Acute Chest Syndrome. Rationale for Red Blood Cell Exchange and/or Simple Transfusion Keith Quirolo, M.D. May 5th 2015 ASFA Annual Meeting
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1 Acute Chest Syndrome Rationale for Red Blood Cell Exchange and/or Simple Transfusion Keith Quirolo, M.D. May 5th 2015 ASFA Annual Meeting
2 Disclosure Consultant: Terumo BCT
3 Discussion Etiology Pulmonary Hypertension Interstitial Lung Disease Diagnosis ACS differential: Pulmonary Thrombotic Embolus Fat embolus Infarct Treatment Simple Transfusion Role Chronic transfusion for ACS Red Cell Exchange Treatment goals, Variables affecting treatment
4 2014 Evidence-Based Report Evidence-Based Recommendations for Managing Acute Complications of SCD Acute Chest Syndrome Antibiotics, O2 sat>95%, monitoring Simple transfusion if Hgb > 1.0 g/dl below baseline, Hgb > 9.0 g/dl elective transfusion SC, SB + Thalassemia, Hematology consult for transfusion Exchange Transfusion for Oxygen Saturation < 90% on supplemental oxygen, progressive infiltrate, decreasing Hgb Incentive spirometry Strong Recommendation Weak Recommendation Strong Recommendation Strong Recommendation Strong Recommendation Quality of evidence Low Quality of evidence Low Quality of evidence Low Quality of evidence Low Quality of evidence Moderate Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014;312:
5 ASFA Recommendations Sickle Cell Disease: Acute Condition Procedure Recommendation Category Acute Stroke RBC EX Grade 1C I Acute Chest Syndrome RBC EX Grade 1C II Priapism RBC EX Grade 2 C III Multiorgan Failure RBC EX Grade 2C III Splenic/Hepatic Sequestration Intrahepatic Cholestasis RBC EX Grade 2C III RBC EX Grade 2C III Schwartz J, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis J Clin Apher 2013;28:
6 Caveats Published Literature primarily pediatric Majority of Studies are Retrospective There are no Prospective Randomized Trials for: Blood transfusion as treatment of acute chest syndrome either simple or exchange Comparing simple with exchange transfusion
7 Definition New pulmonary infiltrate One consolidated segment (not atelectasis) Chest pain Temperature of > 38.5 C Tachypnea Wheezing or cough Various definitions have been used Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med 2000
8 Acute Chest Syndrome Second second most common diagnosis for hospitalization 25% of deaths in sickle cell disease Leading single cause of death Risk factor for stroke Vichinsky 1997 Vichinsky 2000 Overall Death Rate 1.8% 3% Children 0-9 years -- < 1% Children Overall 1.1% 2% Adults 4.1% 9%
9 Cooperative Study episodes in 939 patients Hemoglobin SS: 738 cases (78%) Hemoglobin SC: 127 cases (13%) Hemoglobin SB 0 Thal: 50 cases (5.5%) Hemoglobin SB + Thal: 24 cases (2.5%) Risk factors for death: Respiratory failure in first 48 hours Bacterial sepsis Extremity pain Pulmonary embolus (Fat embolus) Vichinsky, E. P., L. A. Styles, et al. (1997). "Acute chest syndrome in sickle cell disease: clinical presentation and course. Cooperative Study of Sickle Cell Disease." Blood 89(5):
10 Causes and Outcomes Prospectively study 538 patients 671 episodes of acute chest syndrome ~ 80% were hemoglobin SS Male 58% Mean age at onset 13.8 years: all patients» 0-9 years: 5.4 years (49%)» years: 14.6 years (27%)» > 20 years: 30.2 years (24%) Vichinsky, E. P., L. D. Neumayr, et al. (2000).
11 Etiology Cause All (N=670) Age at Episode of Acute Chest Syndrome 0-9 years years 20 years Number of Episodes Fat Emboli 59 (8.8) Chlamydia 48 (7.2) Mycoplasma 44 (6.6) Viral 43 (6.4) Bacterial 30 (4.5) Mixed Infection 25 (3.7) Legionella 4 (0.6) Misc Infection 3 (0.4) Infarct 108 (16.1) Unknown 306 (45.7) % of the episodes did not have an etiology (Infarct + Unknown) Infarct = negative studies / Unknown = incomplete studies Vichinsky, E. P., L. D. Neumayr, et al. (2000).
12 Complications during ACS Variable All (n=537) Age at First Episode of ACS P Value Event % all patients 0-9 yr N= yr N=145 >20 yr N= 128 VOE <0.001 Pulmonary Neurological <0.001 Cardiac GI Renal 2 <1 1 8 <0.001 Death 3 <1 2 9 <0.001 Hospital Days Respiratory Failure, pneumothorax, empyema 2. Arrhythmia, CHF, Hypo-Hypertension 3. GI bleed, ileus, bowel infarction Neurologic complications: 46% Had respiratory failure 92% Received transfusion 23% Died Vichinsky, E. P., L. D. Neumayr, et al. (2000).
13 Pediatric ACS Increased incidence in children Less often require transfusion Seasonal: Presentation with lower respiratory symptoms Fat emboli in 24% 14% occur with bacteremia (1.8% > 10 years old) Upper / Middle lobe disease Without clinical findings 35% to 50% of cases 1. Morris, C., E. Vichinsky, et al. (1999). "Clinician assessment for acute chest syndrome in febrile patients with sickle cell disease: is it accurate enough?" Ann Emerg Med 34(1): 64-9) 2.Vichinsky, E. P., L. A. Styles, et al. (1997) 3.Vichinsky, E. P., L. D. Neumayr, et al. (2000).
14 Pediatric ACS Acute Chest Study Asthma (14%) more common in children than adults (5%) Fat emboli as common in pediatric cases (24%) as adult cases (19%); overall (8.8%) Association with Asthma (Airway Hyper-reactivity, Obstructive disease, Allergy) Vichinsky, E. P., L. A. Styles, et al. (1997).
15 Vichinsky, E. P., L. A. Styles, et al. (1997). "Acute chest syndrome in sickle cell disease: clinical presentation and course. Cooperative Study of Sickle Cell Disease." Blood 89(5):
16 Predicting Recurrent Acute Chest Syndrome in Children Acute Chest Before age of four years Asthma Wheezing with SOB/Wheezing after exercise Female gender and Atopy Outcome Covariate Incidence Rate Ratio Prospective ACS Events 95% Confidence interval Gender (female) 1.80 ( ) ACS < 4 years 2.84 ( ) <0.001 Wheeze with SOB 1.78 ( ) Positive Skin Test 1.87 ( ) P DeBaun MR, Rodeghier M, Cohen R, et al. Factors predicting future ACS episodes in children with sickle cell anemia. Am J Hematol 2014;89:E212-7.
17 Time to Next Episode Outcome after ACS Prevalence of Re-hospitalization 125 children compared recurrence of ACS or VOE After initial episode of ACS Children 4 years versus children > 4 years 6 months 29.6 (37%/125) 1 year 49.6 (62%/125) 2 years 68.8 (86%/125) 3 years 77.6 (97%/125) % with subsequent ACS/VOE Total < 4 years 4 years P Value 26.8 (15%/56) 63.5 (35%/56) 78.6 (44%/56) 83.9 (47%/56) 31.9 (22%/69) 39.1 (27%/69) 60.9 (42%/69) 72.5 (50%/ Vance LD, Rodeghier M, Cohen RT, et al. Increased risk of severe vaso-occlusive episodes after initial acute chest syndrome in children with sickle cell anemia less than 4 years old: Sleep and Asthma Cohort. Am J Hematol 2015.
18 Adolescent-Adult ACS Initial complaint Fever, cough, tachypnea, rib or sternal pain Extremity pain Lower lobe disease with pleural effusion Death 4 times more likely Frequently require transfusion Bacteremia 1.8% (1997) Fat emboli: 16% yrs.; 19% >20 yrs. Vichinsky, E. P., L. D. Neumayr, et al. (2000) Vichinsky, E. P., L. A. Styles, et al. (1997).
19 Fat Emboli Syndrome Marrow necrosis Fat embolization Release of free fatty acids Lung injury Hypoxia VQ mismatch Increased hemoglobin polymerization Gladwin MT, Vichinsky E. Pulmonary complications of sickle cell disease. N Engl J Med 2008;359:
20 Pulmonary Hypertension Interstitial Lung Disease Pulmonary hypertension is not associated with an increased incidence of acute chest syndrome. Pulmonary obstructive disease evolves to restrictive disease. Increased circulating fibrocytes in sickle cell disease No evidence interstitial lung disease associated with acute chest syndrome Pulmonary arterial pressures increase during acute chest syndrome (adult study) TRV < 2.5 m/sec (40%) >2.5<2.9 m/sec (23%) > 3.0 m/sec (37%) 60% with PHT Mortality 30% if TRV >3.0 m/sec Mortality 2% if TRV <2.5 m/sec Mekontso Dessap A, Leon R, Habibi A, et al. Am J Respir Crit Care Med 2008.
21 Presentation ACS Children vs. Adolescents vs. Adults Complaint/Sympto m Percent With Complaint/Symptom Children Adolescence Adults Admission ACS 61% 46% 42% Fever 86% (90.6%) 78% (76%) 70% (64%) Chest Pain 27% (5.5%) 67% (29%) 55% (44%) SOB 31% (17%) 44% (26%) 58% (47%) Extremity Pain 22% 44% 58% Rib Pain 14% (23%) 26% (78%) 30% (84%) Vichinsky, E. P., L. D. Neumayr, et al. (2000). "Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group." N Engl J Med 342(25):
22 Pediatric Versus Adult ACS Pediatric Acute Chest Syndrome presentation Airway hyper-reactivity Obstructive lung disease Inflammation predominates versus Infarct/Emboli Morbidity-Mortality Greater in Adults Pulmonary Hypertension Respiratory Failure Fat emboli syndrome Pulmonary thrombosis/embolism Few studies to base etiology or morbidity
23 Diagnosis New pulmonary infiltrate One consolidated segment (not atelectasis) Chest pain Temperature of > 38.5 C Tachypnea Wheezing or cough
24 Clinical Respiratory Score Pediatric Study Scoring CRS to assess severity (0-12) Treatment Algorithm 1. Asthma treatment with methylprednisolone Q 12 hours, vest, inhaled bronchodilator 2. Add simple transfusion 3. Transfer to ICU 4. Exchange transfusion Crabtree EA, Mariscalco MM, Hesselgrave J, et al. Improving care for children sickle cell disease/acute chest syndrome. Pediatrics 2011;127:e480-8.
25 spla2 Increase in spla2 occurs prior to pulmonary infiltrate Transfusion can prevent ACS Two preliminary studies ACS prevented in patients who had elevated spla2 and received transfusion Multicenter Study 273 patients enrolled Only 10 randomized Only 3 received transfusion per the protocol Positive predictive value was 26% Styles L, Wager CG, Labotka RJ, et al. Refining the value of secretory phospholipase A2 as a predictor of acute chest syndrome in sickle cell disease: results of a feasibility study (PROACTIVE). Br J Haematol 2012;157:
26 Venous Thromboembolism Adults Prevalence and Characteristics of Venous Thromboembolism Variable All Patients Hgb SS S Variant P Median Age 1 st 29.9 yrs 28.0 yrs 34.2 yrs Any VT 25% 22.6% 30.4% DVT 18.3% 18.3% 18.4% PE 13% 10.4% 19.2% Other 1.0% 0.7% 1.6% Non-Cather 18.8% 15.4% 26.4% patients with sickle cell disease 25% with venous thromboembolism 18.8% not related to catheter Increased in non-ss and with Trjet > 2.5 m/sec Mortality: 7.4%; Thrombosis 15.8% vs. 4.6 % P=0.001 Naik RP, Streiff MB, Haywood C, Jr., Nelson JA, Lanzkron S. Venous thromboembolism in adults with sickle cell disease: a serious and under-recognized complication. Am J Med 2013;126:443-9.
27 Pulmonary Emboli Sickle Cell Disease Discharge Database Review: 5 years 2001 to 2006 Rate African American (0.59%) = SCD (0.58%) CT scan African American (46%) = SCD (42%) Mortality SCD without PE: 1.4%, with PE: 6.2% No difference in genotype No clinical features to distinguish PE Novelli EM, Huynh C, Gladwin MT, Moore CG, Ragni MV. Pulmonary embolism in sickle cell disease: a case-control study. J Thromb Haemost 2012;10:760-6.
28 Pulmonary Artery Thrombosis in Acute Chest Syndrome 125 patient screened with CT 144 episodes of ACS 20 Positive Prevalence 17% Only Predictors: Thrombocytosis (P= 0.048) Bilirubin (P=0.048) DVT not increased in SCD versus AA with PE Low percent of main or lobar thrombosis Fat emboli could not be diagnosed with MRI May indicate a local thrombotic process Mekontso Dessap A, Deux JF, Abidi N, et al. Pulmonary Artery Thrombosis during Acute Chest Syndrome in Sickle Cell Disease. American journal of respiratory and critical care medicine 2011.
29 Fat Emboli Syndrome Literature review Increased frequency in patients with high hemoglobin: SC, SS with a-thalassemia trait, other variants. Fetal hemoglobin not protective 81% had respiratory failure, 83% neurologic event 50% of cases were diagnosed with FES at autopsy Mortality overall : 64% 29% Exchange transfusion: mortality 29% 31% received simple transfusion: mortality 61% 38% received no transfusion: mortality 91% Tsitsikas DA, Gallinella G, Patel S, Seligman, Bone marrow necrosis and fat embolism syndrome in sickle cell disease: increased susceptibility of patients with non-ss genotypes and a possible association with human parvovirus B19 infection.blood Rev 2014;28:23-30.
30 Evaluation Clinical diagnosis of acute chest syndrome Clinical respiratory score Low threshold for red cell transfusion Treatment for obstructive lung disease Low threshold for chest CT (adults) Anticoagulation with LMWH (?)
31 Transfusion
32 Transfusion Rheology 15 subjects acute single transfusion with a hemoglobin S of > 50% Oxygen transport declined as the hematocrit and viscosity increased. Optimal hematocrit between 27 and 33% Decrease in oxygen transport hematocrit >35% Jan K, Usami S, Smith JA. Effects of transfusion on rheological properties of blood in sickle cell anemia. Transfusion 1982;22:17-20.
33 Hematocrit to Viscosity 26 subjects Chronic simple transfusion for stroke Hematocrit to Viscosity Ratio: HVR The HVR was decreased at low-shear relative to high shear Detterich J, Alexy T, Rabai M, et al. Low-shear red blood cell oxygen transport effectiveness is adversely affected by transfusion and further worsened by deoxygenation in sickle cell disease patients on chronic transfusion therapy. Transfusion 2013;53:
34 Fluid Balance/Hypertension Five pediatric patients age 3 to 9 with ACS Required ventilation support All had a positive net fluid balance All had hypertension for age at some time during hospitalization All with neurologic events Posterior Leukoencephalopathy Henderson JN, Noetzel MJ, McKinstry RC, White DA, Armstrong M, DeBaun MR. Reversible posterior leukoencephalopathy syndrome and silent cerebral infarcts are associated with severe acute chest syndrome in children with sickle cell disease. Blood 2003;101:415-9.
35 Simple Transfusion 36 children were admitted with 40 episodes of acute chest Clinical severity score Blood gas before and after transfusion in 27 episodes (67.5% of episodes) 6 non-transfused patients had blood gas measurements Oxygenation improved with transfusion Length of stay and symptoms similar between groups Emre U, Miller ST, Gutierez M, Steiner P, Rao SP, Rao M. Effect of transfusion in acute chest syndrome of sickle cell disease. J Pediatr. 1995;127:
36 n Before After P PaO 2 (RA) / / P(A-a)O / / PaO 2 /PAO / / PaO 2 (100% O 2 ) / / P(A-a)O / / PaO 2 /PAO / / Changes in Clinical Status Days of Sx Transfused Not transfused Fever 3.1 +/ /- 3.9 NS Tachypnea 2.6 +/ /- 2.9 NS Retractions 1.3 +/ /- 0.9 NS Hospitalization 7.4 +/ /- 3.4 NS
37 Simple versus Exchange Pediatrics Retrospective study of 81 patients with ACS Simple transfusion (ST): n = 51 Red Cell Exchange (RCE): n =15 RCE + ST: n = 15 Clinical Respiratory Score for all patients 6 variables scored 0 through 2 (max score = 12) Respiratory rate, Auscultation, Accessory muscles, Mental status, O2 saturation, Skin color Turner JM, Kaplan JB, Cohen HW, Billett HH. Exchange versus simple transfusion for acute chest syndrome in sickle cell anemia adults. Transfusion 2009;49:863-8.
38 ACS Simple vs. Exchange Transfusion Laboratory and Clinical Data: Simple (ST), U-RCX, ST+RCE ST (n=51) U-RCX (n=15) ST+RCX (n=15) Overall P value CRS at Dx 3.0 ± ± ± CRS after ST 2.0 ± ± CRS after RCE ± ± HGB at Dx 7.3 ± ± ± HGB after ST 10.2 ± ± HGB after RCE ± ± O2 sat at Dx 92.3 ± ± ± Days on O2 2.4 ± ± ± Pre RCX % S ± ± 13.4 <0.001 Post RCX %S ± ± LOS (days) 5.5 ± ± ±
39 Simple Transfusion Adults 77 patients with 107 episodes / 6 years Mean age 29 +/- 7 years old Transfusion only to the most severe cases: Rapid deterioration in < 24 hours After three days if deterioration Hypoxia, chest pain and/or new infiltrate on CXR 50 transfusions (47.6% of episodes) 35% within 48 hours for severe disease 65% 3 to 14 days after onset Maitre B, Habibi A, Roudot-Thoraval F, et al. Acute chest syndrome in adults with sickle cell disease. Chest 2000;117:
40 Transfused (50) Nontransfused (57) p Patients Temperature / / PaO / / WBC 1000/uL 24 +/ /- 5.1 < Hgb g/dl 7.5 +/ / LDH IU/L 848 +/ / In Hospital / / ICU 25 (52) 4 (7) < Death 5 (10) of the 5 deaths were surgical patients, Fat emboli did not predict more severe course, but hospitalization was longer, 78% presented with extremity pain
41 Exchange versus Simple Adult SS or SB 0 thalassemia, mean age 30 years Retrospective study 20 exchanged, 20 simple transfused Patients: Exchange versus Simple Transfusion Characteristic Exchange (n=20) Simple (n=20) p Value Age (yrs) Genotype 18 SS, 2 SB 0 19SS, 1 SB Prior ACS (%) HU on admission (%) Bronchodilator (%) PAP > 25 mmhg (%) LDH Peak LDH median Turner JM, Kaplan JB, Cohen HW, Billett HH. Exchange versus simple transfusion for acute chest syndrome in sickle cell anemia adults. Transfusion 2009;49:863-8.
42 Exchange versus Simple
43 Outcome Exchange versus Simple Transfusion Variable Exchange (n=20) Simple (n=20) p Value LOS post procedure LOS hospital RBC Transfused (Units) <0.001 Admit Hgb (g/dl) Pre-TX (g/dl) <0.01 Peak Hgb (g/dl) <0.01 DC Hgb (g/dl)
44 Acute Events Pediatrics: Clinical respiratory score Lower score Severe anemia Initial treatment to avoid delay Avoid fluid overload Adult Severe anemia avoid delay No evidence there is benefit Chronic Transfusion Prevents morbidity SIT TRIAL STOP I STUDY Simple to Exchange Control iron Avoid fluid overload Simple Transfusion
45 Exchange Transfusion Acute Goals Hemoglobin 9-10 g/dl %S < 30% Improvement in oxygenation (O2 sat ~ 95%, decreased support Efficacy Late treatment Complications Thrombosis risk in adults
46 Exchange Transfusion May not be the answer for every patient.
47 Plastic Bronchitis Eight year review 26 patients with 29 episodes (72%) Presentation with VOE in 93% Age 3 to 20 years Bronchoscopy at request of hematologist Lower lobe 26 episodes Lipid Laden Macrophage With PB 37% Without 25% Moser C, Nussbaum E, Cooper DM. Plastic bronchitis and the role of bronchoscopy in the acute chest syndrome of sickle cell disease. chest 2001;120:
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