A rare haematological disorder in a Sudanese child: Evans syndrome, case report and literature review

Abstract

Evans syndrome is a condition in which autoimmune-mediated red blood cells and platelet destruction happens consecutively. It may be associated with a reduction in neutrophil count as a result of immune neutropenia. No sex preference is known and it presents in all ages and any ethnic cohort. Generally, this syndrome tends to be chronic and is characterised by remission and exacerbation. We document a case of the immune-mediated disease associated with Epstein-Barr virus infection in an 8-year-old boy from eastern Sudan who presented with both immune thrombocytopenia purpura and autoimmune haemolytic anaemia. Complete blood count and peripheral blood picture revealed features consistent with immune haemolytic anaemia (rouleaux formation and spherocytes) and thrombocytopenia. Direct anti-human globulin test and indirect anti-human globulin test were positive. Evans syndrome is a potentially life-threatening condition due to the concomitant existence with antiplatelet and anti-erythrocyte antibodies distinguished by a positive antiglobulin test and possibly linked to other autoimmune or lymphoproliferative diseases.

INTRODUCTION

Evans syndrome was professed early in 1951. It is an immunological anomaly brought about by the coexistence of autoimmune haemolytic anaemia (AIHA) and immune thrombocytopenia purpura (ITP) and/or immune neutropenia without any overt disorder [1]. It is diagnosed by ruling out other disproving conditions [2]. Evans syndrome is overwhelmingly linked to diseases such as systemic lupus erythematosus (SLE), lymphoproliferative disorders or primary immune deficiencies [3]. It is a rare disorder, as it is formerly reported in 0.8%-3.7% of the patients presenting with combined AIHA and ITP at the onset [2]. In early life, it could demonstrate an autoimmune lymphoproliferative syndrome (ALPS) that is attached to genetic disorders of lymphocytes in the Fas apoptotic pathway [4]. Even though a disturbance of immune regulation occurs, the exact pathological mechanism is unclear. Moreover, after surveying relevant reports, there is proof to consolidate alterations in both cell-mediated and antibody-mediated immunity in Evans syndrome [3]. Regarding treatment, first-line management is usually corticosteroids and/or intravenous immunoglobulin (IVIG) with several patients responding; however, recommencement is frequent. Choices for second-line management encompass immunosuppressive drugs, notably cyclosporine or mycophenolate mofetil, vincristine, danazol or a combination of these agents. Lately, a number of patients have received rituximab, which triggers recovery in most of them, although sustained for less than 12 months and the long-term effects in children are unclear. Splenectomy is possibly regarded despite long-term improvements that are less common than in uncomplicated ITP. In severe and refractory cases, stem cell transplantation shows the only chance of a curative route [5].

CASE REPORT

An 8-year-old Sudanese male child presented with low-grade intermittent fever associated with skin itching for 3 months duration. He had multiple episodes of bleeding manifestations (ecchymosis) throughout the body. The patient had neither a history of congenital bleeding tendencies nor familial haematologic abnormalities. He has no previously known chronic illness, drug allergies or previous surgeries. The patient’s developmental history conformed to his age and vaccination is up to date.

On examination, the child was not icteric, cyanosed or dysmorphic. The body temperature was 37.6°C. Ear, nose and throat examination was unremarkable. He had no skin rash, lymphadenopathy, sore throat or organomegaly with normal cardiopulmonary examination, and normal sensation and reflexes. The coagulation laboratory findings revealed normal prothrombin time, partial thromboplastin time and thrombin time. Complete blood count (CBC), carried out several times, showed haemoglobin ranging between 8.7 and 10.7 g/dl, associated with thrombocytopenia (platelet count ranging from 46 to 71 × 10⁹/l). The peripheral blood picture showed hypochromia, Rouleaux formation and dominant spherocytes (Figure 1). Reticulocyte count was high and the reticulocyte index was indicative of appropriate erythropoietic activity. Urinalysis was clear with no evidence of haemosiderinuria. Serum bilirubin was also high. Subsequently, the child was diagnosed with Evans syndrome [direct antiglobulin test (DAT) was positive], which was consistent with the autoimmune haemolytic condition after excluding the other causes. For more verification, bone marrow aspiration highlighted a mild hypercellular marrow with active micronormoblast maturation, active ordered granulopoiesis with eosinophilia, increased megakaryocytes with juvenile forms, no abnormal cells, no dysplastic cells and no Leishman-Donovani bodies were noted (Figure 2). Unfortunately, the marrow iron content was not evaluated. The results of viral screening, iron profile, immunological and biochemical tests are shown in Tables 1 and 2. Due to the presence of a positive DAT, features of immune haemolytic anaemia and thrombocytopenia, we diagnosed the child with Evans syndrome. Our patient responded well to the initial management of steroids (prednisolone: 1-2 mg/kg/day). Follow-up CBC after 1 week exhibited increases in circulating platelet numbers (128 × 10⁹/l) and haemoglobin levels (12.2 g/dl).

Figure 1.

Peripheral blood smear showing marked anisocytosis, well-defined hypochromia, thrombocytopenia, polychromasia, spherocytes and occasional nucleated erythrocyte precursor in the field (40×).

Figure 2.

Bone marrow aspiration smear manifest erythroid hyperplasia and many micronormoblasts (40×, MGG stain).

Table 1.

Laboratory findings of the case.

Test	Patient results	Reference interval
White blood cells ×109/l	7.6	4-10
Red blood cells ×−1012/l	4.71	3.5-5.5
Haemoglobin g/dl	10.7	12-16
Haematocrit %	32.7	35-47
Mean corpuscular volume fl	69.4	78-98
Mean corpuscular haemoglobin pg	22.7	26-35
Mean corpuscular haemoglobin concentration %	32.7	30-36
Red cell distribution width-CV%	15.9	11.5-14.5
Red cell distribution width-I %	238.3	> 220 (IDA)
		< 220 (BTT)
Absolute lymphocyte count × 109/l	2.38	6-8.3
Absolute neutrophil count × 109/l	2.45	2-6.0
Platelet count × 109/l	71	150-400
Mean platelet volume fl	10.3	7.5-10.4
Platelet distribution width fl	17.1	9-17
Platelet-large cell ratio %	31.2	15-35
Reticulocyte count %	8.5	0.5-3%
Absolute reticulocyte count × 109 × /l	400.4	50-100
Corrected reticulocyte count %	6.2	Up to 3%
Reticulocyte production index	3.1	≥3
Red blood cell morphology	Abnormal	-
Microcytosis	Mild	-
Spherocytes	Many	-
Rouleaux formation	Slight	-
Lactate dehydrogenase U/l	843	110-240
Bilirubin total mg/dl	3.6	< 1.1
Bilirubin direct mg/dl	0.28	< 0.3
Total protein g/dl	6.5	6.6-8.3
Albumin g/dl	3.2	3.5-5.0
Alanine transaminase U/l	19	Up to 41
Aspartate transaminase U/l	33	Up to 40
Alkaline phosphatase U/l	266	< 300
Hepatitis C virus screening	Negative	-
Hepatitis B virus screening	Negative	-
Human immunodeficiency virus screening	Negative	-
Serum iron μg/dl	24.1	50-175
Total iron binding capacity μg/dl	454.2	100-425
Ferritin μg/l	12.8	7-200
Transferrin saturation %	5.3	15-50
Direct anti-human test (DAT) & indirect anti-human test	Positive	-
>Rheumatoid factor	Negative	-
Antinuclear factor antibody (ANA)	Negative	-
Anti-double stranded DNA (dsDNA)	Negative	-
Anti-Sjogren syndrome-related antigen A (Ro)	Negative	-
Anti-Sjogren syndrome-related antigen B (La)	Negative	-

Table 2.

Epstein-Barr virus (EBV) profile.

Test	Result
EBV-IgG
Viral capsid antigen gp 125	Strong positive
Viral capsid antigen p 19	Strong positive
Epstein-Barr nuclear antigen-1	Strong positive
P22	Positive
Early antigen-D	Positive
EBV-IgM
Viral capsid antigen gp 125	Negative
Viral capsid antigen p 19	Negative
Epstein-Barr nuclear antigen-1	Negative

EBV = Epstein-Barr virus.

DISCUSSION

Robert Evans was the first to identify the combination between ITP and AIHA [1], which is currently known as the autoimmune destruction of haematologic blood cells after ruling out other diagnoses [6]. The disease spectrum has been expanded, notably in children, and there is an augmented clue to propose that Evans syndrome commutates a situation of intimate immune dysregulation [3]. Only the lineaments of immune haemolytic anaemia and thrombocytopenia have been interpreted. The subtle incidence of Evans syndrome remains unknown and the differential diagnosis still implies conditions such as thrombotic thrombocytopenic purpura, chronic cold agglutinin disease and other reasons for acquired or congenital haemolytic anaemia as well as drug-induced haemolytic anaemia and/or thrombocytopenia [6]. To avert any misdiagnosis, careful examination of the blood film and DAT are of paramount significance in the case of AIHA and ITP [3]. Generally, in clinical practice, the absolute case of Evans syndrome may demonstrate a diversity of underlying diseases or conditions which possibly impact on both outcome and management. Consequently, it is important to consider that Evans syndrome should not be considered an idiopathic state, but fairly classified as primary (idiopathic) or secondary (associated with an underlying condition) syndrome [7].

Our patient was precluded from having drug-induced haemolytic anaemia and/or thrombocytopenia, the other causes of congenital and acquired haemolytic anaemia and any of the other differential diagnoses of Evans syndrome. Evans syndrome developed by our patient is considered (as far as our knowledge) as the first case reported in Sudan and may raise the existence of this syndrome in the Sudanese community. All laboratory investigations, including bone marrow aspiration, were conducted before prescribing steroid treatment to verify active megakaryopoiesis and exclude the hyporegenerative thrombocytopenia caused by erythroid hypercellularity [8]. Peripheral blood microcytosis and micronormoblastic erythropoiesis seen in our patient could be brought about by iron deficiency (24.1 μg/dl) which is recognised as a feature consistent with ITP [9]. As a further matter, the iron parameter findings considerably are proportionate with iron deficiency anaemia. Other discriminating indices obtained from automated cell counters, such as RDW (> 14) and RDWI (> 220), discriminate iron deficiency anaemia from any other hypochromic conditions [10].

CBC verifies the existence of cytopenias and thin blood smear was carried out to describe the manifestation of AIHA (spherocytes and polychromasia) and to rule out other confounding causes (malignancies and angiopathic haemolytic anaemia). Importantly, a feature of haemolysis should be explored by reticulocytosis, unconjugated hyperbilirubinaemia, decreased or absent haptoglobin and elevated lactate dehydrogenase enzyme. The unusual features of haemolytic anaemia may also be present. Lymphadenopathy or organomegaly are sometimes associated with chronic and, in some patients, possibly apparent during the course of severe aggravation [2]. A polyspecific reagent used for DAT is used to determine the likely type of AIHA (warm or cold) which tends to be warm AIHA in Evans syndrome. However, the mainstay of diagnosis remains the monospecific DAT, which is more confirmative; hence, it has also been used in this case. This technique is positive in 99% of the cases with warm-type AIHA. The indirect antiglobulin test is also positive in 52%-83% of the cases. Investigations for antineutrophil and antiplatelet antibodies have elucidated diverse results [11]. Due to shortage of facilities, haemoglobin electrophoresis was not carried out.

The antibodies in ITP are IgG autoantibodies and are excited against platelet-derived membrane glycoproteins; one of the most common goals is the GPIIb/IIIa glycoprotein (fibrinogen-binding site). These antibodies lead to premature elimination and a shortened platelet lifespan. The exact pathogenesis and evolution of these antibodies are dimly understood. However, equally congenital and acquired mechanisms are supposed to contribute. A number of contiguous and systemic diseases have been connected to the consistency of autoantibodies and the development of this clinical anomaly [11].

Furthermore, other autoimmune cases, especially SLE and Sjogren syndrome were ruled out by estimating the ANA, dsDNA, anti-Sjogren syndrome A, anti-Sjogren syndrome B and rheumatoid factors. Therefore, the gauge of peripheral T-cells’ subsets by using flow cytometry is mandatory in the case of Evans syndrome to exclude ALPS, which gives a dual negative (CD4⁻/CD8⁻, CD3⁺, TCRαβ⁺) for T-cells [10]. Together ITP and AIHA have been approached to develop arterial or venous thrombosis [12]. Steroid therapy (corticosteroids) remains the backbone for treatment of the severe symptomatic blood cytopenias, with the perfect principled results. It has been previously reported that prednisolone at a daily dose of 1-2 mg/kg yields a good response. However, there was a lack of recovery on dose reduction and/or acute viral infection. With regard to toxicity, the most common therapy used is IVIG. The subsequent option of treatment incorporates immunosuppressive agents (cyclosporine), danazol, chemotherapy (cyclophosphamide) and monoclonal antibodies (rituximab) [2].

CONFLICTS OF INTEREST

The authors declare no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

FUNDING

The authors received no financial support for the research, authorship and/or publication of this article.

ETHICAL APPROVAL

Signed informed consent for participation and publication of medical details were obtained from the parents of the child. Ethical approval has been granted from Port Sudan Teaching Hospital. Confidentiality was ensured at all stages.