Acute chest syndrome in adults with sickle cell disease

Acute chest syndrome (ACS) is a leading cause of death for patients with sickle cell disease
(SCD). Defined as a new radiodensity on chest radiograph accompanied by fever and/or
respiratory symptoms

The severity of ACS events is categorized as mild, moderate and severe . A key difference in
the clinical presentation of ACS between children and adults with SCD is the greater disease
severity and a higher mortality rate in adults, largely due to a higher incidence of bone
marrow and fat emboli in adults . In adults with SCD, up to 77 percent of ACS episodes are
the result of bone marrow or fat emboli

approximately 50 percent of SCD will have an episode of ACS . Seventy-eight percent of

these episodes of ACS are associated with a vaso-occlusive pain episode, usually occurring
within 48 to 72 hours after hospital admission for pain ●Although ACS can occur in any
SCD phenotype, including HbS-hereditary persistence of fetal hemoglobin, individuals with
HbSS have the highest rate of ACS ●Risk factors for ACS among adults with HbSS >20
years old include increased white blood cell count, higher hemoglobin levels, and lower fetal
hemoglobin levels. Smoking and vaso-occlusive pain events have also been identified as risk
factors

clinical symptoms : chest pain / pain in the arms and legs, rib and sternal pain / sob
●Episodes of ACS in adults were more likely to be complicating vaso-occlusive pain
episodes; adults commonly had neurological findings during these ACS events . Adults were
more likely to require mechanical ventilation, have a prolonged hospital stay and have a
greater risk of death (9 versus 1 percent) compared with children.

The radiographic findings also differed by age, as adults were more likely than children to
have multilobe involvement of infiltrates

Up to one-fifth of adults with a history of ACS can develop a rapidly progressive ACS
syndrome characterized by respiratory failure and multiorgan failure.

fat embolism as a cause for 44 to 77 percent of acute chest syndrome (ACS) episodes in
adults .Bone marrow aspiration showing bone marrow necrosis and bone marrow imaging
showing recent bone marrow infarction /bronchoalveolar lavage during ACS episodes
demonstrates the presence of fat in alveolar macrophages. Adults with evidence of fat emboli
were more likely to have signs and symptoms consistent with bone marrow infarction,
including pain, neurological symptoms, and a lower platelet count.

Lipemia retinalis and petechiae are not commonly seen in fat emboli in SCD; if observed,
however, these findings would be consistent with the clinical syndrome of fat emboli. ACS
etiologies other than vaso-occlusion may also be associated with bone marrow necrosis and
fat emboli, such as parvovirus B19 infection, and may also be present .Laboratory findings in
patients with pulmonary fat emboli on bronchoscopy showed lower hemoglobin levels,
lower platelet counts, and increased numbers of circulating nucleated red blood cells. These
latter laboratory tests reflect the presence of bone marrow necrosis underlying the generation
of bone marrow and fat emboli.
 Vaso-occlusion within the pulmonary microvasculature is the basis for ACS
pathophysiology. Etiologies for ACS either trigger vaso-occlusion (eg, infection, asthma,
hypoventilation) or are a result of vaso-occlusion (eg, bone marrow and fat emboli). These
etiologies can occur together; once intra-pulmonary vaso-occlusion is initiated, it is
propagated by hypoxia, inflammation, and acidosis.

Bone marrow ischemia and necrosis, characteristic of SCD vaso-occlusive episodes, cause
the release of bone marrow and fat into the venous circulation where they primarily affect the
lungs and the central nervous system by mechanically obstructing the vasculature and
promoting a pro-inflammatory state Inflammation associated with fat emboli is likely due to
the presence of free fatty acids .Free fatty acids are highly pro-inflammatory and cause tissue
injury. Hypoxemia and inflammation associated with bone marrow and/or fat embolism
promote further vaso-occlusion, creating a vicious cycle.

Bone marrow necrosis with attendant bone marrow and fat emboli is also thought to
contribute to the etiology of acute multi-organ failure syndrome .Acute multi-organ failure
syndrome is characterized by acute dysfunction of the lung, liver and/or kidney (dysfunction
of at least two of these three organs are required to meet the definition) occurring during a
vaso-occlusive pain episode. Fever, confusion, decreased hemoglobin levels and decreased
platelet counts are also frequent . ACS associated with fat emboli are often characterized by
infiltrates, hypoxia, confusion, and thrombocytopenia occurring during a painful vaso-
occlusive episode with the predominant organ affected being the lung.

Infection and asthma, common causes of acute chest syndrome (ACS) in children with sickle
cell disease (SCD), also occur in adults The most common organisms associated with ACS
events were atypical bacteria and respiratory syncytial virus., such as Mycoplasma
pneumoniae, Mycoplasma hominis and Chlamydia pneumoniae

Non-infectious causes of ACS in adults with SCD also include etiologies that compromise
ventilation, such as over-sedation or the presence of bone infarcts involving the ribs, sternum,
or vertebrae that predispose to poor inspiratory effort .
Although there have been reports of pulmonary emboli secondary to deep venous thrombosis
associated with ACS ,in many cases these thrombi within the pulmonary vasculature contain
sickle erythrocytes suggestive of in situ thrombi related to vaso-occlusion rather than emboli
originating from deep veins

diagnostic evaluation for all adults with SCD who have a clinical presentation concerning for
ACS includes an electrocardiogram, complete blood count with white blood cell differential,
reticulocyte count, AP and lateral chest radiograph, and blood and sputum cultures.
Additional testing, including a CT of the chest to evaluate for pulmonary embolus or serum
troponin to evaluate for myocardial damage. Bronchoscopy with bronchoalveolar lavage is
typically performed in refractory or atypical cases.

Diagnostic criteria for ACS — ACS is defined as radiographic evidence of consolidation: a

new segmental (involving at least one complete segment) radiographic pulmonary infiltrate,
AND at least one of the following:●Temperature ≥38.5°C●>2 percent decrease in SpO2 (O2
saturation) from a documented steady-state value on room air (FiO2 = 0.21)●PaO2 <60
mmHg●Tachypnea ●Intercostal retractions, nasal flaring, or use of accessory muscles of
respiration●Chest pain●Cough●Wheezing ●Râles
Of importance, the presence of pneumonia can formally be considered as meeting the criteria
for ACS, since the two cannot be reliably distinguished from one another.

ACS severity index — Mild ACS — Meets the diagnostic criteria for ACS plus ALL of the
following:●Transcutaneous oxygen saturation >90 percent on room air ●Segmental or lobar
infiltrates that involve no more than one lobe by chest radiography●Responsive to simple
transfusion of no more than 2 units of red blood cells (or 15 mL/kg of packed RBCs)

Moderate ACS — Meets the diagnostic criteria for ACS plus ALL of the
following:●Transcutaneous oxygen saturation ≥85 percent on room air ●Segmental or lobar
infiltrates that involve no more than two lobes by chest radiography●Responsive to
transfusion of ≥3 units of red cells (or >20 mL/kg packed RBCs)

Severe ACS — Meets the diagnostic criteria for ACS plus one or more of the
following:●Respiratory failure present (PaO2 <60 mmHg or PCO2 >50 mmHg) ●Mechanical
ventilatory support required●Transcutaneous oxygen saturation <85 percent on room air or
≤90 percent despite maximal supplemental O2●Segmental or lobar infiltrates that involve
three or more lobes by chest radiography●Requiring transfusion or exchange transfusion of
RBCs to achieve hemoglobin A levels ≥70 percent

Very severe ACS — Acute respiratory distress syndrome (ARDS) present or sudden, life-
threatening lung failure.

rapidly progressive ACS, in which patients with ACS rapidly develop respiratory failure
within 24 hours after the onset of respiratory symptoms . Multiorgan failure often occurs.. A
decline in platelet count at presentation was the only predictor of developing rapidly
progressive ACS

D. DIAGNOSIS — pulmonary embolus, acute coronary syndrome, and pneumonia.

Pulmonary emboli originating from the deep veins of the lower extremities are challenging
to diagnose in the setting of ACS, as they are difficult to distinguish from in situ thrombi or
bone marrow or fat emboli in the pulmonary vasculature secondary to sickle cell vaso-
occlusion. In situ thrombi, bone marrow, or fat emboli are expected to be present during ACS
episodes and, in comparison to pulmonary emboli associated with deep venous thrombosis,
do not require or respond to anti-coagulation; transfusion of red cells to reduce vaso-
occlusion is the preferred treatment.

CT, ventilation-perfusion, and angiographic imaging studies performed during ACS episodes
show filling defects in pulmonary arteries, often in the area of an infiltrate resulting from
sickle cell vaso-occlusion . Symptoms and signs consistent with a vaso-occlusive pain crisis
(ie, systemic pain and increased hemolysis) are more suggestive of ACS as a causative
etiology than a pulmonary embolus. Although a patient with a pulmonary embolus may
present with shortness of breath and chest pain similar to ACS, pulmonary emboli will
typically have a chest radiograph negative for new radiodensities. However, some cases of
ACS may initially present without evidence of a lung infiltrate, with subsequent ventilation-
perfusion scans yielding evidence of widespread in situ thrombi within the lungs consistent
with ACS
Evidence in favor of the presence of pulmonary emboli includes deep venous thrombosis on
ultrasound imaging of the lower extremities or a recent period of immobility or surgery. If a
pulmonary artery filling defect is seen on imaging studies, regardless of suspected etiology,
our practice is to initiate anticoagulation unless otherwise contraindicated.

Acute coronary syndrome — Acute coronary syndrome secondary to a ruptured

atherosclerotic plaque in a coronary artery is uncommon in adults with SCD .However,
myocardial damage can occur during episodes of pain and ACS secondary to vaso-occlusion
or bone marrow or fat emboli . In the setting a vaso-occlusive pain episode, myocardial
damage can be an indicator of acute multi-organ failure syndrome and transfusion therapy
should be considered

Pneumonia without ACS cannot be reliably distinguished from pneumonia with ACS on
clinical grounds. Therefore, empiric antibiotic therapy for community acquired pneumonia,
including coverage for atypical bacteria, is a mainstay of ACS treatment.

Management of acute chest syndrome (ACS) for adults with SCD can be broadly categorized
as acute and preventative.

Overall approach — Although ACS may present initially as severe episodes in some
patients, in others it may evolve during the first 48 to 72 hours following a pain episode. In
such cases, initial findings may include chest pain with minimal or no hypoxia/hypoxemia
(eg, <4 liters/min of oxygen via nasal cannula required to maintain oxygen saturation ≥92
percent, oxygen pressure ≥70 mmHg) and an infiltrate involving one lobe or no infiltrates at
all. Accordingly, suspicion for the presence of and development of ACS during a pain
episode should be high, and appropriate therapy instituted immediately.

Acute therapy for ACS — ●Adequate and immediate pain control●Fluid management to
prevent hypovolemia●Supplementary oxygen and incentive spirometry●Blood
transfusion●Antibiotics●Venous thromboembolism (VTE) prophylaxis

Pain control — Pain control with parenteral opioids typically delivered by patient-controlled
analgesia is necessary during ACS episodes in adults.

Fluid management . The typical regimen is 1.5 times maintenance fluids of D5 in one-half
normal saline for the first 24 to 48 hours. Thereafter, the rate can be decreased as the patient
begins to drink fluids. Fluid balance should be monitored frequently to avoid fluid overload
and pulmonary edema, which can worsen the ACS process.
Transfusion — the mainstay of acute treatment is transfusion therapy. Mild episodes require
no transfusion, moderate episodes require simple or exchange transfusion, and severe
episodes require exchange transfusion.

There are advantages to exchange transfusion compared with simple transfusion that make
exchange transfusion the preferred method in severely affected adults. Exchange transfusion
performed by automated erythrocytapheresis allows for the rapid transfusion of large
amounts of blood (eg, 6 to 8 units of packed red blood cells for a typical adult), effectively
decreasing hemoglobin S percentage while avoiding the hyperviscosity that may occur when
hemoglobin levels are raised above 11 g/dL
The availability of erythrocytapheresis may depend upon local resources. Knowledge of the
capacity to perform the procedure at one’s local site is an important factor to consider, given
the potential for rapid onset of respiratory failure and the requirement to treat promptly. In
settings where exchange transfusion, either automated or manual, cannot be performed, we
recommend consideration of transfer to a facility that has this capacity.
Our practice is to intervene in cases of mild or developing ACS with simple transfusion to
increase the hemoglobin up to 10 g/dL. If instituted promptly, it is our experience that many
episodes of moderate to severe ACS events can be avoided

For moderate to severe episodes involving >1 lobe and with an oxygen requirement ≥4 liters
nasal cannula to maintain PaO2 >70 mmHg (approximately corresponding to an oxygen
saturation of 92 percent) or signs of clinical deterioration, our practice is to perform an
exchange transfusion. The preferred modality of exchange transfusion is erythrocytapheresis
to achieve a hemoglobin S percentage <30 percent, and we target an end-hemoglobin of 10
g/dL. If an exchange transfusion cannot be performed in a timely manner, we recommend
simple transfusions to temporize the progression of ACS. Usually, cases of moderate to
severe ACS are managed in the intensive care unit.

Regardless of ACS severity, if hemoglobin is <5 g/dL, simple transfusion should be delivered
to increase hemoglobin to 10 g/dL.

Bronchodilators — . Despite the lack of high quality evidence, bronchodilators are commonly
used . Use of bronchodilators should also be considered in the setting of progressive
respiratory distress occurring in ACS.

Antibiotics — Although infections are a less common cause of ACS in adults than in children
with SCD, empiric antibiotics should be started promptly. The most common organisms are
atypical bacteria (Chlamydia and Mycoplasma) along with Streptococcus pneumonia and
Haemophilus influenzae, and therefore a third generation cephalosporin along with a
macrolide, or a fourth generation fluoroquinolone are typical regimens

Glucocorticoids — The use of glucocorticoids is not standard practice for the management of
ACS in adults with SCD. The phenomenon of rebound vaso-occlusion after a course of
steroids has been confirmed in studies.

Incentive spirometry should be encouraged with 10 maximal breaths every two hours while
awake to prevent ACS during vaso-occlusive pain episodes.

Supplemental oxygen — delivery of oxygen when oxygen saturation (Sa02) is <92 percent or
oxygen pressure (PaO2) is <70 mmHg. Oxygen saturation levels <92 percent calculated from
pulse oximetry should be further evaluated with an arterial blood gas sample. If the patient is
known to have a steady state oxygen saturation <92 percent, a comparison to the baseline
value may be helpful. In this case, decreases of ≥3 percent should be evaluated with an
arterial blood gas

ACS predisposes patients to venous thromboembolic (VTE) events. All adult patients with
ACS should receive VTE prophylaxis with low molecular weight heparin, unfractionated
heparin, or fondaparinux.

Bronchoscopy — Due to the invasiveness of bronchoscopy, this procedure is reserved for

atypical cases or cases refractory to conventional therapy. . Since transfusion therapy is the
mainstay of ACS treatment regardless of the underlying etiology, the risks of performing
routine bronchoscopy outweigh the added diagnostic value.

Prevention of ACS — Both hydroxyurea and chronic transfusion therapy decrease the
frequency of acute painful vaso-occlusive episodes and acute chest syndrome .Hydroxyurea
should be the initial therapy used in the prevention of these events. Chronic transfusion
therapy is started when the response to hydroxyurea is inadequate. In patients who are
recovering from a life-threatening acute chest syndrome, a six-month transfusion regimen
with transition to hydroxyurea therapy is often used.

Hydroxyurea — Hydroxyurea is the only treatment that has been shown to decrease the
incidence rate of ACS episodes .Hydroxyurea titrated up to 30 mg/kg or an absolute
neutrophil count of 2000/microL should be administered to all adults with a history of ACS
regardless of genotype, unless contraindicated (ie, renal failure). Furthermore, hydroxyurea
therapy should be considered for all adults with HbSS who are not on a chronic transfusion
program based on data showing improved mortality with hydroxyurea use

Chronic transfusion therapy — Scheduled transfusion therapy has been performed to reduce
the incidence of ACS episodes in adults with SCD; however, there have been no prospective
trials to support this practice. However, in children with SCD who were chronically
transfused for secondary stroke prophylaxis as part of the Stroke Prevention Trial, the
incidence of ACS was reduced . Our practice is to initiate chronic transfusion therapy only in
adults who have had two or more episodes of moderate to very severe ACS in the past 24
months despite maximal hydroxyurea therapy. We perform exchange transfusions either
manually or via erythrocytapheresis every four to six weeks to maintain a hemoglobin S
percentage <50 percent. Of note, this is a less stringent percentage than that used to treat
acute events. Chronic transfusion therapy is continued for one to two years. Thereafter, the
decision to continue transfusion therapy is based on a re-examination of the risk-to-benefit
ratio accounting for factors such as iron overload, alloimmunization, and clinical course.

Hematopoietic cell transplantation — Hematopoietic stem cell transplant, while curative, is

not part of standard practice for adults with SCD due to high toxicity associated with
myeloablative regimens. However, a non-myeloablative conditioning regimen in adults with
SCD is well-tolerated, achieves stable, mixed donor-recipient chimerism, and improves
clinical SCD parameters, including episodes of ACS.

Repeated episodes of ACS might contribute to the development of interstitial lung disease or
pulmonary hypertension.

Overview of the pulmonary complications of sickle cell disease

Sickle cell disease (SCD) encompasses a group of hemoglobinopathies characterized by

amino acid substitutions in the beta globin chain. The most frequently occurring form of SCD
is caused by homozygous presence of hemoglobin S (HbSS). Hemoglobin S results from the
substitution of a valine for glutamic acid as the sixth amino acid of the beta globin chain. The
resulting hemoglobin tetramer (alpha2/betaS2) is poorly soluble when deoxygenated. Other
forms of SCD include HbSC disease, in which an individual is a compound heterozygote for
the sickle mutation and hemoglobin C (created by substitution of lysine for glutamic acid as
the sixth amino acid), and sickle hemoglobin-beta thalassemia0 or + in which one beta chain
allele has the HbS mutation and the other has a beta thalassemia mutation with reduced or
absent production of the beta chain.

Deoxygenated sickle hemoglobin polymerizes into sheets of elongated rope-like fibers,

causing a marked decrease in red cell deformability and distortion of the cell into the classic
crescent or sickle shape . Vaso-occlusive phenomena and hemolysis are the clinical hallmarks
of SCD and result in recurrent painful episodes (previously called sickle cell crisis) and a
variety of serious organ system complications that can lead to life-long disabilities and
premature death.
Chronic pulmonary complications are common in patients with SCD and contribute to
morbidity and mortality ●Chronic dyspnea●Pulmonary function test abnormalities●Asthma
or recurrent wheezing without a diagnosis of asthma ●Pulmonary hypertension●Acute and
chronic venous thromboembolic disease●Pulmonary fibrosis●Sleep-disordered breathing

Dyspnea is a common yet under-reported symptom in SCD, particularly in adults. Many SCD
patients begin to experience subtle declines in their exercise capacity in early to late
adolescence, and a careful history will often reveal self-limitations on previously performed
sports and exertional activities. This subtle dyspnea becomes more overt as these patients
reach adulthood. The etiology of chronic dyspnea in SCD is likely multi-factorial. While
anemia is an important contributor, other explanations for dyspnea often co-exist. A careful
history (including specific questions about exercise limitations and level of conditioning),
physical examination, comparison of hemoglobin level with baseline values, pulmonary
function tests, and ambulatory oximetry are recommended . Common causes of dyspnea in
chronic SCD include anemia, deconditioning, asthma, pulmonary hypertension, venous
thromboembolism, pulmonary fibrosis from recurrent acute chest events, and myocardial
dysfunction.

Pulmonary function tests (PFTs) are often abnormal . The following abnormal PFT patterns
were found ●Restrictive pattern – 74 percent ●Isolated low diffusing capacity for carbon
monoxide (DLCO) – 13 percent . Pulse oxygen saturation (SpO2) is reduced in adults with
SCD, with steady-state baseline values below 96 percent in an appreciable portion of patients.
Significant desaturations occur with exertion and with sleep.

Asthma is common in patients with SCD, particularly among children and adolescents, and
may affect the course of the disease . The diagnosis of asthma in SCD can be challenging
because the symptoms and signs of asthma (eg, shortness of breath, cough, wheeze) overlap
with other pulmonary complications of SCD. The presence of intermittent or chronic
symptoms and wheezing on examination should lead to an evaluation for asthma. As in other
settings, the diagnosis of asthma is based upon the demonstration of variable airflow
limitation, preferably by spirometry before and after bronchodilator, and exclusion of
alternate diagnoses. In addition to asthma, the differential diagnosis of wheezing in a patient
with SCD includes processes such as decompensated heart failure, viral infection,
gastroesophageal reflux, congenital abnormalities (eg, vascular ring, congenital lobar
emphysema), bronchiectasis, tuberculosis, and vocal cord dysfunction.

Pulmonary hypertension (PH) is a relatively frequent (occurring in 6 to 11 percent of adults)

and severe complication of SCD and an independent risk factor for mortality. Exertional
dyspnea is a clue to the presence of PH; initial evaluation typically includes Doppler
echocardiography, measurement of N-terminal-pro-brain natriuretic peptide (NT-pro-BNP),
and a six minute walk test. PH may be suspected on the basis of exertional dyspnea and
noninvasive testing, but definitive diagnosis requires right heart catheterization (RHC) with
demonstration of a resting mean pulmonary arterial pressure (PAP) ≥25 mmHg

SCD is a hypercoagulable state with reported abnormalities in coagulation and platelet

function

the frequencies of venous thromboembolism (VTE) and pulmonary arterial thrombosis are
increased among patients with SCD The evaluation of acute VTE is slightly different in
patients with SCD than without. The D-dimer and the modified Geneva score have limited
value in SCD. D-dimer levels are increased in SCD relative to controls and fluctuate with
vasoocclusive events so perform a computed tomography pulmonary angiogram (CTPA)
when VTE is suspected but delay full anticoagulation pending the results of the CTPA. (

Pulmonary fibrosis (chronic scarring of the lung parenchyma) is occasionally seen in patients
with recurrent episodes of acute chest syndrome (ACS) with pulmonary infarction. The
clinical manifestations of pulmonary fibrosis in SCD include dyspnea and scattered areas of
honeycombing on high resolution computed tomography (HRCT) of the chest. A restrictive
pattern on pulmonary function tests is common in adults with SCD and might be expected to
be present in SCD-associated pulmonary fibrosis, possibly in association with a reduction in
diffusing capacity for carbon monoxide (DLCO). There is no specific therapy for pulmonary
fibrosis in SCD, other than attention to measures to prevent future episodes of ACS.

Sleep disordered breathing (SDB), which is commonly due to obstructive sleep apnea
(OSA), is an important comorbidity in SCD that may contribute to the frequency of acute
pain episodes and possibly chronic cardiopulmonary disease. Nocturnal desaturations can
occur with or without the coexistence of OSA. Treatment with hydroxyurea may reduce
nocturnal hypoxemia. Evaluation for OSA by polysomnography is usually performed in
patients with complaints such as snoring, non-restorative sleep, nocturnal gasping, choking,
observed apneas during sleep, or daytime hypersomnolence, recurrent acute chest or vaso-
occlusive episodes, or enuresis.

SICKLE CELL TRAIT — Respiratory dysfunction is rare in patients with sickle cell trait.
Minimal, if any, differences in exercise tolerance and pulmonary function have been
observed .However, pulmonary infarction, acute chest syndrome, and sudden death during
intense military training have rarely been reported

Overview of the clinical manifestations of sickle cell disease

The clinical manifestations of SCD are protean. The major features are related to hemolytic
anemia and vaso-occlusion, which can lead to acute and chronic pain and tissue ischemia or
infarction. Splenic infarction leads to functional hyposplenism early in life, which in turn
increases the risk of infection.

The clinical manifestations of SCD are protean, but their severity may vary markedly among
the major genotypes and even among patients with the same genotype. As a general rule,
individuals with sickle cell anemia (homozygous HbS) and sickle beta0 thalassemia have
more severe manifestations than those with hemoglobin SC disease or sickle beta+
thalassemia . One exception is retinopathy, which occurs most frequently in individuals with
HbSC disease.
Acute complications — ●Infections –●Severe anemia (eg, due to splenic sequestration,
aplastic crisis, or hyperhemolysis)●Vaso-occlusive phenomena•Acute vaso-occlusive pain –
•Stroke – •Acute chest syndrome – •Renal infarction or medication toxicity –•Dactylitis or
bone infarction – •Myocardial infarction – •Complications related to pregnancy –•Priapism –
•Venous thromboembolism –

Chronic complications — ●Pain ●Anemia●Neurologic deficits or seizure disorder

●Pulmonary conditions – ●Renal impairment and hypertension –●Osteoporosis and
complications of bone infarction –●Cardiomyopathy with diastolic dysfunction –
●Hepatotoxicity (transfusional iron overload or medications) and pigmented gallstones
(chronic hemolysis) – ●Delayed puberty and reduced growth –●Chronic leg ulcers
●Proliferative retinopathy –

Complications of therapy especially complications related to chronic transfusion and iron

chelation therapy, and side effects of chronic opioid pain medication.

VASO-OCCLUSIVE PAIN — Sickled red blood cells (RBCs) have a marked reduction in
deformability and increased adhesion to vascular endothelial cells, inflammation, and
activation of hemostatic mechanisms; all of these changes synergize to cause vascular
obstruction and vaso-occlusion. Pain is one of the major consequences. Patients may have
intermittent episodes of acute pain, which in some cases is accompanied by underlying
chronic pain .

Acute painful episodes — Episodes of acute pain are one of the most common types of vaso-
occlusive events in SCD and are responsible for a large number of patient encounters. While
these episodes were previously called "sickle cell crises" (and still are referred to as crises by
many providers), prefer to use the term painful episodes because not all patients are in true
crisis, and pain should not be allowed to progress to the point of crisis for patients to receive
appropriate analgesia including opioid analgesics if indicated. Importantly, pain can be a
SCD complication in and of itself, and pain can co-occur with (and mask) other potentially
life-threatening complications of SCD. Treatment of pain should be accompanied by
additional evaluations

Vaso-occlusive pain in SCD is intense, although there is significant variability in the severity
and frequency of acute painful episodes. The majority of pain episodes are managed by the
patient at home, with up to a third of patients having pain as often as daily . Pain may be
accompanied by tissue ischemia and inflammation. Many patients have specific triggers for
pain such as cold, wind, low humidity, dehydration, stress, alcohol, and menses, which they
develop strategies to minimize or avoid. However, the majority of painful episodes have no
identifiable cause. Pain episodes can begin as early as six months of age and typically last
throughout life. The sites of pain can include the back, chest, extremities, and abdomen. In
young children, dactylitis (acute pain in the hands or feet) may be the most common site
Acute pain should be assessed rapidly so as not to delay analgesia . The gold standard for the
assessment of pain is the patient’s report. There is no combination of physical findings or
laboratory tests that can be used to determine (or confirm) whether an individual with SCD is
in pain. The absence of hemolysis or the stability of the hemoglobin level cannot be used to
justify withholding or underdosing of pain medication . Placebo should never be used as it
undermines the physician-patient relationship and lengthens the duration of pain.
Management of acute pain is individualized. Pain typically is managed by the patient or
family at home; most patients only present to the hospital or emergency department when
their pain has exceeded what they can manage at home with oral opioids.

Potentially serious complications associated with acute pain — Vaso-occlusive events may
mask other life-threatening complications. These complications may present with pain, but
they require additional evaluations and treatments in addition to analgesia for pain, in order to
avoid missing a potentially serious complication .The following are often present in the
setting of acute pain: ●Acute chest syndrome (over 50 percent of ACS episodes are preceded
by or occur in the setting of acute pain ●Acute multi-organ failure ●Sudden death
syndrome●Acute surgical abdomen (eg, cholecystitis)●Acute papillary necrosis●Delayed
hemolytic transfusion reaction●Acute splenic or hepatic sequestration crises ●Opioid
withdrawal

Less commonly seen events that may be initially misdiagnosed as an acute painful event
include:●Acute coronary syndrome ●Osteomyelitis ●Gout ●Arthritis●Acute synovitis with
avascular necrosis●Deep vein thrombosis and/or pulmonary embolism

Chronic pain — Chronic pain is experienced by a large percentage of patients with SCD.
Mechanisms of chronic pain differ from acute pain and may include bone and joint damage,
chronic ulcers, central sensitization and hyperalgesia, and altered opioid metabolism, among
others.Frequent pain may generate feelings of despair, depression, and apathy that interfere
with daily life and promote an existence that revolves around pain.

Infection is a major cause of morbidity and mortality in patients with SCD. Mechanisms
include functional hyposplenism or asplenism, reduced tissue perfusion, presence of an
indwelling catheter (eg, for chronic transfusion), splinting, and hypoventilation.

Functional hyposplenism develops in early childhood (often starting as early as four months
of age), and infants and young children are at greatest risk of certain infections. Splenic
infarction typically renders patients functionally asplenic by two to four years of age, which
greatly increases the risk of serious infection with encapsulated organisms . Viral infections
may also be more virulent in individuals with SCD (eg, parvovirus, H1N1 influenza, Zika
virus), possibly due to increased sickling and an enhanced inflammatory response
Worldwide, malaria is a common cause of morbidity and mortality in children with SCD
Common sites of infection include bacteremia, meningitis, and pulmonary infections
(pneumonia, acute chest syndrome [ACS]). These may present with fever and leukocytosis,
and in some cases with focal findings (fever, headache, meningismus, seizures in meningitis;
or fever, chest pain, cough, wheezing, and/or hypoxemia in ACS). Some patients also may
have pancytopenia from bone marrow suppression, or signs of disseminated intravascular
coagulation such as prolonged prothrombin time (PT) or activated partial thromboplastin time
(aPTT), decreased fibrinogen, or increased D-dimer .

Common organisms include:

●Bacteremia – Encapsulated organisms, especially Streptococcus pneumoniae and

Haemophilus influenzae Other common organisms include Escherichia coli, Staphylococcus
aureus, and Salmonella species ●Meningitis – Encapsulated organisms, especially S.
pneumoniae. H. influenzae is also seen but has become less common following institution of
the vaccine. Meningitis is often seen in the setting of bacteremia and must be distinguished
from other acute neurologic events such as ischemic stroke or intracerebral hemorrhage.
●Pneumonia/ACS – Mycoplasma pneumoniae, Chlamydia pneumoniae (which together
account for about 20 percent of cases), and Legionella. Respiratory viruses are also common
causes of pulmonary infection, while S. pneumoniae and H. influenza type b are uncommon.
Patients may present with any combination of dyspnea, cough, chest pain, fever, tachypnea,
and leukocytosis, and may develop the acute chest syndrome (ACS).
The use of prophylactic penicillin and vaccination against pneumococci and H. influenzae has
reduced the frequency but has not eliminated them. Reasons include infection with
pneumococcal serotypes not included in the vaccines, and infection in not vaccinated

Acute multiorgan failure is a life-threatening complication in which multiple organ systems

are affected by ischemia and/or infarction. It is typically seen in the setting of an acute
painful episode Management involves prompt and aggressive exchange transfusion therapy.

SCD produces a chronic, compensated hemolytic anemia that may be punctuated with
episodes of acute worsening. Other contributing factors to chronic anemia include
inappropriately low serum erythropoietin (EPO) concentration (eg, due to renal disease or
increased plasma viscosity) and/or folate or iron deficiency. The major causes of an acute
drop in hemoglobin level are aplastic crisis, splenic sequestration crisis, and hyperhemolytic
crisis, all of which are potentially life-threatening. Iron deficiency can occur but is relatively
uncommon.

Chronic compensated hemolytic anemia — Sickled cells undergo hemolysis, with a typical
red blood cell (RBC) lifespan of approximately 17 days (one-seventh that of normal RBCs),
leading to chronic hemolytic anemia. Compensatory increases in RBC production and
adaptation to a lower hemoglobin level typically are sufficient to prevent major symptoms of
anemia.

The baseline complete blood count (CBC) and peripheral blood smear in individuals with
SCD typically shows the following findings ●Hemoglobin level approximately 8 to 10
g/dL●Hematocrit approximately 20 to 30 percent●Polychromasia and reticulocytosis (typical
reticulocyte count approximately 3 to 15 percent)●Sickled cells ●Howell Jolly bodies
(nuclear remnants that have not been phagocytosed, due to reduced splenic function) ●Mildly
increased white blood cell (WBC) count in some cases

The RBC indices typically show normochromic, normocytic cells, unless there is coexistent
thalassemia or iron deficiency, in which case microcytosis and hypochromia may be present.
A high percentage of reticulocytes may cause mild macrocytosis.
Other findings typical of hemolysis may also be seen, including unconjugated
hyperbilirubinemia, elevated serum LDH, and low serum haptoglobin.

The anemia and markers of hemolysis may be less severe in some individuals, including
those with concomitant alpha thalassemia, those undergoing chronic transfusion therapy, and
those receiving hydroxyurea

Important aspects of routine management include:●Supplementation with folic acid.

●Establishment and monitoring of the patient’s baseline values so that it is readily apparent
when these decline in the setting of suspected aplastic, splenic sequestration, or
hyperhemolytic crises. ●Evaluation for possible iron deficiency or other causes of worsening
anemia or inappropriately low reticulocyte count. The diagnosis of iron deficiency may be
obscured by the elevated serum iron concentration associated with chronic hemolysis and the
normal to increased mean corpuscular volume (MCV). A serum ferritin <25 ng/mL or an
elevated serum transferrin should be used to make this diagnosis

●Attention to excess iron stores. Despite limiting transfusion to appropriate indications, many
patients with SCD will develop excessive iron stores if chelation therapy is not used. Excess
iron is a cause of significant morbidity. Hepatic fibrosis and death from hemosiderosis-
related cirrhosis of the liver can occur. Patients can also accumulate cardiac iron

Aplastic crisis is characterized by an acute drop in hemoglobin level caused by a transient

arrest of erythropoiesis, leading to abrupt reductions in red cell precursors in the bone
marrow and a markedly reduced number of reticulocytes in the peripheral blood (typically,
reticulocytes <1.0 percent, absolute reticulocyte count <10,000 per microL).Infection is the
typical cause. Most cases in children follow infection with human parvovirus B19, which
specifically invades proliferating erythroid progenitors.Other reported causes of transient
aplasia are infections by Streptococcus pneumoniae, Salmonella, other streptococci, and
Epstein-Barr virus. Patients with transient aplastic crisis typically have restoration of
erythropoiesis and reappearance of reticulocytes in the peripheral blood within 2 to 14 days.
Recurrent aplasia from parvovirus is rare but recurrence due to other causes is not
uncommon. Aplastic crisis can result in a rapid and life-threatening drop in hemoglobin level
caused by chronic hemolysis without the ability of the bone marrow to compensate.
Management is with transfusion.

Splenic sequestration crisis is characterized by an acute drop in hemoglobin level caused by

vaso-occlusion within the spleen and splenic pooling of RBCs. A large percentage of the total
blood volume can become sequestered in the spleen, leading to hypovolemic shock and
death.

Splenic sequestration typically occurs in individuals whose spleens have not yet become
fibrotic due to repeated splenic infarction. Infants with homozygous sickle mutation (HbSS)
or sickle beta0 thalassemia are most often affected, as well as children or adults with some
residual splenic function. Parvovirus B19 infection may be a risk factor . Patients with splenic
sequestration crisis present with a rapidly enlarging spleen and a marked decrease in
hemoglobin level despite persistent reticulocytosis The mortality rate is as high as 10 to 15
percent, and patients often die before transfusions can be given.

Up to half of individuals who survive a splenic sequestration crisis are reported to have
recurrent sequestration, and splenectomy is often used after the first acute event to prevent. It
has been reported that vaso-occlusive events are more common following splenectomy.

Hyperhemolytic crisis refers to the sudden exacerbation of hemolysis with worsening anemia
despite ongoing reticulocyte production. This complication is rare ●Most cases of
hyperhemolytic crisis probably reflect occult splenic sequestration or aplastic crisis detected
during a period of resolving reticulocytosis ●Some episodes have been documented in
multiply-transfused patients, consistent with a delayed hemolytic transfusion reaction in
which transfused cells as well as the patient's own cells are hemolyzed ("bystander
hemolysis") . The mechanism of bystander hemolysis is unclear
●Accelerated hemolysis has been associated with acute vaso-occlusive events including acute
chest syndrome and acute painful episodes.●Infections and/or drug exposure may be
responsible for increased hemolysis in some cases.

Hyperhemolytic crisis is potentially fatal if the cause of hemolysis is not addressed and
transfusion with compatible blood is not administered rapidly. Anecdotal reports have noted
improvement with immunosuppressive therapies including intravenous immune globulin
(IVIG; eg, 0.4 g/kg daily for five days) plus glucocorticoids (eg, intravenous
methylprednisolone 500 mg/day for two days) Rituximab also has been used

Iron deficiency is relatively uncommon in SCD overall.

NEUROLOGIC COMPLICATIONS

Stroke and TIA — Individuals with SCD are at risk of ischemic as well as hemorrhagic
stroke. Without intervention, up to 11 percent patients with SCD will have a clinically
apparent stroke by 20 years of age and one-fourth will have a stroke by age 45. Ischemic
stroke is more common than hemorrhagic stroke in children and adolescents , hemorrhagic
stroke is more common in adults. Other neurovascular events including transient ischemic
attacks (TIAs) and silent cerebral infarctions can also occur and cause serious morbidity
including neurocognitive and behavioral deficits.

Primary prevention to reduce the risk of a first stroke is based on the use of regular
transcranial Doppler measurements for risk stratification . At-risk children are treated with
chronic prophylactic transfusion. In some cases, a switch to hydroxyurea or evaluation for
hematopoietic cell transplantation may be appropriate . Individuals who have had a stroke are
treated with chronic prophylactic transfusions to prevent recurrent stroke.

Seizures and epilepsy are two to three times more common

Posterior reversible encephalopathy (PRES) is a syndrome of confusion headache, visual

symptoms, and seizures that may accompany a number of medical conditions including
hypertension and endothelial dysfunction. Etiology unknown. PRES is less common than
stroke and present with acute neurologic changes that initially may mimic stroke

PULMONARY COMPLICATIONS — The pulmonary arterial circulation has low oxygen

tension and low flow, both of which facilitate sickling. A number of acute and chronic
complications are seen, including acute chest syndrome (ACS), asthma, sleep disordered
breathing, pulmonary fibrosis, thromboembolic disease, and pulmonary hypertension (PH).

Acute chest syndrome (ACS) refers to a syndrome of fever, chest pain, hypoxemia,
wheezing, cough, or respiratory distress in the setting of a new pulmonary infiltrate.

Preventive approaches to reducing the risk of ACS include one or more of the
following:●Prophylactic antibiotics and immunizations, especially during early childhood.
●Hydroxyurea. ●Transfusions for those who continue to have ACS episodes despite
hydroxyurea therapy. ●Consideration of hematopoietic cell transplantation.)

Asthma — Airway hyperreactivity or asthma is much more common Up to 70 percent of

children with SCD have airway hyperresponsiveness
Sleep disordered breathing and nocturnal hypoxemia

Pulmonary hypertension — 6 to 10 percent of individuals with SCD. However, symptoms are

variable and non-specific (chronic dyspnea, chest pain, presyncope, reduced exercise
tolerance, or merely reduction of daily activities without specific symptoms). screening for
PH by measuring tricuspid jet regurgitant velocity using transthoracic Doppler
echocardiography in late adolescence or adulthood.

RENAL COMPLICATIONS — Renal involvement is common in SCD, with up to one-fifth

of patients eventually developing renal insufficiency.●Urinary concentrating defect with
hyposthenuria; this may cause enuresis ●Painless hematuria due to papillary
infarcts●Proteinuria from albuminuria, which is often a precursor of progressive renal
disease●Contrast-induced nephropathy ●Medication toxicities●Hypertension●Renal
infarction, papillary necrosis, and renal colic●Nephrogenic diabetes insipidus with
polyuria●Focal segmental glomerulosclerosis that can lead to end-stage renal disease
●Renal medullary carcinoma (found almost exclusively in Black patients with HbSC disease
or sickle cell trait)

It is important to avoid unnecessary exposure to nephrotoxic medications. avoid chronic use

of NSAID), treat hypertension with agents other than diuretics (which may cause volume
depletion and precipitate vaso-occlusion), and maintain adequate hydration during acute
hospitalizations or imaging studies that require contrast agents.

SKELETAL COMPLICATIONS — The skeletal system is frequently. Common findings

include dactylitis in infants and younger children, and osteoporosis and/or avascular necrosis
in older individuals.

Dactylitis and vaso-occlusive pain — Dactylitis is vaso-occlusive pain in the small bones of
the hands and feet that typically occurs in infants and children with SCD up to approximately
four years of age. Pain may be severe. The diagnosis is generally made by history and
physical examination, as radiography typically does not show any changes, although repeated
episodes of dactylitis will lead to a mottled appearance of the small bones. Older children and
adults may experience vaso-occlusive pain episodes affecting the bones and joints as well. It
is important to distinguish dactylitis and vaso-occlusive pain from osteomyelitis Management
of dactylitis and vaso-occlusive bone pain involves hydration, analgesics, and warm packs.
Initiation of hydroxyurea therapy is often appropriate

Osteoporosis — Chronic hemolytic anemia in SCD leads to a compensatory increase in

erythropoietic activity. The extension of hematopoietic bone marrow can lead to a number of
skeletal changes including chronic tower skull, bossing of the forehead, and fish-mouth
deformity of vertebrae. These effects in turn cause widening of the medullary space, thinning
of the trabeculae and cortices, and osteoporosis. As a result, individuals with SCD have a
high rate of vitamin D deficiency and osteoporosis . Orbital compression syndrome may
occur in the setting of vaso-occlusion in the periorbital bone marrow space, with
subperiosteal hemorrhage. Patients with this syndrome present with headache, fever, and
palpebral edema. Compression of the optic nerve may also occur and may require surgical
decompression.

Avascular necrosis and osteomyelitis — Avascular necrosis of bone, also called

osteonecrosis, ischemic necrosis, or aseptic necrosis, results from infarction of bone
trabeculae. The femoral and humeral heads may be affected. The femoral heads more
commonly undergo progressive joint destruction as a result of chronic weight bearing. The
changes are best detected by magnetic resonance imaging (MRI)
Bone marrow infarction involving death of hematopoietic cells can also occur, leading to
reduced red blood cell (RBC) production and anemia with reduced reticulocyte response.
Some patients may have a leukoerythroblastic blood picture or pancytopenia. Bone marrow
infarction may be associated with life-threatening pulmonary fat embolism.

The incidence of osteomyelitis is also increased. Long bones are usually affected, often at
multiple sites, resulting from infection of infarcted bone. The most common organisms are
Salmonella species. Staphylococcus aureus, the most common organism in patients without
SCD, accounts for less than a quarter of cases. Articular infection is less common and is often
due to Streptococcus pneumoniae.It may be difficult to distinguish osteomyelitis from vaso-
occlusive events involving bone. Bone imaging studies may be helpful, and cultures are
essential.

CARDIAC COMPLICATIONS — Cardiac complications are a common, often unrecognized

cause of morbidity and mortality in SCD and are a major cause of death in adult patients
Cardiomyopathy and heart failure — especially left-sided diastolic dysfunction, both with
and without concomitant pulmonary hypertension (PH)

Myocardial infarction, dysrhythmia, and sudden death — Acute myocardial infarction in the
absence of epicardial coronary artery disease has been described in patients with SCD, and is
often misdiagnosed / MI in individuals with SCD may reflect increased oxygen demand
exceeding limited oxygen-carrying capacity of abnormal myocardial microvasculature.

Individuals with SCD are also reported to have conduction abnormalities such as QT
prolongation, ventricular arrhythmias, first-degree AV block, and nonspecific ST-T wave
changes . Certain medications such as methadone used in individuals with chronic pain may
also increase the QT interval

Sudden death is often multifactorial due to a combination of cardiopulmonary dysfunction,

pulmonary fat embolism, sudden pulmonary hypertension, unexpected acute sequestration
crisis, and/or intracranial hemorrhage. Cardiopulmonary causes are increasingly recognized
as primary or contributing factors Restrictive cardiomyopathy, which may be associated with
heart chamber enlargement, diastolic dysfunction, and mild pulmonary hypertension, places
patients at high risk for sudden death. During cardiovascular stressors such as vaso-occlusive
events or exercise, dramatic increases in pulmonary pressures have been noted that suggest
these events may be fatal in patients with underlying cardiomyopathy risks . In adults,
microvascular occlusion resulting in acute myocardial ischemia is underdiagnosed.
Individuals with SCD often lack atherosclerotic lesions, but they may have chest pain, with
cardiac microvascular obstruction detected on cardiac magnetic resonance imaging (MRI).].

HEPATOBILIARY COMPLICATIONS — There are multiple causes of hepatic dysfunction

●Acute ischemia●Cholestasis●Hepatic sequestration crisis●Transfusional iron overload
●Pigment gallstones due to chronic hemolytic anemia●Drug toxicity from iron chelators or
other medications ●Hepatitis C virus (HCV) infection●Autoimmune liver disease●Fibrosis

The risk of HCV in SCD is higher than the general population, with a reported prevalence
among adults with SCD from 10 to 30 percent
Leg ulcers — Vaso-occlusion in the skin can produce leg ulcers and myofascial syndromes
When they occur, leg ulcers usually present after the age of 10 years and are more common in
males than females. Ulcers may develop spontaneously or after trauma. Their development
appears to correlate with trauma such as insect bite, animal bite, bicycle injury, barbed wire,
or nails and the degree of hemolysis and/or anemia. Typical sites include the medial and
lateral malleolus]. Bilateral involvement is common.

Leg ulcers in SCD may become superinfected. Staphylococcus aureus, Pseudomonas species,
streptococci, or Bacteroides species may be cultured. Rarely, they may lead to systemic
infection, osteomyelitis, or tetanus. The lesions can be slow to heal and often recur

SCD can cause retinopathy from retinal artery occlusion and ischemia, with associated
proliferative retinopathy, vitreal hemorrhage, and retinal detachment

Pregnancy is associated with both fetal and maternal complications including intrauterine
growth restriction, fetal death, and low birthweight; and acute chest syndrome, infections,
preeclampsia, and thromboembolic events, respectively.

Priapism (unwanted erection in the absence of sexual desire or stimulation) is a common,

serious, and often underdiagnosed problem. Prolonged episodes may lead to irreversible
changes including tissue necrosis, fibrosis, and erectile dysfunction. Priapism lasting more
than two to four hours is considered a medical emergency that requires immediate attention..)

Impaired growth and delayed puberty are common in children with SCD..)

Psychosocial issues — Most individuals with SCD are well adjusted [152]. However, the
stress of living with a chronic medical condition may raise issues involving low self-esteem,
social isolation, poor family relationships, and withdrawal from normal daily living .These
may be compounded by silent cerebral infarctions due to neurovascular vaso-occlusion with
delayed neurodevelopmental maturation

Overview of clinical manifestations of sickle cell disease

Acute Chronic
Acute vaso-occlusive pain episodes, Pain from tissue infarction,
Pain
acute chest syndrome osteonecrosis, ulcers
Infection Sepsis, pneumonia, meningitis Leg ulcers, osteomyelitis
Aplastic crisis, splenic sequestration Compensated hemolytic anemia,
Anemia
crisis, hyperhemolytic crisis chronic hypersplenism
Ischemic stroke, hemorrhagic stroke, Silent cerebral infarctions, cognitive
CNS
seizures, TIA delay, behavioral issues
Acute chest syndrome, asthma, Pulmonary hypertension, sleep
Pulmonary pulmonary fate embolism, disordered breathing, chronic restrictive
pulmonary thromboembolism lung disease
Hypertension, chronic renal failure,
Renal infarction, medication toxicity,
concentrating defect, nephrogenic
Renal hematuria, acute renal failure, acute
diabetes insipidus, renal medullary
nephrotic syndrome
carcinoma
Skeletal Dactylitis, avascular necrosis Osteoporosis, osteomyelitis
 Myocardial infarction, dysrhythmia,
Cardiac Diastolic dysfunction, heart failure
sudden death, autonomic dysfunction
Hepatic sequestration crisis,
Hepatobiliary cholecystitis, liver injury, acute Pigment gallstones
intrahepatic cholestasis
Retinal artery occlusion, hyphema,
Ocular Proliferative retinopathy, blindness
retinal detachment
Obstetric Fetal and maternal complications
Genitourinary Priapism Erectile dysfunction
Endocrine Delayed puberty, reduced growth
Functional asplenia
Other Venous thromboembolism

Acute presentations of sickle cell disease complications, often presenting with pain
Potential Laboratory/imaging/
History Clinical
diagnoses other testing
Acute systemic illness
 Fever, ↑ RR,
↑ HR, BP  ↓ hemoglobin and
changes platelets
 Chronic pain,
 Nonfocal
lung disease, or
neurologic
 ↑ bilirubin, LDH,
Multiorgan failure renal creatinine
changes
insufficiency  Signs of
 Pain is often
rhabdomyolysis
severe with
 Infiltrate on CXR
rapid organ
failure

 Recent
transfusion  ↓ hemoglobin and
(within 24 hours
platelets
for acute HTR;  Jaundice, dark
Hemolytic up to one month urine
 ↑ bilirubin, LDH
transfusion for delayed  Positive Coombs
reaction (HTR) HTR)  Fever, ↑ HR (direct
 History of antiglobulin) test
alloimmunizatio  Hemoglobinuria
n

Headache
  Brain imaging
helpful if positive
 Prior stroke or but may initially
silent cerebral  Headache be negative
infarct  Focal or non-  Presumptive
Stroke  History of ↑ focal treatment with
transcranial neurologic simple transfusion
Doppler findings is done while
velocities obtaining brain
imaging if
suspicion is high

 Usually  Usually
asymptomatic negative if
but may have unruptured but  Positive MRI or
Brain aneurysm headache, loss of may have CT angiography
visual acuity, or cranial
facial pain neuropathies

 Fever,
Meningitis*
meningeal  Meningismus  ↑ WBC count
symptoms

 Aura  May show

 Typical migraine focal or  No diagnostic
Migraine symptoms for nonfocal laboratory test
that patient findings

Chest pain
 ↑ RR, ↓
oxygen
saturation  ↓ hemoglobin
 Children:
 History of  Infiltrate on CXR
Acute chest Fever, cough
pulmonary helpful if present,
syndrome (ACS)  Adults:
disease, prior but may initially
or pneumonia* Afebrile,
ACS, asthma, be negative, and
(indistinguishable severe pain
recent infection absence does not
) that may
eliminate
initially
possibility of ACS
overshadow
the pulmonary
symptoms

 History of DVT
helpful if present  ↑ D-dimer
Pulmonary but often absent
 ↑ RR, ↑ HR  Imaging decisions
embolism  Pregnancy,  ↓ oxygen depend on pretest
recent surgery, saturation probability and D-
indwelling dimer
 catheter, or other  Extremity  Chest imaging
hypercoagulable pain/swelling and/or extremity
state imaging may be
appropriate

 ↓ oxygen
saturation
 History of  ↑ RR  ↓ hemoglobin,
pulmonary  Nonfocal platelets
disease or recent neurologic  ↑ nucleated RBCs
Pulmonary fat
surgery symptoms
embolism  Infiltrate on CXR
 Severe extremity  Patients may
 Diagnosed by
pain deteriorate
bronchoscopy
rapidly and
develop multi-
organ failure

 History of
cardiac disease,
pulmonary
hypertension, or
↑ QT interval
 Patients with
SCD and severe  Atypical chest
vaso-occlusive pain  ↑ cardiac
Acute coronary biomarkers
pain are  Radiation to
syndrome  Abnormal EKG
increasingly arm(s)
recognized to
have acute
myocardial
ischemia without
major vessel
disease

 Focal rib
tenderness
 Pain on
 Negative CXR
 Recurrent sternal inspiration
 Positive bone
Rib infarct pain  Splinting may
imaging
cause
hypoventilatio
n

Abdominal pain
 History of
 Variable
Splenic splenic or
abdominal  ↓ hemoglobin, ↓
sequestration hepatic platelet count
pain, requires a
sequestration
  Infants with high index of  ↑ reticulocyte
hemoglobin SS; suspicion
count
adults with SCD  Hemodynamic
variants instability, ↑
HR, ↑ BP
 Splenic
enlargement
(rapidly
enlarging
spleen needs to
be closely
monitored)

 History of
 Right upper
splenic or
quadrant pain
hepatic
and/or
sequestration
tenderness
 History of
 Hemodynamic  ↓ hemoglobin
underlying
hepatic disease instability, ↑
Hepatic  ↑ PT, ↑ aPTT
 May be HR, ↑ BP
sequestration  hyperbilirubinemi
exacerbated by
 Acute a
hepatic iron
hepatomegaly,
overload, HCV
can progress to
infection, or
acute hepatic
other causes of
failure
liver dysfunction

 ↑ bilirubin, ↑
 Acute RUQ pain transaminases
 History of or tenderness  ↑ WBC
Gallstones or
gallstones  Jaundice  Positive RUQ
cholecystitis*
 Nausea ultrasound or other
imaging

 RBCs on urinalysis
 Hematuria  Variable ↑ in
 Back pain creatinine
Renal infarct and/or flank or  Acute papillary
CVA tenderness necrosis on renal
imaging

 Lower
abdominal pain,  Positive pregnancy
 Sexually active
especially after test
reproductive age
Ectopic pregnancy menses  Diagnosed by serial
female
 Abnormal quantitative HCG
uterine bleeding testing and
or discharge
  Nonspecific transvaginal
symptoms ultrasound
(urinary
frequency,
vaginal
discharge)
 Abdominal and
pelvic
examinations
are often
unremarkable if
the pregnancy
has not
ruptured
 Cervical motion
tenderness,
adnexal
tenderness, or
uterine
tenderness are
common with
rupture
 An adnexal mass
may be palpable
 Excessive
pressure on the
adnexa should
be avoided
because it may
cause rupture

 Lower  Clinical diagnosis

abdominal pain,  ↑ WBC may be
especially after present but is not
menses highly sensitive or
 Abnormal specific
uterine bleeding  Additional testing
or discharge includes pregnancy
 Nonspecific test, urinalysis,
symptoms microscopy of
Pelvic  Sexually active
(urinary vaginal discharge,
inflammatory female
frequency, testing for
disease vaginal chlamydia,
discharge) gonorrhea, HIV, and
 Fever in severe syphilis
cases  Imaging for
 Cervical motion selected cases to
tenderness, evaluate for
adnexal complications such
tenderness, or as tubo-ovarian
uterine abscess or to
 tenderness are exclude ectopic
defining pregnancy
characteristics
 Purulent vaginal
or endocervical
discharge

 Fever
 Suprapubic
tenderness
 Urinary tract  Children: May
infection can not report any
Urinary tract  Positive urinalysis
precipitate an symptoms
infection or and culture
acute pain  Adults: May
pyelonephritis*
episode have urgency,
frequency,
dysuria, flank
pain

 Recent opioid
use, typically
within the
previous 72  Reduced bowel
Opioid-induced
hours movements
constipation
 Lack of a
consistent bowel
regimen

Extremity or bone pain

 Hip pain
 Limp  Radiography is
 Limited range negative in early
 History of
Acute synovitis or of motion stages of AVN
avascular
avascular necrosis  Pain  MRI may be
necrosis
(AVN) of a joint accompanied needed to
by joint document findings
swelling

 Infant or young
 Pain with
child (rarely
swelling and
seen above the
Dactylitis warmth of the
age of four
fingers or toes
years)

 Joint pain in  Variably ↑

 Older adults creatinine, urate
atypical areas
Gout  History of renal  Urate crystals in
such as
disease, joint fluid
phalanges,
 hypertension, or angles, elbows,
gout wrists
 Pain
accompanied
by joint
swelling
 Monoarticular
joint pain may
be
accompanied
by more
diffuse pain
from vaso-
occlusion

 Pregnancy,  ↑ D-dimer
recent surgery,  Compression
indwelling  Pain with leg ultrasonography
DVT catheter, or other swelling or other
hypercoagulable noninvasive
state testing

 Diagnosis often
delayed; often
 Can present confused with
with bone infarct
generalized (much less
bone pain common)
 History of bone  Pain
infarction, accompanied  ↑ WBC
avascular by swelling,  Blood, bone, and
Osteomyelitis joint aspirate
necrosis, or tenderness,
gastroenteritis warmth cultures positive
 Variable joint for salmonella,
involvement staphylococcus
(can be  Imaging may
multifocal) show periosteal
elevation and/or
fluid collection

Generalized/diffuse pain
 Pain described
as burning,
 History of
shooting, or
chronic pain and  No diagnostic
tingling
Neuropathic pain ineffective laboratory tests
 Hyperalgesia
opioids
to touch or
temperature
  No diagnostic
laboratory tests
 A common cause
 Pain may be of readmission
 Recent
severe  When withdrawal
hospitalization
is expected, we
for pain episode  Agitation, ↑ prefer to use the
Opioid or steroid  Sudden tremors Clinical Opiate
withdrawal withdrawal of  Gastrointestina Withdrawal Scale
opioid or steroid l symptoms (COWS), an 11-
without tapering  Sweating item scale
designed to be
administered by a
clinician

TVR= tricuspid regirg velocity

Overview of the management and prognosis of sickle cell disease

●Prevention of complications –. Initial prevention of complications includes the use of

penicillin prophylaxis started in the newborn period, appropriate immunizations, and blood
transfusions for those at risk for stroke. The only approved therapies to prevent pain episodes
in SCD are hydroxyurea and pharmaceutical-grade L-glutamine.

– A life-long cure for SCD is available only through hematopoietic stem cell transplantation.
 Infection is a frequent complication of SCD, and historically it has been the major cause of
death in children. Fever may be the first indication of a serious bacterial infection, and as
such should be considered a medical emergency. The evaluation should include a brief
history for localizing symptoms and an abbreviated physical examination focused on
hemodynamic stability, signs of localized or generalized infection, splenic size, and evidence
of stroke.Blood cultures and complete blood count with differential and reticulocyte count
should be obtained. Empiric parenteral antibiotics should be started as soon as possible,
ideally within 60 minutes of triage. Evaluation for pneumonia is important ; however,
antibiotics should not be delayed while awaiting chest radiography.

If a patient develops a leg ulcer, use lower extremity Doppler to evaluate for deep vein
thrombosis (DVT). Forty-four percent of leg ulcers in SCD are associated with a DVT, likely
due to lower extremity edema [41]. In addition, since pulmonary hypertension is associated
with the development of lower extremity ulcers, we evaluate for pulmonary hypertension
with a transthoracic Doppler echocardiography and obtain a complete blood count (CBC),
lactate dehydrogenase (LDH) level, and serum chemistries. do not routinely evaluate for
peripheral vascular disease with ankle brachial pressure index or for osteomyelitis, unless
there is clinical suspicion.

Management of large skin ulcers requires a multidisciplinary team. , the mainstays of therapy
are wound care, compression, and SCD-based therapy with hydroxyurea or chronic
transfusion. Components of management may include the following :●Immediate attention to
the pain. Many providers use systemic opioids. Topical opioids also have been examined and
found to relieve pain and facilitate healing. Topical opioids also decrease local fluid
extravasation.●Local edema must be minimized with rest, lower extremity elevation, and
compression bandages. In some cases diuresis is also appropriate. Coban compression may be
more beneficial than Unna boots. ●We have found bedrest, though difficult to comply with,
is essential for healing of large and/or recalcitrant ulcers. ●Therapeutic debridement is
important in order to remove fibrotic tissue and stimulate healing. In general, we initially
refer the patient to a wound care specialist for debridement, dressing changes and, if
necessary, topical antibiotics . Wet to dry dressings and Duoderm hydrocolloid dressings may
also facilitate healing.●Infections require treatment, but antibiotics are often not helpful and
should be used appropriately.● repeated transfusion therapy accelerates wound healing and is
often a core therapy Alternatively, hydroxyurea may be beneficial Patients can be managed
initially with hydroxyurea and transitioned to chronic transfusion, or treated with chronic
transfusion initially, depending on other comorbidities and patient factors.●Grafts may be
necessary, but they have a very high failure rate and should be used conservatively

NUTRITION — ●Folic acid 1 mg daily. ● daily multivitamin without iron ●Non-

transfused young women with risk factors for iron deficiency or those who practice breast
feeding also should undergo screening and treatment of iron deficiency ./ oral vitamin D and
calcium.

The use of hydroxyurea is a mainstay in the overall management since it reduces the
incidence of acute painful episodes and hospitalization rates, and prolongs survival.

Pharmaceutical-grade L-glutamine is an oral medication approved in 2017 to reduce acute

complications in children >5 years and adults with SCD, The mechanism is unknown but is
thought to involve an antioxidant effect. While hydroxyurea is first line therapy, L-glutamine
could provide benefit in patients treated with hydroxyurea with a suboptimal response or
those not treated with hydroxyurea due to intolerance or lack of perceived benefit.

Blood transfusion — Blood transfusions are used to treat and prevent complications of SCD,
including preparation for surgery; treatment of symptomatic anemia, acute stroke, multiorgan
failure, and acute chest syndrome; and prevention of stroke, acute chest syndrome, and
recurrent priapism.

ANAGEMENT DURING HOSPITALIZATION — . Hydroxyurea should be continued

during hospitalization as long as there is no excess hematologic toxicity. ●For those who
require transfusion (eg, acute splenic sequestration crisis, transient aplasia from infection),
transfusion should not be delayed while giving other fluids.●If the patient is hypovolemic,
normal saline (ie, 0.9 percent saline) is appropriate to maintain hemodynamic stability. ●If
the patient is euvolemic and receiving maintenance intravenous fluids, we use one-quarter or
one-half normal saline with or without glucose.. Patients with SCD may have a decreased
ability to excrete sodium and may become hypernatremic from receiving normal saline.
Hypernatremia in turn may lead to red blood cell dehydration, which increases sickling.
Incentive spirometry / Thromboembolism prophylaxis

Splenic and hepatic sequestration is characterized by the following four features:●Splenic

enlargement, often tender●A drop in hemoglobin concentration of at least 2
g/dL●Thrombocytopenia●Reticulocytosis. The primary concern in the event of a splenic
sequestration episode is hypovolemic shock resulting from a disproportionate amount of the
intravascular blood volume being sequestered in the spleen because of ensnared red and
white blood cells. Hence, management should be directed at maintaining the individual in a
euvolemic state.

Initial management — ●A high index of suspicion when an individual presents with a sudden
drop in hemoglobin, thrombocytopenia, reticulocytosis, and an enlarged spleen.●Assessment
of volume status and immediate intravenous fluid resuscitation if needed, with the goal of
maintaining the individual in a euvolemic state . When the individual is hypovolemic and is
symptomatic from anemia, a simple blood transfusion therapy should be considered.
However, caution should be used when transfusing the individual, as the blood trapped in the
spleen is still available to re-enter the circulation. Accordingly, following such transfusion
the individual's hemoglobin may rise acutely to levels that result in hyperviscosity syndrome.
To decrease the likelihood of hyperviscosity syndrome occurring after a simple blood
transfusion, we typically transfuse the individual with approximately 50 percent of what we
would commonly transfuse. Thus, instead of transfusing the adult individual with two units of
blood, we transfuse a single unit of blood or calculate (and deliver) the amount of blood
needed to get the individual back to their baseline level and re-evaluate the clinical status
after transfusion.