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Case 30
2-YEAR-OLD WITH SICKLE CELL DISEASE GERARDO
Author: Roger Berkow, M.D., University of Alabama at Birmingham

Learning Objectives
1. Discuss appropriate communication with the child, the family, and the health care team, especially regarding issues of chronic disease. 2. Describe the signs of respiratory distress. 3. Describe health maintenance and expected course for children with sickle cell disease. 4. Recognize the 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. 5. Describe the management of ACS. 6. Work through a differential diagnosis of a child with sickle cell disease with fever and/or cough and/or chest pain. 7. Identify immunization priorities in children with sickle cell disease. Summary of clinical scenario: Gerardo is a 2-year-old African-American boy with sickle cell disease. We initially meet Gerardo at the Comprehensive Sickle Cell Clinic for routine follow-up. He has splenic enlargement, a flow murmur, mild scleral icterus, and a normal neurological exam. All are expected findings in a child with sickle cell disease. Four days later, he returns to the clinic with difficulty breathing, chest pain, and a temperature of 102 degrees. On physical exam, his nares are flaring, he is tachypneic with decreased breath sounds, and abdominal exam reveals splenomegaly. Chest X-ray displays bilateral infiltrates and cardiomegaly. Gerardo is diagnosed with ACS and appropriately treated in the hospital for seven days. At the conclusion of this case, we learn about the course of Gerardos disease over the following several years. Key Findings from History
Chest pain

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Tachypnea with rhonchi

Key Findings from Physical Exam

Decreased breath sounds Hypoxia Fever Increased splenomegaly

Acute chest syndrome Sepsis

Differential Diagnosis

Rib infarction Congestive heart failure Pericarditis

New infiltrates on chest X-ray

Key Findings from Testing

Cardiomegaly Leukocytosis

Final Diagnosis

Sickle cell disease with acute chest syndrome

Case highlights: Students work through the history and physical to arrive at a diagnosis of acute chest syndrome. In the process they learn how to evaluate pain in a child with sickle cell disease, recognize the complications of the disease, and learn how to manage both acute chest syndrome and pain in vaso-occlusive crises. Students also learn about inheritance of an autosomal recessive disorder and how to explain compound heterozygotes. Multimedia features include: Audio of patient wheezing and its interpretation and a photo of enlarged tonsils.

Key Teaching Points

Knowledge
Sickle cell disease (SCD): Pathophysiology Substitution of valine for glutamic acid at the sixth amino acid position of the hemoglobin molecule. This abnormal hemoglobin polymerizes when deoxygenated. Polymers then deform the red blood cell into characteristic sickle cells. Sickle cells have increased adherence and block blood flow in the microvasculature. Result: Local tissue hypoxia, pain, and tissue damage The abnormal hemoglobin also induces hemolysis of the red blood cells

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(RBCs), leading to chronic anemia and elevation of the reticulocyte count. Inheritance Gene mutation frequency 710% among African-Americans living in the United States. Sickle cell trait is also seen in the Hispanic population but with a lower gene frequency. Autosomal recessive: Normal gene (A) Sickle hemoglobin gene (S) If both parents have one copy of the sickle cell gene (S), then: 25% of offspring could have sickle cell disease (SS) 25% are expected to have normal AA globin 50% are expected to have sickle cell trait (AS): A A S AA AS S AS SS

Potential developmental effects of chronic disease Impaired academic progress due to frequent absences from school as a result of hospitalization, illness, or physician appointments Diminished socialization and self-esteem since unable to do many of the things other children may do Disrupted family interactions due to financial hardship from cost of medications and lost work time Sibling issues due to attention imbalance or sibling guilt Because of missed school, complications from stroke, and/or frequent pain, adolescents with SCD have significant challenges in our education system.

Skills
History: Comprehensive visit for SCD Assess how family accesses health care and how they are coping with stress of chronic illness: Teach what to do/where to go for specific issues. Refer to appropriate counseling resources if needed. Ask how they deal with complications: Assess frequency of painful or other vaso-occlusive problems to

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understand if there is an indication for more aggressive interventions (e.g., use of hydroxyurea). Evaluating pain A scale that shows faces (in stages from happy to crying) is validated for children age ! 4 years. Children with SCD who have frequent pain crises sometimes understand the faces scale earlier than age 4 (even as young as 2). Sometimes, even children over 4 years are too ill to comply with the request. In this case, parental judgment is best tool for assessing childs pain. Physical exam: General: Growth impairment common in children with SCD due to chronic anemia, poor nutrition, painful crises, endocrine dysfunction, and/or poor pulmonary function. HEENT: Observe sclera for signs of icterus (clue to the degree of RBC hemolysis). CV: Flow murmur common in SCD Abdomen: Enlargement of the spleen is common during first few years of life in children with SCD. Massive enlargement or rapid change in spleen size can indicate sepsis or splenic sequestration crisis (life-threatening complication that occurs when blood pools in the spleen, leading to severe anemia and shock). Routine assessment of the spleen size by the parents can lead to earlier detection and treatment. Spleen becomes progressively fibrotic and, by the time the child is four to six years old, is no longer palpable. Children with hemoglobin SC or S beta thalassemia can have splenic enlargement into adolescence. Neurologic: Evaluate for potential stroke.

Differential diagnosis
1. Acute chest syndrome (ACS): One of the most common causes of death in patients with SCD. Clinical features: Fever, cough, chest pain, shortness of breath, and decreased oxygenation. Chest X-ray findings: Multilobar infiltrates (more commonly lower and middle lobes), effusions, and atelectasis. Difficult to discern if lung infiltrate due to infection, pneumonia, or atelectasis.

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2. Sepsis: Decreased splenic function in SCD leads to decreased resistance to infection with encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae type b, Neisseria meningitidis). Usually non-focal New infiltrates would not be a usual finding unless the sepsis leads to acquired/adult respiratory distress syndrome (ARDS). 3. Rib infarction: Always consider when child with SCD presents with chest pain (could be vaso-occlusive crisis) 4. Congestive heart failure (CHF): Can occur in patients with SCD and chronic anemia. Tachypnea is common sign of CHF in children. Usually does not cause chest pain on its own. 5. Pericarditis: Uncommon cause of chest pain Presents with tachypnea and fever Can present with effusion and infiltrate

Studies
Newborn screening for SCD: Knowing a newborns screening results is important, because beginning penicillin prophylaxis as soon as possible (definitely by two months of age) is vital in preventing pneumococcal sepsis. Universal screening for inherited blood cell disorders now occurs in virtually all of the states and in the District of Columbia. Nomenclature seen on the newborn screen At birth, the predominant hemoglobin is hemoglobin F (fetal). Normal adult hemoglobin is hemoglobin A. Hemoglobin F is always listed first, followed by other hemoglobins listed in order of concentration: FS would be the most common hemoglobin pattern when looking for sickle cell disease. When one of the globin genes has a mutation for S and the other has a mutation for thalassemia (i.e., produces little or no normal hemoglobin) you may see patterns such as FSA (S-beta thalassemia +) or FS (S-beta thalassemia 0), both of which are sickling disorders. When one gene has the S mutation and one gene has the mutation for hemoglobin C, then the pattern is FSC. Hemoglobin patterns (at birth, hemoglobin F predominant)

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FS

Most common hemoglobin pattern for sickle cell disease One globin gene has a mutation for S, and the other has a mutation for thalassemia, producing sickling disorders of a milder phenotype One gene has the S mutation and the other has the mutation for hemoglobin C

FSA or FS

FSC

Prenatal diagnosis of SCD: Sample fetal blood obtained in utero. DNA extraction from chorionic villi. Complete blood count (CBC): Hemoglobin, hematocrit, and reticulocyte count can be interpreted only in relation to prior values and whether or not the child has had recent transfusion therapy. Baseline hemoglobin for children with sickle cell is often between 6 and 9 mg/dL. Although there is accommodation to the chronic anemia, the lower the baseline hemoglobin, the more difficult it is for the patient to withstand any acute change. Patients with SCD frequently demonstrate an exaggerated leukocytosis and thrombocytosis in response to stress; CBC findings do not usually definitively help to identify pneumonia or which of the ACS causes is present. Transcranial Doppler: Study of intracranial blood-vessel flow to assess risk of stroke.

Management
Chronic issues in SCD: Anemia can cause chronic fatigue; will be more severe due to myelosuppression from infections such as Parvovirus or from hypersplenism (when spleen enlarges and traps blood cells). Signs of medical emergencies in SCD: Fever May be the only sign of serious infection

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Slurred speech Stroke 10% of children with SCD have a stroke by age 15 years. An exchange transfusion may be indicated to lower the hemoglobin-S level and prevent progression or recurrence. Tachypnea, chest pain, cough Lungs are a site of sickling problems: Acute chest syndrome (ACS) May be result of infectious process, intrapulmonary sickling or pulmonary fat embolism (all appear similar on chest X-ray) Requires supplemental oxygen and transfusion therapy Increased jaundice Baseline jaundice typical in SCD and not an emergency Marked increase in the level of jaundice, however, may indicate an increase in the degree of hemolysis and a need for transfusion (may be associated with a viral illness) Increased pallor Baseline pallor is a typical finding from the anemia of SCD and does not constitute an emergency. Increased pallor, however, can be due to splenic sequestration, increased hemolysis, or a temporary inhibition of erythroid production (aplastic crisis). Priapism Sickling in the penile arteries can cause permanent damage. Prevention of complications: Antibiotic prophylaxis Due to decreased splenic function and consequent decreased resistance to infection with encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae type b, Neisseria meningitidis), infants and young children with SCD are at increased risk for sepsis. When given to infants with sickling disorders, penicillin significantly decreases the risk of mortality from overwhelming sepsis. Prophylaxis is usually continued until the child is five or six years of age (after this, little data to support its use except in patients who have had documented sepsis and bacteremia, or who have had their spleens removed). Immunization Hemophilus influenza type B conjugate vaccine and 13-valent pneumococcal

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conjugate vaccine (Prevnar 13) given at two, four, and six months. To expand antibody coverage beyond the 13 initial serotypes, children with sickling disorders also receive the 23-valent pneumococcal polysaccharide vaccine at two years of age, with a repeat dose three to five years later. The meningococcal conjugate vaccine is also given at age two years to children with functional asplenia (most children with SCD), with a booster dose three to five years later. Annual influenza vaccine Management of complications: Acute chest syndrome (ACS) Pain Can decrease the ability to fully expand the lungs. Narcotic analgesia relieves the pain and improves ability to take a deep breath Narcotics are respiratory depressants, however, and therapeutic balance must be carefully maintained. Hydration Intravenous infusion because respiratory distress and tachypnea both increase fluid demands and make it difficult for the child to tolerate oral liquids. Correct dehydration, provide replacement for insensible losses (increased with fever and tachypnea), and give maintenance fluids. 1.5 times normal maintenance because dehydration may contribute to intracellular hemoglobin polymerization and RBC sickling With ACS, avoid hydrating too vigorously and causing pulmonary edema from volume overload Incentive spirometry Encourage deep breathing to avoid atelectasis Antibiotics Practice guidelines and clinical data support the use of antibiotics in ACS Infectious agents causing ACS include: Viruses, chlamydia, mycoplasma, and bacteria. Effective antibiotic choices depend on local patterns of antimicrobial resistance. Transfusion of packed RBCs if: Hemoglobin below baseline Increasing respiratory rate or chest symptoms Declining oxygen saturation

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Progressive infiltrates Exchange transfusion or erythrocytapheresis Reserve for especially severe disease and/or hypoxemia not corrected by oxygen therapy. Sepsis 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 therapy. Children with sickle cell disease also get normal colds and other viral illnesses. Lack of normal splenic function as well as other more subtle immunologic deficiencies call for a rapid and aggressive approach. Waldeyers ring lymphoidal-tissue hypertrophy Common in children with SCD, evidenced by: Excessive snoring Obstructive sleep apnea Treatment: Tonsillectomy with adenoidectomy Bilirubin gallstones Result of increased release of hemoglobin during the breakdown of the abnormal red blood cells. Rare in the first five years of life; found increasingly in adolescents. Treatment: Cholecystectomy (if symptomatic cholelithiasis)

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