What causes anemia in a patient on Anti-Tuberculosis Treatment (ATT)?

Anemia in Patients on Anti-Tuberculosis Treatment

Anemia in patients on ATT is primarily caused by anemia of inflammation (anemia of chronic disease) from tuberculosis itself, which typically resolves with effective tuberculosis treatment, though drug-induced hemolytic anemia from rifampin and other medications must also be considered. 1, 2, 3

Primary Mechanisms of Anemia in ATT Patients

Tuberculosis-Associated Anemia of Inflammation (Predominant Cause)

• Anemia of inflammation (AI) is the dominant anemia type at tuberculosis diagnosis, present in approximately 36% of patients, and is driven by elevated hepcidin and inflammatory cytokines that impair iron absorption and redistribute iron away from erythropoiesis. 2, 4

• The prevalence of anemia in tuberculosis patients ranges from 31.9% to 67%, with anemia of chronic disease accounting for 97.17% of cases compared to only 2.29% iron-deficiency anemia. 3, 5

• This anemia is typically normocytic and normochromic (71.9% of cases), with hemoglobin usually >10 g/dL in most patients (only 5% have Hb <10 g/dL). 3

• Hepcidin levels are markedly elevated before treatment (median 84.0 ng/mL) but decrease dramatically to 9.7 ng/mL after just 2 months of tuberculosis treatment as inflammation resolves. 2, 4

Drug-Induced Hemolytic Anemia

• Rifampin is a well-documented cause of hemolytic anemia and is specifically listed among common drug causes requiring evaluation in the workup of drug-induced hemolysis. 6, 1

• The FDA label for rifampin explicitly lists "hemolytic anemia" and "decreased hemoglobin" as hematologic adverse reactions. 1

• Other ATT medications can contribute: rifampin may also cause leukopenia and thrombocytopenia, while other antibiotics in treatment regimens can cause bone marrow suppression. 6, 1

Evolution and Resolution During Treatment

Expected Timeline for Anemia Resolution

• AI decreases from 36% at diagnosis to only 8% after 6 months of tuberculosis treatment, demonstrating that effective tuberculosis chemotherapy resolves inflammation-driven anemia. 2

• In 64.6% of patients, anemia resolves during or after anti-TB treatment without iron supplementation, with mean resolution time of 118.8 ± 113.2 days (approximately 4 months). 3

• Interleukin-6 and hepcidin levels decrease by approximately 70% within just 2 weeks of starting treatment, while erythroferrone (ERFE) remains elevated until 8 weeks, contributing to hepcidin suppression and hemoglobin repletion. 4

Iron-Responsive Anemia Components

• Iron deficiency anemia (IDA) and multifactorial anemia (IDA+AI) do not resolve with tuberculosis treatment alone and require targeted iron supplementation. 2

• Before treatment, iron absorption is negligible (<1%) due to elevated hepcidin blocking intestinal iron absorption. 4

• Iron absorption increases approximately 20-fold only after tuberculosis treatment completion, indicating that iron supplementation should be reserved for patients who remain anemic after completing treatment. 4

Diagnostic Workup Algorithm

Initial Assessment at Presentation

• Obtain complete blood count with peripheral smear to assess for hemolysis (schistocytes), macrocytosis, and cell line involvement. 6

• Measure reticulocyte count, LDH, haptoglobin, indirect bilirubin, and direct antiglobulin test to evaluate for hemolysis. 6

• Check ferritin, soluble transferrin receptor (sTfR), and transferrin to distinguish iron deficiency from anemia of inflammation. 2

• Assess for glucose-6-phosphate dehydrogenase deficiency, which can predispose to drug-induced hemolysis. 6

Monitoring During Treatment

• Recheck hemoglobin at 2 months (end of intensive phase) to assess response, as this is when hepcidin suppression and erythropoiesis enhancement become evident. 2, 4

• Monitor hemoglobin monthly if anemia persists or worsens, particularly in patients with moderate/severe anemia (Hb <10 g/dL). 7

• If hemolysis is suspected (dropping hemoglobin with elevated LDH/indirect bilirubin), immediately evaluate for drug-induced causes and consider holding rifampin. 6, 1

Management Strategy

For Anemia of Inflammation (Most Common)

• Continue tuberculosis treatment without iron supplementation during the first 6 months, as anemia typically resolves with effective tuberculosis therapy alone. 2, 3, 4

• Close observation is sufficient for mild anemia (Hb >10 g/dL), which represents 95% of tuberculosis-associated anemia cases. 3

• Patients with moderate/severe anemia (Hb <10 g/dL) require closer monitoring due to 7.8-fold increased risk of death (aOR: 7.80,95% CI: 1.34-45.4). 7

For Drug-Induced Hemolytic Anemia

• If rifampin-induced hemolysis is confirmed, permanently discontinue the drug and substitute with a fluoroquinolone-based regimen for 12-18 months total duration. 6

• Alternative regimen without rifampin: Use isoniazid, pyrazinamide, ethambutol, and a fluoroquinolone (levofloxacin 750-1000 mg daily or moxifloxacin 400 mg daily) for at least 6 months. 6

• For severe hemolysis (Grade 3-4), administer prednisone 1-2 mg/kg/day and consider RBC transfusion to maintain hemoglobin 7-8 g/dL in stable patients. 6

Iron Supplementation Timing

• Defer iron supplementation until after tuberculosis treatment completion (6 months), when iron absorption normalizes and iron-responsive anemia can be effectively treated. 2, 4

• If iron deficiency is documented after treatment completion, administer ferrous sulfate 200 mg three times daily (100-200 mg elemental iron daily). 8

• Hemoglobin should increase by approximately 2 g/dL after 3-4 weeks of proper iron therapy. 8

Critical Pitfalls to Avoid

• Do not routinely supplement iron during active tuberculosis treatment, as iron absorption is blocked by elevated hepcidin and supplementation is ineffective until inflammation resolves. 2, 4

• Do not attribute all anemia to tuberculosis without evaluating for drug-induced hemolysis, particularly if anemia worsens during treatment or is associated with other cytopenias. 6, 1

• Do not continue rifampin if drug-induced hemolytic anemia is confirmed, as cerebral hemorrhage and fatalities have been reported with continued administration. 1

• Do not overlook HIV co-infection, diabetes, or advanced age as risk factors for more severe anemia and unfavorable treatment outcomes requiring intensified monitoring. 7, 5