Practice Essentials
Pediatric cold antibody autoimmune hemolytic anemias are generally classified as either Donath-Landsteiner hemolytic anemia (DLHA) or cold agglutinin disease.
DLHA, also known as paroxysmal cold hemoglobinuria, is an intravascular hemolytic anemia caused by a cold-reacting immunoglobulin (Ig). In most cases, the antibody is directed specifically against the P or I antigen on the red blood cell (RBC) surface. Autoantibodies bind in cold temperatures, and fix complement. When warmed to body temperature, complement-mediated red cell lysis occurs, demonstrating the characteristic biphasic nature of the autoantibody.
Most cases are due to polyclonal IgG, but IgM-induced DLHA has been described, [1, 2, 3] and Whipple et al reported a case in which paroxysmal cold hemoglobinuria was caused by an IgA Donath-Landsteiner [DL] antibody. [4]
In contrast to DLHA, cold agglutinin disease is always due to a cold-reacting IgM antibody with anti-I specificity. Cold agglutinin disease is described in a separate Medscape Reference article (see Cold Agglutinin Disease).
As early as 1865, it was known that exposure to cold may result in paroxysms of hemoglobinuria. The etiology of the condition was eventually elucidated, and a diagnostic test was developed. [5] In 1904, Donath and Landsteiner reported their characterization of the causative antibody. [6] The discovery of the DL antibody has permitted DLHA to be distinguished from other causes of hemoglobinuria, [7] with the presence of the antibody being pathognomonic for DLHA.
Signs and symptoms of Donath-Landsteiner hemolytic anemia
The typical signs of DLHA include a sudden onset of hemoglobinuria accompanied by pallor and mild jaundice. [8] Urine color is abnormal and may be described as dark, brown, black, or cola colored.
High fever, chills, back or leg pain, and abdominal cramping often occur. The patient may also have signs and symptoms of the inciting infectious process or complaints related to symptomatic anemia.
Diagnosis and management of Donath-Landsteiner hemolytic anemia
In most cases, DLHA is associated with a sudden onset of hemoglobinuria after exposure to cold temperature. It is important to note, however, that hemoglobinuria may be absent and is not required for diagnosis (see Workup). Furthermore, a history of cold exposure is not always obtained. Symptoms of DLHA usually begin several days after a viral infection, although symptoms of the infection itself may no longer be present.
Laboratory testing is crucial to making the diagnosis of DLHA. Tests include blood typing, complete blood count (CBC), and peripheral blood smear. The peripheral blood smear demonstrates spherocytosis, polychromasia, nucleated red blood cells (RBCs), anisocytosis, and poikilocytosis. [8] Erythrophagocytosis by neutrophils has also been observed. [9]
Blood typing should be performed on all patients even if anemia is mild; hemoglobin may decrease precipitously, requiring transfusion.
The standard method used to definitively identify DLHA is the Donath-Landsteiner bithermic hemolytic test (DL test). In the DL test assay, the patient's serum is incubated with normal RBCs and complement at 0-4°C to allow the early components of complement to be fixed. Subsequently, the specimen is incubated at 37°C (body temperature) to permit the later components of complement to be activated. The membrane attack complex lyses the RBCs. The DL test is positive when the patient's serum demonstrates hemolysis. [10, 11]
Additional tests may be ordered as indicated, including fractionated bilirubin, urinalysis, and tests for specific infections. Secondary (as opposed to idiopathic) DLHA is classically associated with syphilis, but many other infectious conditions have been implicated, including mycoplasmal infection, influenza A, measles, mumps, adenovirus, cytomegalovirus, varicella, and Epstein-Barr virus [EBV]). Sometimes the etiology is unclear.
Treatment of DLHA depends on the severity of the signs and symptoms and the presence of an underlying cause. In children, the condition is usually transient and mild. In such cases, treatment consists of expectant management only. If the anemia is severe or rapidly progressive, however, supportive care with transfusions of packed red blood cells may be warranted. In select moderate or severe cases, medication administration is appropriate (see Treatment). Recurrence of DLHA is rare but has been reported. [12]
Go to Pediatric Chronic Anemia, Anemia of Prematurity, Fanconi Anemia, Pediatric Acute Anemia, and Pediatric Megaloblastic Anemia for complete information on these topics.
Patient education
Teach patients to observe for signs and symptoms of anemia (eg, dyspnea, palpitations, fatigue, pallor) and to observe for signs of hemolysis (eg, jaundice, dark urine, pain). Instruct patients to avoid exposure to extreme cold, if possible. The possibility of hemolysis with strenuous exercise should also be discussed.
Pathophysiology
The autoantibody responsible for Donath-Landsteiner hemolytic anemia (DLHA) is a cold-reacting immunoglobulin known as the DL autoantibody. The DL autoantibody is a biphasic hemolysin capable of causing severe hemolysis even when the titer detected is low. This is due to its ability to detach from lysed RBCs and subsequently bind intact erythrocytes with changes in temperature.
DL antibodies are directed against antigens expressed on the RBC membrane. Most commonly, the target is the P antigen but I antigen specificity and others have been described. [3]
The antibody attaches to RBC surfaces in the peripheral circulation, where temperatures are cooler (< 30°C). After binding, the DL autoantibody activates the complement cascade, resulting in perforation of the RBC membrane (ie, intravascular hemolysis). Complement activation and resulting hemolysis occur only after the RBC travels to an area of warmer temperature (37°C) in the central circulation.
Therefore, the direct antiglobulin test (DAT) results are positive with anti-C3 but negative with anti-IgG or anti-IgM, unless the test is begun at 4°C and subsequently incubated at 37°C (see Workup). [13]
The antibody typically appears days to weeks after the trigger and may persist for months.
Etiology
Donath-Landsteiner hemolytic anemia (DLHA) may be either idiopathic or secondary to an identifiable cause. Historically, the secondary type is most closely associated with late-stage or chronic congenital syphilis. Acute cases are often deemed idiopathic but are generally presumed to be secondary to a preceding viral illness or to an immunization. A definitive causative agent is rarely identified.
Viral infections that have been associated with acute Donath-Landsteiner hemolytic anemia include the following:
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Adenovirus
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Coxsackievirus A9
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Parvovirus
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Influenza A
Respiratory syncytial virus (RSV) has been reported to have caused paroxysmal cold hemoglobinuria in a child, while Leibrandt et al reported the first documented case in which RSV caused the disease in an adult. [14, 15]
Bacterial infections associated with acute DLHA include those caused by the following pathogens [13] :
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Klebsiella pneumonia
Oncologic associations also exist. DLHA has been rarely associated with non-Hodgkin lymphoma [16, 17] and oat cell carcinoma. [18]
Epidemiology
Acute autoimmune hemolytic anemia (AIHA) is relatively rare. [13]
Acute Donath-Landsteiner hemolytic anemia (DLHA) is more common in children than in adults. In children, the DL autoantibody is a common cause of AIHA. However, the condition can occur in patients of all ages, and the diagnosis should be considered when the clinical and laboratory presentations are suggestive of the disorder. [12, 19]
A literature review by Jacobs et al indicated that the epidemiology of DLHA has changed since the mid-20th century. Although currently DLHA generally arises in children, following acute infection, most often upper respiratory infection and gastroenteritis, the investigators reported that between 1950 and 1970, syphilis was present in 53% of patients diagnosed with DLHA. Individuals with DLHA during this 20-year period had a median age of 31 years, with the median age of those whose disease was secondary to syphilis being 42 years. The epidemiology of DLHA is thought to have been impacted by the widespread employment of antitreponemal therapy. [20]
In one review of 52 patients with DL antibodies, the median age was 5 years (range, 1-82 y). [21] Due to under-diagnosis, the true incidence is unknown but DLHA may represent 30-40% of all pediatric AIHA cases cases. [22]
DLHA appears to be more common in males (52 of 77 cases in 3 combined reviews), with a male-to-female ratio of 2.1:1. [23, 24] Estimates differ, however, with the study by Jacobs and colleagues reporting the male-to-female ratio to be nearly equal, at 1.17:1, and the ratio in children aged 5 years or under to be 1.25:1. [20]
No racial or ethnic predilection has been noted.
Prognosis
Most patients with Donath-Landsteiner hemolytic anemia (DLHA) do not require intervention. In rare cases, a severe acute drop in hemoglobin may be life threatening. These children may develop hypovolemic shock and cardiac failure.
Another potential complication of DLHA is acute tubular necrosis due to hemoglobinuria.
In general, however, prognosis in DLHA is very good, with most patients recovering spontaneously within 1 month of disease onset. [25]
Mild chronic hemolytic anemia has been observed in several children with the possibility of recurrence on exposure to cold or with illness. [12]
Analysis of cases of recurrent DLHA suggests that repeated episodes of hemolysis may be likely when the child has a DL antibody to an antigen other than anti-P. [26, 3]
Chronic syphilis-associated DLHA resolves with appropriate treatment of the underlying disease.
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Blood smear showing spherocytosis, polychromatophilia, and erythrophagocytosis by neutrophils.
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Blood smear showing spherocytosis, polychromatophilia, and erythrophagocytosis by neutrophils.
