Autoimmune Hemolytic Anemia in Children - Classification, Clinical Features, and Diagnosis - UpToDate

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4/21/2020 Autoimmune hemolytic anemia in children: Classification, clinical features, and diagnosis - UpToDate

Authors: Russell E Ware, MD, PhD, Jenny M Despotovic, DO, MS


Section Editor: Donald H Mahoney, Jr, MD
Deputy Editor: Carrie Armsby, MD, MPH

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Mar 2020. | This topic last updated: Mar 13, 2019.

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 (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.

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

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


● (See "Autoimmune hemolytic anemia in children: Treatment and outcome".)
● (See "Warm autoimmune hemolytic anemia: Clinical features and diagnosis".)
● (See "Cold agglutinin disease", section on 'Pathogenesis'.)
● (See "Paroxysmal cold hemoglobinuria".)

CLASSIFICATION

Warm and cold agglutinins — AIHA is generally categorized as "warm" or "cold" based on the
thermal reactivity of the autoantibodies (table 1):

● Warm-reactive AIHA – The most common form of primary AIHA in children, accounting for
60 to 90 percent of cases, involves warm-reactive autoantibodies, usually immunoglobulin
(Ig)G, that bind preferentially to the red cells at 37°C, leading to extravascular hemolysis
mainly in the spleen, with resulting anemia, jaundice and, occasionally, splenomegaly. In
some cases, IgG is present in sufficient quantity and proximity to fix complement, resulting
in features of concomitant intravascular hemolysis.

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● Cold agglutinin disease – Cold agglutinin disease is relatively uncommon in children,


amounting to approximately 10 percent of cases, most commonly occurring after
Mycoplasma pneumoniae or Epstein-Barr virus (EBV) infection. In this disorder, IgM
autoantibodies bind erythrocyte I/i or rarely anti-PR antigens at colder temperatures and fix
complement, which leads to anemia, either due to complement-mediated intravascular
hemolysis or immune-mediated extravascular clearance, mainly by hepatic macrophages.

● Paroxysmal cold hemoglobinuria – Paroxysmal cold hemoglobinuria (PCH) is an AIHA


seen almost exclusively in children, most commonly after a viral-like illness. PCH is
characterized by IgG autoantibodies targeting the P antigen that bind preferentially at colder
temperatures, fix complement efficiently, and cause intravascular hemolysis with
hemoglobinemia, hemoglobinuria, and anemia. PCH is discussed in greater detail
separately. (See "Paroxysmal cold hemoglobinuria".)

Primary versus secondary AIHA — AIHA is classified as either primary (idiopathic) or


secondary based on whether or not an underlying disease process is present (table 2).

Primary AIHA — In primary AIHA (also called idiopathic AIHA), red blood cell autoantibodies
are present and cause hemolytic anemia, but no evidence of an underlying systemic illness
exists. Primary AIHA accounts for approximately 40 to 50 percent of pediatric AIHA cases; most
are due to warm-reactive autoantibodies [1,2].

Secondary AIHA — AIHA occurring in association with another systemic illness is referred to
as secondary AIHA (table 2). Secondary AIHA is most commonly due to warm-reactive
autoantibodies, with the exception of postinfectious cases, which are typically caused by cold
agglutinins. More than half of all cases of pediatric AIHA are secondary, and therefore the
possibility of an underlying systemic illness should be considered in all children presenting with
AIHA [3]. (See 'Evaluation for secondary causes' below.)

Autoimmune disease — Systemic autoimmune diseases are common secondary causes


of AIHA, particularly in older children [4]. Autoimmune or inflammatory disorders that have been
reported to be associated with AIHA include [3,5,6]:

● Systemic lupus erythematosus (SLE) (see "Systemic lupus erythematosus (SLE) in children:
Treatment, complications, and prognosis", section on 'Hematologic abnormalities')

● Sjögren syndrome (see "Clinical manifestations of Sjögren's syndrome: Extraglandular


disease", section on 'Hematologic manifestations')

● Scleroderma (see "Juvenile systemic sclerosis (scleroderma): Classification, clinical


manifestations, and diagnosis")

● Juvenile idiopathic arthritis (see "Systemic juvenile idiopathic arthritis: Clinical


manifestations and diagnosis")
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● Dermatomyositis (see "Juvenile dermatomyositis and polymyositis: Epidemiology,


pathogenesis, and clinical manifestations")

● Vitiligo (see "Vitiligo: Pathogenesis, clinical features, and diagnosis")

● Ulcerative colitis (see "Clinical presentation and diagnosis of inflammatory bowel disease in
children")

● Autoimmune hepatitis (see "Overview of autoimmune hepatitis")

● Type 1 diabetes mellitus (see "Epidemiology, presentation, and diagnosis of type 1 diabetes
mellitus in children and adolescents")

● Autoimmune thyroiditis (see "Acquired hypothyroidism in childhood and adolescence",


section on 'Autoimmune thyroiditis')

● Autoimmune lymphoproliferative syndrome (ALPS) (see "Autoimmune lymphoproliferative


syndrome (ALPS): Clinical features and diagnosis")

Children with these disorders probably have a genetic susceptibility to immune dysregulation,
which leads to the expansion and proliferation of autoreactive B lymphocytes. Often, there is a
family history of autoimmune disorders. It should be noted that in some of these disorders (eg,
SLE), the direct antiglobulin test (DAT) may be weakly positive without evidence of clinical or
laboratory hemolysis, and such patients are generally not considered to have AIHA.

Immunodeficiency — Children with primary immunodeficiency may develop secondary


AIHA, almost certainly caused by altered immune regulation [7]. AIHA can present in children as
the initial manifestation of an unsuspected congenital immunodeficiency disorder, particularly
common variable immunodeficiency (CVID) and Wiskott-Aldrich syndrome. (See "Common
variable immunodeficiency in children", section on 'Autoimmune disease' and "Wiskott-Aldrich
syndrome", section on 'Autoimmune manifestations'.)

Children with acquired immunodeficiency, including those infected with the HIV, can develop
erythrocyte autoantibodies and secondary AIHA caused by polyclonal B lymphocyte activation
and poor immune regulation by T lymphocytes. (See "HIV-associated cytopenias", section on
'Anemia'.)

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. Other patients develop ITP initially and subsequently develop AIHA. Evans
syndrome accounts for approximately 15 to 30 percent of pediatric AIHA [1,2]. Compared with
AIHA presenting alone, Evans syndrome is more difficult to treat and tends to have a clinical
course that is chronic and relapsing [8,9]. These patients are also more likely to have or develop

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systemic autoimmunity. (See "Autoimmune hemolytic anemia in children: Treatment and


outcome".)

A variety of immunoregulatory abnormalities in Evans syndrome have been described [10], with
additional novel defects being identified as more detailed testing is being performed.
Autoantibodies apparently are directed against specific antigens on each of the various blood
cell types, without cross-reactivity [11].

A substantial proportion of children who present with Evans syndrome actually have ALPS as
the underlying etiology of their immune dysregulation [12,13]. For this reason, it is imperative
that all children who present with AIHA and another cytopenia be screened for ALPS. In one
study of 45 children with Evans syndrome, nearly half were found to have ALPS [13]. Evans
syndrome is also associated with CVID. (See "Autoimmune lymphoproliferative syndrome
(ALPS): Clinical features and diagnosis" and "Common variable immunodeficiency in children",
section on 'Autoimmune disease'.)

Malignancy — Secondary AIHA can occur in the setting of malignancy, occasionally


presenting before the underlying diagnosis has been made. AIHA can occur in children with
Hodgkin lymphoma, acute leukemia, myelodysplasia, or following allogeneic hematopoietic stem
cell transplantation [14-16]. The pathogenesis of the erythrocyte autoantibodies in association
with malignancy is unknown, but an underlying immune deficiency may lead to both autoimmune
phenomena and malignancy.

Malignancy can present during or even after the episode of hemolytic anemia has occurred,
particularly for children with AIHA secondary to an underlying immune deficiency such as CVID
or ALPS. (See "Causes of anemia in patients with cancer".)

Infection — Infection is another important cause of AIHA. Specific infectious agents that
may trigger AIHA include M. pneumoniae [17], EBV [18,19], measles, varicella, adenovirus,
mumps, and rubella [6]. Most of these infections are associated with cold agglutinins due to IgM
autoantibodies with a specificity for the I/i polysaccharide antigen system on red cells [20],
although reactivity with the P polysaccharide antigen has been reported (table 3) [21,22]. (See
"Cold agglutinin disease", section on 'RBC antigens'.)

Most children who present with PCH have had a recent viral-like illness, though the specific
pathogen often is not identified [23,24].

Acute bacterial infections such as clostridial or pneumococcal infections also can cause
hemolytic anemia, but the mechanism is distinct. (See "Non-immune hemolytic anemia due to
systemic disease", section on 'Bacterial products causing hemolysis'.)

Transplantation — AIHA can develop in the setting of allogeneic hematopoietic stem cell
transplantation, typically in the first two to six months postengraftment. Patients with this

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complication usually do not respond well to traditional therapies, and some end fatally [25-28].

AIHA may also occur following pediatric solid organ transplantation, sometimes in conjunction
with ITP. In this setting, it remains unclear whether the etiology reflects the activity of donor
lymphocytes (from transplants involving liver or small bowel with spleen) or the strong
immunosuppression used to prevent organ rejection [27,29]. In two reports, the most effective
therapy was changing immunosuppression from tacrolimus to another agent such as sirolimus
[27,30].

Drugs — Although not common in children, erythrocyte autoantibodies and hemolysis in


association with drug exposure may cause secondary AIHA. This process was described
classically after therapy with methyldopa, but red cell autoantibodies have been reported in
association with many different pharmaceutical agents (table 4) [31]. Medications that are
particularly important in causing AIHA in children include penicillins, cephalosporins, tetracycline,
erythromycin, probenecid, acetaminophen, and ibuprofen. In a review of the published literature
on this subject, piperacillin was identified as the most frequent etiologic agent [32].

The mechanism of drug-induced hemolytic anemia typically results from generation of


autoantibodies, although the drug may be required to form a hapten or even a ternary complex
with the erythrocyte [33]. (See "Drug-induced hemolytic anemia", section on 'Mechanisms'.)

EPIDEMIOLOGY

AIHA in children is relatively rare, with an estimated annual incidence of 0.8 to 1.25 cases per
100,000 children [6,34], rendering it more common than acquired aplastic anemia but less
common than immune thrombocytopenia.

AIHA can affect children of any race or nationality and can present at any age from infancy
through adolescence [23,35,36]. In a series of 265 children with AIHA, 37 percent were primary,
53 percent had an underlying immunologic disorder (including Evans syndrome), and 10 percent
were postinfectious [1]. Teenagers and children <2 years of age who present with AIHA are more
likely to have an underlying systemic illness (secondary AIHA) and a more chronic course [37-
40].

CLINICAL PRESENTATION

The signs and symptoms of AIHA are nonspecific and are common to other types of hemolytic
anemia. Symptoms are generally determined by the severity of hemolysis, and the clinical
presentation may range from asymptomatic (patients with mild anemia) to severe and life-
threatening (patients with acute profound anemia).

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● Presenting symptoms – Most children with AIHA present with signs and symptoms
referable to anemia, such as weakness, fatigue, shortness of breath, dizziness, and pallor.
Signs of hemolysis are often present, including jaundice, icterus, painless dark urine. Other
nonspecific symptoms include abdominal pain or fever [41]. In a study of 26 children with
warm AIHA, the most common presenting symptoms were pallor (100 percent), jaundice (59
percent), and fever (39 percent) [42].

In most cases of AIHA, the anemia develops gradually and the child is typically well
compensated from a cardiovascular standpoint [6]. Rarely, profound anemia develops
acutely, resulting in a severe, life-threatening presentation. In an observational cohort study
of 265 children with AIHA, 3 percent presented with collapse, coma, or acute kidney injury
due to acute profound anemia [1].

Patients with cold agglutinin disease may have symptoms related to the agglutination of red
cells upon exposure to cold ambient temperatures. The most common manifestation of this
is acrocyanosis, a dark, purple to gray discoloration of the skin on the most acral parts:
fingertips, toes, nose, and ears. These changes disappear upon warming.

Passage of painless dark urine, in colors ranging from gold to red to black, usually signifies
hemoglobinuria secondary to intravascular hemolysis and is suggestive of cold-reactive
AIHA such as cold agglutinin disease or paroxysmal cold hemoglobinuria. In contrast,
patients with warm AIHA do not typically have hemoglobinuria unless there is a component
of complement fixation. (See "Paroxysmal cold hemoglobinuria", section on 'Clinical
manifestations'.)

● Patient history – In reviewing the medical history, it is important to ask about previous
similar episodes. Patients with primary AIHA usually have a benign previous medical history.
Previous blood cell counts (if obtained) are typically normal.

The family history may reveal a history of immune disorders. In an observational study of
265 children with AIHA, a history of autoimmune disease or primary immunodeficiency in
first-degree relatives was noted in 12 percent of cases [1].

The review of systems should focus on any recent acute infectious illness, signs and
symptoms of a potential underlying systemic illness, and concurrent medications (table 4).
(See "Drug-induced hemolytic anemia", section on 'Immune-mediated'.)

● Physical findings – On physical examination, the child with AIHA may be pale and
jaundiced, especially apparent in the conjunctivae and palms. Often, tachycardia is present,
and a systolic flow murmur may commonly be heard, reflecting a high-output anemic state.
Cardiovascular compromise (congestive failure) is uncommon unless the hemoglobin
concentration is <5 g/dL.

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The liver and spleen may be palpable, but the presence of massive organomegaly or lymph
node enlargement should prompt evaluation for other disorders (eg, malignancy [leukemia,
lymphoma], infection [HIV, malaria, tuberculosis], or autoimmune lymphoproliferative
syndrome) [43]. (See 'Evaluation for secondary causes' below.)

INITIAL LABORATORY EVALUATION

The initial laboratory evaluation of the child with AIHA includes all of the following:

● Complete blood count with red blood cell (RBC) indices and platelet count
● Reticulocyte count
● Review of the peripheral blood smear
● Direct antiglobulin test (DAT, formerly called the direct Coombs test)
● Urinalysis, both dipstick and microscopic
● Serum markers of hemolysis, including indirect bilirubin, lactate dehydrogenase (LDH),
aspartate aminotransferase (AST), alanine amino transferase (ALT), and either serum
haptoglobin (for patients ≥18 months old) or plasma free hemoglobin
● Blood urea nitrogen (BUN) and creatinine

In addition, if cold agglutinin disease is suspected based on the clinical presentation (eg,
painless dark urine, M. pneumoniae infection, acrocyanosis upon exposure to cold), a cold
agglutinin titer should be obtained.

Complete blood count findings — AIHA is characterized by anemia, which is often severe (ie,
hemoglobin <7 g/dL). The leukocyte count and platelet count are typically normal or elevated.
Leukopenia and/or thrombocytopenia may suggest other etiologies, including:

● Bone marrow failure syndromes (eg, aplastic anemia) (see "Acquired aplastic anemia in
children and adolescents")

● Microangiopathic hemolytic anemia (eg, hemolytic uremic syndrome, thrombotic


thrombocytopenic purpura) (see "Overview of hemolytic uremic syndrome in children" and
"Acquired TTP: Clinical manifestations and diagnosis")

● Bone marrow involvement secondary to an active infection or infiltrative disease such as


leukemia (see "Overview of the clinical presentation and diagnosis of acute lymphoblastic
leukemia/lymphoma in children")

As described above, AIHA with concurrent immune thrombocytopenia is referred to as Evans


syndrome. (See 'Evans syndrome' above.)

RBC indices (mean corpuscular volume [MCV] and red cell distribution width) can be helpful in
some cases. Abnormalities of the RBC indices occasionally can be seen:

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● In the presence of a cold or warm agglutinin, the red cells may pass through the automated
counter in small clumps rather than one at a time, resulting in a spuriously increased MCV.
Due to RBC clumping, the reported MCV will sometimes be at nonphysiologic or implausible
levels such as 180 to 250 fL, or may be unreportable. Examination of the peripheral smear
can determine whether this phenomenon is present (picture 1). (See 'Peripheral blood
smear' below and "Macrocytosis/Macrocytic anemia", section on 'Evaluation'.)

● In the presence of large numbers of spherocytes, the mean corpuscular hemoglobin


concentration may be elevated, usually to levels >36 g/dL. This finding is not specific to
AIHA, however, as it also is present in patients with congenital (hereditary) spherocytosis.

Reticulocyte count — The absolute reticulocyte count usually is elevated from the normal value
of 50 to 75 x 103/microL and may reach values as high as 600 to 800 x 103/microL. However, in
one large series, an initial and transient reduction in reticulocyte count was encountered in up to
39 percent of children presenting with AIHA and may reflect a concomitant accelerated immune-
mediated destruction of red blood precursors within the marrow, a temporary suppression of
bone marrow activity secondary to infection, and/or a delayed bone marrow response to the
hemolytic event [1,44]. Reticulocytopenia can occasionally persist and may suggest a more
severe clinical course [45].

Peripheral blood smear — Evaluation of the peripheral blood smear is a critical part of the
patient workup in AIHA:

● In warm AIHA, numerous small spherocytes usually are present (picture 2). A few teardrop-
shaped red cells or red cell fragments (schistocytes) may be present, but spherocytes
should predominate. In the presence of especially severe hemolysis, RBC precursors, such
as normoblasts, may be present in the circulation (picture 3). Scattered areas of RBC
dimers can be seen, but large erythrocyte clumps are not common.

● The presence of considerable numbers of clumped or agglutinated red cells suggests the
presence of a cold-reactive AIHA (picture 1). (See "Evaluation of the peripheral blood
smear".)

● Polychromasia, reflecting an increased number of circulating young red cells (reticulocytes),


is commonly observed when an increased number of reticulocytes are released from the
bone marrow to compensate for accelerated erythrocyte destruction (picture 2 and picture
4).

● Howell-Jolly bodies and nucleated red cells may also be seen on the blood smear, reflecting
accelerated erythropoiesis and/or a prior splenectomy for a hemolytic process (picture 5).

Direct antiglobulin test — The DAT establishes the diagnosis of AIHA. In the DAT, patient
RBCs are washed free of adherent proteins and reacted with a polyspecific and, if positive,

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specific antiserum or monoclonal antibodies prepared against IgG and a fragment of the third
component of complement, C3d. The test identifies the presence of antibodies and/or
complement on the surface of the erythrocyte; results are scored in a semiquantitative manner,
based on the amount of red cell agglutination seen in vitro.

Appropriate characterization of the erythrocyte antibodies includes determination of the isotype,


the presence of complement, thermal reactivity of the antibody, and the binding specificity to
erythrocyte antigens (table 5).

When the DAT is accurately and specifically performed, nearly all patients with warm agglutinin
AIHA will exhibit a positive result with anti-IgG or both anti-IgG and anti-C3 (table 5). The
strength of the DAT positivity is generally correlated with the severity of hemolysis. In <5 percent
of childhood cases, the DAT is negative despite good clinical evidence for the presence of warm
AIHA. In such cases, the amount of IgG on the erythrocyte may be below the threshold for
detection by standard DAT, or the AIHA may be caused by another antibody such as IgA [46,47]
or a warm-reactive IgM [48]. Cases of IgA autoantibodies and warm-reactive IgM autoantibodies
require other methods for detection such as gel cards or flow cytometry, which are available only
at specialized centers. (See "Warm autoimmune hemolytic anemia: Clinical features and
diagnosis".)

For patients with cold agglutinin-mediated AIHA, the DAT is typically positive using anti-C3 and
negative with anti-IgG (table 5). When this occurs, the child's serum should be tested for cold-
reactive IgG Donath-Landsteiner autoantibodies characteristic of paroxysmal cold
hemoglobinuria. The details of Donath-Landsteiner antibody testing are provided in a separate
topic review.

Cold agglutinin titer — The titer of cold agglutinins in the serum is the highest dilution of the
serum sample at which agglutination of red cells in the cold is still seen. Cold agglutinins are
present in virtually all normal individuals in low titer (less than 1 in 40). Patients with
postinfectious cold agglutinin disease (which is the most common cause of cold agglutinins in
children) typically have titers higher than 1 in 256 [6]. In contrast, the titers in adults with cold
agglutinin disease associated with lymphoma are much higher (typically higher than 1 in 2000).
Hemolysis is generally mild if the titer is less than 1 in 512. (See "Cold agglutinin disease",
section on 'Antibody titer and thermal amplitude'.)

Urinalysis and kidney function tests — Urinalysis is performed to assess for hemoglobinuria.
In addition, BUN and creatinine should be obtained as part of the initial evaluation because
hemolysis can cause renal insufficiency.

In patients with intravascular hemolysis, hemoglobin is released into the plasma then cleared
through the kidneys into the urine. When hemoglobinuria is present, urine dipstick testing will
identify the presence of blood but microscopic examination will reveal no RBCs. Chronic

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hemoglobinuria will lead to hemosiderin accumulation in uroepithelial cells, which can be


detected as a positive iron stain of cells in the urinary sediment. In contrast, the urinalysis is
usually normal in patients with extravascular hemolysis (warm-reactive AIHA).

Serum markers of hemolysis — Abnormalities of serum markers of hemolysis can be helpful in


establishing the presence of a hemolytic anemia; however, these tests are not specific for AIHA
and are also abnormal in other hemolytic anemias. (See "Overview of hemolytic anemias in
children".)

● Bilirubin – Total bilirubin is elevated in most patients with AIHA because of accelerated
erythrocyte destruction; it should primarily be in the unconjugated (indirect) form. Elevated
direct (conjugated) bilirubin suggests the presence of intrinsic liver disease. (See
"Classification and causes of jaundice or asymptomatic hyperbilirubinemia", section on
'Disorders associated with conjugated hyperbilirubinemia'.)

● LDH, AST, and ALT – Elevated serum concentrations of LDH and AST are seen in AIHA,
reflecting the presence of hemolysis, especially intravascular hemolysis. ALT and other
hepatic enzymes should not be elevated in AIHA.

● Haptoglobin and plasma free hemoglobin – Serum haptoglobin, which binds free plasma
hemoglobin, will be low to absent in most cases of AIHA. However, haptoglobin is not
synthesized well in young infants; it also is an acute phase reactant, and its concentration
may be elevated in the presence of infection or inflammation [49]. For these reasons, we
suggest not routinely measuring the haptoglobin level as part of the evaluation in patients
<18 months old. Plasma free hemoglobin can be an alternative measure in these scenarios.

DIAGNOSIS

The diagnosis of AIHA is established based on laboratory evidence of hemolysis (anemia with
elevated lactate dehydrogenase [LDH] and indirect bilirubin) and positive direct antiglobulin test
(DAT). The degree of anemia and the reticulocyte response are variable. Diagnostic criteria for
the warm and cold AIHA are provided below. The diagnosis of paroxysmal cold hemoglobinuria
(PCH) is discussed separately. (See "Paroxysmal cold hemoglobinuria", section on 'Diagnosis'.)

Warm AIHA — The diagnosis of warm-reactive AIHA is made when both of the following are
present:

● Hemolytic anemia (anemia, high indirect bilirubin, high LDH, low haptoglobin, and/or
elevated plasma free hemoglobin)
● DAT positive for IgG; complement may or may not also be present on red cells (table 5)

Spherocytes on the peripheral blood smear (picture 6) with reticulocytosis and elevated mean
corpuscular hemoglobin concentration are supportive findings but are not required to establish
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the diagnosis.

Cold AIHA — The diagnosis of cold AIHA is made when both of the following are present:

● Hemolytic anemia (anemia, high indirect bilirubin, high LDH, low haptoglobin, and/or
elevated plasma free hemoglobin)
● DAT positive for bound complement and negative for bound IgG (table 5)

Red cell clumping on the peripheral blood smear (picture 1) and a high cold agglutinin titer are
supportive findings but are not required to establish the diagnosis.

Paroxysmal cold hemoglobinuria — The diagnosis of PCH is discussed separately. (See


"Paroxysmal cold hemoglobinuria", section on 'Diagnosis'.)

FURTHER EVALUATION

Once the diagnosis of AIHA is made, further testing is performed to evaluate for possible
secondary causes and to characterize the AIHA.

Evaluation for secondary causes — All children with newly diagnosed AIHA should, at a
minimum, have screening performed to evaluate for secondary causes, which are present in
more than half of cases [6]. These evaluations should generally be performed at the time of
initial diagnosis prior to initiating treatment. However, the evaluation should be deferred in
children who present with severe life-threatening anemia in whom urgent treatment is warranted.
(See "Autoimmune hemolytic anemia in children: Treatment and outcome", section on 'Severe or
life-threatening anemia'.)

Our suggested initial screening tests for secondary causes of AIHA are provided below.
Additional tests may be warranted based on signs, symptoms, family history, and index of
suspicion. If any abnormalities are detected on the initial screening tests, further evaluation
should be performed to confirm the diagnosis of the suspected secondary condition, since in
some cases, the underlying illness may alter the management or prognosis.

Children who have a negative evaluation for secondary causes and are diagnosed with primary
(idiopathic) AIHA should be rescreened yearly, because in many instances the secondary
disease process does not become apparent until after AIHA is diagnosed.

● All children diagnosed with AIHA – We suggest the following evaluation for secondary
causes in all pediatric patients with AIHA [1,43]:

• Antinuclear antibody with reflex to specific antibodies if positive


• Quantitative immunoglobulins

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• Serologic tests for M. pneumoniae and Epstein-Barr virus (for patients with cold AIHA
only)
• Review of the patient's medications for potential drugs that may induce AIHA (table 4)

● Patients with concerning findings – Additional evaluation may be warranted for patients
with unusual characteristics in the medical history, physical examination, or laboratory
studies that suggest an underlying malignancy, immunodeficiency, or a broader autoimmune
disorder. Concerning findings that may suggest an underlying systemic disorder include
history of recurrent infections, family history of immunodeficiency or autoimmune disorder,
other cytopenias (neutropenia and/or thrombocytopenia), lymphadenopathy, and/or
organomegaly. For these patients, additional evaluation may include the following tests:

• Bone marrow aspiration and biopsy – Evaluation of the bone marrow is not routinely
necessary to establish the diagnosis of AIHA; however, if there are concerning clinical
features, bone marrow aspiration can help exclude a malignant process,
myelodysplasia, marrow infiltration with an infectious agent, or one of the bone marrow
failure syndromes. In primary AIHA, the marrow aspirate usually reveals intense
erythroid hyperplasia (picture 7 and picture 8).

• Chest radiograph, abdominal sonography, or computed tomography scan if indicated


based on the clinical findings. (See "Clinical assessment of the child with suspected
cancer", section on 'Lymphadenopathy' and "Clinical assessment of the child with
suspected cancer", section on 'Mediastinal masses' and "Clinical assessment of the
child with suspected cancer", section on 'Abdominal masses'.)

• Screening for autoimmune lymphoproliferative syndrome by flow cytometry. (See


"Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis",
section on 'Diagnosis'.)

• Lymphocyte subpopulations. (See "Flow cytometry for the diagnosis of primary


immunodeficiencies".)

• HIV testing. (See "Diagnostic testing for HIV infection in infants and children younger
than 18 months" and "Screening and diagnostic testing for HIV infection".)

• Screening for systemic lupus erythematosus with anti-double stranded DNA antibody,
complement component 3 (C3), and complement component 4 (C4). (See "Childhood-
onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis",
section on 'Laboratory findings'.)

Antigenic reactivity — Determination of the antigenic specificity of erythrocyte autoantibodies is


important for two reasons. First, an autoantibody with a "panreactive" pattern (which is the most
common finding) will bind all cells, rendering the identification of fully compatible blood for

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transfusion essentially impossible. Second, identification of the antigenic specificity also can help
predict intravascular lysis caused by complement activation. If the antigen is within the Rhesus
(Rh) complex, complement-mediated intravascular hemolysis is unlikely. The P antigen system,
in contrast, is capable of binding sufficient IgG antibody to allow Donath-Landsteiner antibodies
(IgG antibodies that react with the red cell at reduced temperature but not at 37°C) to fix
complement completely and allow intravascular lysis [50]. (See "Cold agglutinin disease",
section on 'RBC antigens' and "Warm autoimmune hemolytic anemia: Clinical features and
diagnosis".)

Presence of alloantibodies — Patients with AIHA who have been exposed to foreign red blood
cells by previous transfusion or pregnancy should be tested for the presence of coexisting
alloantibodies by performing an antibody screen on the patient's plasma. If alloantibodies are
detected, extended blood phenotyping or genotyping is warranted to help find compatible blood.
Alloantibodies may cause major transfusion reactions in such patients if not discovered. (See
"The incompatible crossmatch", section on 'Alloantibodies'.)

DIFFERENTIAL DIAGNOSIS

The differential diagnosis includes nonimmune causes of hemolytic anemia and other causes of
jaundice and dark urine.

● Other hemolytic anemias – Children who present with AIHA usually have clinical, physical,
and laboratory evidence of hemolytic anemia (anemia with jaundice, elevated lactate
dehydrogenase, and indirect bilirubinemia). The main differential diagnosis includes causes
of nonimmune hemolytic anemia, such as hemoglobinopathies, intrinsic red cell membrane
or enzyme defects, and extrinsic causes of hemolysis (table 6). The direct antiglobulin test
differentiates AIHA from other causes of hemolytic anemia. (See "Overview of hemolytic
anemias in children".)

● Jaundice – The child who presents with icterus and jaundice should be evaluated for the
presence of underlying liver disease and Gilbert syndrome, which is a benign condition
associated with unconjugated hyperbilirubinemia. Measurement of transaminases and
coagulation factors can be useful in assessing hepatic function. In hemolytic anemia, the
indirect (unconjugated) bilirubin fraction is typically elevated. In contrast, an elevated direct
(conjugated) bilirubin level suggests the presence of intrinsic liver disease. (See
"Classification and causes of jaundice or asymptomatic hyperbilirubinemia".)

● Dark urine – Patients with AIHA often present with dark urine caused by intravascular
hemolysis and hemoglobinuria. Other causes of dark urine include concentrated urine,
bilirubin or porphyrin precursors in the urine, hematuria, and myoglobinuria. Hemoglobinuria
can be distinguished from most of these on the basis of the urinalysis (in patients with

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hemoglobinuria, the dipstick test is positive for blood and protein, but the microscopic
analysis does not reveal red blood cells). Myoglobinuria produces similar urinalysis findings
and can be distinguished from hemoglobinemia on the basis of the serum haptoglobin level,
which is typically normal in the absence of hemolysis. (See "Urinalysis in the diagnosis of
kidney disease", section on 'Urine color' and "Clinical manifestations and diagnosis of
rhabdomyolysis", section on 'Urine findings and myoglobinuria'.)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer short,
easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

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

● 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 (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. (See 'Introduction' above.)

● 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). Common secondary
causes of AIHA in children include autoimmune disease (eg, systemic lupus
erythematosus), immunodeficiency, Evans syndrome, malignancy, infection, transplantation,
and drugs. (See 'Classification' above.)

● Most children with AIHA present with signs and symptoms referable to anemia, including
weakness, shortness of breath, dizziness, pallor, jaundice, and/or dark urine. Cardiovascular
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compromise is uncommon unless the hemoglobin concentration is <5 g/dL. (See 'Clinical
presentation' above.)

● The initial laboratory evaluation of the child with AIHA includes all of the following (see
'Initial laboratory evaluation' above):

• Complete blood count with red blood cell (RBC) indices and platelet count

• Reticulocyte count

• Review of the peripheral blood smear

• Direct antiglobulin test (DAT, previously called the direct Coombs test)

• Urinalysis and kidney function tests (blood urea nitrogen and creatinine)

• Serum markers of hemolysis, including indirect bilirubin, lactate dehydrogenase (LDH),


aspartate aminotransferase, and either serum haptoglobin (for patients ≥18 months old)
or plasma free hemoglobin

● The diagnosis of AIHA is established based on laboratory evidence of hemolysis (anemia


with elevated LDH and indirect bilirubin) and positive DAT (see 'Diagnosis' above):

• The diagnosis of warm-reactive AIHA is made if both of the following are present:

- Hemolytic anemia (anemia, high indirect bilirubin, high LDH, low haptoglobin)
- DAT positive for immunoglobulin G (IgG); complement may or may not also be
present on red cells (table 5)

• The diagnosis of cold AIHA is made when both of the following are present:

- Hemolytic anemia (anemia, high indirect bilirubin, high LDH, low haptoglobin)
- DAT positive for bound complement and negative for bound IgG (table 5)

• The diagnosis of paroxysmal cold hemoglobinuria is discussed separately. (See


"Paroxysmal cold hemoglobinuria", section on 'Diagnosis'.)

● Once the diagnosis of AIHA is made, further testing is performed to evaluate for possible
secondary causes and to characterize the AIHA. This includes the following (see 'Further
evaluation' above):

• Antinuclear antibody testing with reflex to specific antibodies if positive

• Quantitative immunoglobulins

• Serologic testing for Mycoplasma pneumoniae and Epstein-Barr virus (in patients with
cold AIHA only)

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• Review of the patient's medications to identify potential drugs that may induce AIHA
(table 4)

• Determination of the antigenic specificity of erythrocyte autoantibodies (see 'Antigenic


reactivity' above)

• Antibody screen to detect alloantibodies in patients who have been exposed to foreign
RBCs by previous transfusion or pregnancy (see 'Presence of alloantibodies' above)

Additional testing is performed in patients with concerning clinical findings (eg, history of
recurrent infections, family history of autoimmune disease or immunodeficiency, other
cytopenias [neutropenia and/or thrombocytopenia], lymphadenopathy, and/or
organomegaly). (See 'Evaluation for secondary causes' above.)

● The differential diagnosis of AIHA includes nonimmune causes of hemolytic anemia (table
6) and other causes of jaundice (eg, liver disease) and dark urine. (See 'Differential
diagnosis' above.)

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Topic 5934 Version 35.0

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