CLIPP 30: 2-year-old with sickle cell disease - Gerardo

User: Mitchell Creed

Email: mcreed2@kumc.edu
Date: July 31, 2017 19:15 GMT/UTC

Learning Objectives

The student should be able to discuss appropriate communication with the child, the family, and the health care
team in the context of chronic disease.
The student should be able to describe signs of respiratory distress.
The student should be able to describe health maintenance and expected course for children with sickle cell
disease.
The student should be able to discuss complications of sickle cell disease that may lead to additional morbidity
and mortality, including sepsis, vaso-occlusive crises, acute chest syndrome (ACS), cholecystitis, stroke, and
others.
The student should be able to describe the management of acute chest syndrome.
The student should be able to work through a differential diagnosis of a child with sickle cell disease with fever
and/or cough and/or chest pain.
The student should be able to identify immunization priorities in children with sickle cell disease.

Knowledge

Pathophysiology of Sickle Cell Disease (SCD)

SCD is a group of disorders characterized by substitution of valine for glutamic acid at the sixth amino acid position
of the hemoglobin molecule.

This mutation leads to the formation of polymers of hemoglobin when the hemoglobin becomes deoxygenated.

These polymers lead to deformation of the red blood cell into the characteristic "sickle" cells. Sickle cells have
increased adherence and block blood flow in the microvasculature, which leads to local tissue hypoxia, pain, and
tissue damage.

The abnormal hemoglobin induces hemolysis of the red blood cells leading to chronic anemia with an elevation of
the reticulocyte count.

Hemoglobin Nomenclature and Patterns in the Newborn

Hemoglobin
Comment
Type

Predominant hemoglobin at birth is hemoglobin F (fetal), so this always appears first in the
F naming.

Following the F, hemoglobins are listed in order of concentration.

Hemoglobin A is normal adult hemoglobin.

A
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 Hemoglobin FA (fetal + normal adult) does not cause a sickling disorder.

FAS means the baby is a carrier of one abnormal hemoglobin gene-for hemoglobin S.
FAS
This individual has benign sickle cell trait-i.e., is a carrier of hemoglobin S.

FAC means the baby is a carrier of one abnormal hemoglobin gene-for hemoglobin C.
FAC
This individual has benign hemoglobin C trait-i.e., is a carrier of hemoglobin C.

This means that both of the baby's hemoglobin genes have mutations for hemoglobin S.
FS
FS is the most common hemoglobin pattern causing sickle cell disease.

FSA is sickle cell beta thalassemia, meaning one of the globin genes has a mutation for S and
the other has a mutation for beta thalassemia (which produces no or little normal hemoglobin).
FSA This pattern causes a sickling disorder, although it may behave in a milder fashion than FS (in
which both genes have the sickling mutation). From a clinical management standpoint, these
patients are treated in the same manner.

FSC is sickle cell hemoglobin C disease: one gene has the S mutation and one gene has the
mutation for hemoglobin C.
FSC This pattern causes a sickling disorder, although it may behave in a milder fashion than FS (in
which both genes have the sickling mutation). From a clinical management standpoint, these
patients are treated in the same manner.

Common Procedures for Young Individuals with SCD

Tonsillectomy

Lymphoidal-tissue hypertrophy involving Waldeyer's ring is common in children with sickle cell disease.

Excessive snoring may be observed, as well as obstructive sleep apnea.

Some physicians think tonsillar hypertrophy may relate to desaturation of hemoglobin and increase the risk
of sickling.
Tonsillectomy with adenoidectomy will improve the obstructive apnea for most patients.

Cholecystectomy

Bilirubin gallstones occur frequently in all patients with hemolytic anemias---including sickle cell disease---the result
of increased release of hemoglobin during breakdown of abnormal red blood cells.

Although rare in the first five years of life, an increasing number of children are found to have gallstones
during adolescent ages.
Although many children with sickle cell disease may have evidence of gallstones on screening ultrasounds,
management is conservative and cholecystectomies are reserved for patients who are symptomatic.
If symptoms require it, cholecystectomy preferably is done as an elective procedure, with preoperative
transfusions of packed red blood cells (pRBCs) given to reduce the chances of acute chest syndrome or
other complications following the surgery due to the time under anesthesia.
Cholecystitis can be a serious infection to treat, so treatment is warranted if there are any symptoms from
the cholelithiasis.

Risk of Sepsis in Children with SCD

Infants and young children with SCD are at greatly increased risk for sepsis.
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 The decreased splenic function leads to decreased resistance to infection with encapsulated organisms
(Streptococcus pneumoniae, Haemophilus influenzae type b, Neisseria meningitidis).
When given to infants with sickling disorders, penicillin significantly decreases the risk of mortality from
overwhelming sepsis.
Penicillin is usually continued until the child is 5 or 6 years of age; after this age there is little data to support
its use except in patients who have had documented sepsis and bacteremia, or who have had their spleens
removed.

Below is the citation for the original 1986 article advocating the prophylactic use of penicillin; the science is still
valid, and its recommendations persist to this day.

Goals for the Comprehensive Visit for SCD

During the comprehensive visit for sickle cell disease the following topics are important to cover:

1. How the family deals with the various complications that can occur. This permits the education of the
family in what to do and where to go for various types of problems. For example:

In the first few years of life, pain and febrile illnesses are some of the issues that cause the greatest concern to the
family:

Fever may be the only sign of sepsis in children with sickle cell disease and must be dealt with as a medical
emergency, with rapid evaluation, blood cultures, and institution of broad-spectrum parenteral antibiotics
while waiting for culture results to guide the therapy.
If cultures are negative and the patient is well, usually the child may be discharged in 48-72 hours.
Remember that children with sickle cell disease also get "normal" colds and other viral illnesses.

The lack of normal splenic function as well as several other more subtle immunologic deficiencies call for this rapid
and aggressive approach.

2. The frequency of painful or other vaso-occlusive problems.

This will give an indication of the need for other, more aggressive interventions such as the use of
hydroxyurea.

3. How the family accesses health care.

4. How the family is dealing with a chronic illness.

Chronic illnesses can lead to great stress on the family.

Helping the family deal with these issues is an important component of comprehensive care.

Expected Complications for Children with SCD

Jaundice

With increased breakdown of the red blood cells, sickle cell disease leads to jaundice.

Anemia

The anemia that is seen in sickle cell disease can cause some fatigue, and can sometimes be more severe
due to myelosuppression from infections such as Parvovirus or from hypersplenism when the spleen
enlarges and traps blood cells.

Stroke

Children with sickle cell are at risk of stroke: 10% by the age of 15 years.

Respiratory Problems

The lungs are a site of occasional sickling problems.

This can occur in the form of pneumonia, because of the increased tendency to infections.
It may also occur as a result of vaso-occlusion in the lung parenchyma. This process, called acute chest
syndrome, is a medical emergency requiring supplemental oxygen and transfusion therapy.

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 Immunization Recommendations for Children with SCD

The current immunization recommendations have helped to prevent serious infections in children with sickle cell
disease.

The Haemophilus influenzae type b conjugate vaccine and 13-valent pneumococcal conjugate vaccine (Prevnar
13)-given at 2, 4 and 6 months-have aided in protection against two bacteria that have been major leaders in
morbidity and mortality in children with sickle cell disease.

Conjugation

In a child under the age of 2 years, the immune system has a suboptimal response to purely polysaccharide
vaccine. Conjugating the antigens to a protein allows an infant's immune system to make antibodies.

Pneumococcal Vaccine

The 13-valent pneumococcal conjugate vaccine given in the first year of life provides protection against the
13 serotypes contained in the vaccine.
To expand antibody coverage beyond the 13 initial serotypes, children with sickling disorders receive the
23-valent pneumococcal polysaccharide vaccine at two and five years of age.

Meningococcal Vaccine

Children with anatomic or functional asplenia should also receive the meningococcal conjugate vaccine at
age 2 years.
Unless they have a milder genotype than Gerardo's Hgb SS, most children with sickle cell will have
functional asplenia. They will receive a booster dose 3-5 years later.

And, of course, while all children should receive influenza vaccine annually, children with sickle cell disease are at
higher risk and should be immunized against this also.

Prenatal Testing for Genetic Diseases

A couple of methods are currently available, others are being researched. Ot the tests available:

One samples fetal blood obtained in utero

Another involves extracting DNA from chorionic villi

Learn more about the options for prenatal diagnosis.

Effect of Chronic Illness on Growth and Development

All of the answers listed above are correct. For many reasons, chronic illnesses can affect a child's growth and
development and ability to lead a normal life:

Frequent absences from school as a result of hospitalization, illness or physician appointments can certainly
affect academic progress.
Socialization and self-esteem may be diminished by the child being unable to do many of the things other
children may do, and may make them feel "different" from other children, which can then affect how they
interact.
Problems with the cost of medication, treatment, and equipment-as well as time away from work for the
parents-can produce a financial hardship on the family that can affect all members of the family.
Siblings also can be affected by the child's chronic illness-either because of the parents being pulled away
when the child is in the hospital or clinic, or because the ill child is getting much of the attention.
Feelings of guilt can develop in siblings of chronically ill children because they wonder why their sibling is ill
and they are not.

Be ready to refer families of chronically ill children to appropriate counseling resources. Comprehensive sickle cell
centers have access to social workers and counselors to address those needs.

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 Growth in Sickle Cell Disease

Impairment of growth is common in children with sickle cell disease. This is probably multifactorial and may be due
to any one or combination of the following:

Chronic anemia
Poor nutrition
Painful crises
Endocrine dysfunction
Poor pulmonary function

Important Signs in the Physical Exam in a Patient with SCD

The physical exam in a patient with sickle cell disease must include careful attention to the areas that the disease
process may affect.

Splenic Enlargement

During the abdominal exam, it is important to evaluate the spleen size:

Enlargement of the spleen is common during the first few years of life in children with sickle cell disease;
massive enlargement or rapid change in size can indicate splenic sequestration crisis. This is often
accompanied by other symptoms, including increased pallor, fatigue, and irritability.
This life-threatening complication occurs when blood pools in the spleen and leads to severe anemia and
shock.
The spleen in sickle cell disease becomes progressively fibrotic; by the time the child is 4 to 6 years old, it is
no longer palpable (children with hemoglobin SC or S beta thalassemia can have splenic enlargement into
adolescence).

Sclera

Observation of the sclera for signs of icterus gives a clue about the degree of RBC hemolysis.

Neurologic Exam

The neurologic exam is important for evaluation of signs of potential stroke, which occasionally can be subtle.

Baseline Hemoglobin in SCD

Children with sickle cell disease frequently have baseline hemoglobins between 6 and 9 g/dL (60-90 g/L). They
accommodate to this level of hemoglobin very well, but the lower the baseline hemoglobin, the more difficult it is
for the patient to withstand any acute change.

See the associated reference ranges in conventional and SI units.

Acute Chest Syndrome

In a child with sickle cell disease, cough and breathing difficulty may indicate:

Pneumonia
Intrapulmonary sickling
Pulmonary fat embolism

Acute chest syndrome is the term used for any of these processes, as it can be extremely difficult to distinguish
them on history and physical or with imaging.

In these patients, three problems must be addressed rapidly and appropriately:

The possibility of infection

The pulmonary and respiratory complaints

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 Pain

Comparison of Chest X-ray Findings

Diagnosis Findings on Chest x-ray

Findings in ACS may be due either to fat embolism or to vaso-occlusion of pulmonary vasculature.
Findings include, but are not limited to:

Multilobar infiltrates (more commonly lower and middle lobes)

Acute chest
Effusions
syndrome
(ACS) Atelectasis

It is always difficult to distinguish whether an infiltrate in the lung of a child with sickle cell disease
represents an infectious process (pneumonia) or atelectasis from infarction or pulmonary fat
embolus.

Pericarditis Pericarditis can present with effusion and infiltrate on chest x-ray.

Congestive
heart failure Lower lobe infiltrates and cardiomegaly are both consistent with a diagnosis of CHF.
(CHF)

While there would not be pulmonary infiltrates, a pleural effusion might happen as a
sequela of rib infarction.
Rib infarction
Also, cardiomegaly and hypoxia would not usually be present (though patients with sickle
cell disease may have baseline cardiomegaly).

Cardiomegaly would be present only if patient was in cardiogenic shock (although, as

noted above, patients with sickle cell disease may have cardiomegaly at baseline).
Sepsis
New infiltrates would not be a usual finding unless the sepsis leads to acquired/adult
respiratory distress syndrome (ARDS).

CBC Findings in Stress Response

Patients with sickle cell disease frequently demonstrate an exaggerated leukocytosis and thrombocytosis in
response to stress.

CBC findings do not definitively help to identify if pneumonia or other cause of ACS is present.

Considerations in Treatment of Pain

Pain can decrease the ability to fully expand the lungs, further exacerbating an already compromised pulmonary
status.

Narcotic Analgesia

Narcotic analgesia can relieve the pain and improve the ability to take a deep breath, but it must be remembered
that narcotics are respiratory depressants.

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 Careful monitoring is important to maintaining a therapeutic balance.

NSAIDs

The use of an NSAID can provide an additional mechanism of pain relief due to its anti-inflammatory effect.

Atelectasis

Definition

A collapsed or airless segment of lung due to obstruction with distal collapse of the alveoli.

Risk

Atelectasis is a serious risk in a child with chest pain. It can exacerbate acute chest syndrome, causing it even to
become life-threatening.

Prevention

Therefore, it is critical to encourage deep breathing, often through the use of assistive devices.

Incentive Spirometer

To use this device, the individual places the end piece in his mouth and, as he inhales, the indicator rises. By
increasing the inspiratory effort, the incentive spirometer helps to decrease atelectasis. With a child, making this a
game helps him to not think of this as "treatment."

Incentive spirometry is used in many specialties; most adults who have had surgery are also encouraged to use
incentive spirometry to prevent atelectasis and post-operative pneumonia.

RBC Transfusion in Acute Chest Syndrome

An RBC transfusion is the only way to directly reduce or reverse the sickling process which is the underlying cause
of the acute chest syndrome. Indications for RBC transfusion in ACS are not precise, but if a child experiences one
of the following, a transfusion of packed red cells is recommended:

A fall in hemoglobin from baseline

Increasing respiratory rate
Worsening chest symptoms
Declining O2 sats
Progressive infiltrates on chest x-ray

It should be noted that the vast majority of sickle cell patients with acute chest syndrome will have one or more of
these findings.

Exchange transfusion (erythrocytapheresis) should be reserved for especially severe disease and/or hypoxemia
not corrected by oxygen therapy.

Educational Challenges for Children with SCD

Between frequent hospitalizations, frequent pain, CNS complications (stroke), and missed school, many
adolescents and adults with sickle cell disease have significant challenges in our education system.

Clinical Skills

Assessing Spleen Size

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 Teaching a parent how to palpate the spleen can lead to earlier detection and treatment of splenic sequestration. A
tongue blade can be marked with the baseline splenic size so the parent can tell if the child's spleen is larger than
baseline.

Assessing Pain in Children

Using age-appropriate methods to assess pain is very important in evaluating and following pain in children.

A scale that shows faces (in a spectrum from happy to crying) is validated for children 4 years and above, but may
occasionally be appropriate for a 2-year-old. Developmentally, most children under age 4 are unable to understand
the faces pain scale, but because of frequent pain crises, children with SCD sometimes will understand the faces
scale earlier than age 4.

At other times, even children older than 4 years are too ill to comply with the request; in these instances, parental
judgment will be your best tool in assessing how much pain the child is in.

Management

When to Seek Emergency Care for a Patient with SCD

The following situations warrant emergency medical attention:

Fever in children with sickle cell disease is a medical emergency.

Fever
It is sometimes the only sign of serious infection.

Splenic
Massive enlargement or rapid change in size can indicate splenic sequestration crisis.
enlargement

Slurred speech can indicate a stroke and should be rapidly evaluated.

Slurred
speech An exchange transfusion may be indicated to lower the hemoglobin-S level to help prevent
progression and to prevent recurrent stroke.

Tachypnea and chest pain may indicate acute chest syndrome, and either one warrants
Chest pain
emergency evaluation.

Rapid Tachypnea and chest pain may indicate acute chest syndrome, and either one warrants
breathing emergency evaluation.

Pallor is a typical finding from the anemia of SCD, and does not constitute an emergency.
Increased
pallor However, an increase in pallor can be caused by splenic sequestration, increased hemolysis
(as discussed above) or a temporary inhibition of erythroid production (aplastic crisis).

Baseline jaundice is typical in sickle cell disease, so on its own is not an emergency.
Increased
jaundice Marked increase in the level of jaundice may indicate an increase in the degree of hemolysis
and a need for transfusion (may be associated with a viral illness).

Priapism Priapism from sickling in the penile arteries can cause permanent damage.

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 Hydration of Children with SCD

Because dehydration may contribute to intracellular hemoglobin polymerization and RBC sickling, we often
vigorously hydrate children with sickle cell disease.

With acute chest syndrome, however, we must be careful to avoid being too vigorous and cause pulmonary edema
from volume overload.

Antibiotics in Acute Chest Syndrome

Practice guidelines and clinical data support the use of antibiotics in children with acute chest syndrome.
Unfortunately, the clinical and laboratory features of ACS do not allow one to easily distinguish whether the cause
is pulmonary fat embolism and/or infarction from acute infectious pneumonitis.

Various infectious agents have been reported in ACS including:

Viruses
Chlamydia
Mycoplasma
Bacteria

One large prospective study treated all ACS patients with a third-generation cephalosporin and a macrolide
antibiotic. However, the overall rate of positive cultures was < 10%.

As every community has different rates and patterns of antimicrobial resistance, it is important to understand
antibiotic choices selected by sickle cell hematologists at local centers.

Clinical Reasoning

Differential Diagnosis of Fever, Respiratory Distress, and Chest Pain in Child with SCD

All of the following choices are important to consider in a child with sickle cell disease with fever, respiratory
distress, and chest pain.

Diagnosis Comment

ACS often develops in children admitted for a painful vaso-occlusive crisis. It is one of the
most common causes of death in patients with sickle cell disease.

Clinical features of ACS include:

Fever
Acute chest
Cough
syndrome (ACS)
Chest pain (this can lead to difficulty with expansion of the lower lung and result in
atelectasis)

Shortness of breath

Decreased oxygenation

Typically presents with tachypnea and fever.

Pericarditis Uncommonly causes chest pain.

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 The increased splenomegaly speaks against this diagnosis.

CHF can occur in patients with sickle cell disease and chronic anemia.
Congestive heart
Tachypnea is one of the most common signs of CHF in children.
failure (CHF)
Usually does not cause chest pain on its own.

A rib infarction should always be suspected when child with sickle cell disease presents
with chest pain.

Rib infarction Fever may be present with a vaso-occlusive crisis.

Tachypnea may be due to the need to avoid taking deep breaths.

Rhonchi are not consistent with this diagnosis.

Sepsis can happen at any time with sickle cell disease and must be a consideration.
Sepsis Because sepsis is usually non-focal, however, it is unlikely that chest pain would be
present.

References

Gaston MH, Verter JL, Woods G. et al. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized
trial. NEJM. 1986;314:1593-1599.

Feldman L, et al. Long-term Use of Hydroxyurea for Sickle Cell Anemia. JAMA. 2003;289:1645-1651

Platt, O. Hydroxyurea for the treatment of sickle cell disease. NEJM 358:1362-9, 2008

Adams, R et al. The use of Transcranial Ultrasonography to predict stroke in Sickle Cell disease. NEJM 326:605, 1992

Verduzco, LA, and Nathan DG. Sickle Cell Disease and Stroke. Blood 114 (25) 5117,2009

American Academy of Pediatrics, Section on Hematology/Oncology and Committee: Health supervision of children with
sickle cell disease. Pediatrics.2002; 109 (3)

Woodard P, Jeng M, Handgretinger R, Wang W, Cunningham J. Summary of symposium: the future of stem cell
transplantation for sickle cell disease. J Pediatr Hematol Oncol. Oct 2002;24(7):512-4.

Xu K, Shi ZM, Veeck LL, Hughes MR, Rosenwaks Z. First unaffected pregnancy using preimplantation genetic
diagnosis for sickle cell anemia. JAMA. May 1999;12;281(18):1701-6.

Vichinsky EP, Neumayr LD, Earles AN, et al. National Acute Chest Syndrome Study Group. Causes and outcomes of
the acute chest syndrome in sickle cell disease NEJM. 2000;3429(25):1855.

Turner, JM et al. Exchange vs simple transfusion for acute chest syndrome in sickle cell anemia adults. Transfusion.
49; 863, 2009

Steinberg MH. Management of Sickle Cell Disease. NEJM. 1999;340:1021-1030.

Gill FM, Sleeper LA, Weiner SJ, Brown AK , Bellevue R, et al. Clinical events in the first decade in a cohort of infants
with sickle cell disease. Cooperative Study of Sickle Cell Disease. Blood Journal. 1995;86:776-783.

Oringanje, C, Nemecek, E, Oniyangi, O. Hematopoietic stem cell transplantation for children with sickle cell disease.
Cochrane Database of Systematic Reviews 2009, Issue 1, Art. No.:CD007001.

Wang, W, et al. A multicenter randomised controlled trial of hydroxyurea (hydroxycarbamide) in very young children
with sickle cell anaemia. Lancet. 2011 May 14; 377(9778): 1663-1672.

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Segal J, Strouse J, Beach M, et al. Hydroxyurea for the treatment of sickle cell disease evidence report (publication no.
08-e007). Washington, D.C.: Agency for Healthcare Research and Quality; 2008

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