Hematologic Adverse Effects of Standard TB Therapy

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