Autoimmune hemolytic anemia (AIHA) in children: Treatment and outcome

INTRODUCTION — Autoimmune hemolytic anemia (AIHA) is a collection of disorders characterized by the presence of autoantibodies that bind to the patient's own erythrocytes, leading to premature red cell destruction due to hemolysis and, when the rate of hemolysis exceeds the ability of the bone marrow to replace the destroyed red cells, to anemia and its attendant signs and symptoms. AIHA is generally categorized as "warm" or "cold" based on the thermal reactivity of the autoantibodies (table 1) and is classified as primary (idiopathic) or secondary based on whether or not an underlying disease process is present (table 2).

The treatment and prognosis of AIHA in children are reviewed here. A general overview of hemolytic anemias in childhood is presented separately, as are other aspects related to AIHA, including pathophysiology, classification, clinical presentation, and diagnosis, as well as the diagnosis and management of paroxysmal cold hemoglobinuria (PCH):

●(See "Overview of hemolytic anemias in children".)

●(See "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis".)

●(See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Pathogenesis'.)

●(See "Cold agglutinin disease".)

●(See "Paroxysmal cold hemoglobinuria".)

GENERAL TREATMENT PRINCIPLES — AIHA in children is relatively rare, and, therefore, available studies concerning the treatment of AIHA in children are generally small, retrospective, and/or anecdotal. Randomized controlled studies are entirely lacking. Optimal treatment of a child with AIHA depends initially upon the:

●Severity and chronicity of anemia

●Degree of signs and symptoms

●Characteristics of the autoantibodies (table 1)

●Nature of the underlying disease, if present (table 2)

Children with AIHA can be managed in the ambulatory setting if the anemia is not severe and there are no signs of cardiovascular compromise. At the time of initial disease presentation, however, hospitalization may be warranted to expedite the diagnostic evaluation, closely monitor the patient, and begin therapy before the anemia worsens.

SEVERE OR LIFE-THREATENING ANEMIA — There is no consensus regarding the threshold for transfusion in AIHA; the decision to transfuse depends upon the degree and onset of anemia. Rarely, the anemia in a child with AIHA is severe and causes cardiovascular compromise (eg, when the hemoglobin is <5 g/dL). In such cases, urgent treatment is required and includes the following:

●Red blood cell (RBC) transfusion (following urgent discussion with blood bank personnel regarding blood compatibility), and

●Pharmacotherapy (glucocorticoids in patients with warm AIHA, rituximab in patients with cold AIHA) (see 'Warm-reactive AIHA' below and 'Cold agglutinin disease' below)

Although transfusion can lead to additional hemolysis in patients with AIHA, it must be emphasized that despite the risks, transfusion therapy should not be withheld from a patient with life-threatening anemia. For patients who require urgent or emergency transfusion, joint decision making by the clinician and transfusion medicine specialist should occur. (See "Red blood cell (RBC) transfusion in individuals with serologic complexity".)

Identification of compatible RBCs to transfuse into a child with AIHA can be difficult. Discussions with blood bank personnel should be initiated as early as possible in order to minimize delays in providing blood and to avoid misunderstandings concerning the degree to which available blood units are compatible with the patient. (See "Red blood cell (RBC) transfusion in individuals with serologic complexity", section on 'AIHA and concurrent alloantibodies'.)

Acute symptomatic transfusion reactions are uncommon in children with AIHA who require RBC transfusions, even when transfusing "least incompatible" units of blood [1]. Because transfused donor cells survive in patients with AIHA similar to the patient's own erythrocytes, transfusion is generally helpful to ameliorate the signs and symptoms of anemia, even if the transfused erythrocytes last in the circulation for only a short period of time.

Severe hemolytic transfusion reaction is more likely in patients with cold-reactive autoantibodies that fix complement and cause intravascular hemolysis (table 1). In such patients, strategies to reduce the likelihood of a hemolytic transfusion reaction include:

●Warming the blood to 37°C before and during the infusion

●Beginning the transfusion at a slow rate and checking both plasma and urine samples periodically for the presence of free hemoglobin

On the rare occasion when a transfusion results in more severe hemolysis, with substantial hemoglobinemia and hemoglobinuria, vigorous hydration should be provided to help prevent renal dysfunction.

Transfusions are required at some point in approximately 65 percent of children with AIHA [2,3]; however, in some cases, particularly those with active reticulocytosis, transfusion is not necessary.

PAROXYSMAL COLD HEMOGLOBINURIA — Children with paroxysmal cold hemoglobinuria (PCH) usually have an abrupt but self-limited hemolytic process. Keeping the patient warm and avoiding exposure to cold fluids are the mainstays of management. Transfusion may be required at presentation, particularly in patients with severe anemia. Treatment of PCH is discussed in greater detail separately. (See "Paroxysmal cold hemoglobinuria", section on 'Treatment'.)

COLD AGGLUTININ DISEASE — Most pediatric cases of cold agglutinin (immunoglobulin M [IgM]) AIHA are due to Mycoplasma pneumoniae or Epstein-Barr virus infection. The anemia tends to be mild at physiologic temperatures, and pharmacologic therapy is not necessary in most cases. As with PCH, management involves keeping the patient warm and avoiding exposure to cold fluids. Treatment of the underlying cause (eg, antibiotics in the case of Mycoplasma infection) is also an important aspect of management. (See "Mycoplasma pneumoniae infection in children", section on 'Management'.)

Pharmacologic therapy is warranted in patients with severe symptomatic anemia. Rituximab is the agent used most commonly (this is an off-label use of this drug). Rituximab and other treatments for cold agglutinin disease are discussed in greater detail separately. (See "Cold agglutinin disease", section on 'Management'.)

In addition to pharmacotherapy, transfusion may be warranted in patients with severe symptomatic anemia. (See 'Severe or life-threatening anemia' above.)

WARM-REACTIVE AIHA

Rationale for treatment — In contrast with cold agglutinin disease and paroxysmal cold hemoglobinuria (PCH), which tend to have an acute onset but are generally self-limited diseases in children, warm-reactive AIHA typically has a more relapsing and chronic disease course and usually does not resolve without treatment. For this reason, we suggest initial pharmacotherapy for children with warm-reactive AIHA.

First-line therapy (glucocorticoids) — Glucocorticoids are the first-line therapy for warm-reactive AIHA. Glucocorticoids are preferred over other therapies because the response is generally more rapid, short-term side effects are usually manageable, and there is greater experience with glucocorticoids in children with AIHA.

Initial dose — This initial dose is dependent on the severity of anemia:

●Severe anemia – Children who present with severe and symptomatic anemia (eg, hemoglobin <6 to 7 g/dL) requiring hospitalization are initially treated with intravenous methylprednisolone 0.5 to 1 mg/kg per dose every six to eight hours for the first 24 to 72 hours (after which they are transitioned to oral prednisone at the dose provided below). Occasionally, pulse high-dose methylprednisolone (30 mg/kg with maximum dose of 1 g once daily for three days) may be warranted for the most severely affected patients, such as those with rapidly evolving and severe hemolysis [4-6].

●Mild or moderate anemia – Children with mild or moderate anemia (eg, hemoglobin ≥7 to 8 g/dL) and appropriate reticulocytosis can be initially treated with oral prednisone 2 mg/kg per day in two or three divided doses.

Tapering — Steroid tapering in children with AIHA can be challenging, and relapse is common, particularly if the medication is tapered too quickly or discontinued abruptly [3,7-10]. (See 'Response to treatment' below.)

The goal of the taper is to minimize the risk of relapse while avoiding complications associated with long-term glucocorticoid use (eg, weight gain, growth impairment, psychiatric and cognitive symptoms, hypertension, hyperglycemia, osteoporosis, osteonecrosis of the femoral head, and cataracts). (See "Major adverse effects of systemic glucocorticoids".)

Our general approach is as follows:

●First few months – Once an adequate response has been achieved (ie, hemoglobin >9 to 10 g/dL), which typically occurs within two to four weeks, the steroid dose can be tapered to a single daily dose as tolerated over two to three months, based on serial evaluation of the hemoglobin concentration, reticulocyte count, lactate dehydrogenase (LDH), and direct antiglobulin test (DAT) results (see 'Monitoring' below). Most patients tolerate tapering prednisone to a dose ≤1 mg/kg per day within this time frame. If this cannot be accomplished, a second-line therapy should be started to facilitate steroid weaning. (See 'Second-line therapies' below.)

●Subsequent tapering – Once the patient is tolerating a dose ≤1 mg/kg per day, prednisone is slowly tapered but not stopped until there is normalization of the hemoglobin, reticulocyte count, and LDH/haptoglobin, although the DAT may remain weakly positive (see 'Monitoring' below). For most patients, the goal is to taper steroids off completely. However, some patients may require long-term, low-dose prednisone (ie, ≤0.2 mg/kg per day) to avoid remission. Patients who chronically require doses >0.2 mg/kg per day and those who experience frequent relapses should generally be started on a second-line therapy. (See 'Second-line therapies' below.)

Monitoring — Monitoring of patients with AIHA consists of regular clinical assessments and laboratory testing, including:

●Hemoglobin level

●Reticulocyte count

●LDH

●DAT (previously called the Coombs test)

The frequency of monitoring depends on disease severity and treatment. In the outpatient setting, laboratory studies are typically monitored once weekly, initially, particularly to guide the early tapering of glucocorticoids. The interval between testing can be gradually increased as the clinical picture stabilizes, but monitoring should continue until the hemoglobin level and reticulocyte count have returned to normal (ie, hemoglobin ≥11 g/dL, reticulocyte count ≤100 × 10³/microL) and the patient is stable on low-dose glucocorticoids. LDH and DAT can be tested periodically, especially after the initial therapeutic response.

We typically continue monitoring patients for one year after remission has been achieved as the risk of relapse is greatest during this time. The DAT may remain weakly positive, even after complete remission has been attained. A persistent positive DAT suggests ongoing autoimmune disease and warrants further exploration for secondary etiologies such as Evans syndrome or systemic lupus erythematosus (SLE). (See "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis", section on 'Evaluation for secondary causes'.)

Response to treatment — Children with immunoglobulin G (IgG) warm-reactive AIHA tend to have a chronic disease course characterized by intermittent relapses.

●Expected response – Approximately 70 to 80 percent of patients have an initial response to glucocorticoid therapy [3,7,10]. The initial treatment response is a stabilization of the hemoglobin concentration, followed by a slow increase in the hemoglobin level and decreased reticulocytosis. Glucocorticoids have a rapid effect, within 24 to 48 hours, likely due to inhibition of the Fc receptor-mediated clearance of sensitized erythrocytes [11]. They also diminish the production of autoantibodies, but this effect requires several weeks.

In one study of 246 pediatric patients with AIHA who were initially treated with glucocorticoids, hematologic recovery occurred within one month in the majority of patients but three-quarters of the cohort required ≥6 months of treatment [3].

●Poor response to initial therapy – A minority of patients have an inadequate response to treatment during the first one to two months and/or do not tolerate initial tapering of glucocorticoids (ie, require prednisone doses >1 mg/kg per day to maintain remission). Such patients should be started on a second-line treatment, as discussed below. (See 'Second-line therapies' below.)

In one series of 265 pediatric patients with AIHA, 37 percent required multimodal therapy [3].

●Relapses – Relapses are common in patients with AIHA, occurring in 15 to 40 percent of patients in the initial six months to one year after initial response [2,3,7,10]. Treatment of relapses generally involves restarting the lowest prednisone dose that was previously effective in maintaining the patient in remission. Patients with frequent relapses, and those in whom remission cannot be maintained off of prednisone or on a low prednisone dose (≤0.2 mg/kg per day), should generally be started on a second-line therapy. (See 'Second-line therapies' below.)

Refractory disease

Second-line therapies — Second-line treatment options for children with AIHA refractory to or dependent on glucocorticoids include rituximab and splenectomy. Limited data on the use of rituximab in children and adults with AIHA are encouraging. For this reason, and because splenectomy in children is associated with a lifelong risk of sepsis and other potential complications (especially thrombosis, including portal vein thrombosis) [12,13], our practice is to treat with rituximab before resorting to splenectomy.

●Rituximab – Rituximab, which is an anti-CD20 monoclonal antibody, is our preferred second-line choice for treatment of children with AIHA refractory to or dependent on glucocorticoids. Rituximab is typically given in conjunction with steroid therapy in an attempt to allow weaning or even discontinuation of glucocorticoids. This is an off-label use of rituximab, based on one small prospective study and several case series in children with AIHA that have demonstrated response rates of 60 to 85 percent [14-18].

The standard dose of rituximab is 375 mg/m² per dose given intravenously once a week for four weeks. Some providers administer 750 mg/m² per dose as two doses two weeks apart.

In a prospective study of 15 children with AIHA treated with rituximab, 13 children responded to therapy; most responded within two to four weeks [15]. Relapse occurred in three patients at 7 to 10 months after treatment. The children who relapsed were treated with a second course of rituximab and again achieved remission. Monitoring lymphocyte subpopulations every few months can help assess the treatment response. In our experience, relapse most commonly occurs when CD20-positive B cells recover.

In some cases, rituximab therapy can induce prolonged absence of circulating B cells, especially CD19+27+ memory B cells, and profound hypogammaglobulinemia [14]. Replacement therapy with intravenous immune globulin (IVIG) may be useful in patients who develop severe hypogammaglobulinemia after rituximab use [15,19]. Consultation with an immunologist may be beneficial. The authors' practice is to evaluate lymphocyte subpopulations and immunoglobulin levels prior to administering rituximab to ensure baseline evaluation is available if inadequate reconstitution should occur.

Although the toxicity profile of rituximab is generally favorable, rare infusion reactions can occur. Pretreatment with acetaminophen and an antihistamine is standard practice. "Boxed Warnings" in the United States warn of severe infusion-related reactions, reactivation of hepatitis B infection, and severe mucocutaneous reactions, as well as progressive multifocal leukoencephalopathy, any one of which may be fatal. Most infusion reactions have occurred in association with the first infusion. Second and subsequent infusions can potentially be run at a more rapid rate in selected patients who tolerated the first infusion without any reactions or dose modifications [20]. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab'.)

●Splenectomy – Splenectomy is an effective treatment for children with chronic or recalcitrant primary AIHA; approximately two-thirds of patients show a short-term improvement, usually evident within two weeks following surgery [8,21,22]. Splenectomy works by removing the main site of erythrocyte destruction (figure 1) and also may benefit the patient with AIHA by removing a major site of autoantibody production.

In a study of 52 adult and pediatric patients with AIHA who underwent splenectomy, an excellent response (no further steroid therapy) was reported in 64 percent and an improved status (with ongoing low-dose steroid therapy) in 21 percent [23].

Because of the risk of post-splenectomy sepsis caused by encapsulated bacterial organisms in young children, splenectomy should be avoided in children <3 years old and preferably delayed until >6 years old.

Patients undergoing splenectomy should receive appropriately timed preoperative immunization against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b. (See "Prevention of infection in patients with impaired splenic function", section on 'Vaccinations'.)

In addition, children who have undergone splenectomy should receive antibiotic prophylaxis and should be instructed to seek immediate medical attention in the event of fever due to the possibility of bacterial sepsis. (See "Prevention of infection in patients with impaired splenic function", section on 'Emergency antibiotic supply'.)

Care should be taken to rule out secondary causes of AIHA prior to splenectomy. The risk of infection after splenectomy is markedly increased in some of the conditions that cause secondary AIHA (particularly autoimmune lymphoproliferative syndrome [ALPS], common variable immunodeficiency [CVID], and other immune deficiency and dysregulation syndromes). The procedure should be avoided when possible in these subgroups of patients. (See "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis", section on 'Evaluation for secondary causes'.)

Third-line therapies — For children with refractory AIHA who have failed therapy with glucocorticoids, rituximab, and/or splenectomy and for those who remain steroid dependent despite treatment with rituximab and/or splenectomy, more aggressive therapy may be required. Several treatment options are available for such children, although each is less effective than either glucocorticoids, rituximab, or splenectomy. The aim of adjunctive therapy is generally to reduce or eliminate the need for continued steroid therapy (ie, "steroid-sparing" effect) since the long-term use of glucocorticoids is associated with unacceptable side effects in children. Decisions regarding adjuvant therapy should be individualized for each patient, based upon the hematologic response and side-effects.

●IVIG – IVIG has been used in pediatric and adult patients with AIHA; however, only approximately 30 percent of children respond and, in those that do, the effect is usually transient [24,25]. Replacement IVIG therapy may be warranted in children who develop clinically significant hypogammaglobulinemia as a consequence of treatment with rituximab. (See 'Second-line therapies' above.)

●Danazol – Danazol is a semisynthetic androgen that can reduce cell-bound IgG and complement and decrease IgG production [26]. Limited data in adults suggest that danazol use in combination with prednisone may help reduce the prednisone dose in glucocorticoid-dependent patients [27]. The drug has not been studied in children with AIHA. The primary adverse side effects of danazol are elevations in the hepatic transaminases and mild masculinizing effects; as a result, females typically do not tolerate use of this agent.

●Azathioprine and 6-mercaptopurine – 6-mercaptopurine and its prodrug, azathioprine, are immunosuppressive agents that primarily affect T lymphocyte helper function, thereby diminishing autoantibody synthesis and exerting a steroid-sparing effect. Clinical responses to either agent may require more than two to three months of therapy [8,28].

●Cyclosporine – Cyclosporine A is another immunosuppressive agent that also primarily affects T lymphocytes. Long-term use of cyclosporine has been associated with nephrotoxicity, hypertension, and a risk of second malignancy, and it should be reserved for children with refractory AIHA. The suggested starting oral dose is in the range of 1 to 3 mg/kg per day divided into two doses 12 hours apart.

●Mycophenolate mofetil, tacrolimus, and sirolimus – These immunosuppressive agents have been employed in patients with relapsed, resistant AIHA, including those following solid organ or stem cell transplantation, or complicated by Evans syndrome, acquired pure red cell aplasia, and/or ALPS [29-34]. As with danazol, their use may allow "steroid sparing," resulting in reduced doses of glucocorticoids required to maintain remission.

●Cytotoxic agents – Cytotoxic agents that can reduce autoantibody formation include vincristine, vinblastine, and cyclophosphamide. Although few data exist on their efficacy in children with AIHA, these agents can be considered for the extremely refractory patient [35,36]. These agents generally are myelosuppressive and potentially mutagenic, and they should be used with caution in children.

●Monoclonal antibodies – A number of monoclonal antibodies targeting various lymphocyte antigens have been suggested as potential therapies for refractory AIHA [37,38]. Such targeted therapies hold promise; however, for the most part, the data supporting these agents in this setting are limited to case reports and small case series.

•Other anti-CD20 monoclonal antibodies – After the success of rituximab, other anti-CD20 monoclonal antibodies such as obinutuzumab have been developed. These agents have enhanced ability to bind FcRIIIa and their use has been reported in small numbers of patients with refractory AIHA [37].

•Anti-CD52 monoclonal antibody – Alemtuzumab, a humanized anti-CD52 monoclonal antibody, targets predominantly T and B lymphocytes and has been reported in a few small case series [39,40].

●Bortezomib – Bortezomib is a proteasome inhibitor that depletes circulating plasma cells and affects antigen presentation. Its use in refractory AIHA has been described in small case series [41].

●Fostamatinib – Fostamatinib is a spleen tyrosine kinase (Syk) inhibitor. It has been studied in adults with AIHA but not children [42].

●Plasmapheresis – Plasmapheresis may be used as adjunctive treatment in patients with cold agglutinin (IgM-mediated) AIHA; however, its use in warm AIHA is considered a category III intervention (ie, disorders for which the optimum role of apheresis therapy is not established). (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology", section on 'ASFA therapeutic categories' and "Cold agglutinin disease", section on 'Management'.)

●Hematopoietic cell transplantation – Successful hematopoietic cell transplantation for AIHA has been reported, including a single case report of a child with AIHA [43-45]. This treatment option is reserved for patients with severe disease in whom all other therapies have failed and for whom a thorough investigation for underlying treatable genetic disorders driving immune dysregulation has been nondiagnostic.

●Complement inhibitors – Some cases of refractory AIHA feature complement-mediated erythrocyte destruction. In these cases, agents designed to inhibit the complement cascade have anecdotally been used (eg, sutimlimab, pegcetacoplan, eculizumab) [46]. There is a substantial risk of developing serious bacterial infections while on treatment, especially infections due to Neisseria meningitis. Thus, patients receiving complement inhibitor therapy should receive vaccinations for N. meningitis, Streptococcus pneumoniae, and Haemophilus influenza type b prior to starting therapy. (See "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria", section on 'Complement inhibitors'.)

Secondary AIHA — The above treatment recommendations apply to patients with primary and secondary AIHA. For some causes of secondary AIHA, there are additional important management considerations.

Evans syndrome — Evans syndrome is characterized by AIHA, immune thrombocytopenia (ITP), and/or autoimmune neutropenia. Some patients present with isolated AIHA and then develop additional cytopenias months or even years after the initial clinical presentation. The management of children with Evans syndrome is challenging as many patients are refractory to glucocorticoid therapy and require multimodal therapy. The most commonly used agents are glucocorticoids and IVIG [22]. Because patients with Evans syndrome have concurrent ITP, IVIG is used more commonly to treat these patients compared with patients with isolated AIHA. (See "Immune thrombocytopenia (ITP) in children: Initial management", section on 'Intravenous immune globulin'.)

Rituximab, mycophenolate mofetil, sirolimus, and various monoclonal antibodies described above may be effective therapeutic agents as well [34,39]. (See 'Second-line therapies' above and 'Third-line therapies' above.)

Although some patients with Evans syndrome initially respond to glucocorticoids, most relapse after stopping therapy and adjuvant or alternative therapy is often required. In the previously described study of 265 children with AIHA, 65 percent of children with Evans syndrome required multimodal therapy (compared with only 37 percent of children with isolated AIHA) [3]. Rituximab appears to be an effective second-line treatment for children with Evans syndrome. In a retrospective study of 17 children with Evans syndrome, rituximab therapy in combination with prednisone (14 patients) or other immunosuppressive drugs (3 patients) was associated with complete or partial remission in 13 patients (76 percent) [47]. Relapse occurred in 3 patients at a median follow-up of 2.4 years. Glucocorticoid therapy was able to be discontinued or tapered to <50 percent of the baseline dose in all long-term responders.

Splenectomy can improve cytopenias in patients with Evans syndrome, but the response rate is lower than in patients with isolated AIHA or ITP [22]. In addition, relapses following splenectomy are common. For this reason, splenectomy is typically reserved for patients who fail medical therapy.

A substantial proportion of children who present with Evans syndrome actually have ALPS as the underlying etiology of their immune dysregulation [48]. For this reason, it is imperative that all children who present with AIHA and another cytopenia be screened for ALPS. (See "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)

Immunodeficiency — AIHA may occur in patients with primary immunodeficiency, such as CVID, Wiskott-Aldrich syndrome, CTLA4 haploinsufficiency with autoimmune infiltration disease, LRBA deficiency, and STAT3 gain-of function mutations. It also can occur with acquired immunodeficiency (eg, HIV infection). Treatment of AIHA in patients with underlying immunodeficiency is similar to treatment of primary AIHA, and most patients respond to glucocorticoid therapy. However, with the increasing availability of targeted therapies for some genetic mutations, the frontline response rates may improve with successful control of immune dysregulation. Severe infections can occur following splenectomy or rituximab therapy in patients with underlying immunodeficiency, particularly CVID [22]. Close monitoring for infectious complications during treatment is advised in these patients.

Autoimmune lymphoproliferative syndrome — ALPS is characterized by dysregulation of the immune system due to an inability to regulate lymphocyte maturation and clonal expansion. The consequences of this include lymphoproliferative disease (eg, lymphadenopathy, hepatomegaly, splenomegaly, lymphoma) and autoimmune disease, typically involving blood cells.

Development of AIHA in patients with ALPS often signals a transition in the natural history and the need to initiate or escalate therapy. Patients with autoimmune manifestations typically have a more difficult time coming off of immunosuppressive therapy than patients with lymphoproliferation only. A combination of immunosuppressive and immunomodulating agents (eg, glucocorticoids, rituximab, IVIG, mycophenolate, and sirolimus) may be necessary in these patients.

Treatment of ALPS is discussed in greater detail separately. (See "Autoimmune lymphoproliferative syndrome (ALPS): Management and prognosis", section on 'Autoimmune manifestations'.)

Systemic lupus erythematosus — Patients with SLE who have mild to moderate AIHA can generally be treated with prednisone as described above (see 'First-line therapy (glucocorticoids)' above). It should be noted that the DAT may be weakly positive in SLE without evidence of clinical or laboratory hemolysis, and such patients are generally not considered to have AIHA.

Cases of severe rapidly progressive anemia may require high-dose intravenous methylprednisolone (30 mg/kg per day for three days; maximum daily dose 1 g), followed by tapering daily oral doses of prednisone as the response to therapy allows. Patients with SLE and other autoimmune disease-induced AIHA may benefit from earlier initiation of rituximab therapy. (See "Systemic lupus erythematosus (SLE) in children: Treatment, complications, and prognosis".)

Drug-induced autoimmune hemolytic anemia — In patients with suspected drug-induced AIHA (table 3), it is imperative that the offending drug be discontinued. In many cases, corticosteroids are used to slow the rate of hemolysis and plasmapheresis can be considered if the patient has clinical deterioration. (See "Drug-induced hemolytic anemia", section on 'Management'.)

PROGNOSIS

Mortality — Reported mortality rates in contemporary case series range from 3 to 4 percent [2,3]. Mortality rates in earlier case series were considerably higher (10 to 15 percent) [49-51]. The main causes of death in these reports were overwhelming sepsis in splenectomized patients, catastrophic bleeding in patients with Evans syndrome (ie, concurrent immune thrombocytopenia [ITP]), and complications of underlying diseases (eg, malignancy or immunodeficiency syndromes). The lower mortality rate observed in the later studies may reflect improvements in supportive care (particularly post-splenectomy care) and improvements due to newer therapies (eg, rituximab, sirolimus).

Remission — Patients with paroxysmal cold hemoglobinuria (PCH) and cold agglutinin disease secondary to M. pneumoniae or Epstein-Barr virus infection tend to have a self-limited course, and, although the acute presentation may be severe, the long-term outcome is generally good and most patients make a complete recovery within weeks to a few months after disease onset. (See "Paroxysmal cold hemoglobinuria" and "Cold agglutinin disease", section on 'Clinical manifestations'.)

In contrast, children with IgG warm-reactive AIHA tend to have a chronic disease course characterized by intermittent relapses. (See 'Response to treatment' above.)

In the largest series of children with AIHA, involving 265 patients followed for a median of 3 years, 90 percent had achieved complete remission at the time of last follow-up [3]. Of the patients who achieved remission, 44 percent had maintained stable complete remission without any specific treatment for >1 year; 29 percent still required therapy to maintain remission. Mean duration of therapy was 1.6 years among children with isolated AIHA and 4.3 years among children with Evans syndrome.

Factors associated with poor prognosis include:

●Family or personal history of immunodeficiency or autoimmune disease

●Concurrent thrombocytopenia or lymphocytopenia

●Positive direct antiglobulin test (DAT) for both IgG and complement component 3

In contrast, abrupt onset of symptoms and documented infection at the time of diagnosis are associated with a greater likelihood of complete remission.

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Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)

●Basics topic (see "Patient education: Autoimmune hemolytic anemia (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Treatment principles – Optimal treatment of a child with autoimmune hemolytic anemia (AIHA) depends initially upon the severity and chronicity of the anemia, signs and symptoms, characteristics of the autoantibodies (table 1), and nature of the underlying disease if present (table 2). (See 'General treatment principles' above.)

●Severe or life-threatening anemia – Children with AIHA who present with severe anemia of sudden onset that is associated with cardiovascular compromise require urgent red blood cell (RBC) transfusion, which requires prompt discussion with blood bank personnel. Although transfusion can lead to additional hemolysis in patients with AIHA, it must be emphasized that, despite the risks, transfusion therapy should not be withheld from a patient with life-threatening anemia. (See 'Severe or life-threatening anemia' above and "Red blood cell (RBC) transfusion in individuals with serologic complexity".)

●Paroxysmal cold hemoglobinuria (PCH) – Children with PCH usually have a self-limited hemolytic process. Keeping the patient warm and avoiding exposure to cold fluids are the mainstays of management. Transfusion may be required in patients with severe anemia. Treatment of PCH is discussed in greater detail separately. (See "Paroxysmal cold hemoglobinuria", section on 'Treatment'.)

●Cold agglutinin disease – Most pediatric cases of cold agglutinin AIHA are due to Mycoplasma pneumoniae or Epstein-Barr virus infection. The anemia tends to be mild, and pharmacologic therapy is not necessary in most cases. Management involves keeping the patient warm and avoiding exposure to cold fluids. Pharmacologic therapy and/or transfusion is warranted in patients with severe symptomatic anemia. Rituximab is the most commonly used agent. Treatment of the underlying cause (eg, antibiotics in the case of Mycoplasma infection) is also an important aspect of management. Treatment of cold agglutinin AIHA is discussed in greater detail separately. (See "Mycoplasma pneumoniae infection in children", section on 'Management' and "Cold agglutinin disease", section on 'Management'.)

●Warm-reactive AIHA – For most children with warm-reactive AIHA, we suggest initial pharmacotherapy with glucocorticoids (Grade 2C). In contrast with cold agglutinin disease and PCH, which tend to be self-limited diseases in children, warm-reactive AIHA typically has a more chronic disease course and usually does not resolve without therapy. For most patients, we suggest glucocorticoids for first-line therapy rather than other therapies (Grade 2C) because the response is generally more rapid, short-term side effects are usually manageable, and there is greater experience with glucocorticoids in children with AIHA. (See 'Rationale for treatment' above and 'First-line therapy (glucocorticoids)' above.)

●Refractory AIHA – Most patients with warm-reactive AIHA respond to initial therapy with glucocorticoids, though relapses are common. For patients with refractory AIHA (ie, failure to respond to glucocorticoid therapy within one to two months or unable to taper off or to low-dose prednisone), we suggest rituximab rather than splenectomy as the preferred second-line treatment (Grade 2C). This is because splenectomy in children is associated with a lifelong risk of sepsis and other potential complications (eg, portal vein thrombosis). (See 'Response to treatment' above and 'Second-line therapies' above.)

Third-line treatment options for patients who remain steroid dependent despite treatment with rituximab and/or splenectomy include intravenous immune globulin (IVIG), danazol, immunosuppressive agents (eg, azathioprine, 6-mercaptopurine, cyclosporine, mycophenolate mofetil, tacrolimus, sirolimus), cytotoxic agents (eg, vincristine, vinblastine, cyclophosphamide), complement blocking agents, plasmapheresis, and hematopoietic cell transplantation. Data on these treatment modalities in children are extremely limited, and, in general, they appear to be less effective than glucocorticoids, rituximab, or splenectomy. (See 'Third-line therapies' above.)

●Treatment considerations for the underlying disease – Secondary AIHA is treated in the same manner as primary AIHA; however, depending on the nature of the underlying disease, there may be additional important management considerations. (See 'Secondary AIHA' above.)

●Prognosis – The mortality rate in pediatric AIHA is approximately 3 to 4 percent. Long-term remission is achieved in approximately 90 percent of patients, though a substantial proportion require ongoing therapy to maintain remission. Factors associated with poor prognosis include family or personal history of immunodeficiency or autoimmune disease, concurrent thrombocytopenia or lymphocytopenia, and positive direct antiglobulin test (DAT) for both immunoglobulin G (IgG) and complement component 3. Abrupt onset of symptoms and documented infection at the time of diagnosis are associated with a good prognosis. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jenny Despotovic, DO, MS, who contributed to earlier versions of this topic review.