
which increases his hemoglobin level to 8.5 g/dl (85 g/L). Esophagogastroduodenoscopy
(EGD) reveals nodularity in the antrum of the stomach and a large ulceration with a visible,
actively bleeding vessel in the duodenum. The ulcer is coagulated with an argon plasma
coagulation (APC) laser. Biopsy specimens taken during the procedure reveal Helicobacter
pylori, and the patient is treated by continuing esomeprazole therapy and initiating amoxicillin
and clarithromycin therapy. No further bleeding occurs, and he is discharged 4 days later.
Gastrointestinal (GI) bleeding is a relatively common and
potentially serious problem in pediatrics. It is important for
practitioners taking care of children to be familiar with the
Abbreviations
causes, evaluation, and treatment of GI bleeding. In this article, the etiology of bleeding at different ages and the moAPC: argon plasma coagulation
dalities of evaluation and treatment are discussed. Newer
EGD: esophagogastroduodenoscopy
technologies for diagnosis are also addressed.
GI:
gastrointestinal
The spectrum of causes of GI bleeding in children ranges
HAEC: Hirschsprung-associated enterocolitis
from a small amount of bleeding as seen in an infant with an
NEC: necrotizing enterocolitis
anal ssure to severe bleeding that may be present in a child
*Department of Pediatrics, Sanford School of Medicine of the University of South Dakota, and Sanford Childrens Specialty Clinic,
Sioux Falls, SD.
gastroenterology
gastrointestinal bleeding
with varices from underlying chronic liver disease. It is

important for the clinician to quickly evaluate the patient
with GI bleeding and to differentiate the extent and severity of the bleeding.
GI bleeding in children presents in a number of different ways. Upper GI tract bleeding may present as hematemesis, melena, or hematochezia from rapid transit of
blood through the intestinal tract due to acute bleeding. The most common causes of bleeding when investigated by endoscopy in the upper GI tract include gastric
and duodenal ulcers, gastritis, esophagitis, varices, prolapse gastropathy, and Mallory-Weiss tears.
Lower GI tract bleeding may present as either melena
or hematochezia. The most common causes of lower GI
tract bleeding include ssures, allergic colitis, enteric infections, and juvenile polyps. Severe bleeding may be
seen with Meckel diverticulum, inammatory bowel disease, vascular anomalies, and intussusception.
The initial evaluation of a child after presenting with GI
bleeding should focus on stabilizing the patient and determining the severity of the bleed. Vital signs should be measured and reviewed. A focused history should be quickly
obtained when feasible because it may provide clues to
the cause of bleeding. Signs of a signicant bleeding episode may include symptoms of hypovolemia, such as
tachycardia and hypotension. Orthostatic changes may
also be present. Capillary rell may be prolonged. Children
with signs and symptoms of signicant bleeding and children with active blood loss should be hospitalized in a pediatric intensive care unit if possible. Stabilizing the patient
should generally take precedence over evaluation and therapeutic considerations. Large bore venous access should
be instituted and uid resuscitation initiated with Ringers
lactate or normal saline. Transfusion with packed red
blood cells may be indicated, and coagulation factors or
platelets may need to be administered in specic cases.
The presence of coffee ground emesis or melena generally implies a slower rate of bleeding when compared
with emesis or passage per rectum of bright red blood.
Guaiac of stool or emesis is helpful in dening whether
blood is present. Red emesis or stool may reect ingested
red-colored food or other material. Newer guaiac methods using buffered and stabilized hydrogen peroxide are
preferred because they have lower false-positive and falsenegative detection.
An initial focused physical examination may be helpful
in determining the cause of the bleeding. The presence of
hepatomegaly and splenomegaly may point to variceal
bleeding from liver disease. Scleral icterus, palmer erythema, and spider telangiectasias may be noted with
chronic liver disease. Perianal disease may point to the
presence of Crohn disease. Careful nasal examination may

determine epistaxis as the cause of bleeding. Skin lesions
may be seen with Peutz-Jeghers, Cronkhite-Canada (a rare
syndrome of multiple intestinal polyps), Osler-Weber-Rendu,
and other syndromes, and the presence of multiple skin
hemangiomas may be associated with visceral hemangiomas
as a cause of GI bleeding.
Laboratory studies should be performed to help elicit
the cause and dene the extent of bleeding. A complete
blood cell count documents the hemoglobin level and hematocrit to help determine the extent of bleeding and
whether platelet numbers are adequate. A low mean corpuscular volume may point to chronic loss of blood and
the presence of iron-deciency anemia. Abnormal coagulation study results may point to underlying liver disease or
malabsorption. Measurement of alanine aminotransferase,
aspartate aminotransferase, and bilirubin may point to the
presence of liver disease. Blood urea nitrogen and creatinine may help determine uid status and the presence
of renal insufciency. A low serum albumin level suggests
hypoproteinemia, which may herald signicant liver disease or protein-losing enteropathy, such as inammatory
bowel disease. With any sign of signicant bleeding, blood
should generally be obtained for type and cross-match.
Many clinicians favor placing a nasogastric tube for lavage in a patient with suspected GI bleeding. Presence of
blood from lavage indicates bleeding in the upper GI
tract proximal to the ligament of Treitz. Sources in the
small bowel, including the duodenum, may or may not
lead to blood being present in the stomach, which can
be noted when lavage is performed. Lavage should be
performed with warmed normal saline to reduce the risk
of hyponatremia and hypothermia. In the past, lavage was
often performed using cold or iced saline. This is no longer recommended because it may be associated with hypothermia. Clearing of blood from returned lavage uid
indicates that active bleeding may have ceased.
Hematochezia generally indicates a colonic source of
bleeding, although hematochezia may be seen with upper
GI tract bleeding sites, such as bleeding ulcers when brisk
bleeding causes rapid transit of blood through the intestine. Melena is more commonly seen from bleeding proximal to the ligament of Treitz and from more proximal
colonic sites due to slow loss of blood.
Abdominal radiography may be performed for evaluation of possible obstruction or bowel perforation. In the
past, barium studies were performed to evaluate for ulcer
disease and other causes of bleeding, but now endoscopy
is preferable because this method is more sensitive and
specic and can provide therapeutic intervention. On
occasion, ultrasonography may be useful to identify portal
gastroenterology
hypertension or an intussusception. A Meckel scan should

be considered in children with painless rectal bleeding.
EGD and colonoscopy are helpful in the evaluation of
the child with bleeding. Endoscopy is generally the favored
method for evaluating the cause of bleeding and may
provide a method of therapy as well. In general, these
procedures are performed once the patient is stabilized,
although this procedure may be necessary to control
bleeding in an unstable patient. Administration of an intravenous proton pump inhibitor is helpful before endoscopy for upper GI tract bleeding to aid in control of
bleeding and in reducing the chance of additional bleeding. Some practitioners administer a prokinetic agent,
such as metoclopramide or erythromycin, before the procedure in an attempt to empty material from the stomach
and better visualize the mucosal lining. EGD and colonoscopy are performed with the child asleep under either
conscious sedation or anesthesia. Endoscopy allows the
direct visualization of the mucosal lining and identication of any visible bleeding lesions. With active bleeding
or when therapeutic measures are being considered, general anesthesia with endotracheal intubation is generally
preferred to best protect the childs airway.
Complications of endoscopy have been reported in approximately 2% of cases. The most frequent complications
include hypoxia or bleeding during the procedure, although both are relatively uncommon. Perforation of
the intestinal tract may occur but is infrequent.
Control of bleeding from gastric or duodenal ulcers may
be accomplished with cautery or an APC laser. Figure 1
shows a large duodenal ulcer with a cherry red bleeding
spot, indicating a bleeding vessel. Coagulation with cautery
by heater probes or electrocautery is accomplished by application of electrical current through a probe to or around the
bleeding lesion. Epinephrine may be injected locally via the
scope before cautery to decrease the risk of rebleeding. The
bleeding lesion may then be compressed and coagulated.
Laser coagulation using ACP lasers is an alternative procedure. With this technique, argon gas is passed through
a probe introduced through the endoscope. The gas is electrically activated to an ionized state, causing tissue coagulation. Figure 2 shows the ulcer in Figure 1 after use
of the APC laser. Endoscopically placed clips are also useful
to control bleeding from ulcers that have a visibly bleeding
vessel. Preloaded clips are attached to the end of an endoscope and deployed over vessels believed to be at high risk
of bleeding. All these techniques have been reported to be
effective. Technique preference varies, depending on the
endoscopists experience and institution resources. On occasion, these techniques can cause bleeding, which may require surgical intervention to correct.
Variceal bleeding may be controlled with sclerotherapy or elastic band ligation. Sclerotherapy is performed
by injecting varices with a solution of varying sclerosants,
causing clotting of the varix. Complications include the
development of esophageal strictures. Endoscopic variceal ligation may also be accomplished by the placement
of small elastic bands with an endoscope. An apparatus
designed to place small bands to a varix is attached to
the end of an endoscope. Suction is applied through the
channel of the endoscope, drawing the varix into the apparatus and placing a band around the vessel. In general,
banding is preferred by most pediatric gastroenterologists
because it has a lower risk of complications.
Identied polyps may generally be removed endoscopically using cautery applied via an endoscopic snare.
Electrical current is passed through a snare deployed
through an endoscope. The snare is carefully closed as
the current is applied. The polyp may then be retrieved
and sent to the laboratory for histologic evaluation.
There are instances when EGD and colonoscopy may
not be able to determine the source of bleeding. In these
circumstances, a number of other modalities may be helpful. Nuclear medicine scans with technetium Tc 99m
labeled red blood cells may point to a source of bleeding
and are capable of detecting bleeding at a rate greater than
0.1 ml/min. However, these scans may not always accurately localize the source of bleeding because false-positive
and false-negative scan results occur. Blood may pool in
areas such as the ascending colon when the actual source
is higher in the intestinal tract. Angiography may be more
helpful in localizing bleeding sites when the rate of bleeding is as little as 1 to 2 ml/min.
Figure 1. Large duodenal ulcer. The arrow points to the cherry

red spot that is the site of the bleeding vessel.
gastroenterology
and polyp removal. Enteroscopy is more commonly

performed in adults yet has been performed in children.
Laparoscopy should be considered when other measures cannot identify a bleeding source. Examples include
patients who have a Meckel diverticulum, bowel duplication, or other bleeding conditions not identied on scans.
The following sections discuss the common causes of
GI bleeding, depending on age at presentation. Table 1
lists common and less common yet important causes of
GI bleeding for different age groups.
Newborns and Infants

Causes of Upper GI Tract Bleeding
Figure 2. Ulcer in Figure 1 after argon plasma coagulation.
Recently, capsule endoscopy has been used to identify

bleeding sites in the small intestine in areas that are inaccessible by upper and lower endoscopy. Endoscopy capsules
contain a camera that can take several pictures per second.
These pictures are transmitted wirelessly to a recording device attached to the patient. Pictures are viewed at a computer workstation after completion of the study to
determine whether bleeding lesions are present. A disadvantage to using capsule endoscopy is that the capsule cannot
precisely locate a bleeding lesion and cannot obtain biopsy
specimens or perform therapeutic interventions. The capsule
is either swallowed or placed endoscopically if the child is
unable to swallow it. A complication of capsule endoscopy
is retention of the capsule by a narrowed lumen due to intestinal strictures or other causes, a situation that may require
surgery to correct. To reduce the chance of a retained capsule often an imaging study of the small intestine to exclude
narrowing (such as small intestinal followthrough, MRI with
enterography or CT with oral contrast) is obtained. As an
alternative a dissolvable patency capsule may be swallowed
with an abdominal radiograhy obtained 24 hours later to
show that the capsule has transversed the small intestin.
The patency capsule will dissolve if it becomes stuck in
the small intestine showing that the capsule study would
likely result in capsule retension. The size of the capsule
limits the use of this technique in children younger than
2 years.
Identication of occult bleeding in select patients may
require small intestinal enteroscopy, a technique using specialized, longer endoscopes that have single or double balloons attached to the distal end of the scope. Enteroscopy
may help identify bleeding in the distal small bowel in
areas inaccessible by conventional endoscopes and may allow therapeutic intervention, such as control of bleeding
Swallowed maternal blood is a common cause of

hematemesis in a newborn. Blood may be ingested during birth and may also occur from blood swallowed during nursing. The Apt test is helpful in dening the source
of blood as being maternal. This test uses the fact that
fetal hemoglobin resists alkali denaturation, leading to a
positive test result in infants who have ingested maternal
blood. A positive test result generally eliminates the need
for further evaluation of causes of bleeding.
Hematemesis from esophagitis is another relatively
common cause of bleeding in this age group. Esophagitis
from underlying gastroesophageal reux may lead to ulcerations and subsequent bleeding. The amount of blood
seen from esophagitis is generally relatively small.
Ulcers, particularly in stressed, hospitalized infants, may
also present with hematemesis. Gastric stress ulcerations are
more common than duodenal ulcers in this age group, as
opposed to older children where duodenal causes are more
common. The amount of bleeding may be signicant.
Gastritis may develop for a number of reasons in infants.
It is seen with stress from severe illness, trauma, burns, and
increased intracranial pressure. Gastritis may also be seen
with viral infections, including cytomegalovirus.
Bleeding from hemorrhagic disease of the newborn may
be seen if vitamin K has not been administered. Bleeding
due to thrombocytopenia may occur and should be considered in this age group as well. Of note, as the infant ages,
coagulopathies may also be seen in children with underlying malabsorption due to cystic brosis or liver disease.
Intestinal duplications, although relatively rare, may
present with GI bleeding and should be in the differential
diagnosis at this age.
Causes of Lower GI Tract Bleeding

Cows milk protein sensitivity may cause bleeding early in
life. Milk protein may be associated with a proctocolitis.
Melena or hematochezia may also be signs of this
gastroenterology
always initiate evaluation for a volvulus or other serious cause of intestinal obstruction. Volvulus can also
present with hematemesis along
Often With More
Often With
with abdominal distention; such a preAge Group
Severe Bleeding
Milder Bleeding
sentation suggests bowel ischemia and
Infants
Coagulopathies, including
Gastritis
is a surgical emergency. Abdominal
vitamin K deficiency
Esophagitis
radiographs may suggest obstruction,
Necrotizing enterocolitis
Anal fissure
an indication for further additional
Hirschsprung enterocolitis
Protein intolerance
imaging studies or surgical consultaVolvulus
Enteric infection
Stress ulcer
Nodular lymphoid hyperplasia
tion. Volvulus treatment is prompt
surgical intervention.
Children
Varices
Esophagitis
Necrotizing enterocolitis (NEC)
Ulcer
Enteric infection
needs
to be considered in the perinaIntussusception
Juvenile polyp
tal period as a cause of bleeding.
Volvulus
Nodular lymphoid hyperplasia
Meckel diverticulum
Perianal streptococcal cellulitis
NEC may present as blood in the
Gastritis
stool. Abdominal radiographs may
Henoch-Schonlein purpura
reveal bowel wall pneumatosis.
Mallory-Weiss tear
NEC commonly occurs in premaHemolytic uremic syndrome
ture infants who have begun enteral
NSAID use
Adolescents
Varices
Hemorrhoids
feedings, usually after 2 to 3 weeks
Ulcer
Enteric infections
of life. Treatment is supportive with
Gastritis
Esophagitis
the use of antibiotics and cessation
Ulcerative colitis
Anal fissure
of enteral feeds. Surgical intervenCrohn disease
tion is often indicated to treat bowel
Meckel diverticulum
Henoch-Schonlein Purpura
ischemia or infarction due to NEC.
Mallory-Weiss tar
Hirschsprung disease classically
Meckel diverticulum
presents
with failure to have a bowel
NSAID use
movement in the rst 2 days of life,
NSAIDnonsteroidal anti-inammatory drug.
severe constipation, or symptoms
Adapted from Boyle J. Gastrointestinal bleeding in infants and children. Pediatr Rev. 2008;29(2):3952.
of abdominal obstruction. A few
infants, particularly if the diagnoproblem. Blood in the stool is generally the presenting
sis has been delayed, may present with an enterocolitis.
Hirschsprung-associated enterocolitis (HAEC) also occurs
symptom and is seen most commonly in the rst 3
after surgical repair of Hirschsprung disease and should
months of life. Children who are nursed may also develop
be considered in any child with a history of Hirschsprung
sensitivity to cows milk protein, a relatively common endisease who presents with diarrhea or abdominal distentity. b-lactoglobulin and casein are the most commonly
sion. Children with HAEC may appear toxic and letharassociated immunogens. Infants with sensitivity to cows
gic and are often febrile. Blood loss may be severe. HAEC
milk are likely to react to soy protein too. Laboratory
studies may reveal anemia and eosinophilia. Treatment
should be considered in an infant who appears toxic and
is with hypoallergenic formula. Both hydrolyzed and
has bloody diarrhea. Recommended treatment includes
bowel rest, intravenous uid administration, and antibiamino acidbased formulas may be used, depending on
otics that include coverage for anaerobic bacteria. Careful
the severity of the sensitivity. Sigmoidoscopy may show
rectal irrigation with normal saline is often performed as
friable mucosa and increased eosinophils on biopsy; howwell. HAEC is a signicant problem that in the past was
ever, sigmoidoscopy is generally not needed for diagnoassociated
with a high mortality rate and should be treated
sis. Allergy is the second most common cause of bleeding
aggressively.
in this age group, with only anal ssures being more common. Guaiac-positive stools may continue for up to sevAnal ssures are the most common cause of rectal bleederal weeks after elimination of the offending protein.
ing in this age group. They are most commonly seen in the
midline and usually present with streaking of blood on the
Volvulus is a serious yet less common cause of GI
outside of the stool. A careful examination of the rectal area
bleeding. The occurrence of bilious vomiting should
Common Causes of Gastrointestinal

Bleeding in Children
Table 1.
gastroenterology
is an important part of the physical examination of a child

with blood in the stool. Most commonly, anal ssures are
associated with the passage of hard stools. Less commonly,
ssures that cause bleeding may be seen with diarrhea. Pain
with passage of stool is often present. Conservative therapy
with stool softeners is almost always effective.
Intussusception is another of cause of GI bleeding in
children. The classic presence of currant jelly stools is
a relatively late manifestation of bowel ischemia. Intussusception usually presents with abdominal pain along
with lethargy. Abdominal radiographs may suggest intestinal obstruction, and the diagnosis may be conrmed
with ultrasonograms demonstrating a doughnut-appearing
sign. Most cases involve intussusception of the ileum into
the cecum. Reduction of the intussusception may be accomplished by air or hydrostatic reduction by barium.
A pediatric surgeon should be available during reduction
attempts in case bowel perforation occurs during the procedure. Surgical intervention is indicated if the intussusception cannot be reduced by air or hydrostatic enema.
Less common causes of bleeding in this age group include intestinal duplications and vascular lesions. Vascular
lesions may include arterial-venous malformations, venous malformations, and hemangiomas. Vascular lesions
are rare causes of bleeding at any age.
Children
Many of the causes of bleeding in infants, such as esophagitis, also occur in older children. Pill esophagitis may
develop from retention of ingested medications. Esophagitis may be severe after caustic ingestion.
Mallory-Weiss tears from forceful vomiting are more
common in this age group and may be diagnosed at endoscopy. Tears can occur in the lower esophagus and the gastroesophageal junction or in the cardia of the stomach just
below the gastroesophageal junction. Prolapse gastropathy,
in which forceful vomiting or retching propels the proximal
stomach into the distal esophagus and produces submucosal
bleeding and supercial ulceration, also presents with hematemesis. Blood loss may be signicant after forceful emesis.
Mallory-Weiss tears may be treated during endoscopy.
Gastritis in children may be caused by stress and viral
infections as in infants. Gastritis at this age may also occur
after ingestion of nonsteroidal anti-inammatory drugs.
In addition, caustic ingestion, bile reux, and vasculitis
may have manifestations of gastritis.
H pylori is now frequently diagnosed in childhood. H
pylori may cause bleeding from gastritis and may also be
associated with bleeding from gastric or duodenal ulcers.
At endoscopy, the gastric antrum is noted to be diffusely

nodular as seen in Figure 3. Published recommendations
from the European and North American Societies for Pediatric Gastroenterology Hepatology and Nutrition recommend initial diagnosis from EGD biopsies based on
positive histologic and urease test results or positive culture
results. Eradication of the organism may be based on stool
antigen testing or carbon 13labeled urea breath testing.
The stool antigen test is up to 90% sensitive and specic.
The urea breath test is performed by orally administering
carbon 13labeled urea. If present, H pylori converts urea
into carbon dioxide and ammonia. The resulting labeled
carbon dioxide is absorbed in the gut, exhaled, and measured. This test is up to 95% sensitive and 95% specic.
Neither stool antigen testing nor carbon 13labeled urea
breath testing is recommended if the patient has been taking antibiotics, histamine2 (H2) antagonists, proton pump
inhibitors, or bismuth preparations in the preceding 2
weeks. Serologic assays are available but less useful in children because they are not as accurate as the above tests and
are not recommended for diagnosis.
Ulcers have become more commonly diagnosed in
children, and both duodenal and gastric ulcers may
present with hematemesis, melena, and hematochezia
from rapid transit through the intestine. They are often
diagnosed at endoscopy. The incidence of ulcers is higher
in children with burns, stress due to severe or critical illness, and increased intracranial pressure.
Varices are another source of GI bleeding. Varices can
develop from underlying cirrhotic liver or extrahepatic
portal vein thrombosis. Portal vein thrombosis can be
a complication of umbilical venous catheter placement
Figure 3. Antral area of stomach in a patient with

Helicobacter pylori. Note the nodularity that is typically
present.
gastroenterology
during the newborn period. Portal hypertension causes

dilatation of esophageal vessels that can lead to severe
bleeding. Chronic liver disease can also lead to coagulopathy due to decreased production of blood clotting factors
and to thrombocytopenia seen in hypersplenism due to
portal hypertension. Both coagulopathy and thrombocytopenia increase the risk of GI bleeding.
Causes of Lower GI Tract Bleeding

Enteric infections are a frequent cause of colitis and
bleeding. Pathogens, including Salmonella, Shigella,
Campylobacter, Escherichia coli O157:H7, and other organisms, can cause diarrhea and colicky abdominal pain.
When bloody diarrhea with cramping is present, appropriate stool cultures for these organisms should be obtained. Shigalike toxin may also be obtained to look
for non-O157:H7 strains of E coli and other organisms.
Other bacteria, such as Aeromonas and Plesiomonas, may
cause colitis on occasion.
Clostridium difcile colitis is now commonly seen without preceding use of antibiotics and may also present with
melena or hematochezia. Polymerase chain reaction testing
of the stool for C difcile toxin is the preferred method for
identifying presence of this organism. However, C difcile
can be part of normal bowel ora up to 1 year of age and
rarely causes symptoms in this age group. Figure 4 shows
the appearance of the colonic mucosa in a patient with
pseudomembranous colitis due to C difcile infection.
Meckel diverticulum commonly presents with painless
rectal bleeding, which is often severe. Ulceration of the
Figure 4. Colonic mucosa showing yellowish plaques typically

seen with Clostridium difficile.
ileal mucosa is caused by acid secretion from the gastric

mucosalined epithelium of the Meckel diverticulum.
Meckel diverticula are often 2 ft from the ileal cecal valve
and 2 in long, are commonly present in children younger
than 2 years, and occur in 2% of the population. Meckel
diverticulum may also cause volvulus around an associated
remnant of the vitelline duct or present as diverticulitis in a
manner similar to appendicitis. Diagnosis is frequently based
on a Meckel scan using technetium Tc 99m pertechnetate,
which is taken up by gastric mucosa. This scan will detect
diverticula that contain gastric mucosa (Figure 5). Pretreatment with H2-receptor antagonists or proton pump
inhibitors can increase the sensitivity of the Meckel scan.
Treatment is by surgical removal.
Intussusception may present in this age group as well,
most commonly caused by a lead point of hypertrophied lymphoid tissue due to a recent viral infection. At older than 5
years, the presence of a pathologic lead point, such as a polyp
or Burkett lymphoma, can also lead to an intussusception.
Vasculitis may also cause GI bleeding. Henoch-Schnlein
purpura can cause signicant bleeding and is also associated with an increased risk of intussusception. Most typically, a purpuric rash, rst apparent on the lower back
and buttocks, precedes GI bleeding. Henoch-Schnlein
purpura often develops after a viral infection. Signicant
abdominal pain, frequently accompanied with bloody
stools, can occur in Henoch-Schnlein purpura. Symptoms frequently last for weeks.
Figure 5. Technetium Tc 99m pertechnetate scan in a patient with

Meckel diverticulum. The arrow points to the Meckel diverticulum.
gastroenterology
Hemolytic uremic syndrome is also associated with GI

bleeding caused by colitis from Shiga toxinproducing E
coli, most commonly from E coli O157:H7. Systemic complications, including renal failure and seizures, may also be
associated with this disease. Bloody diarrhea is followed by
the development of hemolytic anemia and thrombocytopenia generally 3 to 10 days later if hemolytic uremic syndrome colitis develops. Children who have been identied
as having enterohemorrhagic E coli should be followed up
closely for the development of hemolytic uremic syndrome.
Lymphoid hyperplasia is another cause of lower GI
tract bleeding in children; colonoscopy reveals small nodules of lymphoid tissue. Lymphoid hyperplasia may occur
after viral infections and also from allergies. Lymphoid hyperplasia is more common in children with IgA deciency
and also those with hypogammaglobulinemia. Bleeding
can present as small amounts of red blood in the stool
or as melena. Lymphoid hyperplasia is a common nding
during colonoscopy in children; however, most lymphoid
hyperplasia is not associated with bleeding.
Children may develop polyps that can bleed. Juvenile
polyps are the most common form in children, typically
seen during the childhood years, most commonly between
1 and 7 years of age. Juvenile polyps are one of the most
common causes of bleeding in this age group. Children
with juvenile polyps usually have painless rectal bleeding;
occasionally a polyp prolapses through the rectum. Less often, juvenile polyps are associated with abdominal pain. Juvenile polyps are usually 1 to 3 cm in diameter and
generally attached to the mucosa via a thin stalk. Autoamputation of the stalk can occur with consequent rectal
bleeding, which may be severe. Bleeding occurs from erosion of the mucosal lining of the polyp. Figure 6 shows the
appearance of a juvenile polyp visualized during colonoscopy. Juvenile polyps are benign hamartomas and do
not undergo malignant transformation. Pathologic analysis
reveals dilated mucin-lled cysts and an inammatory inltrate in the lamina propria. Colonoscopy is indicated to remove the polyp and to evaluate for additional ones. More
than three-fourths of juvenile polyps are found in the rectum or distal colon. Most polyps are solitary, but multiple
polyps may occur in up to 40% of patients. Recurrent polyps may occur in 5% of children with a juvenile polyp, but
routine follow-up colonoscopy is not recommended unless
symptoms redevelop. However, if 3 or more polyps are
present, the child may have juvenile polyposis and should
have colonoscopies performed every few years.
Patients with juvenile polyposis syndrome most commonly have 10 or more hamartomatous polyps noted at
colonoscopy. In approximately one-third of patients, juvenile polyposis is familial (familial polyposis syndrome).
Figure 6. Juvenile polyp.
Patients with juvenile polyposis are at increased risk of colon cancer, which may occur in up to 20% of patients with
this syndrome. A number of genes have been identied in
this syndrome, including SMAD4, BMPR1A, and ENG,
which are found in approximately 50% of patients. Hamartomas may also develop in the small intestine in juvenile
polyposis. Although there is no consensus regarding frequency of screening, colonoscopy has been recommended
every 1 to 2 years beginning in adolescence. Evaluation for
small intestinal polyps also needs to be considered using
imaging techniques, including magnetic resonance imaging and/or small intestinal capsule endoscopy.
Hamartomas may also occur from PTEN mutations.
Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome,
and Proteus syndrome are rare genetic syndromes with defects in the tumor suppressor gene PTEN. Peutz-Jeghers
syndrome is characterized by hamartomatous polyps
throughout the GI tract along with pigmentation in the
perioral area. Children with this syndrome may present with
intestinal obstruction due to polyps in the small intestine.
Patients with a family history of familial adenomatous
polyposis may be seen. Familial adenomatous polyposis is
a genetic disorder in which hundreds to thousands of
adenomatous polyps develop and in which there is a high
risk of developing colon cancer over time. Polyps begin
to appear in childhood and continue to develop throughout life. Extra intestinal features may include osteomas of
the mandible and maxilla, desmoid tumors, and pigmented ocular lesions. Gastric fundic polyps are often
present. In addition to colon cancer, patients are at increased risk for ampullary, thyroid, central nervous system,
gastroenterology
and gastric cancers. Children are also at risk for development

of hepatoblastoma. Genetic testing may be performed if
a proband has an identied gene after appropriate discussion with the child and family. Mutations in the APC gene
are responsible for familial adenomatous polyposis and
may be identied in 70% to 90% of patients. New mutations occur in up to 25% of cases. Screening colonoscopy
should be performed yearly beginning at ages 10 to 14
years. Surgical consultation for timing and discussion of
colectomy and options should also be obtained.
Lower GI tract bleeding may be seen with C difcile
colitis. Pseudomembranes may develop in association with
toxins produced by this organism. Although originally associated with antibiotic use, C difcile colitis occurs relatively often without the preceding use of antibiotics.
Rectal prolapse may cause blood in the stool. At times,
sigmoidoscopy reveals a solitary rectal ulcer due to ischemia from repetitive episodes of prolapse. Rectal prolapse
is often accompanied with a history of tenesmus and mucous. Hemorrhoids may accompany ssures but are a less
common cause of bleeding in childhood.
Group A b-hemolytic streptococcus can cause a proctitis
that can lead to blood in the stool. This condition can present
with moderate to severe erythema of the rectum and perianal
area. Treatment with appropriate antibiotics is indicated.
Adolescents and Older Children

The most common causes of bleeding in this age group
include esophagitis, gastritis, and ulcers, which have been
discussed in the sections above. Variceal bleeding is another, less common, cause.
Esophagitis and gastritis due to nonsteroidal antiinammatory drug use may cause GI bleeding. Alcohol
may also cause gastritis and should be considered as a cause
of hematemesis in adolescents. The concentration of ingested
ethanol needs to be 10% or greater for gastritis to develop.
Alcohol use is also associated with prolapse gastropathy.
Ulcers and gastritis from H pylori are more common in
this age group. In addition, enteric infections, mentioned
in the above section, are a common cause of hematochezia
in this age group. Patients usually will present with cramping
abdominal pain, tenesmus, and blood and mucus in the
stool. Fever may be present with some of the bacterial
infections, particularly from Salmonella. On occasion,
cytomegalovirus and other viral infections may also cause
signicant bleeding.
Crohn disease and ulcerative colitis may present with
melena or hematochezia. When bleeding is present, it
may range from stools that are guaiac positive to massive
hemorrhage due to extensive colitis or ulcerations that

have eroded blood vessels. Rapid bleeding is more common in ulcerative colitis and Crohn colitis than with small
intestinal Crohn disease. However, signicant bleeding
can occur from affected vessels in the small intestine with
Crohn disease. Chronic blood loss is common with both
diseases. Abdominal pain is often but not always present.
Chronic blood loss may be suggested by the presence of
a low mean corpuscular volume. Growth failure is more
common in Crohn disease. Endoscopic studies are useful
for diagnosis. Figure 7 shows pictures from the small intestine obtained during capsule endoscopy in a patient with
chronic blood loss and anemia from Crohn disease. Differentiation between Crohn disease and ulcerative colitis
helps to guide therapy, hence the need to obtain biopsy
specimens during colonoscopy. Both diseases may have associated gastritis, which may also contribute to bleeding.
There are many other causes of GI bleeding in children.
Common causes and some of the less common causes of GI
bleeding in children at varying ages are listed in Table 1.
Pharmacologic Therapy
Upper GI tract bleeding related to acid secretion may be
controlled by medications that suppress acid production.
Intravenous H2-receptor antagonists and proton pump
inhibitors may both be used. With acute bleeding of signicant extent, proton pump agents given intravenously
are generally used because they are more effective. A bolus
Figure 7. Pictures from capsule endoscopy in a patient with

Crohn disease.
gastroenterology
dose followed by continuous infusion of esomeprazole or

pantoprazole may be considered. After signicant bleeding,
the chance for subsequent bleeding is greatest in the rst 3
days, and use of intravenous proton pump inhibitors is usually continued during this time. After control of the bleeding,
the patient may be switched to an oral agent for longer-term
administration. Table 2 lists the doses of these agents.
Sucralfate may be useful for esophagitis and peptic disease. This aluminum salt is classied as a protectant and
binds to the mucosal lining of eroded areas. Sucralfate
Table 2.
forms a complex that protects the erosion from acid and

helps the lesion heal. It also increases prostaglandin release,
also helping with protection and healing. Sucralfate is available in both liquid and pill form. Doses are listed in Table 2.
Vasoactive medications, including vasopressin and
octreotide, may be useful in controlling upper GI tract
bleeding. Vasopressin has been used for variceal bleeding
because it causes splanchnic vasoconstriction. Potential
complications include cardiac toxic effects, such as infarction and arrhythmias, mesenteric ischemia, renal failure,
Medications Used for Gastrointestinal Bleeding
Agent
Drug Category
Dosagea
Intravenous gastric acid inhibition

(active bleeding) agents
Ranitidine
Histamine2 antagonist
Pantoprazole
Proton pump inhibitor
Esomeprazole
Proton pump inhibitor
Continuous: 1 mg/kg followed by infusion of

24 mg/kg/d
Bolus: 35 mg/kg/d divided every 8 hours
Children <40 kg: 0.51 mg/kg/d; >40 kg: 2040 mg/d
Continuous dosing: bolus of 80 mg followed by 8 mg/h
has been used in adults. This has been adapted in
some centers to a bolus of 1 mg/kg followed by an
infusion of 0.1 mg/kg/h (maximum to adult dose)/
Infants: 0.5 mg/kg/d
Children 117 years old: <55 kg: 10 mg; >55 kg: 20 mg
Continuous dosing: bolus of 80 mg followed by 8 mg/h
has been used in adults. This has been adapted in
some centers to a bolus of 1 mg/kg followed by an
infusion of 0.1 mg/kg/h (maximum to adult dose).
Intravenous vasoactive agents

Octreotide
Somatostatin analog
Vasopressin
Antidiuretic hormone
Evidence-based standards are

not well established for children.a
Oral inhibitors of gastric
acid secretion
Ranitidine
Histamine2 antagonists
Famotidine
Omeprazole
Lansoprazole
Esomeprazole
Proton pump inhibitors
Oral adhesive protectant
Local adhesive paste
1-mg/kg bolus (maximum, 50 mg) followed by 1 mg/

kg/h may increase every 8 hours to 4 mg/kg
(maximum, 250-mg dose every 8 hours)
Taper by 50% for 12 days when bleeding controlled
by 50% every 12 hours
0.0020.005 U/kg/min for 12 hours then taper for
12 days (maximum, 0.2 U/min)
1
23 mg/kg per dose 2-3 times a day (maximum,

300 mg)
0.5 mg/kg per dose twice daily (maximum, 40 mg
daily)
11.5 mg/kg/d 12 times daily (maximum, 40 mg/d)
11.5 mg/kg/d 12 times daily (maximum, 60 mg/d)
Infants: 3.55 kg: 2.5 mg/d; 57.5 kg: 5 mg/d
Children 111 years old: <20 kg: 10 mg/d; >20
kg 20 mg/d
Children >12 years old: 2040 mg/d
4080 mg/kg/d in 4 divided doses (maximum, 1 g per
dose)
a
Doses for these medications are often not well studied, and higher doses are sometimes used in individual cases by pediatric gastroenterologists.
Adapted from Boyle J. Gastrointestinal bleeding in infants and children. Pediatr Rev. 2008;29(2):3952.
gastroenterology
and cerebrovascular accidents. Octreotide has a vasodilatory effect on mesenteric vascular smooth muscle and reduces portal blood ow. Experience with this agent is
limited in children, but it may be helpful in selected patients. Octreotide is helpful in controlling variceal bleeding. Octreotide may also be helpful in controlling other
causes of upper GI tract bleeding, particularly in patients
who are not able to undergo endoscopy or in whom endoscopy has been unable to determine or successfully treat
the cause of bleeding. Adverse effects include bradycardia
and problems with hyperglycemia. Overall, it has fewer
complications compared with vasopressin. Octreotide is
given rst as a bolus dose followed by continuous infusion.
The dose is tapered after bleeding has been controlled.
Medication doses are listed in Table 2.
Overall, medications in combination with endoscopy are
at times effective in controlling GI bleeding. However,
sometime such measures are ineffective. Arteriographic embolization has been reported to control GI bleeding due to
vascular anomalies. Surgery may be indicated when bleeding cannot be effectively controlled by medications or endoscopy. With portal hypertension, portosystemic shunts
may be useful.
Conclusions
Practitioners caring for children should be familiar with
the diagnosis and treatment of gastrointestinal bleeding.
The initial goals are to establish the extent and severity of
the bleeding and, when indicated, to hospitalize and stabilize the patient as quickly as possible. Once stabilized,
diagnostic testing with a variety of modalities is indicated
to establish the cause of bleeding. Endoscopic studies are
often used to help determine the site of bleeding and for
therapeutic intervention in specic cases. Newer diagnostic modalities, such as video capsule endoscopy and small
intestinal endoscopy, may be useful when bleeding sites
are unable to be detected. Pediatricians should be familiar
with the common and some of the less common causes of
GI bleeding in children and should also be familiar with
medications used for these conditions.
Summary
On the basis of strong research evidence, children with
severe upper gastrointestinal tract bleeding should be
treated with intravenous proton pump inhibitors.
On the basis of some research evidence and consensus,
children with severe gastrointestinal bleeding should
be evaluated by endoscopy.
On the basis of some research evidence and consensus,

children in whom endoscopy has not been able to
confirm a bleeding source should be considered for
capsule endoscopy.
Suggested Reading
Alkhouri N, Franciosi JP, Mamula P. Familial adenomatous
polyposis in children and adolescents. J Pediatr Gastroenterol
Nutr. 2010;51(6):727732
Autret-Leca E, Bensouda-Grimaldi L, Maurage C, Jonville-Bera
AP. Upper gastrointestinal complications associated with
NSAIDs in children. Therapie. 2007;62(2):173176
Boyle JT. Gastrointestinal bleeding in infants and children. Pediatr
Rev. 2008;29(2):3952
Calvet X, Vergara M, Brullet E, Gisbert JP, Campo R. Addition of
a second endoscopic treatment epinephrine injection improves
outcome in high-risk bleeding ulcers. Gastroenterology. 2004;
126(2):441450
Chawla S, Seth D, Mahajan P, Kamat D. Upper gastrointestinal
bleeding in children. Clin Pediatr. 2007;46(1):1621
Fox V. Gastrointestinal bleeding in infancy and childhood. Gastroenterol Clin North Am. 2000;29(1):3766
Friedlander J, Mamula P. Gastrointestinal hemorrhage. In: Wylie R,
Hyams J, Kay M. Pediatric Gastrointestinal and Liver Disease.
Philadelphia, PA: Elsevier; 2011:146153
Hwang JH, Fisher DA, Ben-Menachem T, et al; American Society
for Gastrointestinal Endoscopy. The role of endoscopy in the
management of acute non-variceal upper GI bleeding. Gastrointest Endosc. 2012;75(6):11321138
Koletzko S, Jones N, Goodman K et al. Evidence-based guidelines from
ESPGHAN and NASPGHAN for Helicobacter pylori infection in
children. J Pediatr Gastroenterol Nutr. 2011;53(2):230243
Lau JY, Sung JJ, Lee KC et al. Effect of intravenous omeprazole on
recurrent bleeding after endoscopic treatment of bleeding
peptic ulcers. N Engl J Med. 2000;343(5):310316
Manickam P, Kanaan Z, Cappell M. Transfusion for acute upper
gastrointestinal bleeding. N Engl J Med. 2013;368(14):13611363
Ohmiya N, Yano T, Yamamoto H, et al. Diagnosis and treatment of
obscure GI bleeding at double balloon endoscopy. Gastrointest
Endosc. 2007;66(3 suppl):S72S77
Ramsook C, Edom E. Diagnostic approach to lower gastrointestinal bleeding in children. 2013. www.uptodate.com.
Sidhu R, Sanders DS, Kapur K, Hurlstone DP, et al. Capsule
endoscopy changes patient management in routine clinical
practice. Dig Dis Sci. 2007;52(5):13821386
Solana MJ, Lpez-Herce J, Snchez A, et al. 0.5 mg/kg versus 1
mg/kg of intravenous omeprazole for the prophylaxis of
gastrointestinal bleeding in critically ill children: a randomized
study. J Pediatr. 2013;162(4):776782, e1
Sung JJ, Tsoi KK, Lai LH, Wu JC, et al. Endoscopic clipping versus
injection and thermo-coagulation in the treatment of nonvariceal upper gastrointestinal bleeding: a meta-analysis. Gut.
2007;56(10):13641372
Thakkar K, El-Serag HB, Mattek N, Gilger MA. Complications of
pediatric EGD: a 4-year experience in PEDS-CORI. Gastrointest Endosc. 2007;65(2):213221
Villa X. Approach to upper gastrointestinal bleeding in children.
2013. www.uptodate.com.
gastroenterology
PIR Quiz Requirements

1. A female patient with chronic abdominal pain and poor growth presents with melena and anemia. After
endoscopy and colonoscopy fail to reveal a source of bleeding, a capsule endoscopy is attempted. Which of the
following is a current limitation of the capsule endoscopy procedure?
A.
B.
C.
D.
E.
It
It
It
It
It
cannot
cannot
cannot
cannot
cannot
be
be
be
be
be
used
used
used
used
used
if
if
if
if
if
bleeding is occurring at a rate faster than 0.1 mL/min.

child is younger than 2 years.
child is unable to swallow.
esophagogastroduodenoscopy results are equivocal.
previous capsule endoscopy has been attempted.
2. A 4-year-old boy presents with a 1-week history of intermittent painless rectal bleeding. The boy has no other
symptoms, and the findings of physical examination, including absence of anal fissures and skin or oral lesions,
are within normal limits. On colonoscopy, 2 polyps are visualized and removed from the distal colon, which on
histologic analysis reveals dilated mucin-filled cysts and inflammatory infiltrates in the lamina propria. A total
of 5% of children with these findings will develop which of the following conditions?
A.
B.
C.
D.
E.
Colon cancer.
Dermoid tumors.
Intestinal obstruction.
Recurrent polyps.
Small intestinal hamartomas.
3. A 2-month-old breastfed infant presents with a history of blood in the diaper and occasional vomiting. His
growth is within normal limits but lower than expected. He has occasional vomiting, intermittent diarrhea, and
occasional hard stools. Behavior and development are otherwise normal. He is slightly anemic and his
eosinophil count is slightly elevated. Which of the following is the most likely explanation for these findings?
A.
B.
C.
D.
E.
Anal fissure.
Esophagitis.
Milk protein allergy.
Meckel diverticulum.
Vascular lesion.
4. A 14-year-old girl presents with hypotension, tachycardia, and melanotic stools. Which of the following
should be intially performed?
A. Begin octeotride IV.
B. Begin vasopressin IV.
C. Begin esoprazole orally.
D. Establish IV access and begin fluid resuscitation.
E. Begin oral Sucralate.
5. A 5-year-old boy presents with blood-streaked stools. On physical examination there is significant erythema
surrounding the rectum in the perianal area. He is otherwise well except for pain and itching around the anus
and some constipation. Which of the following is the most likely diagnosis?
A.
B.
C.
D.
E.
Anal fissure.
Hemorrhoid.
Perianal streptococcus.
Rectal hamartoma.
Rectal prolapse.
that our patient had FPIES because his diarrhea resolved

after discontinuing use of cows milkbased formula,
and we excluded other causes of his diarrhea, such as
infection.
and the patient is now gaining weight and growing

appropriately.
Lessons for the Clinician

Management
First-line treatment for severe methemoglobinemia involves
giving intravenous methylene blue (2 mg/kg) in patients
who are not decient in glucose-6-phosphate dehydrogenase. Glucose-6-phosphate dehydrogenase helps convert
nicotinamide adenine dinucleotide phosphate to its reduced
form, hydrogenated nicotinamide adenine dinucleotide
phosphate, which in turns reduces the methemoglobin
level. After administration of methylene blue, our patients
methemoglobin level decreased from 33% to 2.7%, with an
eventual rebound to a maximum of 4.5%.
Infants with FPIES should be given an amino acid
formula as a denitive treatment. Our patient was changed
to an elemental formula after which the diarrhea resolved,
It may be prudent to check methemoglobin levels in

infants younger than 2 months with severe diarrhea and
clinical signs of shock.
FPIES is a nonIgE-mediated hypersensitivity condition
that causes inammation of the gastrointestinal tract,
leading to vomiting and diarrhea, and should be considered in all formula-fed infants with intolerance to
feedings.
(Corrie Fletcher, DO, Nga Le, MD, Advocate Childrens Hospital,
Oak Lawn, IL)
To view Suggested Reading lists for these cases, visit https://
pedsinreview.aappublications.org and click on the Index of
Suspicion link.
Parent Resources from the AAP at HealthyChildren.org

Case 1:
English: http://www.healthychildren.org/English/health-issues/conditions/fever/Pages/When-to-Call-the-Pediatrician.aspx
Spanish: http://www.healthychildren.org/spanish/health-issues/conditions/fever/paginas/when-to-call-the-pediatrician.aspx
Case 2:
English: http://www.healthychildren.org/English/health-issues/conditions/chronic/Pages/Anemia-and-Your-Child.aspx
Spanish: http://www.healthychildren.org/spanish/health-issues/conditions/chronic/paginas/anemia-and-your-child.aspx
English only: http://www.healthychildren.org/English/health-issues/conditions/chronic/Pages/Iron-Deciency-and-Anemia.aspx
Case 3:
English only: http://www.healthychildren.org/English/safety-prevention/all-around/Pages/Where-We-Stand-Testing-of-Well-Water.aspx
CME Quiz Correction

In June Pediatrics in Review, there was an error in Question 4 of the CME quiz for Gastrointestinal Bleeding (Neidich GA
and Cole SR. Pediatrics in Review. 2014;35(6):243, DOI: 10.1542/pir.35-6-243). The correct answer to Question 4 should be:
D. Establish IV access and begin uid resuscitation. The online version of the journal and the online CME quiz have been
corrected. The journal regrets the error.
ANSWER KEY FOR JULY 2014 PEDIATRICS IN REVIEW:

Pediatric Asthma in a Nutshell: 1. E; 2. E; 3. B; 4. C; 5. E.
Preventing and Managing HIV Infection in Infants, Children, and
Adolescents in the United States: 1. A; 2. D; 3. D; 4. C; 5. E.
Pneumococcal Infections: 1. E; 2. B; 3. D; 4. A; 5. B.
Vol. 35 No. 7
JULY 2014
317
index of suspicion
Case 1: Episodic Lower Abdominal Pain in an 11-YearOld Girl

Case 2: Epigastric Pain and Weight Loss in a 9-YearOld Boy
Case 3: Swelling in Inguinal Region in a 4-Year-Old
Girl
Case 1
The reader is encouraged to write
possible diagnoses for each case before
turning to the discussion.
We invite readers to contribute case

presentations and discussions. Please
use the Submit and Track My
Manuscript link on the Pediatrics in
Review homepage: http://
pedsinreview.aappublications.org.
Author Disclosure
Drs Didion, Nerland, Trotter, Scerbo,
Rosenberg, and Vasireddy have
disclosed no financial relationships
relevant to this article. This
commentary does not contain
a discussion of an unapproved/
investigative use of a commercial
product/device.
Presentation
An 11-year-old girl presents to the

emergency department (ED) with
a 1-day history of severe abdominal
pain. The patient characterizes the
pain as episodic, cramping, and localized to the suprapubic area and right
lower quadrant. The episodes occur
approximately every 2 to 4 weeks,
during which she experiences pain
several times a day for 3 to 5 days.
The pain self-resolves, and she is pain
free between episodes. There are no
alleviating or exacerbating factors.
She reports associated nausea but no
vomiting, diarrhea, constipation, or
fever. The patient denies menarche.
On presentation, she is tachycardic with a heart rate of 124 beats
per minute. Other vital signs are normal. Her height is 1.67 m (>95th
percentile) and weight is 59.3 kg
(95th percentile). She appears to be
in signicant pain; she is lying on
her side in a fetal position. There is
diffuse abdominal tenderness, which
is most notable over the suprapubic
region, with no rebound or guarding.
The abdominal examination ndings
are otherwise normal, with normal
bowel sounds and no distention,
masses, or organomegaly. Genitourinary examination ndings are consistent with a sexual maturity rating of
2. The hymenal ring is open and intact without notches or tears. The
breast sexual maturity rating is 3.
Results of initial laboratory evaluation are as follows: white blood cells,
1500/mL (1.5 109/L); hemoglobin, 12 g/dL (120 g/L); and platelets,
256 103/mL (256 109/L). The
urinalysis result is positive for trace

ketones with 1 white blood cell, and
no bacteria are seen on microscopic examination. A urine pregnancy test result
is negative. Abdominal ultrasonography
reveals a uterine mass. Additional evaluation and imaging studies reveal the
diagnosis.
Case 2
Presentation
A 9-year-old boy presents to the ED

with a 12-hour history of epigastric
pain and vomiting. The pain is intermittent, does not radiate, and has no
exacerbating factors. The emesis is
nonbloody and nonbilious. He had
similar symptoms 3 weeks ago. There
is no history of recent travel or sick
contacts. His medical history is otherwise unremarkable. On further questioning, the parents report a poor
appetite with a possible 8-lb weight
loss during the preceding 3 months.
The physical examination reveals
a comfortable and well-appearing child.
His vital signs are normal, and his
body mass index is in the 50th percentile. The abdominal examination ndings are signicant for a
1- to 2-cm, poorly dened epigastric mass with hepatomegaly spanning 2 cm below the right costal
margin. There is neither splenomegaly nor icterus. The remainder
of the physical examination ndings are unremarkable.
Results of laboratory studies include the following: normal complete
blood cell count; normal serum levels
of electrolytes, bilirubin, albumin, amylase, lipase, and lactate dehydrogenase;
index of suspicion
alanine aminotransferase, 268 U/L

(reference range, 041 U/L); aspartate aminotransferase, 330 U/L (reference range, 038 U/L); and alkaline
phosphatase, 262 U/L (reference
range, 39117 U/L). The results
of laboratory tests for hepatitis B,
hepatitis A, hepatitis C, and, hepatitis E infections are negative. The results of the monospot test, as well as
serologic tests for cytomegalovirus
and Epstein-Barr virus, are negative.
Abdominal imaging leads to the
diagnosis.
Case 3
Presentation
A 4-year-old girl presents with a 3day history of left inguinal swelling

that initially was the size of an olive
but is progressively increasing in size.
She has fever, pain, and redness of
skin at the site. She has no weight
loss, night sweats, bone pain, sick
contacts, recent travel, trauma, or animal contacts. Her prenatal, natal,
and postnatal history is unremarkable. Her immunizations are up to
date.
On physical examination she is in
moderate distress attributed to pain
and is afebrile. Her heart rate is 95
beats per minute, blood pressure is
101/65 mm Hg, and respiratory rate
is 20 breaths per minute. Her weight
is 22.7 kg and height is 115 cm, both
greater than the 97th percentile, and
her body mass index is 17.16 (75th
percentile). She has left-sided inguinal swelling that measures 4 2
cm, extending into the left labia.
The swelling is rm, tender, and nonuctuant on palpation. It does not
enhance on coughing and is nonreducible. The overlying skin is warm
and erythematous, with no evidence
of trauma or discharge. The rest of
the physical examination ndings
are unremarkable.
Results of laboratory evaluation
are as follows: white blood cells,
16,800/mL (16.8 109/mL), with

67% neutrophils, 30% lymphocytes,
and 3% monocytes; hemoglobin,
13.1 g/dL (131 g/L); hematocrit,
39.4% (0.39); and platelets, 298
103/mL (298 109/L). Ultrasonography reveals a conuent nodal
mass in the left inguinal region suggestive of an abscess. Incision and
drainage of the abscess are performed with lymph node excision,
and she is discharged home with
a prescription for oral clindamycin.
Twelve days after discharge, a pathology report of the resected necrotic inguinal lymph nodes reveals
the diagnosis.
Case 1
Discussion
The patient was treated with ketorolac

and morphine as needed for pain
control. Pelvic magnetic resonance
imaging (MRI) performed to further
evaluate the uterine mass revealed
a vaginal obstruction with hematocolpos with mild distention of the
uterus (Figure 1). The cervix and
ovaries were normal. Pelvic examination with the patient under general
anesthesia revealed a transverse vaginal septum. She underwent surgical
resection of the septum and evacuation of retained blood. Intraoperative vaginal ultrasonography conrmed
Figure 1. Pelvic magnetic resonance imaging reveals a distended vagina with layering
of blood and a mildly distended uterus and bladder.
index of suspicion
complete evacuation of hematocolpos.

Her pain resolved postoperatively.
Differential Diagnosis
The differential diagnosis of abdominal pain in a girl of this age is vast but
can be narrowed by classifying the
pain as acute, chronic, or recurrent.
The major organ systems to consider
are the gastrointestinal, urologic, and
gynecologic. This girl was experiencing recurrent abdominal pain, as such
the differential diagnosis included
constipation, peptic ulcer disease, urinary tract infection, dysmenorrhea,
and ruptured ovarian cyst. Less common diagnoses would include inammatory bowel disease, cyclic vomiting
syndrome, kidney stones, heavy metal
poisoning, ovarian torsion, and imperforate hymen with hematocolpos.
The possibility of a functional abdominal pain disorder should be considered when an organic origin of pain is
not detected on thorough evaluation.
Certainly, many children with organic abdominal pain may also have
a component of functional pain, which
makes diagnosis and management
more challenging.
The Condition
Embryologically, the vagina is formed
from 2 evaginations that originate
from the urogenital sinus and mullerian duct. A transverse vaginal septum
results from failure of fusion and/or
canalization of these evaginations.
These septae may be located at various
levels in the vagina; approximately
46% are found in the upper portion
of the vagina, 35% to 40% in the middle portion, and 15% to 20% in the
lower portion. Most septae are generally less than 1 cm in thickness and
have fenestrations and therefore do
not cause a complete obstruction.
A girl born with a vaginal septum
will have normal-appearing external female genitalia. Younger children may present with mucocolpos,
whereas adolescents commonly present with hematocolpos. Ascending

infection is also possible through
a perforation or fenestration, leading
to pyohematocolpos. Occasionally, a
mass may be palpated on abdominal
or rectal examination, which may
lead to symptoms secondary to a mass
effect on the urinary system, such as
urinary retention or hydronephrosis.
Hematocolpos is a condition where
the vagina becomes distended with
blood due to accumulation of menstrual products. Hematometra is a
related condition that refers to a distended uterus lled with blood caused
by large accumulation of menstrual
products. The most common causes
of hematocolpos and hematometra
are imperforate hymen, vaginal agenesis (1:5000), and complete transverse
vaginal septum (1:30,0001:80,000).
Vaginal agenesis is also known as mullerian aplasia or Mayer-RokitanskyKuster-Auser syndrome and refers to
congenital absence of the vagina with
variable cervical and uterine development. Symptoms secondary to hematocolpos or hematometra generally
present at the time of menarche and
include periodic lower abdominal pain
and primary amenorrhea.
Approximately 25% to 50% of females with uterine or vaginal anomalies
will have an associated urologic anomaly, such as unilateral renal agenesis,
horseshoe kidney, or abnormalities of
the collecting system. Skeletal anomalies of the spine, ribs, and extremities
are also associated with uterine or vaginal anomalies in 10% to 15% of cases.
Management
Once the diagnosis is conrmed, the
septum should be surgically excised
with end-to-end anastomosis of vaginal mucosa. Endometriosis is a known
complication of hematocolpos and often requires continued follow-up with
a gynecologist. Although not completely understood, the endometriosis
is presumed to be related to retrograde menstruation and implantation
of endometrial cells.
As stated earlier, uterine and vaginal
anomalies have been associated with
other congenital anomalies and therefore may require additional evaluation.

The differential diagnosis of abdominal pain is vast; however, a genitourinary cause of abdominal pain
in children, particularly in young
girls with recurrent or cyclic symptoms, should be considered.
Girls with a vaginal septum will have
normal-appearing external genitalia
and often present with hematocolpos or pelvic mass.
Vaginal septum is diagnosed with
imaging studies, such as abdominal
or pelvic ultrasonography or MRI.
Surgical resection is the primary
treatment for vaginal septum.
Congenital anomalies of the uterus
and vagina may be associated with
urologic or skeletal anomalies and
require additional evaluation.
(Lisa Didion, MD, Ryan Nerland,
MD, Blair E. Batson Childrens Hospital, University of Mississippi Medical
Center, Jackson, MS)
Diagnosis
Denitive diagnosis is usually made by
ultrasonography or pelvic MRI. Imaging is required to dene the level and
thickness of the septum. It is also important to differentiate between a high
septum and a congenital absence of
the cervix and to delineate any additional genitourinary abnormalities.
Case 2
Discussion
An ultrasonogram of the abdomen revealed a round heterogeneous structure

in the left hepatic lobe. Serum uric acid,
a-fetoprotein (AFP), and human chorionic gonadotropin levels were within
index of suspicion
normal limits. Abdominal computed

tomography (CT) revealed multiple
hepatic masses with necrotic areas.
Histopathologic ndings of an
endoscopically ultrasonogram-guided
biopsy were consistent with hepatocellular carcinoma (HCC). MRI of
the abdomen revealed stage 3 disease,
with extensive intra-abdominal metastasis without distant metastasis. The
patient underwent an extended left
hepatectomy (segments 2, 3, 4, and
8) and resection of the perihepatic
and celiac lymph nodes. It was determined that the patient was not a candidate for liver transplantation. He was
prescribed sorafenib, a chemotherapeutic agent. Approximately 18 months
after the diagnosis was made, the patient died of complications of HCC.
The Condition
HCC is a primary malignant tumor of
the liver, which may occur in multiple
sites within the liver. It can metastasize to other abdominal structures
and to the lungs.
Primary liver tumors are uncommon in children and adolescents, accounting for approximately 0.5% to
2% of all neoplasms in these age
groups. HCC is the second most common hepatic malignant tumor in children after hepatoblastoma. Annual
incidence of HCC in children varies
widely, depending on geographic location due to regional variations in exposure to hepatitis viruses. In low
incidence regions, such as North and
South America, Australia, and parts
of Europe and the Middle East, the
incidence is approximately 0.5 cases
per million and is rare before the age
of 15 years. However, in regions such
as Peoples Republic of China, Hong
Kong, Sub-Saharan Africa, and Taiwan,
where hepatitis B infection is prevalent,
the incidence can be as high as 0.5 per
100,000 population.
Most cases of HCC result from
conditions that cause chronic liver
disease, such as hepatitis B and C infections and cirrhosis. Less common

causes associated with an increased
risk of HCC are conditions causing
long-term inammation of the liver,
such as autoimmune diseases of the
liver, and some congenital diseases,
such as hereditary tyrosinemia type
1, Wilson disease, type 1 glycogen
storage disease, a1-antitrypsin deciency, progressive familial intrahepatic
cholestasis type 2, and hemochromatosis. Prolonged exposure to hepatic
toxins, such as androgenic steroids
in adolescent athletes and mycotoxins (aatoxin B1 and ochratoxin A),
which are contaminants of staple
foods in tropical subsistence farming communities, has been linked
to HCC.
Patients with HCC may be asymptomatic in the early course of the disease but can present with right upper
quadrant pain due to stretching of the
Glisson capsule. Other symptoms may
include jaundice, nausea, vomiting, diarrhea, anorexia, weight loss, and fever.
Physical examination may reveal a tender, enlarged liver and icterus. In rare
cases, paraneoplastic syndromes, manifested as hypoglycemia, erythrocytosis, hypercalcemia, or watery diarrhea,
can occur. Complications are associated with extension of the tumor into
hepatic or portal veins, resulting in arteriovenous shunting and gastrointestinal bleeding. As hepatic failure ensues,
manifestations of coagulopathy, encephalopathy and ascites develop.
Diagnostic evaluation involves
laboratory and imaging studies. Elevated liver enzyme levels, abnormal
liver function test results, and elevated serum AFP levels are common
but not seen in all patients. Serum
AFP levels do not correlate with the
size or the stage of HCC, although
an elevated AFP level can be used
to gauge response to therapy. Abdominal ultrasonography can be used
as an initial imaging modality. CT or
MRI is used to delineate the tumor

and assess for vascular invasion and
extrahepatic metastasis. Final diagnosis is conrmed by image guided needle biopsy.
The differential diagnosis of a child
presenting with an epigastric mass
and associated elevated liver enzyme
levels can be limited primarily to liver
conditions. Viral hepatitis is a systemic
viral infection in which the predominant manifestation is that of hepatic
injury. Ninety percent of cases of
hepatitis are caused by hepatotropic
viruses, which include hepatitis A to
E. Ten percent of cases are due to
other viruses, such as Epstein-Barr virus, cytomegalovirus, herpes simplex
virus, varicella-zoster virus, rubella,
parvovirus, adenovirus, or enteroviruses.
Tender hepatomegaly and jaundice
may or may not be present. Twothirds of children with hepatitis A
present with jaundice, and there may
be dark urine and pale stools. Marked
elevation in aspartate aminotransferase
and alanine aminotransferase levels is
seen during acute infection, although
these levels may be normal or mildly elevated in chronic infections. Viral serologic testing helps clinch the
diagnosis.
Primary liver tumors are uncommon in children. Of these, approximately two-thirds are benign, and
one-third is malignant. In general,
the most common clinical manifestation of pediatric liver neoplasms is an
asymptomatic abdominal mass. Hemangiomas are the most frequently observed benign liver tumor in children
and are usually incidental ndings in
asymptomatic patients.
Hepatoblastoma is the most common pediatric liver malignant tumor
(incidence of 0.9 per 1 million children)
followed by HCC. Hepatoblastoma
presents usually within the rst 2
years of life, with more than 90% of
index of suspicion
children having elevated AFP levels.

Occasionally, precocious puberty or
virilization, secondary to excess androgen secretion, is seen. Other nonspecic
features include weight loss, abdominal
pain, loss of appetite, anemia, fever,
vomiting, and jaundice. In contrast to
HCC, hepatoblastoma arises in an otherwise healthy liver and is usually sensitive to chemotherapy. It occurs in
association with Beckwith-Wiedemann
syndrome and hemihypertrophy.
A transitional liver cell tumor is
a rare neoplasm that is found in older
children. The tumor cells vary between
those of classic hepatoblastoma and
HCC, and much like HCC, response
to chemotherapy is poor. Other primary liver malignant tumors, including
liver sarcomas and choriocarcinoma,
are extremely rare in children.
Treatment and Prognosis

HCC is an aggressive tumor that is
usually detected at an advanced stage.
The median survival after diagnosis is
approximately 6 to 20 months.
Treatment options for patients with
HCC are dictated by the functional reserve of the liver. Only 10% to 20% of
HCCs can be removed completely by
surgery. The Milan criteria are applied
to patients with cirrhosis and HCC
when determining eligibility for hepatic transplantation. Transplant candidates should have a singular lesion
less than 5 cm or up to 3 lesions
smaller than 3 cm each with no extrahepatic manifestations and no vascular
invasion.
Other treatment modalities that
have been used in adults are only relatively recently being used in children.
Chemotherapy has not been used
routinely for patients with advanced
HCC; however, there are ongoing
studies using multiple chemotherapeutic agents. Sorafenib tosilate (Nexavar),
a receptor tyrosine kinase inhibitor
that blocks tumor growth and has
been reported by several studies to
increase medial overall survival, is approved for patients with advanced

and unresectable HCC.
Prevention
Avoidance of hepatotoxic agents and
childhood vaccination against hepatitis B have been reported to reduce
the future risk of HCC. In Taiwan
on July 1, 1984, a mass hepatitis B
vaccination program was launched,
primarily aimed at immunizing newborn infants. Twenty years after the
implementation of this program, there
was an 85% parallel decrease of hepatitis B prevalence, as well as HCC and
cirrhosis.
Surveillance for HCC in selected
groups of patients known to be at
high risk for HCC, such as certain
metabolic diseases or chronic liver
diseases, may lead to prompt diagnosis and aggressive treatment.

Although rare, hepatic malignant
neoplasms should be considered
in the differential diagnosis in patient with hepatomegaly and elevated liver enzyme levels.
Prognosis of HCC is dependent
on early diagnosis; hence, prompt
diagnostic evaluation is crucial.
In general, HCC carries a poor
prognosis, and the treatment options are limited.
Implementation of a childhood
hepatitis B vaccination program
has signicantly decreased the
childhood incidence of HCC.
Schiller-Duval body, which is pathognomonic for yolk sac tumor (Figure 2).
The Schiller-Duval body consists of
a central blood vessel surrounded
by germ cells, which together lie in
a cystic space surrounded by attened
germ cells. Further laboratory studies
revealed a lactate dehydrogenase
level of 410 IU/L and an AFP level
of 16,766.3 ng/mL (16,766.3 mg/L).
The patient underwent whole-body
CT with contrast, which revealed a lobulated, rim-enhancing, precoccygeal
mass suggestive of sacrococcygeal
teratoma (SCT) (Figure 3). Lymphadenopathy most likely due to metastasis was found in the bilateral
pelvic sidewalls, right external iliac,
right paraspinal, left inguinal, and
presacral regions. Soft tissue implants
were noted within the bilateral gluteus
maximus muscles. Mediastinal and
bilateral hilar lymphadenopathy with
multiple lung nodules were also detected (Figure 4). The culture from
the pus drained yielded Staphylococcus
aureus. Thus, our patient had acute
lymphadenitis of a metastatic lymph
node in the inguinal region.
Acute lymphadenitis was high on the
differential diagnosis. Isolated inguinal lymphadenopathy can be seen in
lower-extremity suppurative infection, vector-born diseases (tularemia,
plague, brucellosis, and cat-scratch
(Zola Noni Trotter, MD, Jessica

Scerbo, MD, Jacob Rosenberg, MD,
Nassau University Medical Center,
East Meadow, NY)
Case 3
Discussion
The pathology report of the resected inguinal lymph nodes revealed
Figure 2. The histopathologic analysis of

the resected inguinal lymph nodes
reveals a Schiller-Duval body pathognomonic for yolk sac tumor.
index of suspicion
Figure 3. Computed tomography with

contrast reveals a lobulated, rimenhancing, precoccygeal mass suggestive
of sacrococcygeal teratoma.
disease), perineal infections, venereal

disease, and malignant tumors. Among
the malignant tumors, rhabdomyosarcomas and nonrhabdomyosarcomas,
Hodgkin and non-Hodgkin lymphoma, and primary neuroblastoma
have been reported to present with
inguinal lymphadenopathy. Inguinal
hernia was one of the differential diagnoses, but the mass did not enhance on coughing, had no audible
bowel sounds on direct auscultation,
and was rm on palpation.
The Condition
SCT is the most common germ cell
tumor of childhood and comprises
40% of all germ cell tumors. They
are seen in approximately 1 in every
27,000 live births and are more
Figure 4. Computed tomography of the
chest reveals mediastinal and bilateral

hilar lymphadenopathy with multiple
lung nodules.
common in females in ratios of 3:1

to 4:1. Teratomas include components from all 3 embryonic layers: endoderm, mesoderm, and ectoderm.
They may be classied as mature or
immature on the basis of the presence
of immature neuroectodermal elements within the tumor. The tumor
was found to be malignant in 48%
of girls and 67% of boys when they
were older than 2 months at the time
of the diagnosis of SCT compared
with 7% in girls and 10% in boys when
SCT was diagnosed in infants younger
than 2 months. SCTs are more likely
to recur when compared with teratomas in the ovary and at other sites.
Diagnosis
Fetal sacrococcygeal tumors may be
diagnosed on prenatal ultrasonography, especially when located partly
or entirely externally. Some fetuses
may develop high-output cardiac failure, hydrops, and maternal mirror
syndrome. Maternal mirror syndrome
refers to the association of fetal and
placental hydrops with preeclampsia.
The edematous states of both fetus
and mother mirror each other. Neonatal SCT can present as a visible lump
or mass under the skin at the top of
the buttocks crease. In infants and
young children, a small SCT, if it is
entirely inside the body, may not develop clinical manifestations for years,
until it grows large enough to cause
mass effects, such as pain and constipation, or until it begins to extend
out of the pelvis. When not externally
visible, even large teratomas may be
missed because they are concealed
within the bony pelvis.
SCTs are classied according to their
relative extent outside and inside the
body by the American Academy of Pediatrics Surgical Section classication:
Altman type Ientirely outside,
sometimes attached to the body
only by a narrow stalk
Altman type IImostly outside

Altman type IIImostly inside
Altman type IVentirely inside;
this is also known as a presacral
teratoma or retrorectal teratoma
CT of the abdomen and pelvis is
essential for the staging of abdominal
and pelvic tumors at the time of presentation. MRI can be substituted for
CT, and if so, it should be used
throughout therapy to maintain consistency in imaging studies.
Treatment
For benign SCTs, surgical resection is
sufcient, where typically the coccyx
is resected en bloc with the tumor
to minimize risk of recurrence as the
tumor lacks a capsule. For malignant
SCTs, postsurgery platinum-based
chemotherapy that consists of a combination of bleomycin, etoposide, and
cisplatin is the most common rst-line
therapy used. Our patient underwent
surgical resection of the tumor and
is undergoing bleomycin, etoposide,
and cisplatin chemotherapy.

The most common cause of localized
inguinal lymphadenitis is lowerextremity suppurative infection.
Inguinal lymphadenitis may be seen
in vector-born diseases, perineal infections, and venereal diseases.
Other inguinal masses, such as
hernias, should be ruled out.
The possibility of a malignant tumor should always be considered in a child presenting with
lymphadenopathy.
(Deepa Vasireddy, MD, Jessica Scerbo,
MD, The Unterberg Childrens Hospital at Monmouth Medical Center, NJ)
To view Suggested Reading lists
for these cases, visit http://pedsinreview.
aappublications.org and click on the
Index of Suspicion link.
in brief
In Brief
Shigella
Lucy C. Holmes, MD
University at Buffalo and Women and
Childrens Hospital of Buffalo, Buffalo,
NY
Author Disclosure
Dr Holmes has disclosed no financial
relationships relevant to this article.
This commentary does contain
a discussion of an unapproved/
investigative use of a commercial
product/device.
Antibiotic Therapy for Shigella

Dysentery. Christopher PRH, David KV,
John SM, Sankarapandian V. Cochrane
Database System Rev. 2010;8
CD006784.
Notes From the Field: Outbreak of
Infections Caused by Shigella
sonnei With Decreased
Susceptibility to Azithromycin Los
Angeles, California, 2012. Centers
for Disease Control and Prevention.
MMWR Morb Mortal Wkly Rep.
2013;62:171171.
Shigella Infections. American Academy
of Pediatrics. In: Pickering LK, Baker
CJ, Kimberlin DW, Long SS, eds. Red
Book: 2012: Report of the
Committee on Infectious Diseases.
Elk Grove Village, IL: American
Academy of Pediatrics; 2012:
645647.
Transmission Risk Factors and Treatment
of Pediatric Shigellosis During
a Large Daycare CenterAssociated
Outbreak of Multidrug Resistant
Shigella sonnei. Arvelo W, Hinkle CJ,
Nguyen TA, et al. Pediatr Infect Dis J.
2009;28:976980.
Treatment and Prevention of Shigella
Infections in Children. Ashkenazi S.
Up to Date. http://www.upto date.
com. Accessed May 20, 2013.
Shigella is a gram-negative bacillus in the

family Enterobacteriaceae. It consists of 4
species (with >40 serotypes), including
Shigella sonnei, Shigella dysenteriae, Shigella flexneri, and Shigella boydii, and
each is more predominant in different
areas of the world. In the United States,
approximately 86% of shigella infections
were caused by S sonnei in 2009, whereas
in African and Asian countries, S flexneri
is more common. S dysenteriae serotype
1 produces Shiga toxin that may cause
hemolytic uremic syndrome.
Shigellosis commonly occurs in children in developing countries where there
is overcrowding and poor sanitation. In
the United States, it is the third most
common cause of bacterial gastroenteritis and is frequently spread in daycare
centers and other areas where people
are in close contact. Transmission occurs
via the fecal-oral route, person-to-person
contact, and contact with contaminated
food, water, and inanimate objects. Only
a small number of bacteria (10100 organisms) are required to cause disease.
The incubation period varies between 1
and 7 days, although it is usually 1 to
3 days. Patients not undergoing antimicrobial therapy may shed the organism
for up to 4 weeks, whereas immunocompromised patients may shed for a longer
time frame. Chronic carrier states are uncommon and do not correlate with a patients underlying intestinal disease.
Symptoms of shigella most commonly
present as diarrhea and/or dysentery with
frequent watery stools, often with blood
and/or mucus, and associated with pain,
tenesmus, fever, and/or dehydration. In
some children, the infection may be
asymptomatic. Rarely, in severe cases,
shigella may cause bacteremia or sepsis.
S dysenteriae serotype 1 is associated
with more severe disease and more
complications. These complications include pseudomembranous colitis, intestinal perforation, toxic megacolon,
hemolysis, hemolytic uremic syndrome,
seizures, and electrolyte abnormalities.
Reiter syndrome may develop in approximately 3% of patients infected
with S flexneri, who are genetically
predisposed by expression of HLA-B27,
and leads to symptoms of chronic arthritis. Mortality, although rare, may
occur in infants, malnourished children,
and those with S dysenteriae serotype 1
infections.
Fecal leukocytes seen in a methylene
bluestained stool sample suggest the
presence of colitis. Diagnosis of shigella
infection is confirmed with a stool culture from feces or a rectal swab specimen. In some centers, shigella DNA with
polymerase chain reaction analysis may
be available for diagnostic testing.
The first line of treatment is replacement of fluid and electrolyte losses, preferably with oral rehydration. Most infections
caused by S sonnei are mild and resolve
within 48 to 72 hours. Empiric antibiotic
treatment is indicated for patients who
are very ill with suspected bacteremia
and patients who are immunocompromised. Treatment, once the diagnosis is
confirmed by culture, may be indicated
in patients who remain symptomatic and
are in daycare settings, live in long-term
facilities, or are involved in food handling
because antibiotics reduce fecal excretion
and may shorten duration of symptoms.
For many patients, symptoms have resolved by the time the stool culture has
identified shigella, and in these patients
treatment is unlikely to be warranted.
The choice of which antibiotic to administer is another treatment question. A
2010 Cochrane review of 16 randomized
controlled trials evaluating antibiotics for
in brief
shigella dysentery found all classes of antibiotics had similar efficacy, and the authors
were not able to identify a superior class
of antibiotics. In the United States, the
2010 National Antimicrobial Resistance
Monitoring System found 41% of Shigella
species resistant to ampicillin, 48% resistant to trimethoprim-sulfamethoxazole,
2% resistant to ciprofloxacin, and less
than 1% resistant to ceftriaxone. Antibiotic resistance in outbreaks has been reported to be much higher. Arvelo et al
found 90% of the Shigella strains involved
in a large daycare centerassociated outbreak resistant to both ampicillin and
trimethoprim-sulfamethoxazole. Knowing
regional resistance patterns and the susceptibility pattern of the pathogen once
available is essential to guide therapy.
Patients with strains susceptible to ampicillin or trimethoprim-sulfamethoxazole
may be treated for 5 days. Amoxicillin
is less effective because of its rapid absorption from the intestine and should
not be used. Patients with unknown susceptibility or known resistance to ampicillin
and trimethoprim-sulfamethoxazole may
be treated with 5 days of azithromycin,
cefixime, or a ciprofloxacin. Azithromycin

does not have standard guidelines for
interpreting susceptibility testing for
shigella, which may allow resistance
to the drug to develop unnoticed with
increased use. The first reported outbreak in the United States of a S sonnei
strain with decreased susceptibility to
azithromycin was recently reported. Although ciprofloxacin is not approved for
use by the US Food and Drug Administration in patients younger than 18
years, it can be considered if susceptibility patterns indicate it is the best
agent and treatment is imperative. Patients requiring parenteral therapy may
be prescribed ceftriaxone, and a 2-day
course may be all that is needed if there
is a good clinical response and no infection beyond the gastrointestinal tract.
Medications that inhibit intestinal
peristalsis may prolong symptoms and
increase potential complications, and
therefore are contraindicated.
morbidity and potential mortality from

a global health perspective. Mortality
rates have been found to be 1 million
associated deaths worldwide, with
60% of deaths in children younger than
5 years. Mortality rates are high in children who are severely dehydrated, malnourished, human immunodeficiency
virus positive, or recovering from measles. Treatment with vitamin A or zinc
may improve resolution in children at
risk for malnutrition in addition to continued oral rehydration and enhancing
protein intake as soon as possible.
In the United States, shigella infections are important considerations in
schools and daycare centers where infection may spread quickly. Control measures include scheduled hand washing of
children attendees, thorough hand washing by staff, and no diaper changing in
staff who are food handlers. Shigella infections should be reported to the local
health department so control measures
can be initiated in case of outbreaks.
Comments: Although shigella remains an important pathogen in the

United States, it is a cause of significant
Janet Serwint, MD
Consulting Editor, In Brief
Parent Resources From the AAP at HealthyChildren.org

http://www.healthychildren.org/English/health-issues/conditions/abdominal/Pages/Shigella-Infections.aspx (English
only)
Answer Key for June 2014 Issue:

Influenza and Parainfluenza Viral Infections in Children: 1. B; 2. E; 3. C; 4. B; 5. C.
Noncontraceptive Use of Contraceptive Agents: 1. E; 2. B; 3. A; 4. E; 5. B.
Gastrointestinal Bleeding: 1. B; 2. D; 3. C; 4. A; 5. C.

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visual diagnosis

Chronic Diarrhea and Failure to

Figure 1. Endoscopic view showing edematous and friable

A 5-year-old girl presents to the clinic with a history of

Pediatrics in Review Vol.35 No.6 June 2014 e29

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allogeneic hematopoietic cell transplantation involving multiple sites

Pathogenesis, Risk factors,

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Chronic GVHD usually develops 100 days after BMT

2. Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host

3. Zecca M, Prete A, Rondelli R, et al; AIEOP-BMT Group. Italian

Association for Pediatric Hematology and Oncology-Bone Marrow

Pediatrics in Review Vol.35 No.6 June 2014 e31

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Influenza and Parainfluenza Viral Infections

After completing this article, readers should be able to:

Describe the epidemiology of influenza and parainfluenza virus infections.

inactivated inuenza vaccine

The avian origin H1N1 inuenza pandemic of 19181919

Pediatrics in Review Vol.35 No.6 June 2014 217

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infectious diseases influenza & parainfluenza

the last 100 years. Inuenza epidemics can be traced back

Influenza Genetics and the Pandemic Threat

a limited number of inuenza subtypes. Human infection

2009 Novel H1N1 Pandemic

Epidemiology and Transmission

218 Pediatrics in Review Vol.35 No.6 June 2014

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infectious diseases influenza & parainfluenza

children and individuals with compromised immunity can

Clinical Comparison of Influenza and Parainfluenza Viral

Coryza and pharyngitis are common with PIV

Croup by influenza virus is more severe: thicker

PIVparainuenza virus; URIupper respiratory tract infection.

Pediatrics in Review Vol.35 No.6 June 2014 219

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infectious diseases influenza & parainfluenza

Rapid Antigen Testing

inuenza-like illness could be falsely negative. If that same

Other Testing Choices

220 Pediatrics in Review Vol.35 No.6 June 2014

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infectious diseases influenza & parainfluenza

inuenza should receive therapy. Patients at high risk for

Candidates for Antiviral

Antiviral treatment is recommended as soon as possible

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infectious diseases influenza & parainfluenza

Antiviral Agents for Treatment and Chemoprophylaxis of Influenza

3 mg/kg per dose twice daily

<38 weeks: 1.0 mg/kg per

3 mg/kg per dose once daily

10 mg (two 5-mg inhalations)

attenuated intranasal vaccine (LAIV) and a recombinant

222 Pediatrics in Review Vol.35 No.6 June 2014

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infectious diseases influenza & parainfluenza

Influenza Vaccines, 2013-2014

Vaccine Trade Name

Presentation and Route of

0.5 mL single-dose prefilled

0.5 mL single-dose prefilled