Pediatrics 30: 2-year-old male with sickle cell disease

User: Emily Symes

Email: emily.symes@rockets.utoledo.edu
Date: January 26, 2020 5:56PM

Learning Objectives

Upon completion of the case, 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.
Describe signs of respiratory distress.
Describe health maintenance and expected course for children with sickle cell disease.
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.
Describe the management of acute chest syndrome.
Work through a differential diagnosis of a child with sickle cell disease with fever and/or cough and/or chest pain.
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 naming.
F
Following the F, hemoglobins are listed in order of concentration.

Hemoglobin A is normal adult hemoglobin.

A
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.

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 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.

Hemoglobins are listed in order of quantity. For example, FAS is sickle cell trait, and FSA is sickle beta-thalassemia. In the case of FAS, there is
more Hgb A than Hgb S, so the Hgb A is able to dilute out the Hgb S, preventing polymerization and the clinical manifestations of sickle cell disease.
In FSA, there's less Hgb A, and so the dilution effect is not enough to prevent polymerization.

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.

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 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

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 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 potential site of 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.

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.

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

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

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 Sepsis cell disease may have cardiomegaly at baseline).

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, in part due to higher
baseline white blood cell and platelet counts.

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.

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

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 Assessing Spleen Size

Teaching a parent how to palpate the spleen can lead to earlier detection and treatment of splenic sequestration. Using the parent's fingers, you can
demonstrate the baseline size of the spleen at the nipple line and show the parent how to find the edge.

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.

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

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

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.

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:

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 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 syndrome
(ACS) Cough

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.

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.

Fever may be present with a vaso-occlusive crisis.

Rib infarction
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

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

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

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

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.

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

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Reviews 2009, Issue 1, Art. No.:CD007001.

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

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

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

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

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

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.

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.

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.

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