Three Cases of Autoimmune Hemolytic Anemia following Primary Varicella Infection and Vaccination: Possible Pathogenesis in the Context of Current Information

Case Presentation

Ann Hematol Oncol. 2019; 6(5): 1250.

Three Cases of Autoimmune Hemolytic Anemia following Primary Varicella Infection and Vaccination: Possible Pathogenesis in the Context of Current Information

Biçakci Z1*, Bozkurt HB2 and Olcay L3

1Association Professor, Department of Pediatric Hematology and Oncology, Medicine Faculty, Kafkas University, Kars, Turkey

2Asistant Professor, Department of Pediatrics, Medicine Faculty, Kafkas University, Kars, Turkey

3Professor, Department of Pediatric Hematology and Oncology, Medicine Faculty, Baskent University, Ankara Turkey

*Corresponding author: Zafer Biçakci, Association Professor, Department of Pediatric Hematology and Oncology, Kafkas University, Kars, Turkey, Fax:+904742251430; GSM:+905325137271; E-mail:zaferbicakcib@yahoo.com.tr

Received: March 20, 2019; Accepted: April 26, 2019;Published: May 03, 2019

Abstract

The direct complement-mediated destruction of erythrocytes coated with auto antibodies mainly occurs in the circulation and the liver in autoimmune hemolytic anemia while the antibody-dependent cellular cytotoxicity (NK), cytotoxicity (CD8+ T) and phagocytosis primarily occur in the spleen and lymphoid organs. Since primary varicella infection causes a decrease in the CD4+/CD8+ ratio, CD4+ T cells specific to varicella mainly appear in the Th1 type and produce high levels of interferon-γ (IFN-γ). Th1 cells that produce IFN-γ play a pathogenic role in many autoimmune disorders. IFNγ stimulates the conversion to IgG isotypes and also increases phagocytic functions through the Fcγ receptor of macrophages. We present three patients with autoimmune hemolytic anemia and thrombocytopenia developing secondary to varicella infection and vaccination in a manner similar to Evans syndrome, and discuss the possible pathogenesis in the context of current information. Direct antiglobulin test (IgG and C3d)-positive autoimmune hemolytic anemia and thrombocytopenia were present after primary varicella infection in two of our cases and after varicella vaccination in one case. Growth retardation, decreased CD4+/CD8+ lymphocyte ratio, diffuse large B cell lymphoma and hypergammaglobulinemia were present in case 1; cerebral palsy, growth and development retardation, and decreased CD4+/CD8>sup>+

lymphocyte ratio in case 2; and hypergammaglobulinemia in case 3. Clarifying the pathogenesis of autoimmune hemolytic anemia could facilitate the development of new treatment approaches for this disorder with high morbidity and mortality. Decreasing the effect of INF-γ, which plays an important role in the pathogenesis of autoimmune hemolytic anemia, could be one of these approaches.

Keywords: Vaccine; Autoimmune hemolytic anemia; Varicella; Regulator t lymphocyte deficiency

Introduction

Childhood autoimmune hemolytic anemia is a rare and potentially life-threatening disease. Antibodies developing against erythrocytes may lead to early destruction and the development of the disorder. Autoimmune hemolytic anemia can be divided into two as primary and secondary [1]. The development of autoimmune hemolytic anemia requires a general disturbance due to deterioration of the differentiation between self and non-self in the immune system. T-cell mediation has been shown to have a crucial role in the regulation of the humoral immune system [2].

Varicella is a benign disease with a rash and usually affects children. Autoimmune hemolytic anemia is a rare complication [3]. Although primary immunodeficiency and varicella infection have been reported after varicella vaccination, primary immunodeficiency, varicella infection and autoimmune hemolytic anemia after varicella vaccination has been reported in only a single patient [4,5]. The varicella-specific CD4+T lymphocytes that appear during primary infection are predominantly of the T helper 1 (Th1) type and produce high levels of interferon-γ (IFN-γ) supporting the clonal growth of varicella-specific T lymphocytes [6].

Activation of helper CD4+ T lymphocytes is important regarding the autoimmune pathology in rats deficient in IL-2. Th1 lymphocytes producing IFN-γ play a pathogenic role in many autoimmune disorders. IFN-γ stimulates the conversion to IgG isotypes and increases the phagocytic function of macrophages [7].

A decrease in the CD4+/CD8+ lymphocyte ratio in the peripheral blood has been reported in patients with Evans syndrome [8]. A significant increase in the percentage of CD8+ lymphocytes and a significant decrease in the percentage of CD4+ lymphocytes with a decrease in the CD4+/CD8+ ratio has been reported in primary varicella infection [9]. We found a decreased CD4+/CD8+ lymphocyte ratio in two of our cases. This may indicate an imbalance of the immunoregulatory cells (CD4+ T lymphocytes) causing irregular cytokine production. The numerical and functional deficiency of CD4+ T lymphocytes due to varicella could therefore trigger autoimmune hemolytic anemia.

We present three patients with autoimmune hemolytic anemia and thrombocytopenia developing in a manner similar to Evans syndrome secondary to varicella infection and vaccination, and discuss the possible pathogenesis in the context of current information.

Case 1

A 14-month-old female patient was administered a measlesmumps- rubella and varicella vaccine at the age of one. She suffered from a varicella infection one month after the vaccine was administered and recovered afterwards. She presented to another hospital due to a widespread rash on her body a month after the varicella infection. The IgA, IgM, IgG and IgE levels were normal but the CD3+ CD4+ lymphocyte value was low and CD3+ CD8+ lymphocyte value high in tests conducted with a suspicion of immunodeficiency when she was ten months old (Table 1). She was referred to our hospital for the investigation of anemia and thrombocytopenia etiology. We found out that her sister and brother had died with high fever when two months old. The physical examination revealed body measurements (height, body weight) under 3% and widespread petechial lesions and varicella marks on the extremities, trunk and back together with splenomegaly (the spleen was 2 cm below the costal margin). The hemogram and other laboratory findings are presented in (Table 1). The peripheral smear revealed 18% atypical lymphocytes, 51% neutrophils, 2% monocytes, 8% rods, 16% lymphocytes, and 5% normoblasts together with macrocytosis, polychromacia and microspherocyte formation in the erythrocytes. The viral (hepatitis A,B,C and etc.) and bacterial serology was negative. Varicella zoster IgM was (-), varicella zoster IgG (+), ANA (-), and Anti dsDNA (-). C3 and C4 levels were normal. The diagnosis was Evans syndrome/ immune hemolytic anemia and 2 mg/kg of prednisolone was started together with an erythrocyte suspension transfusion. The platelets increased to 266 x109/L during follow-up. However, the steroids were discontinued when the patient developed bronchopneumonia on the third day of steroid treatment and an antibiotic (meropenem) was started. Inappropriate anti-diuretic hormone secretion syndrome then developed. Fluid restriction was started with sodium deficit treatment to increase sodium by 10 mEq. Intravenous (iv) Immunoglobulin G (IgG) at a dose of 800 mg/kg was started when the thrombocytopenia recurred. The platelets again increased to normal levels. Areas with increased density were noted in the left lung on chest x-ray (Figure 1). Thoracic computed tomography ordered on the suspicion of a mass revealed a peripheral nodular lesion 17x11 mm in size with its base on the pleura at the level of the left lower lobe superior segment (Figure 2). The patient underwent a pulmonary lymph node biopsy. She was immunohistochemically diagnosed with diffuse large B cell lymphoma. Meanwhile, the patient developed myoclonic seizures followed 5 days later by herpetic keratitis. Meningoencephalitis was considered and acyclovir administered for a month. The seizures were only controlled with multiple antiepileptics. The inappropriate anti-diuretic hormone secretion syndrome, immune hemolytic anemia and thrombocytopenia resolved with medical treatment. The patient’s swallowing function was disrupted after the treatment and feeding via gastrostomy was started. The patient suffered frequent infections treated at the hospital and the positive direct and indirect antiglobulin test results continued. However, a transfusion was not required. The patient did not come for regular follow-up after chemotherapy and was found to have died one year later at home. Informed consent was received from the family for publication.