Internal Medicine Sickle Cell Crisis Case File

Internal Medicine Sickle Cell Crisis Case File

Eugene C. Toy, MD, Gabriel M. Aisenberg, MD

Case 58

A 25-year-old African American man is admitted to your service with the diagnosis of a sickle cell pain episode. He was admitted to the hospital six times last year with the same diagnosis, and he was last discharged 2 months ago. This time, he presented to the emergency department complaining of abdominal and bilateral lower extremity pain, his usual sites of pain. When you examine him, you note his temperature is 101 °F, blood pressure is 110/81 mm Hg, heart rate is 100 beats per minute (bpm), and respiratory rate is 25 breaths per minute. Lung examination reveals bronchial breath sounds and egophony in the right lung base. His oxygen saturation on 2 L/min nasal cannula is 92%. Besides the usual abdominal and leg pain, he is now complaining of chest pain, which is worse on inspiration. Although he has tenderness on palpation of his extremities, the remainder of his examination is normal. His laboratory examinations reveal elevated white blood cell and reticulocyte counts and a hemoglobin and hematocrit that are slightly lower than baseline. Sickle and target cells are seen on the peripheral smear.

▶ What is the most likely diagnosis?

▶ What is the most appropriate next step in management?

▶ What are the potential complications of this condition?

▶ What are the best treatment options for the probable condition?

ANSWERS TO CASE 58:

Sickle Cell Crisis

Summary: A 25-year-old African American man presents with

• A history of numerous pain crises
• Fever, tachypnea, oxygen saturation of 92% on 2 L via nasal cannula, and slight tachycardia
• Abdominal pain, lower extremity pain, and chest pain that is worse on inspiration
• Bronchial breath sounds and egophony in the right lung base
• Leukocytosis, elevated reticulocyte count, and lower than baseline hemoglobin and hematocrit
• Sickle and target cells on the peripheral blood smear

Most likely diagnosis: Acute chest syndrome (ACS) since the patient has fever and chest pain with respiratory symptoms.

Next step in management: Chest radiograph and empiric antibiotic therapy.

Potential complications: Respiratory failure, possible death.

Best treatment options: Aside from empiric antibiotic therapy, oxygen, pain control, incentive spirometry, and blood transfusion (simple if mild symptoms or exchange transfusion if severe).

ANALYSIS

Objectives

1. Understand the pathophysiology of sickle cell anemia and acute painful episodes. (EPA 12)
2. List the acute and chronic complications of sickle cell anemia. (EPA 10, 12)
3. Describe the treatment options available for the complications of sickle cell anemia. (EPA 4)

Considerations

The patient in this case, a 25-year-old man with known sickle cell disease and a history of numerous pain crises, is admitted with abdominal pain and bilateral leg pain. He also has the acute onset of chest pain, cough, fever, and abnormal findings on pulmonary auscultation. His oxygen saturation is only 92% on 2 L oxygen via nasal cannula, which is concerning. Pulmonary embolism, pneumonia, and ACS should be considered as possible diagnoses. ACS is a constellation of symptoms that includes chest pain and tachypnea. It can result from infection or from noninfectious causes such as pulmonary infarction or fat embolism. It usually presents with some combination of chest pain, fever, hypoxia, and a new pulmonary infiltrate on chest radiography. Often, ACS and pneumonia cannot be initially distinguished.

Therefore, it is prudent to treat these patients with antibiotics, obtain a Gram stain and culture of the sputum, and admit them to the hospital. The treatment for ACS is supportive and includes oxygen, intravenous fluid hydration, broad-spectrum antibiotics, analgesia, and transfusion. With significant disease, an exchange transfusion may be necessary. These patients should be carefully evaluated because significant morbidity or mortality can result.

APPROACH TO:

Sickle Cell Anemia

DEFINITIONS

ACUTE CHEST SYNDROME: A condition found in individuals with sickle cell disease; the condition is characterized by fever, tachycardia, chest pain, leukocytosis, and pulmonary infiltrates.

SICKLE CELL ANEMIA: A congenital defect in hemoglobin formation such that both genes code for hemoglobin S, leading to hemolysis and an abnormal shape of the red blood cell. Affected individuals have numerous complications, including pain crises.

CLINICAL APPROACH

Pathophysiology

Sickle cell anemia is the most common autosomal recessive disorder and the most common cause of hemolytic anemia in African Americans. Approximately 8% of African Americans carry the gene (ie, sickle cell trait), with 1 in 625 affected by the disease.

The molecular structure of a normal hemoglobin molecule consists of two alpha-globin chains and two beta-globin chains. Sickle cell anemia is an autosomal recessive disorder resulting from a substitution of valine for glutamine in the sixth amino acid position of the beta-globin chain. Individuals in whom only half of their beta chains are affected are heterozygous, a state referred to as sickle cell trait. When both beta chains are affected, the patient is homozygous and has sickle cell anemia. In patients with sickle cell disease, the altered quaternary structure of the hemoglobin molecule causes polymerization of the molecules under conditions of deoxygenation. These rigid polymers distort the red blood cell into a sickle shape, which is characteristic of the disease. Sickling is promoted by hypoxia, acidosis, dehydration, or variations in body temperature.

Pain Crises. These are also called acute painful episodes and result from microvascular occlusion of bones by sickled cells. The most common sites are the long bones of the arms and legs, the vertebral column, and the sternum. Acute painful episodes are precipitated by infection, hypoxia (ie, at high altitude), cold exposure, dehydration, venous stasis, or acidosis. They usually last 2 to 7 days.

Infections. Patients with sickle cell disease are at greater risk for infections, especially with encapsulated bacterial organisms. Infarction of the spleen occurs during early childhood secondary to microvascular obstruction by sickled red blood cells. The spleen gradually regresses in size and by age 4 is no longer palpable. As a consequence of infarction and fibrosis, the immunologic capacity of the spleen is diminished. Patients with sickle cell disease are at greater risk for pneumonia, sepsis, and meningitis by encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae. For the same reason, patients with sickle cell disease are at greater risk for osteomyelitis with Salmonella spp.

Acute Chest Syndrome. This a vaso-occlusive crisis in the lungs and may be associated with infection or pulmonary infarction. It is characterized by the presence of the following signs and symptoms: new pulmonary infiltrate, chest pain, fever, and respiratory symptoms such as tachypnea, wheezing, or cough. These episodes may be precipitated by pneumonia causing sickling in the infected lung segments or, in the absence of infection, intrapulmonary sickling can occur as a primary event. It is virtually impossible to clinically distinguish whether or not infection is present; thus, empiric antibiotic therapy is recommended.

Aplastic Crisis. This occurs secondary to viral suppression of red blood cell precursors, most often by parvovirus B19. It occurs because of the very short half-life of sickled red blood cells and consequent need for brisk erythropoiesis. If red blood cell production is inhibited, even for a short time, profound anemia may result. The process is acute and usually reversible, with spontaneous recovery.

Other Complications. Other complications include hemorrhagic or ischemic stroke as a result of thrombosis, pigmented gallstones, papillary necrosis of the kidney, priapism, pulmonary hypertension, and heart failure.

Treatment

Patients admitted with sickle cell crises should have a complete blood cell count and reticulocyte count upon admission. While this intervention does not change management substantially, it helps determine baseline values, risk stratify patients with suspected concomitant infection, and rule out aplastic crisis. To protect against encapsulated organisms, all patients with sickle cell disease should receive penicillin prophylaxis and a vaccination against pneumococcus.

The mainstays of treatment of a pain crisis are hydration and pain control with nonsteroidal anti-inflammatory agents and narcotics. It is important to also provide adequate oxygenation to reduce sickling. One must search diligently for any underlying infection and start empirical treatment with antibiotics when infection is suspected. ACS is treated with oxygen, analgesia, and antibiotics.

In general, blood transfusions may be required for aplastic crisis, for severe hypoxia in ACS, or to decrease viscosity and cerebral thrombosis in patients with stroke. Transfusion does not shorten the duration of a pain crisis. In severe disease, especially when simple transfusions do not control the severity, exchange transfusions have shown benefit.

Hydroxyurea is often used to reduce the occurrence of painful crises or ACS. This medication works by stimulating hemoglobin F production and thus decreasing hemoglobin S concentration. The antineoplastic agent 5-deoxyazacytidine (decitabine) may also elevate levels of hemoglobin F without excessive side effects.

Phosphodiesterase type 5 inhibitors such as sildenafil promote smooth muscle relaxation in the lungs and can treat pulmonary hypertension. Endothelin receptor agonists such as bosentan can improve pulmonary hypertension caused by sickle cell disease. The mechanism of this agent is competitive binding to endothelin 1 (ET-1) receptors A and B in the pulmonary vascular endothelium. Because of the numerous transfusions, sometimes iron chelators are needed to prevent iron overload (which may lead to heart or liver failure).

Emerging Concepts. Research is being concentrated on allogeneic hematopoietic stem cell transplantation, which can be curative. In children with severe disease, myeloablative stem cell transplantation has been effective if there is a sufficiently matched donor such as a sibling. There are side effects in approximately 10% of patients. Adults usually have more complications. Gene therapy is only in its initial stages of research but holds promise.

CASE CORRELATION

• See also Case 54 (Iron-Deficiency Anemia), Case 55 (Symptomatic Anemia and Transfusion Medicine), and Case 56 (Immune Thrombocytopenia Purpura/Abnormal Bleeding).

COMPREHENSION QUESTIONS

58.1 A 32-year-old woman with a known history of sickle cell anemia presents to the emergency department for the fifth time this year, complaining of diffuse abdominal pain and severe bilateral lower extremity pain typical of her previous pain crises. Normally, she takes hydrocodone/acetaminophen every 8 hours, but for the past day she has required doses every 4 hours without relief. Which of the following therapies would most likely decrease her number of sickle cell crises?

A. Hydroxyurea

B. Folate supplementation

C. Prophylactic penicillin

D. Pneumococcal vaccination

58.2 A 31-year-old man with a history of diabetes mellitus and sickle cell anemia presents to the emergency department with 2 days of cough, chest pain, and difficulty breathing. His temperature is 100.7 °F, blood pressure is 112/65 mm Hg, heart rate is 117 bpm, respiratory rate is 22 breaths/min, and pulse oximetry shows 94% on room air. White blood cell count is 13,000/mm3, and hemoglobin is 9.9 g/dL (baseline of 10.1 g/dL). Chest x-ray reveals a right lower lobe opacity. Blood and sputum cultures are collected. Which of the following is the most appropriate empiric antibiotic therapy for this patient?

A. Vancomycin

B. Ceftriaxone

C. Cefotaxime and azithromycin

D. Penicillin

58.3 A 6-year-old boy with a history of sickle cell anemia is brought to the emergency department by his parents because of the boy’s 4 days of fatigue. The patient is up to date on all his immunizations. His home medications include penicillin and folic acid. His temperature is 99.3 °F, blood pressure is 102/70 mm Hg, heart rate is 116 bpm, respiratory rate is 22 breaths/min, and oxygen saturation shows 96% on room air. On physical examination, he appears pale, but he has normal chest, respiratory, and abdominal examinations. His white blood cell count is 7000/mm3, hemoglobin is 6.5 g/dL, platelet count is 27,000/mm3, and reticulocyte count is 0.2%. Which of the following is the most likely diagnosis?

A. Acute chest syndrome

B. Splenic sequestration

C. Aplastic anemia

D. Aplastic crisis

58.4 Which of the following is the most likely organism responsible in

Question 58.3?

A. Streptococcus pneumoniae

B. Salmonella spp

C. Parvovirus B19

D. Staphylococcus aureus

ANSWERS

58.1 A. Hydroxyurea and decitabine may decrease the incidence of sickle cell crises by increasing levels of hemoglobin F. Penicillin prophylaxis (answer C) and pneumococcal vaccine (answer D) protect against encapsulated organisms. While folate supplementation (answer B) is needed for hematopoiesis, it has no effect on the number of sickle cell crises.

58.2 C. In patients with suspected ACS and/or pneumonia, the third-generation cephalosporin cefotaxime, together with a macrolide such as azithromycin, is optimal to provide coverage for the most common pathogens, such as S. pneumoniae and Moraxella, respectively. Azithromycin or erythromycin provides coverage for atypical organisms, such as Mycoplasma and Chlamydia. Although a cephalosporin such as ceftriaxone (answer B) is appropriate to cover for common gram-positive and gram-negative etiologies of pneumonia, this patient with likely autosplenectomy requires broader coverage. In very ill patients or if a large and/or increasing infiltrate concerning for methicillin-resistant Staphylococcus aureus (MRSA) is suspected, vancomycin (answer A) can be added, but it is not routinely used as an initial stand-alone agent. Answer D (penicillin) is insufficient coverage for pneumonia due to high resistance.

58.3 D. In sickle cell patients, aplastic crisis can result from a temporary stop in red blood cell production, characterized by a very low hemoglobin and reticulocyte count less than 1%. In contrast, aplastic anemia (answer C) is defined as pancytopenia in patients without sickle cell disease. Splenic sequestration (answer B) is associated with abdominal pain, increased reticulocytes, and an acute drop in hemoglobin due to vaso-occlusion and pooling of red blood cells in the spleen. In ACS (answer A), chest pain and respiratory symptoms are commonly seen.

58.4 C. In children with sickle cell anemia, aplastic crisis is most commonly associated with parvovirus B19. Staphylococcus aureus (answer D) and Salmonella (answer B) are the most common causes of osteomyelitis in sickle cell patients. It is important to remember the association between sickle cell anemia and Salmonella osteomyelitis. S. pneumoniae (answer A) is the most common causative agent for pneumonia in sickle cell patients.

CLINICAL PEARLS

▶ Treatment of an acute painful episode in sickle cell anemia includes hydration, narcotic analgesia, adequate oxygenation, and the search for an underlying infection.

▶ Acute chest syndrome is characterized by chest pain, fever, new radio-graphic pulmonary infiltrate, and respiratory symptoms; it can be caused by pneumonia, vaso-occlusion, or pulmonary embolism.

▶ Blood transfusion may be required for aplastic crisis, for severe hypoxemia in ACS, or to decrease viscosity and cerebral thrombosis in patients with stroke.

▶ In sickle cell patients, parvovirus B19 is commonly associated with aplas-tic crisis, and Salmonella is commonly associated with osteomyelitis.

▶ Hydroxyurea and decitabine increase hemoglobin F production (decreasing hemoglobin S concentration) and thus reduce the frequency of pain crises and other complications.

REFERENCES

Benz EJ. Disorders of hemoglobin. In: Kasper DL, Fauci AS, Hauser SL, et al, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw Hill; 2015:631-639. 

Bernard AW, Venkat A. Full blood cell count and reticulocyte count in painful sickle crisis. Emerg Med J. 2006;23(4):302-303. 

Howard J, Hart N, Roberts-Harewood M, et al. Guideline on the management of the acute chest syndrome in sickle cell disease. Br J Haematol. 2015;169(4):492-505 

Steinberg MH. Management of sickle cell disease. N Engl J Med. 1999;340:1021-1030. 

Vichinsky E. New therapies in sickle cell disease. Lancet. 2002;360:629-631. 

Vichinsky EP, Styles LA, Colangelo LH, Wright EC, Castro O, Nickerson B. Acute chest syndrome in sickle cell disease: clinical presentation and course. Cooperative Study of Sickle Cell Disease. Blood. 1997;89:1787-1792.

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