QUESTION 1: B.C. is a 4-month-old girl who has recently been diagnosed with sickle cell anemia (both
How does B.C.’s diagnosis affect her risk of infections?
B.C. is at an increased risk for infections because sickle cell anemia causes
defects in splenic function, complement activation, granulocyte function, and B-cell
immunity, as well as micronutrient deficiencies.
increases B.C.’s risk for infection from polysaccharide-encapsulated bacteria such as
Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and
Salmonella typhimurium. These infections occur most frequently in early childhood,
although B.C. will have a lifelong increased risk of infection. Pneumonia caused by
S. pneumoniae, mycoplasma, or viruses can worsen hypoxia, causing progression to
vaso-occlusion and acute chest syndrome (discussed in more depth below).
Pulmonary complications from pneumonia or vascular occlusion can also lead to
right-sided heart failure. Other infectious conditions such as osteomyelitis from
Staphylococcus aureus or S. typhimurium or urinary tract infections caused by
Escherichia coli are common complications in patients with sickle cell anemia.
CASE 92-6, QUESTION 2: What preventive measures should be taken to prevent infections in B.C.?
Patients with sickle cell anemia should use general preventive measures, such as
frequent hand-washing, avoiding sick contacts,
and thoroughly cooking foods that may carry Salmonella (e.g., chicken or eggs).
Children should be closely monitored for symptoms and antibiotic therapy should be
instituted at the earliest sign of infection. Prophylactic administration of penicillin
has significantly reduced morbidity and mortality from pneumonia in children
50 and is recommended to be continued through age 5.
Patients such as B.C. should receive 62.5 mg twice daily during the first year of life,
increased to 125 mg twice daily for ages 1 through 3, then 250 mg twice daily until
the age of 5. The US guidelines recommend discontinuing penicillin prophylaxis at
age 5 unless the child has undergone splenectomy or has had an invasive
Vaccines that are recommended for patients with homozygous sickle cell include
all standard pediatric and adult vaccines. B.C. also should receive the pneumococcal
23-valent polysaccharide vaccine at 2 and 5 years of age with a booster every 10
47 Because patients with sickle cell typically respond
poorly, only 50% of patients will be protected by vaccination. Therefore, there is a
continued need for penicillin prophylaxis in young children.
CASE 92-6, QUESTION 3: B.C. is now 3 years old and presents with pallor and significantly decreased
and rash. Her pediatrician obtains a CBC with the following results:
What is a potential cause of B.C.’s symptoms and how should they be managed?
Human parvovirus (HPV) B19 is a common cause of transient RBC aplasia, with
up to 67% of infections resulting in a hematologic change typical of aplasia.
common, highly contagious childhood infection with more than 70% of adults testing
49 Nearly 70% of all homozygous sickle cell patients are HPV B19
seropositive by 20 years of age.
In normal individuals, the infection is
asymptomatic or presents as mild flu-like symptoms with or without a generalized
maculopapular rash. The virus also infects RBC progenitor cells in the bone marrow,
causing a temporary 7- to 10-day cessation of erythropoiesis in 65% to 80% of
infected individuals. In normal individuals, RBC lifespan is 120 days and this does
not typically produce symptoms. Patients with sickle cell anemia have an RBC
lifespan of 5 to 15 days, so the temporary break in erythropoiesis leads to a severe
anemia. Thrombocytopenia has been noted in approximately one-fourth of those
infected with less than 20% of patients experiencing neutropenia. Although most
children recover within 2 weeks, the majority will require blood transfusions to
QUESTION 1: J.T. is an 18-year-old man with sickle cell anemia who presented to the emergency
department with rapid onset of abdominal pain and shortness of breath.
clear. Splenomegaly is noted, and a chest radiograph reveals only cardiomegaly.
A CBC is obtained. Notable results include the following:
consistent with sickle cell anemia? What is J.T.’s current complication?
Vaso-occlusive crisis, or “sickle cell crisis,” is caused by severe pain and organ
damage. These may be precipitated by many factors including hypoxia, dehydration,
55 Based on the presence of splenomegaly and anemia with
target and sickled cells, J.T. currently is presenting with an acute splenic
sequestration crisis. Acute splenic sequestration is caused by the trapping of RBCs
within the spleen. This causes splenomegaly and progressive anemia. The low
reticulocyte count is consistent with acute sequestration because a reticulocyte
response would be expected if the anemia had developed in recent days. J.T.’s
inadequate reticulocyte response may reflect rapid progression of the anemia, HPV
B19 infection, or a blunted EPO response secondary to compromised renal
CASE 92-7, QUESTION 2: How should J.T. be treated?
J.T.’s signs and symptoms are sufficiently serious to justify transfusion therapy.
In addition, J.T. should be adequately hydrated, considering his elevated serum
creatinine and blood urea nitrogen. Because patients with sickle cell anemia often
lose the ability to concentrate urine, they may become dehydrated, which further
contributes to cell sickling. The pain associated with a crisis typically lasts at least 2
to 6 days and should be managed with analgesics including parenteral opioids for
severe pain. Pain control should be aggressively instituted for J.T.’s comfort and
should be continued for a few days after hospital discharge (also see Chapter 55,
Pain Management). It is important not to withhold opioids because of a fear of
Splenectomy may be indicated in instances of severe splenomegaly, repeated
infarction, or pain in adults and it is indicated when crises occur in children. Those
patients with sickle cell anemia who are bedridden should be placed on chronic
heparin therapy to prevent vascular occlusions and deep vein thrombosis.
CASE 92-7, QUESTION 3: J.T. presents to the emergency department 3 months later with complaints of
admission within the last year. Notable laboratory results include the following:
should he be treated for this condition?
J.T. is experiencing acute chest syndrome, a leading cause of morbidity and
mortality in patients with sickle cell disease. The diagnosis of acute chest syndrome
is determined by new pulmonary infiltrates on chest radiograph with one or more of
the following: fever, cough, worsening anemia, and pleuritic or nonpleuritic chest
pain. Patients may also experience shortness of breath, rales, hypoxia, and wheezing
51 Causes of acute chest syndrome include pulmonary
fat embolism, pulmonary infarction, and infection.
3 Commonly implicated organisms
i nc l ude Chlamydia pneumoniae, Mycoplasma pneumoniae, S. pneumoniae,
Haemophilus influenzae, and various viruses.
The primary goal of treatment is to prevent progression to acute respiratory
failure; therefore, treatment should involve pain management, hydration, oxygen
supplementation, incentive spirometry, antibiotics, and, potentially, transfusion.
Optimal pain control and incentive spirometry are important to prevent
hypoventilation and atelectasis, as well as to increase patient comfort. Oxygen should
be administered nasally to patients who are moderately hypoxemic (O2 saturation,
, 70–80 mm Hg), as J.T. is. Patients who are febrile or severely ill
should receive IV broad-spectrum antibiotics as it is difficult to exclude bacterial
causes of acute chest syndrome. Empiric antibiotic therapy should take into account
the commonly implicated organisms described above.
Transfusions are used to increase the oxygen affinity of blood and are indicated in
patients with hypoxemia or whose clinical status is deteriorating and with a
hemoglobin >1.0 g/dL less than baseline. J.T. should be monitored closely for
deteriorating respiratory function and should receive transfusions if his clinical status
TREATMENT FOR FREQUENT VASO-OCCLUSIVE CRISES
Hemoglobin F has a protective effect against Hgb polymerization. Investigators
have observed that patients with HbF levels greater than 20% experience a relatively
mild or benign course with fewer vaso-occlusive crises.
found to increase HbF synthesis which may decrease RBC sickling and the
occurrence of disease-related complications.
prophylactically in patients with recurrent moderate-to-severe vaso-occlusive crises
but not in acute treatment. The use of hydroxyurea in the sickle cell population should
be carefully weighed for risk versus benefit, because it is a cytotoxic agent
associated with bone marrow suppression. The US guidelines recommend
hydroxyurea for adult patients who have three or more sickle cell-associated
moderate-to-severe pain crises in a 12-month period.
51 Patients taking hydroxyurea
should have bone marrow studies performed before therapy and periodically during
therapy. Other adverse effects of hydroxyurea include GI effects (nausea, vomiting,
diarrhea), dermatologic effects (maculopapular rash, pruritus), and potential risk of
developing a secondary neoplasm (leukemia) with prolonged use. The treatment dose
of hydroxyurea for sickle cell anemia is 15 to 35 mg/kg/day. Goals of therapy include
improvement in pain and well-being, increase in HbF, increased Hgb (if severely
anemic), and maintenance of acceptable platelet and granulocyte counts. After
initiation of therapy, blood counts should be monitored closely and the dose adjusted
based on efficacy and tolerability. Several clinical trials evaluating hydroxyurea
show improvement in the clinical course of patients with sickle cell anemia.
Other areas of potential promise for the treatment of sickle cell anemia include bone
marrow transplantation and gene therapy.
CASE 92-7, QUESTION 5: Despite optimal treatment with hydroxyurea, J.T. continues to experience
J.T.’s serum ferritin is noted to be 1,050 mcg/L. What potential adverse effect of treatment is the
hematologist’s concern? What other tests may be performed to detect this?
Patients requiring chronic transfusions of PRBCs are at an increased risk for iron
toxicity due to iron overload.
62 Normally, plasma iron binds with transferrin;
however, if transferrin becomes saturated, patients will have higher levels of toxic
nontransferrin-bound iron. As nontransferrin-bound iron increases, it deposits in
other organs, most frequently the liver. Therefore, nontransferrin-bound iron
produces free radicals, causing tissue damage and fibrosis.
Patients with sickle cell disease should be monitored for iron overload.
Obtaining a serum ferritin level is the most commonly used method of screening for
iron overload, although the accuracy of this test is affected by inflammatory
processes. Thus, serial serum ferritin values should be obtained when patients are
not experiencing an acute crisis (i.e., steady-state values). More specific tests such as
magnetic resonance imaging measure iron levels in organs such as the heart, liver,
pancreas, and spleen although may not be routinely used because of cost.
standard for assessing iron overload is liver iron concentration by biopsy, although
this is an invasive procedure that should be performed by specialists.
Does J.T. meet the criteria to receive iron chelation therapy? What options are available?
J.T. meets criteria for iron chelation therapy because of his steady-state serum
ferritin levels being consistently more than 1,000 mcg/L and his liver iron
concentration being greater than 7 mg/g dry weight.
patient to receive iron chelation therapy include transfusion of approximately 100
mL/kg of PRBCs, or 20 units for a 40-kg or more patient.
There are three iron chelators currently approved for use in patients with sickle
cell disease; their dosing and adverse effects are summarized in Table 92-10. These
agents work by binding free iron present in circulation and tissues. The iron is then
excreted in the urine and bile.
Deferoxamine (DFO) is the oldest agent and has the most clinical experience.
Deferoxamine and deferasirox have been studied in patients with sickle cell disease
who are as young as 2 years old; deferiprone is not approved for use in children.
Because of its short half-life, DFO must be administered daily via continuous IV or
subcutaneous infusion for 5 days. Deferasirox has a longer half-life, allowing for
once-daily oral administration and enhanced patient convenience and adherence. A
study of 195 patients with sickle cell disease observed similar reductions in iron
levels between patients receiving DFO and patients receiving deferasirox at
63 Additionally, more patients in the deferasirox group reported
their treatment was convenient.
62 Deferiprone has predominantly been studied in
patients with transfusional iron overload with inadequate response to other iron
chelating therapies although it has been shown to be similar to deferasirox in patients
64 Deferoxamine is associated with more dose-dependent
oculotoxicity and audiotoxicity, although both agents may cause this.
has been associated with more nephrotoxicity, hepatotoxicity, and cytopenias. Either
DFO or deferasirox is appropriate for J.T. at this time.
FDA-Approved Iron Chelation Therapies
Medication Dose Frequency Route
Deferiprone 75 mg/kg/day 3 times Oral tablet Common: chromaturia, Urine may be
daily nausea, vomiting, abdominal
FDA, Food and Drug Administration; GI, gastrointestinal; SC, subcutaneously.
J.T. should also receive appropriate monitoring consisting of serial serum ferritin
levels and annual audiology and ophthalmology assessments. Some centers obtain a
liver biopsy every 2 years during treatment to assess efficacy.
deferasirox should have serum creatinine monitored weekly for the first month after
initiation or a dose alteration and monthly thereafter.
proteinuria and assessment of liver function tests should also be initiated for patients
Other Complications of Sickle Cell Disease
Neurologic complications are age dependent. Stroke most commonly occurs in the
first decade of life, whereas intracerebral hemorrhage is a complication associated
with adulthood. Primary prevention of stroke with RBC transfusions targeted to
maintain HbS level less than 30% reduces the incidence of stroke in high-risk
If a stroke occurs, approximately 50% of patients experience
recurrent strokes within 3 years unless they are treated by chronic RBC transfusion
45 A concern with RBC transfusion therapy is iron overload. Conflicting
evidence exists regarding the benefit of chronic hydroxyurea plus phlebotomy
(removal of blood to reduce iron burden) as an alternative option to prevent
RENAL AND GENITAL COMPLICATIONS
Renal and genital complications are common in sickle cell disease because the
environment (hypoxic, acidotic, and hypertonic) predisposes the renal medulla or
corpus cavernosum to infarction. As a result, patients might experience reduced
potassium excretion, hyperuricemia, hematuria, hyposthenuria, and renal failure.
Patients with renal disease generally have inappropriately low levels of EPO as
well. Men experiencing occlusion of the corpus cavernosum can experience acute or
chronic priapism. Conservative management includes IV fluid administration and
pain control. Refractory cases may require surgery.
Microinfarctions often produce ophthalmic, hepatic, orthopedic, and
obstetric/gynecologic complications as well. Patients with sickle cell anemia may
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