Hematologic Adverse Effects of
Standard TB Therapy
Pennan Barry, MD MPH
California Department of Public Health
TB Control Branch
Hematologic Adverse Effects of
Standard TB Therapy
↓WBC
↓PMN
↓Plt
X
X
X
INH
X
X
EMB
X
X
Rif
PZA
X
↓RBC
X
X
Drug-Resistant TB: A Survival Guide for Clinicians, 2nd ed.
Red Cell
Aplasia
Hemolytic
Anemia
X
X
X
X
Aplastic
Anemia
X
Hematologic Adverse Effects of
Standard TB Therapy
↓WBC
↓PMN
↓Plt
X
X
X
INH
X
X
EMB
X
X
Rif
PZA
X
↓RBC
X
X
Drug-Resistant TB: A Survival Guide for Clinicians, 2nd ed.
Red Cell
Aplasia
Hemolytic
Anemia
X
X
X
X
Aplastic
Anemia
X
Thrombocytopenia: Rifampin
• Risks
– high dose intermittent regimens (up to 6% on biweekly)
– cessation and rechallenge
• Immune mediated
– Rif antigenic as hapten-albumin complex
– Rif dependent Ab fix complement on platelets (GPIb/IX)
• Extremely rapid onset
• Can be severe requiring steroids and platelet
transfusion
• Complications: subdural hematoma, melena
Holdiness Tubercle 1987 | Mori J Infect Chemotherapy 2010 | Kang Neurological Sciences 2010 |
Mehta Tubercle and Lung Dis 1996 | Pereira Br J Haematol 2000
Thrombocytopenia: Ethambutol
• 2 case reports
• Rapid onset after treatment initiation (4-6
days)
• Rapid resolution after discontinuation
Holdiness Tubercle 1987 | Prasad Tubercle 1989 | Rabinowitz Chest 1982
Thrombocytopenia: PZA
• Case reports
• Associated with sideroblastic anemia
• 1-2 months into treatment
Holdiness Tubercle 1987 | Jain Tubercle 1988 | Roseau Rev Mal Respir 2008
Thrombocytopenia: INH
• No case reports in last 50 years
• package insert :
http://www.versapharm.com/media/productinserts/
INH: Anemia
• Sideroblastic anemia responsive to B6 (also caused by PZA)
– 4-16 weeks into treatment
– Microcytic; Normal iron studies
– Marrow: normoblastic hyperplasia and ringed
sideroblasts
– result of INH effects on pyridoxine metabolism
• Pure red cell aplasia
– Quick recovery with INH cessation
– Can occur up to 6 mos into Rx
– Induced autoimmunity to RBC precursors
• Hemolytic anemia: Coombs’ negative and positive
Holdiness Tubercle 1987 | Loulergue Emerg Infect Dis 2007 | Robinson JAMA 1969 | Liu JAMA 1987
Bone marrow aspirate shows ringed sideroblasts, Prussian Blue stain; 1000x -- Liu JAMA 1987
Bone marrow aspirate shows ringed sideroblasts, Prussian Blue stain; 1000x -- Liu JAMA 1987
Rifampin: Hemolytic anemia
• Associated with rifampin “flu” syndrome
• Acute renal failure
• RBC-specific antibodies (recognize Lu and I
Ag)
• Patterns:
– Escalating antibodies with successive
intermittent doses
– Rapid reaction following reintroduction
– Random reaction with continuous daily dosing
Holdiness Tubercle 1987 | Neunert Pediatr Blood Cancer 2008 | Pereira Ann Hematol 1991
INH and Rif: Leukopenia
• Case control study of 1,525 TB patients at a Tokyo
hospital 1987-2000
• 36 had WBC fall to <3.0 on TB Rx (1.2% of men;
5.9% of women); 2 had agranulocytosis
• 30 had meds continued:
– 19 recovered on Rx; 11 remained leukopenic on Rx
• No difference by regimen (HRE, HRS, HREZ)
• Leukopenic pts had lower baseline WBC than
controls (7.2 vs 5.5, p<.001)
Nagayama Kekkaku 2004
Agranulocytosis
•
•
•
•
•
At least 14 cases reported
Incidence 0.06% at one Japanese hospital
Rif and INH (PZA: 2 case reports)
Can occur simultaneously with hepatotoxicity
1-3 months into Rx
Shishido Kekkaku 2003 | www.adverse-effects.com+case_reports.html_ | Jenkins Br Med J 1980 |
Wong Chest 1994