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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 103F + rhinorrhea, no cough Reduced oral intake and activity PE: T105.2F, P198, R62, O2sat:97% • Chest reduced breath sounds R base Chest xray: R base infiltrate HISTORY OF SICKLE CELL DISEASE 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 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 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 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 >38.5C: • laboratory studies (CBC, culture, UA and culture, chest x-ray) • admission • antibiotics SPECIFIC PROBLEMS IN SICKLE CELL PATIENTS Bacterial sepsis • Other infections 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) 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 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 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 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) 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) 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) Clinical and radiological similarity to bacterial pneumonia • • • • 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) 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 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) 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) 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) 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) 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 HAND-FOOT SYNDROME 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 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 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 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 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) 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 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 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 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.