Mixed autoimmune hemolytic anemia in a 2-year-old girl

Asim Abdullah Alamri; Abdulmohsen AlSubhi; Ibrahim Bali; Abdullah Alsarrani; Arwa AlHujaili; Ahmad Tarwah

doi:10.4103/joah.joah_95_22

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CASE REPORT

Year : 2023 | Volume : 14 | Issue : 2 | Page : 167-170

Mixed autoimmune hemolytic anemia in a 2-year-old girl

Asim Abdullah Alamri¹, Abdulmohsen AlSubhi², Ibrahim Bali³, Abdullah Alsarrani⁴, Arwa AlHujaili², Ahmad Tarwah¹
¹ Department of Pediatric, Pediatric Hematology and Oncology Unit, King Salman Medical City, Taibah University, Madinah, Saudi Arabia
² Department of Pediatric, King Salman Medical City, Taibah University, Madinah, Saudi Arabia
³ Department of Pediatric, Pediatric Endocrinology Unit, King Salman Medical City, w, Saudi Arabia
⁴ Department of Family and Community Medicine, College of Medicine, Taibah University, Madinah, Saudi Arabia

Date of Submission	27-Oct-2022
Date of Decision	26-Jan-2023
Date of Acceptance	06-Feb-2023
Date of Web Publication	27-Jul-2023

Correspondence Address:
Dr. Asim Abdullah Alamri
Department of Pediatric, Pediatric Hematology and Oncology Unit, King Salman Medical City, Madinah
Saudi Arabia

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/joah.joah_95_22

Abstract

Immune hemolytic anemia is diagnosed when it exhibits the clinical symptoms and laboratory findings of hemolytic anemia, such as pallor, jaundice, anemia, high indirect bilirubin, increased reticulocyte count, and a positive direct antiglobulin test. Depending on the type of antigenic stimulation, this condition can be divided into three distinct subtypes: (1) autoimmune hemolytic anemia (AIHA), (2) alloimmune hemolysis, and (3) drug-induced hemolysis. In addition, the thermal amplitude of autoantibodies is used to categorize AIHA as either a warm (most common), cold, or mixed (rare) subtype. Mixed autoimmune hemolytic anemia is diagnosed when both warm and cold autoantibodies are present. Here, we report a case of a mixed AIHA in a 2-year-old girl who responded well to corticosteroids. Due to the rarity of the condition and the lack of rigorous diagnostic criteria, it is crucial to report this case.

Keywords: Complement, corticosteroids, mixed autoimmune hemolytic anemia

How to cite this article:
Alamri AA, AlSubhi A, Bali I, Alsarrani A, AlHujaili A, Tarwah A. Mixed autoimmune hemolytic anemia in a 2-year-old girl. J Appl Hematol 2023;14:167-70

How to cite this URL:
Alamri AA, AlSubhi A, Bali I, Alsarrani A, AlHujaili A, Tarwah A. Mixed autoimmune hemolytic anemia in a 2-year-old girl. J Appl Hematol [serial online] 2023 [cited 2023 Oct 2];14:167-70. Available from: https://www.jahjournal.org/text.asp?2023/14/2/167/382418

Introduction

Autoimmune hemolytic anemia (AIHA) is an uncommon type of hemolytic anemia that is caused by autoantibodies that target antigens on the surface of the patient's red blood cells.^[1]

The incidence of AIHA is approximately 0.2/100,000 in adolescents between 11 and 20 years. However, it is a rare cause of hemolytic anemia in children. The occurrence of mixed types of AIHA is extremely rare with <5% of all cases of AIHA reported.^[2],[3]

The classification of AIHA is determined by the temperature of the erythrocyte-autoantibody reaction.^[1] This reaction can result in two distinct subtypes.^[1] First, the warm type is an IgG antibody and the most common subtype that appears in children aged 2 and older.^[1] The reaction between the erythrocytes and autoantibodies that is specific for the warm type generates no agglutination in vitro and only needs a temperature of 37°C or higher for the reaction to happen.^[1] Second, the cold type is different from the worm type as it belongs to IgM antibodies and agglutination in vitro.^[1] For the erythrocyte-autoantibody interaction to occur in the cold type, complement activation and temperatures below 37°C are also required.^[1] Mixed autoimmune hemolytic anemia (MAIHA), on other hand, is a specific type of AIHA that combines a mix of features of the other AIHA types with the agglutination that can occur at a temperature≥ 30°C.^[4]

In addition to the thermal amplitude characteristics that distinguish MAIHA from other subtypes of AIHA, the erythrocyte-autoantibody reaction specific for MAIHA does not require complement activation, although it can occur.^[5] Diagnosis of MAIHA can be made by the monospecific direct antiglobulin test (DAT), which reveals cold agglutination of IgG autoantibodies and complement C3d.^[6] In addition, MAIHA can be either primary or secondary to drugs, infections, lymphoproliferative syndromes, or autoimmune diseases^[4],[5] Moreover, MAIHA responds to steroids and typically has a long-term course with a high risk of relapse.^[3],[7]

Case Report

A previously healthy female toddler was admitted to the emergency department with fever, vomiting, and yellowish discoloration of the eyes for 2 days. The patient had never experienced bleeding from any orifice. There was no history of a change in the color of urine or feces, as well as no history of a skin rash or abnormal movement. In addition, the patient had no prior travel or hospitalization. She had also never received a blood transfusion before her admission. Furthermore, there was no family history of hematological disease. The parents were consanguineous. Examinations revealed pallor, fever, tachycardia, 3/6 systolic murmur, icterus, and a palpable spleen 3 cm below the left costal margin. Other examination findings were unremarkable.

The white blood cell count was in the normal range while the platelet count was low with a level of 65,000 according to the peripheral blood smear. Complete blood counts showed severe anemia (Hb = 2.1 g/dl), evidence of macrocytosis (mean corpuscular volume = 104.1 fl), and increases in mean corpuscular hemoglobin (40.9 pg.) and mean corpuscular hemoglobin concentration (39.7 g/dl) as well. Red blood cells were seen to be agglutinated in a peripheral smear, and they were separated upon warming the slides [Figure 1]. The smear showed an anisopikilocytosis with macrocytic predominance, hypochromic, erythrophagocytosis, and nucleated red blood cells. No malarial disease was present. The percentage of reticulocytes was 29%, and lactate dehydrogenase (LDH) was 2324. The DAT resulted in a robust positive. Regarding liver function tests, the patient's total serum bilirubin (TSB) was 6.2 mg/dl, with a 3.2 mg/dl indirect fraction, and normal enzyme levels. A working diagnosis of AIHA was made based on the clinical picture and the laboratory results.

Figure 1: Patient's peripheral blood smear showed red blood cell agglutination (white circles)

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The significant agglutination of red blood cells made grouping and cross-matching difficult. However, transfusions with the “least incompatible” packed red blood cells were given. Additional testing, including a mono-specific DAT, an indirect antiglobulin test (IAT), and antibody screening, was performed to validate our diagnosis. While IAT was positive at 4°C and negative at 22°C and 37°C, monospecific DAT demonstrated both anti-IgG and anti-C3d antibodies. The findings above suggested a mixed warm–cold form of AIHA.

Hepatitis B surface Ag and hepatitis C virus antibody, Epstein–Barr virus, cytomegalovirus, and antinuclear antibodies screening were negative. Immunoglobulin levels were normal for her age. Splenomegaly was documented by abdominal ultrasound with no other positive finding.

The patient was started on intravenous antibiotics and given the least incompatible packed red blood cells preceded by diphenhydramine and hydrocortisone 5 mg/kg in addition to methylprednisolone 2 mg/kg. Due to acute hemolysis, three blood transfusions were given in the following 3 days, and her hemoglobin level rose to 4 g/dl. A 3-day course of intravenous immunoglobulin at 0.4 g/kg/dose was initiated. Her hemoglobin recovered and reached 9 g/dl on day 9 of treatment, the hepatosplenomegaly regressed, and reticulocyte counts started to normalize concerning TSB and LDH on day 6 after admission. When the blood culture was reported negative, the antibiotic was discontinued. Intravenous methylprednisolone was changed to oral prednisolone with the same dose (2 mg/kg/day).

The patient's hemoglobin, reticulocytes, and bilirubin levels returned to normal after 1 month of prednisolone withdrawal, which was tapered off over 3 months. The DAT became negative following the withdrawal, and the patient has been in remission for 3 months at the time this case is reported.

Discussion

AIHA occurs when the immune system abnormally identifies the normal reticulocytes as foreign antigens, resulting in hemolysis.^[8] It was described for the first time in 1985.^[9] While AIHA can develop in response to a disease that disrupts one's immune system function, it can also emerge spontaneously in the absence of any illness.^[8] Nevertheless, the current medical literature and guidelines do not offer reliable diagnostic criteria for AIHA and its subtypes.^[8] “Diagnosis of AIHA is based on evidence of hemolytic anemia consisting of anemia, jaundice, splenomegaly, reticulocytosis, raised serum bilirubin, and a positive DAT.”^[10] The latter, DAT, is one of the most important diagnostic indicators of AIHA because it is positive in nearly all (95%) patients with AIHA.^[9],[11]

Of those with AIHA who show positive DAT results, IgG autoantibodies only, or a combination of IgG and C3 appear in nearly 7 out of 10 of the patients, whereas only C3 appears in nearly 15% of the cases.^[9],[11] As the IgM autoantibodies detach from the reticulocytes after interacting with C3, its identification in vitro is uncommon.^[11] In previous research of 43 AIHA patients, five cases of mixed AIHA with IgG, IgM, IgA, and C3, as well as two cases of mixed AIHA with only IgG and IgM autoantibodies, were identified.^[4],[11] Since IgG antibodies and complement are responsible for extravascular hemolysis, cold antibodies should be considered while performing DAT on patients with this condition.^[11]

Due to the different management plans, the diagnosis of mixed AIHA should only be made after it has been differentiated from a specific type of warm AIHA that has negligible cold agglutinins and cold hemagglutinin disease^[6],[11] The differentiation between cold and warm antibodies is crucial and usually done through performing an IAT in conjunction with a monospecific DAT.^[11],[12] Because alloantibodies are prevalent in AIHA patients, a comprehensive history and laboratory examination are required to detect them and thus, reduce the risk of hyperhemolysis.^[11] Doing so also helps determine whether AIHA is primary or secondary and hence a patient is treated accordingly. Our patient was evaluated using the same diagnostic standards. Her laboratory findings revealed a positive DAT and no alloantibodies after extended phenotyping.

Mixed AIHA is usually treated with corticosteroids and assuring patients to avoid colds, while secondary AIHA is treated according to the condition that causes it.^[11],[13] Blood transfusion should not be based on the laboratory results of the patient but rather than the clinical condition of the patient and only be given to those with life-threatening conditions or who have undergone careful evaluation.^[11] In addition to the likelihood of alloimmunization and rapid hemolysis that might be caused by the autoantibodies after the patient receives a blood transfusion, there is a considerable possibility for slow erythropoiesis following blood transfusion.^[4],[11] Our patient was treated with the same approach. Corticosteroid was used as first-line therapy. Moreover, four blood transfusions were administered as the patient was in a life-threatening condition. However, refractory and relapse are one of the complications of mixed AIHA.^[11] Patients who have not responded to standard treatments may benefit from receiving rituximab therapy in conjunction with splenectomy.^{[11],[14],[15]}

Conclusion

MAIHA is extremely rare in the pediatric age group and well-responsive to steroids. Due to different management approaches, both warm and cold AIHA as well as secondary causes should be excluded. In cases of severe anemia with hemodynamic instability, blood transfusion with the least incompatible blood should be considered.

Acknowledgment of Informed Consent

The authors acknowledge that informed consent for the publication of this case was obtained from the legal guardian of the patient. The legal guardian provided consent, demonstrating their understanding of the purpose, risks, benefits, and confidentiality aspects associated with the publication.

Furthermore, the Institutional Review Board (IRB) at King Salman Medical City in Madinah, Saudi Arabia, carefully reviewed the study and determined that it meets the necessary ethical standards while safeguarding patient privacy. The study was assigned case number (IRB22-055) by the IRB, signifying their comprehensive evaluation of the ethical considerations involved.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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