Autoimmune Hemolytic Anemia (AIHA) is a rare autoimmune disorder characterized by the body’s immune system’s destruction of red blood cells (RBCs). In AIHA, the immune system mistakenly recognizes the body’s RBCs as foreign and produces antibodies that target and attack these cells, leading to their premature destruction.

AIHA can be classified into two main types based on the characteristics of the antibodies involved:

Warm antibody AIHA: This is the most common form of AIHA, accounting for approximately 70-80% of cases. Immunoglobulin G (IgG) antibodies bind to RBCs at body temperature (37°C) in warm antibody AIHA. The immune system recognizes and removes these IgG-coated RBCs, primarily in the spleen. The destruction of RBCs leads to anemia and associated symptoms.

Cold antibody AIHA: In cold antibody AIHA, immunoglobulin M (IgM) antibodies bind to RBCs at lower temperatures, typically below body temperature (20-30°C). These antibodies can cause RBC agglutination (clumping) and subsequent destruction when exposed to cold temperatures. Cold antibody AIHA is less common than warm antibody AIHA and is often associated with underlying conditions such as infections or lymphoproliferative disorders.

The estimated frequency of AIHA is between one and three cases per 100,000 people per year, making it quite rare. It should be noted that the incidence varies depending on geographic area and population demographics.

Warm autoimmune hemolytic anemia (w-AIHA) is the most prevalent subtype among the several kinds of AIHA. It causes about 70% to 80% of all cases in adults and about 50% in children.

The pathophysiology of AIHA involves several mechanisms:

• Autoantibody Production: In AIHA, the immune system produces autoantibodies that recognize and bind to antigens present on the surface of red blood cells. The most common autoantibodies involved in AIHA are immunoglobulin G (IgG) antibodies.
• Complement Activation: In some cases of AIHA, autoantibodies can activate the complement system, which is part of the immune response. The complement system, when activated, leads to the formation of membrane attack complexes that cause direct damage to red blood cells, leading to their destruction.
• Opsonization and Phagocytosis: Autoantibodies can also bind to red blood cells and act as opsonins, marking the cells for recognition and phagocytosis by macrophages in the spleen and liver. These macrophages recognize the opsonized red blood cells as “foreign” and engulf and destroy them, resulting in hemolysis.
• Antibody-mediated Membrane Damage: Autoantibodies binding to red blood cells can induce physical changes in the red blood cell membrane, increasing fragility and susceptibility to mechanical stress. This membrane damage can further promote hemolysis.
• Ineffective Erythropoiesis: In some cases, AIHA can also disrupt the average production of red blood cells in the bone marrow, leading to ineffective erythropoiesis. Autoantibodies and activated immune cells can interfere with erythropoiesis, decreasing the production of new red blood cells.

Idiopathic/Autoimmune Factors: In many cases, the exact cause of AIHA is unknown and classified as idiopathic or primary AIHA. In these cases, the immune system mistakenly targets the individual’s red blood cells, destroying them.

Autoimmune Disorders: AIHA can be a secondary manifestation of other autoimmune disorders, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjögren’s syndrome, and autoimmune thyroid diseases. In these cases, the underlying autoimmune condition contributes to the development of AIHA.

Infections: Certain infections have been associated with the development of AIHA. These include viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), and hepatitis. Bacterial infections, such as Mycoplasma pneumoniae and Helicobacter pylori, have also been implicated.

Medications: AIHA can be drug-induced, which is triggered by certain medications. Some AIHA-associated drugs include antibiotics (e.g., penicillin, cephalosporins), nonsteroidal anti-inflammatory drugs (NSAIDs), alpha-methyldopa, and specific antineoplastic agents.

Lymphoproliferative Disorders: AIHA can occur in the setting of lymphoproliferative disorders, such as lymphomas, chronic lymphocytic leukemia (CLL), and autoimmune lymphoproliferative syndrome (ALPS). In these cases, abnormal lymphocytes or malignant cells produce autoantibodies that target red blood cells.

Immunodeficiency Syndromes: Some primary immunodeficiency syndromes, such as common variable immunodeficiency (CVID), can be associated with the development of AIHA

Type of AIHA: The classification of AIHA into different subtypes based on the type of autoantibodies involved can have prognostic implications. Warm antibody AIHA (w-AIHA) generally has a better prognosis than cold agglutinin disease (CAD) or mixed-type AIHA.

Antibody Specificity: The autoantibodies’ specificity in AIHA can influence the prognosis. For example, AIHA associated with specific autoantibodies, such as those targeting Rh antigens, may have a more severe clinical course.

Underlying Cause: The underlying cause or associated condition can impact the prognosis. AIHA secondary to autoimmune or lymphoproliferative disorders may have a more difficult clinical course and require additional management strategies.

Disease Severity: The severity of AIHA during diagnosis is an important prognostic factor. Parameters such as the degree of anemia, reticulocyte count, presence of symptoms, and the extent of red blood cell destruction can help assess disease severity and guide treatment decisions.

Response to Treatment: The response to initial therapy is a crucial prognostic factor. Individuals who achieve a complete or partial response to treatment have a better prognosis than those who do not respond adequately.

Relapse Rate: The frequency of disease relapse can affect the long-term prognosis. Individuals with frequent relapses or refractory disease may require more aggressive management and have a less favorable prognosis.

Complications: Complications, such as severe anemia, hemolysis-related organ dysfunction, or thrombotic events, can impact the prognosis and overall outcome.

Age and Comorbidities: Advanced age and other comorbidities can influence the prognosis in AIHA, as they may affect the individual’s ability to tolerate and respond to treatment.

Age Group:

• Pediatric Population: In children, AIHA may present with symptoms such as fatigue, weakness, pallor (pale skin), poor appetite, and irritability. They may also exhibit signs of jaundice (yellowing of the skin and eyes) due to increased bilirubin levels.
• Adults: AIHA can occur at any age in adults. The symptoms are like those in children and may include fatigue, weakness, pallor, jaundice, and dark urine.

The physical examination findings associated with AIHA:

• Pallor: AIHA can cause a reduction in red blood cell count, leading to pallor (paleness) of the skin, mucous membranes, and conjunctiva.
• Jaundice: Increased breakdown of red blood cells in AIHA can result in elevated bilirubin levels, leading to jaundice.
• Hepatosplenomegaly: In some cases, AIHA may be associated with liver enlargement (hepatomegaly) and spleen (splenomegaly). This can be detected by palpating the abdomen during the physical examination.
• Tachycardia: Due to anemia and the body’s compensatory mechanisms, patients with AIHA may exhibit a rapid heart rate (tachycardia).
• Systolic Murmur: In severe cases of AIHA with increased blood flow through the heart, a systolic murmur may be audible upon auscultation. This is due to increased blood velocity and turbulent flow.
• Lymphadenopathy: In some cases, AIHA may be associated with lymphoproliferative disorders, such as lymphoma or chronic lymphocytic leukemia. In these cases, lymphadenopathy (enlarged lymph nodes) may be observed during the examination.

Underlying Autoimmune Disorders: AIHA can be associated with autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis, or autoimmune hepatitis. These comorbidities may contribute to the development of AIHA.

Lymphoproliferative Disorders: AIHA can also be associated with lymphoproliferative disorders such as chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma.

Certain medications: such as certain antibiotics (e.g., penicillin) or antineoplastic agents, have been associated with AIHA.

Acute Onset: In some cases, AIHA may have an acute onset with rapid development of symptoms, leading to severe anemia and hemolysis. This can be life-threatening and requires immediate medical attention.

Chronic or Subacute Presentation: AIHA may present with a more indolent course, with symptoms gradually progressing. This type of presentation may allow for a better adaptation of the body to anemia, and the severity of symptoms can vary.

AIHA (Autoimmune Hemolytic Anemia) involves a stepwise approach based on the severity of the disease and the response to initial treatments. The general treatment options for AIHA include:

Corticosteroids:

Glucocorticoids such as prednisone are the first-line treatment for AIHA. They work by suppressing the immune response and reducing autoantibody production. In many cases, corticosteroids alone can induce remission. The dose is typically high initially and then tapered down over several weeks.

Second-line immunosuppressive agents:

If corticosteroids are ineffective or cannot be tapered down without disease recurrence, second-line immunosuppressive agents may be added. These include:

• Azathioprine: It is commonly used as a steroid-sparing agent and can take several months to exert its full effect.
• Mycophenolate mofetil: This medication inhibits lymphocyte proliferation and antibody production.
• Cyclosporine: As mentioned earlier, cyclosporine primarily affects T lymphocytes and can be effective in refractory cases.
• Rituximab: This monoclonal antibody targets B cells and can be used in cases that do not respond to other treatments.

Splenectomy:

In some cases, removal of the spleen (splenectomy) may be considered. The spleen is responsible for the destruction of antibody-coated red blood cells, and splenectomy can reduce autoantibody clearance. It is generally reserved for patients who are unresponsive to medical therapies or have recurrent relapses.

Other therapies:

In certain situations, additional therapies may be used, including:

• IVIG (Intravenous immune globulin): Used to increase the levels of immunoglobulins and modulate the immune response.
• Plasmapheresis: This procedure involves removing plasma from the blood to eliminate autoantibodies and replacing it with donor plasma or albumin.
• Hematopoietic cell transplantation: A potential option for severe or refractory cases, but it is considered a high-risk procedure and requires careful consideration.

Hematology

Infectious Disease

Infections can trigger or exacerbate AIHA episodes, so minimizing the risk of infections is crucial.

Good hand hygiene: Regularly washing hands with soap and water for at least 20 seconds can help reduce the transmission of infectious agents. If soap and water are unavailable, alcohol-based hand sanitizers can be an alternative.

Avoiding exposure to infectious individuals: Minimize close contact with individuals who have contagious illnesses, such as respiratory tract infections or viral illnesses.

Hematology

Infectious Disease

Air pollution: Avoid spending prolonged periods in highly polluted areas, and consider using air purifiers or filters in indoor spaces.

Water quality: Ensure access to clean and safe drinking water. If there are concerns about water quality, consider using filtration systems or bottled water.

Food safety: Practice good food safety habits, such as washing fruits and vegetables thoroughly, ensuring proper storage of perishable items, and avoiding consumption of contaminated or expired food.

Hematology

Pediatrics, General

Rheumatology

Glucocorticoids are the first-line therapy for warm-reactive AIHA in children due to their rapid response and manageable short-term side effects. The initial dose of glucocorticoids depends on the severity of anemia, with intravenous methylprednisolone used for severe anemia and oral prednisone for mild or moderate anemia.

Tapering glucocorticoids can be challenging to minimize the risk of relapse and avoid long-term complications. The general approach involves gradually tapering the steroid dose over a few months once an adequate response is achieved. Prednisone is slowly tapered but not stopped until there is normalization of hemoglobin, reticulocyte count, and other relevant laboratory parameters.

Monitoring through regular clinical assessments and laboratory testing is essential. Hemoglobin level, reticulocyte count, LDH, and DAT are monitored to evaluate the response to treatment. The frequency of monitoring depends on disease severity and treatment stage, and it should continue until hemoglobin level and reticulocyte count return to normal and the patient is stable on low-dose glucocorticoids. Patients should be monitored for one year after remission is achieved, as relapses are common during this period.

Approximately 70 to 80 percent of patients with warm-reactive AIHA have an initial response to glucocorticoid therapy. Glucocorticoids stabilize hemoglobin concentration within 24 to 48 hours and gradually increase the hemoglobin level. However, relapses can occur in 15 to 40 percent of patients within the first six months to one year after the initial response.

Hematology

rituximab:

rituximab is an anti-CD20 monoclonal antibody used as a second-line therapy in AIHA. It is administered alongside steroid therapy to reduce or discontinue glucocorticoids.

Studies have shown response rates of 60 to 85 percent in children with AIHA treated with rituximab.

Monitoring lymphocyte subpopulations can help assess treatment response, as relapse often occurs when CD20-positive B cells recover.

Hypogammaglobulinemia may occur as a side effect of rituximab therapy. In severe cases, replacement therapy with IVIG may be necessary.

Splenectomy:

Splenectomy is an effective treatment option for children with chronic or refractory primary AIHA.

About two-thirds of patients show improvement within two weeks following splenectomy. By removing the spleen, the main site of erythrocyte destruction is eliminated, and autoantibody production may also be reduced.

Splenectomy is generally avoided in children under 3 years old due to the increased risk of post-splenectomy sepsis caused by encapsulated bacterial organisms. Ideally, splenectomy is delayed until children are over 6 years old.

Prior to splenectomy, patients should receive immunization against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b.

Antibiotic prophylaxis is recommended after splenectomy, and patients should seek immediate medical attention if they experience fever, as it may indicate bacterial sepsis.

These second-line treatment options can be considered when glucocorticoids alone are insufficient or not well-tolerated, aiming to achieve better control of AIHA and reduce reliance on glucocorticoid therapy.

Hematology

Intravenous Immunoglobulin (IVIG):

IVIG is a therapy that involves infusing purified antibodies obtained from healthy donors. It can be used as a second-line treatment for refractory AIHA, especially in acute severe cases or when other treatments have failed. IVIG helps to suppress the immune response and reduce the destruction of red blood cells.

azathioprine and 6-mercaptopurine:

These are immunosuppressive medications that can be used as second-line or third-line therapies for refractory AIHA. They work by suppressing the immune system, specifically targeting cells involved in the destruction of red blood cells. These medications are often used in combination with corticosteroids.

danazol:

danazol is an androgenic steroid that can be considered as a third-line therapy for refractory AIHA. It helps to increase the production of red blood cells and may also have immunosuppressive effects. However, its use in children is limited due to potential side effects and the availability of other treatment options.

cyclosporine:

cyclosporine used as a third-line therapy for refractory AIHA as it is an immunosuppressive agent. Its mechanism of action includes inhibition of activation of T-cells, a type of immune cell involved in the destruction of red blood cells. Cyclosporine is often used in combination with corticosteroids and may take several weeks to show a therapeutic effect.

Other Therapies:

In some cases, other immunosuppressive medications may be considered for refractory AIHA. These can include mycophenolate mofetil, rituximab (an anti-CD20 monoclonal antibody), rituximab plus cyclophosphamide, or vincristine.

Hematology

Immunosuppressive therapy controls the autoimmune response and reduces red blood cell destruction, stabilizing anemia. Response to treatment is typically monitored by regular blood tests, including complete blood count (CBC), reticulocyte count, and markers of hemolysis.

Blood transfusions may be required in AIHA to manage severe anemia, alleviate symptoms, and improve oxygen-carrying capacity. Transfusion decisions are based on clinical judgment, symptoms, and hemoglobin levels.