1. Hematologic Adverse Effects of Standard TB Therapy Pennan Barry, MD MPH California Department of Public Health TB Control Branch

2. Hematologic Adverse Effects of Standard TB Therapy Drug-Resistant TB: A Survival Guide for Clinicians, 2 nd ed. ↓WBC↓PMN↓Plt↓RBC Red Cell Aplasia Hemolytic Anemia Aplastic Anemia RifXXXXX INHXXXXXX EMBXX PZAXX

3. Hematologic Adverse Effects of Standard TB Therapy Drug-Resistant TB: A Survival Guide for Clinicians, 2 nd ed. ↓WBC↓PMN↓Plt↓RBC Red Cell Aplasia Hemolytic Anemia Aplastic Anemia RifXXXXX INHXXXXXX EMBXX PZAXX

4. 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

5. 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

6. Thrombocytopenia: PZA Case reports Associated with sideroblastic anemia 1-2 months into treatment Holdiness Tubercle 1987 | Jain Tubercle 1988 | Roseau Rev Mal Respir 2008

7. Thrombocytopenia: INH No case reports in last 50 years package insert : http://www.versapharm.com/media/productinserts/

8. 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

9. Bone marrow aspirate shows ringed sideroblasts, Prussian Blue stain; 1000x -- Liu JAMA 1987

11. 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

12. 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

13. 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