Transcript Sickle Cell Disease/Acute Chest Syndrome 8/13/10

Sickle Cell Disease/Acute
Chest Syndrome
Chairman’s Rounds
August 13, 2010
David H. Rubin, MD
Department of Pediatrics, St. Barnabas
Hospital
Professor of Clinical Pediatrics,
Albert Einstein College of Medicine
OBJECTIVES
Case presentation
 History of sickle cell disease
 Pathophysiology
 Complications
 Treatment
 Competency Based Summary

CASE PRESENTATION
12 month old SC patient with fever for
2 days; tmax 103F
 + rhinorrhea, no cough
 Reduced oral intake and activity
 PE: T105.2F, P198, R62, O2sat:97%

• Chest reduced breath sounds R base

Chest xray: R base infiltrate
HISTORY OF SICKLE CELL
DISEASE
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
1910
• First description (in western literature) of
sickle cell disease by Chicago physician
James B. Herrick
• Patient from West Indies with anemia
characterized by unusual red cells: “sickle
shaped”
1927
• Hahn and Gillespie showed sickling of red
cells was related to low oxygen
HISTORY OF SICKLE CELL
DISEASE

1948
• Janet Watson (pediatric hematologist in New
York) noted newborn fetal hemoglobin lacked
abnormal sickle hemoglobin seen in adults
• Linus Pauling and Harvey Itano showed that
hemoglobin from patients with sickle cell disease
is different from normals
• First disorder in which abnormality in protein
known to be at fault
HISTORY OF SICKLE CELL
DISEASE

1984
• Bone marrow transplantation in a child with sickle
cell disease produced the first reported cure
• Transplantation was performed to treat acute
leukemia-child's sickle cell disease was cured as a
side-event

1995
• Hydroxyurea became the first (and only) drug
proven to prevent complications of sickle cell
disease in the Multicenter Study of Hydroxyurea in
Sickle Cell Anemia
HEMOGLOBIN MOLECULE
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Hemoglobin - two pairs of nonidentical globin and polypeptide
chains; each chain associated with one
heme group
Four polypeptide chains (alpha, beta,
gamma and delta) in the globin portion
• HbA - 2 alpha and 2 beta chains
• HbF - 2 alpha and 2 gamma chains
• HbA2 - 2 alpha and 2 delta chains
Heme group - iron containing pigment
responsible for oxygen transport
Hemoglobin A
SICKLE CELL DISEASE
The chain of colored boxes
represent the first eight
amino acids in the beta
chain of hemoglobin. The
sixth position in the normal
beta chain has glutamic
acid, while sickle beta
chain has valine. This is the
sole difference between the
two.
SICKLE CELL DISEASE

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1/400 African American infants
8% of African Americans are heterozygous
carriers of the gene – they have trait
Also found in: African, Mediterranean,
Middle Eastern, Indian, or Caribbean
ancestry
Pathology directly related to polymerization
of deoxygenated sickle hemoglobin
•
•
•
•
Distortion of erythrocyte morphology
Reduced RBC life span
Increased viscosity
Episodes of vasoocculsion
SICKLE CELL DISEASE
 Antenatal diagnosis by
amniocentesis or chorionic villus
DNA
 Hb S identified by electrophoresis
and solubility testing
• Affected newborns express small
quantities of Hb S – even with
predominance of Hb F
SICKLE CELL DISEASE

Clinical course:
•
•
ischemic changes
intermittent “crises”
Anemia, increased reticulocyte
count
 Splenomegaly in early childhood
 High risk of bacterial sepsis

PATHOPHYSIOLOGY
OXYGEN SATURATION CURVES in (a) 41 normals and (b) 53
subjects with sickle cell anemia. For any given pO2, the saturation for
Hb SS cells is less than that for normal erythrocytes. (Johnson CS,
Verdegem TV. Pulmonary complications of sickle cell disease. Semin
Resp Med 1988;9:291)
LABORATORY FINDINGS
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Hemoglobin: 5-9 g/dl
Target cells,
poikilocytes, sickled
cells
Reticulocyte count 515%
WBC count: 1215,000/mm3
Platelet count increased
Increased LFT’s,
bilirubin
DIFFERENTIAL
DIAGNOSIS
 Surgical
abdomen
 Rheumatic fever
 Rheumatoid arthritis
 Osteomyelitis
 Leukemia
COMPLICATIONS I
Priapism - GU tract infarction
 Retinopathy – sequestration of
blood in conjunctival vessels;
retinal hemorrhage
 Cholelithiasis - chronic
hemolysis
 Osteonecrosis of femoral head

COMPLICATIONS II
Hematuria, hyposthenuria,
renal failure - papillary necrosis
 Jaundice - hepatic infarct
 Stroke, seizures, weakness,
sensory hearing loss - CNS
ischemia
 Respiratory distress pulmonary infarction

“ROUTINE” TREATMENT
Maintain full immunization status
 Administer polyvalent
pneumococcal vaccine (may be

poorly immunogenic in children
with Hb SS and < 5 yrs of age)
 Administer H. influenzae vaccine

Folic acid daily
“ROUTINE” TREATMENT
Prophylactic penicillin 4 mo- 5 yrs
(<5y: 125mg/12h; >5y:
250mg/12h)
 Aggressive ED approach to
temperature >38.5C:

• laboratory studies (CBC, culture, UA
and culture, chest x-ray)
• admission
• antibiotics
SPECIFIC PROBLEMS IN
SICKLE CELL PATIENTS
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Bacterial sepsis
• Other infections
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Acute chest syndrome
Vasoocclusion crises
Splenic sequestration crises
Aplastic crises
Hemolytic crises
Treatment
BACTERIAL SEPSIS
Impaired immunologic function,
functional asplenia
 Increased risk from: streptococcus

pneumoniae, H. influenzae, n.
meningitidis, salmonella, E. coli,
mycoplasma pneumoniae,
staphylococcus aureus

Greatest risk 6 months - 3 years of
age
BACTERIAL SEPSIS

Impaired immunologic function
• Loss of splenic activity
• Fulminant nature of illness
• Most dangerous period: 6m-3y (protective
antibodies limited with diminished splenic
function)
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Risk of sepsis = 100X normal population
Streptococcus pneumoniae, h. influenza
most common in young children
E. coli and salmonella most common in
older children
BACTERIAL SEPSIS
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Differentiating the patient with viral
illness vs serious bacterial illness (SBI)
difficult
ONLY a blood culture can identify
difference – MUST obtain rapidly and
administer antibiotics
Clinical deterioration is VERY rapid
Treat for septic shock EARLY
BACTERIAL SEPSIS

Emergence of penicillin resistant
streptococcus pneumoniae
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Rapid blood work and IV ceftriaxone
or cefotaxime and vancomycin (if area
of high resistance)
If not acutely ill on physical exam (no
pallor, rales, increased spleen, rales)
with guaranteed follow-up within 24H,
may treat with ceftriaxone 50 mg/kg,
otherwise admit
BACTERIAL SEPSIS
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Short stay outpatient unit also
appropriate
If “low risk” for SBI, may give PO or
IV antibiotics and discharge….BUT
MUST SEE WITHIN 24 HRS for
FOLLOWUP
Older child with any fever…may not
have high WBC and may not have
high fever….BEWARE – admit for
antibiotics and close observation
BACTERIAL BLOOD CULTURES
IN CHILDREN WITH SCD
(Rogovik 2009)
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Retrospective chart review of 692 pediatric
SCD patients with or without fever from
2005-2007 in Toronto Sick Children’s
Hospital (inclusion in study limited to 530
with blood cultures)
77% of febrile children admitted; 7 positive
cultures; 3 in febrile children
No s.pneumoniae species – “all identified
microorganisms part of normal skin or oral
flora and could be contaminants…”
• Thought to be due to 7-valent pneumococcal
vaccine
SEPTIC
ARTHRITIS/OSTEOMYELITIS
VERY difficult to diagnose
clinically; similar to bone
infarction
 Diagnostic tests prior to
antibiotics: Gram stain and culture

• bone aspiration (osteomyelitis)
• joint aspiration (septic arthritis)

Antibiotics
INFLUENZA A (H1N1) AND
SICKLE CELL DISEASE
(Inusa 2010)
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Review of cases of H1N1 disease in patients
with SS disease in children in London: April–
August 2009
21 positive cases among 2200 patients with
SCD; 19 were admitted; 11 needed blood
transfusions due to falling Hg and ACS (10
patients had acute chest syndrome)
All successfully treated with oseltamivir
ACUTE CHEST SYNDROME
(Vichinsky 2000)

Defined as a new infiltrate on a chest
radiograph associated with one or
more symptoms such as
•
•
•
•
•
•
Fever
Cough
Sputum production
Tachypnea
Dyspnea
New onset hypoxia
ACUTE CHEST SYNDROME
(Vichinsky 2000)
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Clinical and radiological similarity to
bacterial pneumonia
•
•
•
•
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Fever, leukocytosis
Pleuritic chest pain
Pleural effusion
Cough with purulent sputum
Clinical course is unique
• Multiple lobe involvement possible
• Duration of clinical illness and of radiologic
clearing of infiltrates prolonged (10-12
days)
ACUTE CHEST
SYNDROME/Pathophysiology

Process may be initiated by
• Microbial infection
• In situ vaso-occlusion
• Fat embolism from ischemic/necrosis bone
marrow
• Thomboembolism

?Activation of endothelium by oxygen
radicals of erythrocytes or infection
process that induces secretion of
inflammatory cytokines
ACUTE CHEST SYNDROME
Most cases are infectious origin
 Difficult to identify organism
although more common organisms
are
• Mycoplasma pneumoniae
• S pneumoniae
• Chlamydia trachomatis

ACUTE CHEST SYNDROME
Clinical Presentation
(Johnson 2005)

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Fever > 38.5°C and cough most
common – especially in children
compared with adolescents
Tachypnea and bronchospasm more
common in children
However – 35% of patients had
normal PE; “additional data support
unreliability of the physical
examination in the detection of ACS…”
ACUTE CHEST SYNDROME

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Symptoms: tachypnea, rales, ronchi, ?lobar
consolidation
Workup: oxygen saturation, CBC, blood
culture, chest x-ray (may be negative in 50%
of cases)
Treatment:
• Start antibiotics early
• Initiate IV ampicillin or ceftriaxone (plus
erythromycin in young child); consider streptococcus
pneumoniae or Mycoplasma
• RBC transfusion or exchange transfusion for severe
anemia (Hg < 5), hypoxia, radiographic evidence of
rapidly progressive disease
• Therapy with steroids may prevent clinical
deterioration in ACS
STEROIDS AND ACS
(Strouse 2008)
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Retrospective cohort study to examine risk
factors for readmission and prolonged
hospitalization at Johns Hopkins in patients
< 22 yrs of age 1998-2004
Identified 65 patients with 129 episodes of
ACS (mean age 12.5 yrs)
Readmission strongly associated with use of
corticosteroid (OR 20, p<.005)
Suggest limited use of steroids
STEROIDS AND ACS
(Kumar 2010)
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Retrospective study of 63 patients with 78
episodes of ACS from 2005-2007 at SUNY
Downstate
“Asthma Regimen” of prednisone used
(2mg/kg/d max 80 mg in 2 divided doses
for 5 days
15% of 53 children receiving steroids and
8% of the 25 children who did not receive
steroids were readmitted (NS)
No significant readmission rate from
steroids
STEROIDS AND ACS
(Sieff 2010)
 “Therapy
with steroids not
usually needed unless patient
has a history of asthma and
signs of asthma exacerbation….”
ACUTE CHEST SYNDROME
(Kikiska 2004)
Increased incidence following
abdominal surgery (15-20%)
 ACS was associated with
• Age (young  vs old)
• Weight (lighter  over heavier)
• Operative blood loss (more > less)
• Lower final temperature

CAUSES OF ACUTE CHEST SYNDROME
1. Hb S–Related
*Direct consequences of Hb S
• Pulmonary vaso-occlusion (16.1%)
• Fat embolism from bone marrow
ischemia/infarction (8.8%)
• Hypoventilation secondary to rib/sternal
bone infarction or to narcotic use
• Pulmonary edema induced by narcotics
or fluid overload
*Indirect consequences of Hb S
• Infection
Atypical bacterial
Chlamydia pneumoniae (7.2%)
Mycoplasma pneumoniae (6.6%)
Mycoplasma hominis (1.0%)
CAUSES OF ACUTE CHEST SYNDROME*
•Bacterial
•Staphylococcus aureus, coagulase-positive
(1.8%)
•Streptococcus pneumoniae (1.6%)
•Haemophilus influenzae (0.7%)
•Viral
•Respiratory syncytial virus (3.9%)
•Parvovirus B19 (1.5%)
•Rhinovirus (1.2%)
•2. Unrelated to Hb S
•Fibrin thromboembolism
•Other common pulmonary diseases (eg,
aspiration, trauma, asthma)
*Vichinsky et al., NEJM, 2000 and Johnson, Semin Resp
Med, 1988
POOR PROGNOSIS/POTENTIAL INDICATIONS FOR
EXCHANGE TRANSFUSION IN ACUTE CHEST
SYNDROME
(Vichinsky 2000, Johnson 1988, Fine 1997)
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Altered mental status and other acute
neurologic findings
Persistent tachycardia >125/min
Persistent respiratory rate >30/min or
increased work of breathing (nasal
flaring, use of accessory muscles,
sternal retractions)
Temperature >40°C
Hypotension compared with baseline
POOR PROGNOSIS/POTENTIAL INDICATIONS FOR
EXCHANGE TRANSFUSION IN ACUTE CHEST
SYNDROME
(Vichinsky 2000, Johnson 1988, Fine 1997)
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Arterial pH <7.35
Arterial oxygen saturation persistently <88%,
despite aggressive ventilatory support
Serial decline in pulse oximetry or increasing
A-a gradient
Hemoglobin concentration falling by 2 g/dL or
more
Platelet count <200,000/μL
Evidence for multiorgan failure
Pleural effusion
Progression to multilobe infiltrates
ASTHMA AND ACS
(Boyd 2004)
Does asthma increase the risk of ACS
in children with sickle cell disease?
 Retrospective case control study
(cases: ACS, controls: no ACS)
 Cases of physician diagnosed asthma
4 times (95% CI: 1.7, 9.5) more likely
to develop ACS and longer
hospitalization

ACS AND LUNG FUNCTION
(Sylvester 2006)


Hypothesis: children with sickle cell disease
hospitalized with ACS have poor lung
function compared with those with SCD not
hospitalized with ACS
Results
• Higher resistance, TLC and RV in ACS group
• No difference in PFTs pre/post bronchodilator
therapy, but ACS group had lower FEV25 and
FEF75 pre and lower FEF75 post

Conclusion – ACS hospitalized children had
significant differences in PFT
VASOOCCLUSION
Infarction of bone, soft tissue, and
viscera by sickled red cells
 Young children: usually painful
crises involve extremities
 Older children/adolescents: head,
chest, abdominal, back pain
 Intercurrent illness may
precipitate crisis
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HAND-FOOT SYNDROME
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Acute sickle
dactylitis
1st manifestation of
disease
Pain symmetrical
swelling of hands
and feet
Ischemic necrosis of
small bones; rapidly
expanding bone
marrow chokes off
blood supply
Radiographs helpful
in chronic stage
VASOOCCLUSION


Occlusion of mesenteric vessels vs.
appendicitis; pain may mimic acute
surgical condition
Hepatic infarction - acute onset of
jaundice and abdominal pain (similar
to hepatitis, cholycystitis and biliary
obstruction)

GU Tract - renal papillary necrosis,
priapism
• Antifibrinolytic drugs -aminocaproic acid or
tranexamic acid may cause ureteral clot
VASOOCCLUSION/
Treatment

Mild/Moderate Pain
• 1½ maintenance with oral or IV fluids or
D5½NS or D5¼NS
• Acetaminophen with or without codeine
• Admit if poor pain control, poor hydration
status, or repeated ED visits

Severe Pain
• 1½ maintenance with oral or IV fluids or
D5½NS or D5¼NS
• Morphine 0.1-0.15 mg/kg IV
• Admit
CNS INFARCTION
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Spectrum of initial complaints: mild
symptoms of TIA to seizures, coma,
hemiparesis, death
Cortical infarction seen on MRI or CT
Immediately start 1½ - 2 volume exchange
to reduce Hb S to < 30% of total Hb
• whole blood < 5 days old OR
• packed red cells < 5 days reconstituted with fresh
frozen plasma

Preserve pre-transfused sample for red cell
antigen identification
PRIAPISM
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Admit with severe pain or persistent erection
Hydration: 1½ - 2X maintenance for 24-48
hours with IV fluids D5½NS or D5¼NS
If swelling does not decrease, transfuse with
red cells to raise Hb to 9-10g/dl
If no improvement, exchange transfusion to
reduce Hb S to < 30% of total Hb
If no improvement, corporal aspiration or
surgical procedure
SPLENIC SEQUESTRATION
CRISIS
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Symptoms: left upper quadrant pain,
pallor, lethargy
Signs: hypotension, tachycardia,
enlarged and firm spleen
Laboratory: severe anemia,
thrombocytopenia, neutropenia,
increased reticulocytes
Treatment: Immediate volume
replacement, transfusion with packed
red cells or whole blood
APLASTIC CRISIS
Symptoms: progressive pallor,
lethargy, may be caused by
parvoviral infection
 Signs: absence of jaundice
 Laboratory: severe anemia,
decreased reticulocytes
 Treatment: transfusion with
packed red cells or whole blood

HEMOLYTIC CRISIS
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Symptoms: viral/bacterial infection
Signs: sudden pallor, jaundice,
scleral icterus
Laboratory: severe anemia,
increased reticulocytes, active
hemolysis
Treatment: rarely needs
transfusion; await resolution of
infection
TREATMENT
(Sieff 2010)

Fluids
• Primarily for vaso-occlusive crisis
• 1½ maintenance with oral or IV fluids or D5½NS
or D5¼NS

Pain management
• Mild/moderate: oral medications acetaminophen
with codeine or oxycodeine
• Severe: IV morphine or hydromorphine, patient
controlled analgesia, NSAIDs
TREATMENT
(Sieff 2010)

Sepsis – antibiotics
• Due to emergence of resistant strains of s.
pneumoniae, treat with 3rd generation
cephalosporin (cefotaxime or ceftriaxone) and
vancomycin
• Watch for secondary organ damage due to
sickling in presence of acidosis, stasis, and
hypoxia – consider transfusion (packed RBC or
exchange transfusions)

Acute chest syndrome – cover for
appropriate organisms
TREATMENT
(Roseff 2009)

Transfusion
• Consider in patients with signs and
symptoms of anemia
• Increases patient hemoglobin
• Dilutes Hg S with Hg A
•
RBC’s with Hg A - longer survival than Hg S
• Suppresses patient’s own erythropoiesis
TREATMENT
(Roseff 2009)

Simple transfusion (peripheral IV)
• Technical ease, low risk of exposure,
dilution of Hg S
• Increases viscosity, risk of Fe overload

Exchange transfusion (automated
machine)
• Rapid reduction in Hg S, no risk of Fe overload
• Requires large gauge catheter, expertise in
special equipment, higher risk of exposure
TREATMENT
(Roseff 2009)

Indications for transfusion
•
•
•
•
•
•
•
Aplastic crisis
Hemolytic crisis (extremely rare)
Splenic sequestration
Priapism
Presurgical prophylaxis
Acute chest syndrome
Stroke
OTHER TREATMENT
(Sieff 2009, Steinberg 2010)
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Stem cell transplantation
Hydroxyurea
• Introduced 25 years ago based on ability to
increase fetal hemoglobin (Hg F)
• Observational studies in children have shown
benefits and safety
• Often used for maintenance therapy in patients
with stroke
• In long term study (17.5 years f/u) mortality
reduced in those treated with hydroxyurea
TRANSITION TO ADULT CARE
(Hunt 2010)

30 day rate of return to acute care
• 10-17 yrs: 27.4%
• 18-30 yrs: 48.9%

Why the increase?
• Lack of insurance
• Poor follow-up contacts
• Too much reliance on emergency
departments for ongoing care
SUMMARY
 Chronic
hemolytic anemia
 Crises: vasoocclusive (any
organ, acute chest syndrome,
stroke), hemolytic,
sequestration, aplastic
 Watch for sepsis
 Continuity of care critical:
immunizations, antibiotics
COMPETENCY BASED
OBJECTIVES

Medical Knowledge
• knowledge about the established and
evolving biomedical, clinical, and
cognate (epidemiological and socialbehavioral) sciences and their
application to patient care
•
Diagnosis, management of sickle cell
disease
COMPETENCY BASED
OBJECTIVES

Patient Care
• family centered patient care
developmentally and age appropriate
compassionate and effective for
treatment of health care problems
and promotion of health
•
Medical home for treatment of
multispecialty disease
COMPETENCY BASED
OBJECTIVES

Practice Based Learning
• investigation and evaluation of patient
care, and the assimilation of scientific
evidence

Communication Skills
• interpersonal and communication skills
resulting in effective information
exchange and learning with patients,
families and professional associates
COMPETENCY BASED
OBJECTIVES

System Based Practice
• understanding systems of health care
organization, financing, and delivery,
and the relationship of one’s local
practice and these larger systems

Professionalism
• carrying out professional
responsibilities, adherence to ethical
principles, and sensitivity to diverse
patient populations
REFERENCES
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Vichinsky et al., NEJM, 2000
Fine et al, NEJM 1997
Johnson CS. The acute chest syndrome. Hematol
Oncol CLin N am 19 (2005) 857-879.
Sylvester KP et al. Impact of acute chest syndrome
on lung function of children with sickle cell disease.
J Pediatr 2006;149:17-22.
Sylvester KP. Airway hyperresponsiveness and
acute chest syndrome in children with sickle cell
anemia. Pediatr Pulmonol 2007;42:272-276.
Sieff, CA. Hematologic emergencies. In Fleisher
Ludwig. Pediatric Emerg Med 6th ed., Phila,
Lippincott. 2010
REFERENCES
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Caboot JB and Allen JL. Pulmonary complications of
sickle cell disease in children. Curr Opin Pediatr
2008;20:279-287.
Boyd JH et al. Asthma and acute chest in sickle cell
disease. Pediatr Pulmonol 2004;38:229-232.
Kumar R et al. A short course of prednisone in the
management of acute chest syndrome of sickle cell
disease. J Pediatr Hematol Oncol 2010;32:e91-e94.
Strouse JJ et al. Corticosteroids and increased risk
of readmission after acute chest syndrome in
children with sickle cell disease. Pediatr Blood
Cancer 2008;50:1006-1012.
REFERENCES
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Inusa B et al. Pandemic influenza A (H1N1) virus
infections in children with sickle cell disease. Blood
2010;115;110:2329-2340.
Rogovik AL et al. Bacterial blood cultures in children with
sickle cell disease. Amer J Emerg Med 2010:28:511-514.
Roseff SD. Sickle cell disease: a review. Immunohematol
2009;25:67-74.
Steinberg et al. Risks and benefits of long term use of
hydroxyurea in sickle cell anemia; a 17.5 year followup.
Am J Hematol 2010;85:403-408.
Hunt SE. Transition from pediatric to adult care for
patients with sickle cell disease. JAMA 2010;304:408409.