Hematologic Adverse Effects of Standard TB Therapy

Pennan Barry, MD MPHCalifornia Department of Public Health

TB Control Branch

Hematologic Adverse Effects of Standard TB Therapy

Drug-Resistant TB: A Survival Guide for Clinicians, 2nd ed.

↓WBC ↓PMN ↓Plt ↓RBC Red Cell Aplasia

Hemolytic Anemia

Aplastic Anemia

Rif X X X X X

INH X X X X X X

EMB X X

PZA X X

Hematologic Adverse Effects of Standard TB Therapy

Drug-Resistant TB: A Survival Guide for Clinicians, 2nd ed.

↓WBC ↓PMN ↓Plt ↓RBC Red Cell Aplasia

Hemolytic Anemia

Aplastic Anemia

Rif X X X X X

INH X X X X X X

EMB X X

PZA X 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