Referral
Subject: Urgent Referral for Evaluation of Severe Anaemia and Related Symptoms in a Pediatric Patient
Dear Colleague,
I am writing to refer a 5-year-old male patient who presented with a concerning constellation of symptoms that require specialized evaluation and management. Initially healthy, he has over the past 10 days developed increasing fatigability and weakness, which are now significantly impacting his daily activities and overall well-being.
The clinical picture has been further complicated by the appearance of severe pallor and intermittent fever, along with a noticeable decline in his nutritional intake due to poor feeding. These symptoms together prompted an immediate laboratory investigation, which revealed a critically low haemoglobin level of 3 gm/dl, suggesting severe anaemia. His white blood cell count was recorded at 7,000 per µL, and his platelet count was relatively stable at 160,000 per µL.
Given the severity of the anemia and the acute nature of his symptoms, an urgent transfusion of packed red blood cells (PRBCs) was deemed necessary. However, we encountered a significant challenge as we were unable to find suitably cross-matched blood, which has raised concerns about potential underlying complexities in his case.
Due to the unusual presentation and the difficulties encountered in managing his condition, further comprehensive evaluation is crucial. The inability to crossmatch blood could suggest an underlying immunological component or other non-standard interactions, which require advanced diagnostic approaches.
We seek your guidance on both the diagnostic and therapeutic fronts to address this perplexing case.
Reply
Dear Colleague,
Thank you for your detailed referral of the 5-year-old male patient. We have thoroughly reviewed and evaluated the child, who presented with a significant acute history of decreased activity, marked fatigability, and associated symptoms. His symptoms, spanning a duration of 10 days, include the development of fever, poor oral intake, and notable pallor. No other concerning symptoms were reported.
Upon examination, the patient was alert, conscious, and appeared comfortable while resting in bed. Notably, he exhibited tinged jaundice and moderate to severe pallor. His respiratory examination revealed no abnormalities, and his abdominal assessment showed a lax, soft abdomen with no organomegaly or lymphadenopathy. A comprehensive review of other systems did not reveal any additional abnormalities.
Based on the initial clinical presentation, we have undertaken the following diagnostic investigations:
- Complete Blood Count (CBC) with differential and peripheral blood smear to assess the cellular components of the blood.
- Reticulocyte count, Lactate Dehydrogenase (LDH), and Serum Bilirubin levels to evaluate hemolysis.
- Direct Coombs Test to identify autoimmune components.
- Glucose-6-Phosphate Dehydrogenase (G6PD) level and Hemoglobin Electrophoresis to rule out enzymatic deficiencies and hemoglobinopathies.
- Virology Screening including tests for HIV, Hepatitis, Parvovirus B19, Varicella, Cytomegalovirus (CMV), and Epstein-Barr Virus (EBV) to exclude infectious causes of hemolysis.
Initial Impression:
The clinical findings and initial tests suggest Autoimmune Hemolytic Anemia (AIHA). However, it is imperative to exclude other potential causes of severe anemia, including hematological malignancies such as leukemia.
Investigation Results:
- White Blood Cells (WBC): 6,000/µL
- Hemoglobin (HGB): 3.1 gm/dl
- Platelets: 155,000/µL
- Absolute Neutrophil Count (ANC): 0.2 x 10^9/L
- Lymphocytes: 77%
- Blood Smear: No abnormal cells, atypical lymphocytes present
- Reticulocytes: 0.7%
- Direct Antiglobulin Test (DAT): Positive for IgG
- G6PD Level: Normal
- Hemoglobin Electrophoresis: Normal pattern
- LDH: 400 U/L
- Total Bilirubin: 15 mg/dL
- Virology Screen: All results within normal limits
Recommendations:
Given the positive DAT and the clinical context, our working diagnosis leans towards AIHA. Immediate management should focus on stabilizing the patient’s hemoglobin levels, possibly through carefully matched blood transfusions despite previous difficulties in cross-matching. Furthermore, immunosuppressive therapy may be considered as a treatment option depending on ongoing evaluations and response to initial management.
We will continue to monitor the patient closely and plan to conduct a follow-up assessment after the initial treatment phase to reevaluate his condition and adjust our management plan accordingly.
Discussion
Autoimmune haemolytic anaemia (AIHA) characterized by the presence of warm agglutinins is primarily mediated by IgG antibodies. These antibodies target protein antigens on the surface of red blood cells (RBCs) and are active at body temperature, hence the designation “warm agglutinins.” Interestingly, despite their name, these antibodies seldom cause direct agglutination of RBCs.
Warm agglutinin AIHA differs significantly from AIHA triggered by cold agglutinins, which involve IgM antibodies reacting with polysaccharide antigens on the RBC surface at temperatures below the body’s core temperature. This interaction often results in both RBC agglutination and haemolytic anaemia.
The etiology of warm agglutinin AIHA remains elusive in most cases, though it can sometimes be linked to various underlying disorders. Notable associations include:
- Viral infections, typically observed in pediatric cases
- Autoimmune conditions, such as systemic lupus erythematosus
- Lymphoproliferative disorders, for example, chronic lymphocytic leukemia
- Immunodeficiency disorders, such as common variable immunodeficiency
- Certain medications, like penicillin
- Complications from allogeneic blood transfusions or ABO-incompatible hematopoietic cell transplantation
The circulating RBC are coated with IgG. Complement is activated. Besides, components of complement are present on RBC. A warm autoantibody is mostly against Rh antigen. Typically, these coated RBC are sequestered in the spleen and occasionally in the liver (extravascular haemolysis).
In the case under discussion, the patient’s low reticulocyte count is atypical for AIHA and suggests potential complicating factors such as an aplastic crisis or bone marrow suppression from other aetiologies. The presence of haemolysis is supported by elevated indirect bilirubin and lactate dehydrogenase levels, along with reduced haptoglobin levels. The peripheral blood smear typically exhibits spherocytes and an increased number of polychromatophilic red cells (reticulocytes).
Diagnosis of warm agglutinin AIHA is confirmed through the detection of antibody and/or complement components on the RBC surface, predominantly assessed via the direct antiglobulin (Coombs) test. Between 97% and 99% of patients with this form of AIHA show a positive Coombs test result for anti-IgG, anti-C3, or both.
The initial treatment approach for warm agglutinin AIHA involves corticosteroids, which are effective in approximately 70–85% of cases. These should be tapered gradually over a period of 6–12 months. Blood transfusions are generally reserved for critically ill patients at risk of heart failure, using the least incompatible blood as a diagnostic clue and therapeutic option when typical cross-matching is unsuccessful.
For refractory or relapsed cases, treatment progresses to second-line therapies including splenectomy, which is effective in about two-thirds of cases but only cures about 20%, and rituximab, which has an efficacy rate of approximately 80–90%. If these are insufficient, further treatment options include immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, and mycophenolate mofetil. Additional interventions may involve intravenous immunoglobulins, danazol, plasma exchange, and, in severe cases, alemtuzumab or high-dose cyclophosphamide.
Recent developments suggest an evolving role for rituximab, potentially positioning it earlier in the treatment sequence for warm AIHA, ahead of more toxic immunosuppressants and as an alternative to splenectomy in certain cases.
Check the correct answers.
Question-1:
Correct Answer: C) Elevated serum thymidine kinase
Explanation: Thymidine kinase is an enzyme involved in the DNA synthesis pathway, and its elevated levels are often associated with active cell turnover, particularly in lymphoproliferative disorders such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. In the context of AIHA, identifying an elevated thymidine kinase level can suggest an underlying lymphoproliferative disorder, which may significantly influence the choice of subsequent therapies, including the potential use of agents specifically targeting these conditions, such as rituximab. Elevated LDH and decreased haptoglobin are common in hemolysis and do not specifically indicate lymphoproliferative activity. Elevated IgM levels could suggest a cold agglutinin disease rather than a direct indication of a lymphoproliferative disorder in the context of warm AIHA.
Question-2:
Correct Answer: C) Rituximab
Explanation: Rituximab, a monoclonal antibody targeting CD20 on B cells, has shown high efficacy rates of approximately 80-90% in the treatment of warm agglutinin AIHA, especially in patients who are refractory to corticosteroids. Recent developments in the management of AIHA suggest positioning rituximab earlier in the treatment sequence due to its favorable safety profile and effectiveness, potentially ahead of more invasive or toxic options like splenectomy and high-dose cyclophosphamide. Splenectomy and high-dose cyclophosphamide are effective but associated with higher risks and long-term side effects. Intravenous immunoglobulin (IVIG) is generally used for rapid, temporary suppression of autoantibody production but is less effective as a long-term treatment strategy in AIHA compared to rituximab.
References
- Alberto Zanella, Wilma Barcellini. Treatment of Autoimmune Hemolytic Anemias, Haematologica October 2014 99: 1547-1554; Doi:10.3324/haematol.2014.114561.
- Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hematol 2002; 69:258.
- Petz LD. Treatment of autoimmune hemolytic anemias. Curr Opin Hematol 2001; 8:411.
- J. Manuel Zarandona, Mark H. Yazer. The role of the Coombs test in evaluating hemolysis in adults. CMAJ January 31, 2006 vol. 174 no. 3 doi: 10.1503/cmaj.051489.
- Chapter 27: Autoimmune diseases: Autoimmune Hemolytic Anemia (AHA) – Labpedia.net
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