pulmonary complications of bone marrow transplantation complications... · pulmonary complications...
TRANSCRIPT
©2014 MFMER | slide-1
Pulmonary Complications of Bone Marrow Transplantation:When infection isn’t the answer
Shannon Piche, PharmD, BCPSPGY-2 Critical Care Resident
©2014 MFMER | slide-2
Objectives• List the American Thoracic Society diagnostic
criteria for idiopathic pneumonia syndrome• Identify key clinical differences between diffuse
alveolar hemorrhage, peri-engraftment respiratory distress syndrome, and non-cardiogenic capillary leak syndrome
• Determine the role of corticosteroid therapy in treatment of diffuse alveolar hemorrhage
DAH: diffuse alveolar hemorrhagePERDS: peri-engraftment respiratory distress syndromeCLS: capillary leak syndrome
©2014 MFMER | slide-3
65 y/o M with respiratory distress• Past Medical History:
• Type II Diabetes Mellitus • Atrial fibrillation• Anxiety/depression• Myelodysplastic syndrome (MDS)
10/2011: Biopsy, MDS
7/2012:5-azacitidine
9/2014: Decitabine x7 cycles
7/2015:Cyclosporine + prednisone
©2014 MFMER | slide-4
History of Present Illness
Day -6: • Conditioning regimen:
fludarabine, melphalan
Day 0: • Allogeneic, peripheral
blood stem cell transplant
Day +8:• Hospital admission• Mucositis• ANC: 0 cells/μL
Day +16: • Transferred to ICU• Increased WOB• ANC: 280 cells/μL
ANC: absolute neutrophil countWOB: work of breathing
©2014 MFMER | slide-5
Idiopathic Pneumonia Syndrome
Peri-engraftment respiratory distress syndrome
Non-cardiogenic capillary leak syndrome
Diffuse alveolar hemorrhage
Cryptogenic organizing pneumonia
Delayed pulmonary toxicity syndrome
Bronchiolitis obliterans syndrome
Panoskaltsis-Mortari A, et al. Am J Respir Crit Care Med. 2011;183:1262-79.
©2014 MFMER | slide-6
Pathophysiology
Conditioning chemotherapy
Previous infections
Total body irradiation
Inflammatory cytokines
T-cell activation
Alveolus
Capillary
Panoskaltsis-Mortari A, et al. Am J Respir Crit Care Med. 2011;183:1262-79.
©2014 MFMER | slide-7
Pathophysiology, Example: DAH
Conditioning chemotherapy
Previous infections
Total body irradiation
Inflammatory cytokines
T-cell activation
Alveolus
Capillary
Panoskaltsis-Mortari A, et al. Am J Respir Crit Care Med. 2011;183:1262-79.
©2014 MFMER | slide-8
Pathophysiology
Damage
Panoskaltsis-Mortari A, et al. Am J Respir Crit Care Med. 2011;183:1262-79.
©2014 MFMER | slide-9
IPS: American Thoracic Society Definition 1. Evidence of widespread alveolar injury2. Absence of infection3. Absence of cardiac dysfunction, acute decline
in renal function as a sole explanation
Where do we go from here?
Panoskaltsis-Mortari A, et al. Am J Respir Crit Care Med. 2011;183:1262-79.
©2014 MFMER | slide-10
Back to the Case• Vital signs
• T 39.0°C• SaO2: 88%• RR: 28
• Physical exam: notable for bilateral lower extremity edema
• Blood cultures, tracheal secretions pending• Chest x-ray
• HR: 112 bpm• BP: 151/72 mmHg
©2014 MFMER | slide-11
Bilateral, Multi-lobar Pulmonary Infiltrates
©2014 MFMER | slide-12
• HR: 112 bpm• BP: 151/72 mmHg
BAL: broncheoalveolar lavage
• Vital signs• T 39.0°C• SaO2: 88%• RR: 28
• Physical exam: notable for bilateral lower extremity edema
• Blood cultures, tracheal secretions pending• Chest x-ray• Considering CT chest, BAL
Back to the Case
©2014 MFMER | slide-13
Respiratory distress in a BMT patient
Infection?
Days 1-30: • Diffuse alveolar hemorrhage• Peri-engraftment respiratory
distress syndrome• Non-cardiogenic capillary leak
syndrome
Timeline
• Work-up ongoing• Initiated on broad
spectrum antibiotics
Days 100+: • Delayed pulmonary toxicity
syndrome• Bronchiolitis obliterans
syndrome• Cryptogenic organizing
pneumoniaPanoskaltsis-Mortari A, et al. Am J Respir Crit Care Med. 2011;183:1262-79.
©2014 MFMER | slide-14
• i.e., pulmonary edema
• Weight gain• Peripheral edema• Responsive to
diuresis
• Fever• Cutaneous rash• Days surrounding
engraftment
• Fever +/-• Hemoptysis (~60%)• Diagnosis: BAL
- Progressively bloody return
- >20% Hemosiderin-laden macrophages
DAH:
PERDS: CLS:
Respiratory distress
©2014 MFMER | slide-15
Back to the Case: What’s the Verdict?• PERDS
Previous day, first detectable ANCNo rash on physical exam
• CLSDown 2kg from admissionPeripheral edema on physical exam
• DAHProgressively bloody return on BAL26% hemosiderin-laden macrophages
©2014 MFMER | slide-16
Diffuse Alveolar Hemorrhage • Epidemiology:
• Median onset day +19 (range, day +5-34)• 5-12% incidence in BMT population• Reported 21-day mortality 60-100%
• Risk factors:• Age >40 years• Full-intensity conditioning regimen, total body
irradiation• Underlying acute leukemia or MDS• Type of transplant?
• PT/PTT, thrombocytopenia are NOT risk factorsAfessa B, et al. Am J Respir Crit Care Med. 2002;166:641-45
Wanko SO, et al. Biol Blood Marrow Transplant. 2006;12:949-53Lewis ID, et al. Bone Marrow Transplant. 2000;26:539-43.
©2014 MFMER | slide-17
Diffuse Alveolar Hemorrhage Use of Corticosteroids in Bone Marrow Transplant Patients
©2014 MFMER | slide-18
Treatment Outline1. Steroids2. Steroids3. Steroids
©2014 MFMER | slide-19
Diffuse Alveolar Hemorrhage
Immune Mediated• ANCA-associated vasculitis• Systemic lupus erythematosus• Rheumatoid arthritis• Antiphospholipid antibody
syndrome
Non-Immune Mediated• Infection• Acute respiratory distress
syndrome• Coagulopathy• Left ventricular dysfunction
Bone Marrow Transplantation
Krause ML, et al. Immunol Allergy Clin North Am. 2012;32(4):587-600.
©2014 MFMER | slide-20
Pathophysiology
Alveolus
Capillary
Krause ML, et al. Immunol Allergy Clin North Am. 2012;32(4):587-600.
©2014 MFMER | slide-21
Treatment Outline1. Steroids2. Steroids3. Steroids4. Others?
• Management of coagulopathy• rVIIa• Etanercept
Let’s take a walk down memory lane…
©2014 MFMER | slide-22
Metcalf, et al. • Retrospective cohort, descriptive analysis • Patient population
• January 3, 1985 – November 9, 1990• 603 BMT patients reviewed for DAH diagnosis
• Treatment (N = 63; 3 groups)• No steroids• Low-dose: ≤ 30mg methylprednisolone or equivalent• High-dose: > 30mg methylprednisolone or
equivalent (125-250mg q6h)
Metcalf JP, et al. Am J Med. 1994;96:327-34.
©2014 MFMER | slide-23
Mortality
No steroids (N = 12)
Low-dose(N = 10)
High-dose(N = 43)
P-value
Death priorto discharge 11 9 29 P <0.05
#1
90% 67%
Metcalf JP, et al. Am J Med. 1994;96:327-34.
©2014 MFMER | slide-24
Mortality
No steroids (N = 12)
Low-dose(N = 10)
High-dose(N = 43)
P-value
Death priorto discharge 11 9 29 P <0.05
No steroids (N = 12)
Low-dose(N = 10)
High-dose(N = 43)
P-value
Death (at studyconclusion?) 11 9 35 Not evaluated
#1
#2
90% 81%Metcalf JP, et al. Am J Med.
1994;96:327-34.
©2014 MFMER | slide-25
Mortality: Kaplan-Meier Curve
#3
P <0.01
Metcalf JP, et al. Am J Med. 1994;96:327-34.
©2014 MFMER | slide-26
Study Conclusions• Three different representations of mortality
• Somewhat contradicting, confusing• Statistical methods unclear
• Difficult to interpret• Only available data• Doesn’t seem harmful? – ADE not well reported• Let’s go with it…
©2014 MFMER | slide-27
Raptis, et al. • Retrospective case-series• Patient population
• September 1993 – January 1998• 74 BMT patients evaluated, 4 with DAH
• Treatment
Case #1 #2 #3 #4Methylprednisoloneregimen 1g daily 1g daily 2g x1, 1g
daily 0.5g daily
Raptis P, et al. Bone Marrow Transplant. 1999;24:879-83.
©2014 MFMER | slide-28
Study Conclusions• 50% mortality due to DAH-related complications• Authors’ perspective:
• DAH is life-threatening• Potentially reversible with high-dose steroid
treatment
• Even smaller population• Again, doesn’t seem harmful?
Raptis P, et al. Bone Marrow Transplant. 1999;24:879-83.
©2014 MFMER | slide-29
Rathi, et al. • Retrospective cohort, descriptive analysis• Inclusion:
• October 2007 – June 2011• BMT patients w/ DAH that received steroids +/-
aminocaproic acid
• Exclusion: • Age <18 years• Steroids +/- aminocaproic acid for non-DAH
illnesses
ACA: aminocaproic acid Rathi NK, et al. Bone Marrow Transplant. 2015;50:420-26.
©2014 MFMER | slide-30
Treatment
BMT + DAHn = 119
Steroids onlyn = 37
High dose: ≥1 g/dayn = 23
Low dose: <0.25 g/dn = 19
Medium dose: 0.25-<1 g/dn = 50
High dose: ≥1 g/dayn = 8
Low dose: <0.25 g/dn = 18
Medium dose: 0.25-<1 g/dn = 11
Steroids + ACAn = 82
Rathi NK, et al. Bone Marrow Transplant. 2015;50:420-26.
©2014 MFMER | slide-31
Mortality
Outcomes Low-dose Medium-dose High-dose P-valueSteroids only n = 18 n = 11 n = 23Mortality – n (%)
ICU 4 (22.4) 7 (63.6) 6 (75) 0.02Hospital 9 (50) 9 (81.8) 8 (100) 0.02
Steroids + ACA n = 19 n = 40 n = 23Mortality – n (%)
ICU 6 (31.6) 23 (57.5) 15 (65.2) 0.07Hospital 13 (68.4) 33 (82.5) 18 (78.3) 0.45
*No difference when evaluating 30-d, 60-d, and 100-d mortality between steroid doses
Rathi NK, et al. Bone Marrow Transplant. 2015;50:420-26.
©2014 MFMER | slide-32
A Closer Look…
Variables ICU Mortality Hospital MortalityOR 95% CI P-value OR 95% CI P-value
Steroids + ACA vs. steroids alone 0.81 0.29-2.27 0.69 1.02 0.38-2.75 0.96
Medium-dose vs. low-dose steroids 3.93 1.31-11.77 0.01 2.91 1.03-8.21 0.04
High-dose vs. low-dose steroids 4.79 1.45-15.90 0.01 2.99 0.87-10.34 0.08
*No difference when evaluating 30-d, 60-d, and 100-d mortality between groups
Rathi NK, et al. Bone Marrow Transplant. 2015;50:420-26.
©2014 MFMER | slide-33
Study Conclusions• Strongest study published – both size, design
• Limitations still exist
• No benefit conferred with ACA• Makes sense, DAH not thought to be a result of
coagulopathy
• Medium-, high-dose steroids potentially harmful• No benefit in any group beyond hospital stay
©2014 MFMER | slide-34
Mortality: Kaplan-Meier Curve
P <0.01
Metcalf JP, et al. Am J Med. 1994;96:327-34.
©2014 MFMER | slide-35
Study Conclusions• Strongest study published – both size, design• No benefit conferred with ACA
• Makes sense, DAH not thought to be a result of coagulopathy
• Medium-, high-dose steroids potentially harmful• No benefit in any group beyond hospital stay
©2014 MFMER | slide-36
Harmful Effects of Steroids• Not well described in aforementioned literature• Infection• Blood glucose control• Delirium• Myopathy• Concurrent use of paralytic
©2014 MFMER | slide-37
Clinical Practice• Clinicians recognize high risk for mortality• Data scarce, conflicting• Mayo Clinic – Rochester practice
• Supportive cares + steroids • Methylprednisolone 250mg q6h x4-5 days followed
by taper• Monitor for ADE, check in the ‘con’ column for
considering short course
• Should practice shift away from the use of high-dose steroids?
©2014 MFMER | slide-38
ConclusionList the American Thoracic Society diagnostic
criteria for idiopathic pneumonia syndromeIdentify key clinical differences between diffuse
alveolar hemorrhage, peri-engraftment respiratory distress syndrome, and non-cardiogenic capillary leak syndrome Determine the role of corticosteroid therapy in
treatment of diffuse alveolar hemorrhage
©2014 MFMER | slide-39
Which of the following is true?A. Use of aminocaproic acid
for the treatment of DAH is the standard of care as it has been shown to significantly reduce 60-d mortality
B. Mortality associated with DAH s/p BMT is reported to be <10%
C. Treatment of DAH with steroids is controversial as studies have shown both positive and negative results
D. None of the above are true
A. B. C. D.
0% 0%0%0%
©2014 MFMER | slide-40
JW is a 38y/o M s/p allogeneic PBSCT in the setting of ALL. He presents to the ICU day +14 with acute respiratory distress, a fever, and a diffuse cutaneous rash. What non-infectious pulmonary complication s/p BMT might JW be experiencing?
A. Diffuse alveolar hemorrhage
B. Cryptogenic organizing pneumonia
C. Non-cardiogenic capillary leak syndrome
D. Peri-engraftment respiratory distress syndrome
A. B. C. D.
0% 0%0%0%
©2014 MFMER | slide-41
RM is a 66 y/o F s/p autologous PBSCT in the setting of MDS. She presents to the ICU day +20 with acute respiratory distress and was found to have DAH requiring intubation and subsequent paralysis. Which of the following would be a reason to consider avoiding use of steroids?
A. Advanced ageB. Use of paralyticC. BMT associated
DAH is a non-immune mediated process
D. Timing of DAH onsetA. B. C. D.
0% 0%0%0%
©2014 MFMER | slide-42
Questions & Discussion