Case Report: Tuberculosis-Induced Autoimmune Hemolytic Anemia

ABSTRACT.

Tuberculosis (TB) is an infectious disease that affects different organs, causing multiple complications, including hematological sequelae. One of the most common TB-hematological complications is anemia of chronic disease. Very rarely autoimmune hemolytic anemia (AIHA) has been reported as an uncommon manifestation of TB. In this case, we present a female who presented with refractory AIHA, which was attributed to disseminated TB. The patient responded well to steroids, anti-TB medications, and rituximab.

INTRODUCTION

Autoimmune hemolytic anemia (AIHA) is a rare hematological abnormality. It is caused by autoantibody binding to the surface antigens on the red blood cells (RBCs), leading to RBC destruction.¹

There are two different types of AIHA based on immunochemistry and etiology.^1,2 Autoimmune hemolytic anemia is either primary or secondary. Primary (or idiopathic) AIHA occurs when there is no association with an underlying disease.¹ Secondary AIHA is due to infections, myeloproliferative disorders, autoimmune diseases, or drugs.²

Tuberculosis (TB) is associated with diverse hematological manifestations, such as anemia, pancytopenia, or thrombocytopenia.^3–5 Anemia is often seen with TB infection; the most common type is anemia of chronic disease.⁴ However, hemolytic anemia, particularly AIHA, is rarely associated with TB.⁶ Herein, we report a case of cold agglutinin AIHA secondary to probable disseminated TB. Initially, the patient received anti-TB treatment and steroid. However, she was readmitted shortly with refractory hemolytic anemia, which improved after receiving rituximab.

CASE REPORT

A 32-year-old Indian female, who was previously healthy, presented to the emergency department with a 1-month history of fatigue and generalized weakness. She reported yellowish discoloration of her skin and dark urine. Additionally, she had anorexia and a weight loss of 15 kg. She did not have a fever, cough, shortness of breath, or night sweat. She did not have close contact with persons with confirmed TB. She arrived in Qatar 1 month before, and she was sexually inactive.

The physical examination revealed a cachectic patient with pallor and scleral icterus. There were palpable supraclavicular and cervical lymph nodes bilaterally. The patient was afebrile, and her heart rate and blood pressure were within normal limits. However, during her hospital stay, she spiked a fever of 39°C. Chest examination showed good air entry bilaterally. The abdominal examination was remarkable for a well-healed cesarean incision scar and hepatosplenomegaly.

INVESTIGATIONS

Laboratory findings on admission revealed the following: hemoglobin 2.5 g/dL (12.0–15.0 g/d), white blood count 5.9 × 10³/μL (4.0–10.0 × 10³/μL), platelet count 417 × 10³/μL (150–400 × 10³/μL), mean corpuscular volume 101 fL (83–101 fL), mean corpuscular hemoglobin 45.5 pg (27–32 pg), and reticulocyte 36.6%. Peripheral smear showed severe macrocytic anemia with anisocytosis, poikilocytosis, and red cell agglutination. Biochemical markers showed total bilirubin 54 μmol/L (0.0–21.0 μmol/L), unconjugated bilirubin 44 μmol/L (0.0–3.0 μmol/L), conjugated bilirubin 10 μmol/L, lactate dehydrogenase 297 U/L, and haptoglobin < 10 mg/dL. In addition, the vitamin B12 level was 354.0 pmol/L (145–596 pmol/L), and the folate level was 8 nmol/L (10–70 nmol/L). The iron profile was within normal limits (iron of 9 μmol/L, total iron-binding capacity was 19 μmol/L, transferritin was 40 g/L, transferrin was 1.6 g/L, and Fe % saturation was 48%). A direct Coomb’s test was positive. Bone marrow studies showed hypercellularity with trilineage hematopoiesis and increased erythropoiesis. Urea and electrolytes were within normal limits. Serology tests for antinuclear antibodies and the autoimmune profile (including anti-neutrophil cytoplasmic antibodies, complement 3, complement 4, rheumatoid factor, anti-citrullinated peptide, anti-Ro, and anti-La) were negative. Viral serology for human immunodeficiency virus, hepatitis B and C virus, dengue, and cytomegalovirus were all negative. Epstein-Barr virus (EBV) IgM was positive; however, EBV polymerase chain reaction (PCR) was not done.

A QuantiFERON test was positive. A chest X-ray showed opacity in the left upper zone. Sputum acid-fast bacilli smear, culture, and Gene-Xpert PCR were negative. Ultrasound abdomen showed mild splenomegaly and distal small bowel loop thickening.

Computed tomography scans of the neck, thorax, and abdomen showed enlarged cervical and supraclavicular lymph nodes bilaterally, hepatosplenomegaly, enlarged abdominal lymph nodes, ascending and transverse colon thickening with pericolic fat stranding, and a left apical lesion in the chest (Figures 1–4).

Figure 1.

Axial contrast-enhanced computed tomography scan of the chest of a 35-year-old female with tuberculosis-induced autoimmune hemolytic anemia. (A and B) Pleural-based lesion at the left upper lobe apicoposterior segment (yellow arrows), showing heterogeneous enhancement with central hypodensity (curved white arrow). (C) Close maximum intensity projection images showing surrounding nodularity and tree-in-bud appearance (green arrow).

Figure 2.

Contrast-enhanced computed tomography scan of the abdomen of a 35-year-old-female with tuberculosis-induced autoimmune hemolytic anemia. (A) Axial image at the level of the upper abdomen demonstrates enlarged liver (yellow arrow) and spleen (blue arrow), that is, hepatosplenomegaly; note the distended splenic vein (blue star). (B) Axial image at the level of the mid-pelvis shows enlarged homogeneously enhancing right external iliac lymph nodes (red arrow).

Figure 3.

Contrast-enhanced computed tomography scan of the abdomen of a 35-year-old female with tuberculosis-induced autoimmune hemolytic anemia. (A) Axial image at mid-abdomen shows thickened enhancing wall of a long segment of the transverse colon (yellow arrow) and hepatic flexure with adjacent mesenteric vascular congestion (blue arrow). (B) Coronal image at mid-abdomen demonstrates similar contiguous findings at the right colon (red arrow).

Figure 4.

Contrast-enhanced computed tomography scan of the neck of a 35-year-old-female with tuberculosis-induced autoimmune hemolytic anemia. (A) Axial and (B) coronal images demonstrate multiple bilateral enlarged homogenously enhancing cervical lymph nodes at the posterior triangle; level V, more on the right.

Right cervical lymph node excisional biopsy was performed. The histopathology examination showed necrotizing granulomatous lymphadenitis (Figure 5). Tuberculosis PCR and culture of the lymph node biopsy were not performed. Lymph node biopsy, laboratory work, and imaging made us diagnose the patient with disseminated TB infection complicated by AIHA.

Figure 5.

Microscopic description. Microphotograph of necrotizing granulomatous lymphadenitis illustrating a granuloma composed of a peripheral rim of epithelioid histiocytes surrounding a central necrotic area (star). Some histiocytes are also forming multinucleated giant cells (arrows). Hematoxylin and eosin stain; original magnification ×200.

MANAGEMENT

On the initial presentation, for her symptomatic anemia, she was transfused with 5 U of packed RBCs. As the diagnosis of AIHA was established, she received prednisolone (1 mg/kg/day) while hospitalized. Despite the lack of proven TB diagnosis by stain, PCR, or culture, the presence of necrotizing granulomatous lymphadenopathy, apical pleural lesion, and the patient’s ethnicity, it was decided to start her on anti-TB medications along with pyridoxine. This decision was made after consulting the infectious disease and hematology teams. She improved clinically and biochemically, and her hemoglobin improved to 8.0 g/dL. She was discharged home with anti-TB medications.

Two weeks later, a follow-up complete blood count showed a decline in hemoglobin to 4.3 g/dL. She was compliant with her medications.

The patient was readmitted for blood transfusion and further workup. The laboratory investigations revealed persistent hemolytic anemia. It was decided to resume prednisolone (1 mg/kg/day). Due to her initial unresponsiveness to the treatment and having refractory AIHA, the decision was to start her on rituximab after 2 weeks of anti-TB therapy.

Her hemoglobin increased to 11 g/L, and she was discharged in a good clinical condition on anti-TB medications and prednisolone (1 mg/kg/day). Thus, she was discharged with anti-TB, and a tapering dose of prednisolone was planned for another dose of rituximab after 4 weeks. However, she did not present to the hematology follow-up clinic.

Nine months after discharge, she continues to follow up in the TB clinic. Her hemoglobin remains stable with no evidence of hemolysis.

DISCUSSION

Autoimmune hemolytic anemia is relatively a rare hematologic manifestation. Autoimmune hemolytic anemia occurs due to the host antibodies binding to red cell surface antigens. The antibodies–antigens bond results in red blood cell destruction and activation of the reticuloendothelial system and complement systems.¹

Different types of AIHA are classified according to the chemical and immunological features of the RBC autoantibodies. Autoimmune hemolytic anemia is either warm agglutinins, cold agglutinins, mixed-type, or drug-induced AIHA. Moreover, AIHA can be subdivided into idiopathic (or primary) and secondary, based on the etiology,² and idiopathic AIHA accounts for half of the cases.⁷

Causes of secondary AIHA include infections, lymphoproliferative disorders, autoimmune disease, and certain medications. The common infectious causes of AIHA include Mycoplasma pneumoniae, EBV, cytomegalovirus, HIV, and very rarely TB.^6,8,9

Mycobacterium tuberculosis is the microorganism responsible for developing TB infections in the human body. It creates and matures following the primary, latent, and reactivation phases of pathogenesis, respectively.¹⁰ TB infection lowers the autoimmune responses and increases the mortality rates, especially targeting adults > 50 years of age.¹¹ The pulmonary tract is infused with chronic infections and adverse responsive mechanisms of action delivered by the macrophages. Apart from the pulmonary destructions, TB can damage the cardiovascular system and nervous system and cause many blood-related disorders, including anemia, thrombocytopenia, basophilia, leukocytosis, and many other diseases that can potently affect the RBCs shapes, production, and effectiveness.¹²

When the action of the M. tuberculosis suppresses the autoimmune responses, the antigen and antibody complexes start their activity against the blood cells and destroy them by subsiding the efficiency and lifespan of the red blood cells.¹² The inefficacy of RBCs is due to less oxygen availability and increased cell toxicity; the condition is generally termed AIHA. The altered immune response is exaggerated with the increase in the declination of RBCs and hemoglobin levels in the body.³

Anemia has been increasingly reported in association with TB infection. Early on, Glasser et al.⁴ first described different hematologic abnormalities observed in 40 patients infected with military TB. The study concluded that TB affects all three cell lines, including anemia along with leukopenia, leukocytosis, monocytosis, basophilia, thrombocytopenia, and pancytopenia. Anemia, leukopenia, leukocytosis, and monocytosis have an excellent response to TB therapy.

TB patients rarely develop AIHA. Several mechanisms in TB-induced anemia have been proposed in the literature. One of the most common causes is erythropoiesis suppression, secondary to inflammatory mediators.¹³ Furthermore, nutritional deficiencies, malabsorption syndrome, anorexia, failure of iron utilization, and bone marrow suppression are other causes of anemia in TB.^5,6 However, AIHA is rarely observed in TB patients; only very few cases have reported the association between TB and AIHA in the literature.^3–6

Our patient’s cold agglutinin-induced hemolytic anemia diagnosis was made based on laboratory evidence of hemolysis and a positive Coomb’s test. Workups for secondary causes of AIHA such as lymphoproliferative disorders and autoimmune disease were negative. TB diagnosis was made based on the clinical and radiological findings and tissue biopsy. Although we cannot exclude EBV infection as a contributing factor to secondary AIHA, the lack of response to initial management and complete recovery with anti-TB, steroids, and monoclonal antibodies favor the diagnosis of TB.

The prognosis of secondary AIHA is usually excellent and complete resolution occurs within 4–6 weeks.¹⁴ Based on the previous reports, TB-induced AIHA is traditionally managed with antimicrobials and blood transfusion when indicated. The use of steroids has been reported as a treatment of secondary cold AIHA, whereas rituximab is used for warm AIHA and primary cold AIHA.^14,15

The corticosteroids are referencing first-line treatment of the disease, as they are potent immune-suppressing agents.¹⁶ Such treatment stabilizes the hemoglobin levels in the blood, representing the effective production of RBCs and the enhanced ability of the blood cells to carry oxygen and iron molecules with efficacy, improving the immune responses.¹⁷ However, the prolonged use of corticosteroids is harmful because it harbors adverse effects on the cardiovascular system, muscle tone and strength, and the central nervous system’s endocrine and exocrine responses.

Rituximab is a monoclonal antibody usually found on the surface of the B cells of the immune system. It binds to the protein CD20 and elicits cell death.¹⁸ When administered in the patient with hemolytic anemia, this drug destroys the B cell malignant cells by attaching to the surface proteins (CD20).¹⁹ Therefore, it is considered an efficient second line of choice for patients suffering from AIHA. Rituximab leads to B cell depletion and converts them into the cytokines fabricating precursors.²⁰ This second-line treatment appears more efficient in treating blood disorders, as the research emphasizes, rather than the excessive use of immunosuppressive agents and corticosteroids.

CONCLUSION

Tuberculosis infection should be considered a potential etiology in patients with hemolytic anemia. TB-induced AIHA might present a diagnostic and therapeutic challenge, especially cold AIHA. Anti-TB and blood transfusion remain the mainstay of treatment; however, corticosteroids and rituximab should be considered in refractory cases. Our patient responded well after receiving rituximab and a tapering dose of steroids.