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 Table of Contents  
Year : 2014  |  Volume : 39  |  Issue : 1  |  Page : 20-24

Spectrum and outcome of autoimmune hemolytic anemia in children: single-center experience in 10 years

Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission28-Aug-2013
Date of Acceptance28-Oct-2013
Date of Web Publication29-Jan-2014

Correspondence Address:
Mohammed M Al-Tawil
Department of Pediatrics, Faculty of Medicine, Ain Shams University, Ramsis St. Abbasseya, Cairo, 11566
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1110-1067.124840

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Background Autoimmune hemolytic anemia (AIHA) is a rare disease in children. Little is known about its spectrum and outcome. The objective of this study was to analyze the clinical and hematological presentation, treatment response, and disease outcome in a cohort of children and adolescents whose initial presentation was acute AIHA.
Patients and methods This was a retrospective analysis of children who presented with acute AIHA over 10 years. These cases presented to the Hematology Department, Children Hospital, Ain Shams University, Cairo, Egypt, from 2002 to 2012. Thirty-two children and adolescents were assessed for initial presentation, treatment received, and its response and disease outcome.
Results In all, 78% of the patients were females. All presented with pallor, 81% with jaundice, and 34% with concomitant acute nonspecific febrile illness. Positive serology against the Epstein-Barr virus, cytomegalovirus, or mycoplasma was shown by 37.5% of the patients. Hepatosplenomegaly on initial presentation or evolving during the first year occurred in 53% of the patients. The direct antiglobulin test was negative in 6% and reticulocytopenia occurred in 12% of the patients. Ninety-four percent of patients received corticosteroids as initial therapy and 28% needed additional treatment subsequently. Complete remission (CR) at 1 month was achieved in 46.9% of patients and was highly correlated with disease outcome at 3, 12 months, and at last follow-up. Evans' syndrome was diagnosed in 50% of cases and was significantly associated with a lower subsequent CR rate.
Conclusion CR of AIHA at 1 month was predictive of subsequent CR. Concordance with Evans' syndrome occurred in half of the cases with less favorable outcome.

Keywords: autoimmune hemolytic anemia, children, complete remission, continuous complete remission, Evans′ syndrome

How to cite this article:
Tantawy AA, Al-Tawil MM. Spectrum and outcome of autoimmune hemolytic anemia in children: single-center experience in 10 years. Egypt J Haematol 2014;39:20-4

How to cite this URL:
Tantawy AA, Al-Tawil MM. Spectrum and outcome of autoimmune hemolytic anemia in children: single-center experience in 10 years. Egypt J Haematol [serial online] 2014 [cited 2020 Oct 23];39:20-4. Available from: http://www.ehj.eg.net/text.asp?2014/39/1/20/124840

  Introduction Top

Autoimmune hemolytic anemia (AIHA) is characterized by premature destruction of red blood cells, induced by autoantibodies that bind red cells' surface membrane with subsequent destruction by the reticuloendothelial system or by a complement-mediated mechanism [1] . It is a relatively uncommon disorder, with an estimated incidence of 1-3 cases per 100 000 population per year, and there is no evidence that AIHA is confined to any particular race [2] .

The main dichotomy in childhood AIHA is that patients may develop Evans' syndrome (ES). ES was first defined as an autoimmune disorder characterized by simultaneous or sequential development of AIHA and immune thrombocytopenia (ITP) and/or immune neutropenia in the absence of any underlying cause [3] . Currently, it is defined as autoimmune destruction of at least two hematologic cell lines after exclusion of other diagnoses [4],[5] . ES has been reported to occur in 13-73% of children with AIHA [4],[6],[7] .

Because of the rarity of the disease, childhood AIHA is less well characterized. The recent literature contains information from small series from a few centers [8-11] . The largest reported study of childhood AIHA was a nationwide multicenter French observational study [12] . Moreover, to date, compared with ITP [13] , there is no panel consensus on standardization of terminology, definitions, and outcome criteria of AIHA in both children and adults. Even the CEREVANCE criteria, used in the French national study, qualified the status of AIHA only at 1 month and last follow-up, aiming at identifying a favorable subgroup. However, outcome criteria on the basis of disease duration have not yet been established.

The aim of this study was to present a single-center experience on presentation and outcome of childhood AIHA according to preset criteria and to describe potential factors affecting outcome.

  Patients and methods Top

This was a retrospective case record analysis of children and adolescents younger than 16 years old, diagnosed with AIHA in the period between January 2002 and January 2012, to allow for at least a 1-year follow-up for outcome evaluation. Data were collected and analyzed between January and May 2013. This cohort of children was recruited from the Pediatric Hematology and Oncology Clinic, Children Hospital, Ain Shams University, Cairo, Egypt. The research was approved by the hospital ethics committee.

Data collection from patients' records included clinical findings and blood test results on presentation, history of preceding drug intake, evolving clinical findings during follow-up, initial treatment and its response, any subsequent treatment and its response, and disease outcome at 1, 3, and 12 months from the onset of disease in addition to remission status at last follow-up.

AIHA was diagnosed by a hemoglobin level of 11 g/dl or less at presentation with at least one of the features of hemolysis (low haptoglobin level, elevated lactate dehydrogenase, reticulocytes more than 120 × 10 9 /l, or total bilirubin more than 1 mg/l) and a positive direct antiglobulin test (DAT) or when the DAT was negative, after the exclusion of any other cause of acquired or hereditary hemolytic anemia [14] . ES was defined as the association of AIHA and ITP with a platelet count less than 100 × 10 9 /l, occurring simultaneously or subsequently on at least two occasions, throughout the disease course [12] . Low platelet count was confirmed by manual counting to avoid spurious counts of analyzers during the hemolytic states. Specific infection detection by IgM-positive serology against mycoplasma, Epstein-Barr virus, or cytomegalovirus was performed in 24 cases according to physician discretion. Exclusion criteria were as follows: (a) other causes of hemolysis including hereditary or drug-induced hemolysis and (b) secondary causes of thrombocytopenia, including hereditary and drug-induced cases.


Throughout the 10-year study duration, 45 children fulfilled the inclusion and exclusion criteria and 13 patients were excluded because the recorded data lasted less than 1 year; thus, 32 patients were assessed.

Disease outcome

We qualified the status of AIHA at 1, 3, and 12 months since the onset of the disease using the CEREVANCE criteria [12] , no response: hemoglobin less than 7 g/dl; partial remission: hemoglobin 7-11 g/dl and/or reticulocytosis greater than 120 × 10 9 /l; complete remission (CR): hemoglobin greater than or equal to 11 g/dl and reticulocytes less than or equal to 120 × 10 9 /l, irrespective of the DAT and treatment; continuous complete remission (CCR): stable CR without any specific treatment for at least 1 year.

Statistical analysis

Descriptive statistics included mean (SD) for continuous variables and frequency (percentage) for categorical variables. Univariate analysis included χ2 -test or Fisher's exact test as appropriate to compare categorical variables and either an unpaired Student t-test or a z-test to compare continuous variables. Differences were considered significant when P values were less than 0.05. The statistical analysis was carried out using SPSS II software version 17.0 (Chicago, IL, USA).

  Results Top

Among the 32 cases assessed, 25 (78%) were females and more than half of the cases occurred below the age of 6 [Figure 1].
Figure 1: Age and sex distribution of the cases studied.

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Important clinical and laboratory data of all cases are presented in [Table 1]. All patients presented with pallor and 26 (81%) presented with jaundice. Associated acute febrile illness on presentation occurred in 11 (34%) cases with positive specific serology for the Epstein-Barr virus, cytomegalovirus, and mycoplasma in three out of nine, seven out of 13, and two out of two tested cases, respectively. Hepatosplenomegaly (HSM) on presentation or that developed throughout the first 1 year of the disease was detected in 17 (53%) patients. DAT was negative in two (6%) and reticulocytopenia during the initial presentation occurred in four (12%) patients. Except for two patients, all received corticosteroids as an initial treatment (94%). CR at 1 month occurred in 15 out of 32 patients (46.9%) and was highly correlated with disease outcome at 3, 12 months, and at last follow-up (P < 0.001). Additional therapy was required in nine (28%) patients and included cyclosporine A, intravenous immunoglobulin (IVIG), cyclophosphamide in seven, five, and two patients, respectively. Two patients underwent splenectomy.
Table 1 Clinical and laboratory characteristics of all patients (n = 32)

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ES was diagnosed in 16 (50%) patients. ITC preceded AIHA in three patients (by 2-5 years) and occurred concomitantly in seven patients or within 18 months of initial presentation of AIHA in six patients. Among cases of ES, four patients had positive antinuclear antibody; two of them subsequently developed systemic lupus erythematosus (SLE) within 1 year from the initial presentation. [Table 2] shows the characteristics of isolated AIHA and ES. The ES group included predominantly females of significantly older age on presentation. The proportion of patients who had HSM was significantly higher in ES cases. CR at 1, 3, and 12 months were significantly lower in ES cases [Figure 2]. None of them attained CCR.
Table 2: Characteristics of isolated AIHA and AIHA with ES

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Figure 2: CR throughout the first year in AIHA and AIHA/ES. AIHA, autoimmune hemolytic anemia; CR, complete remission; ES, Evans' syndrome.

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  Discussion Top

In the current study, 78% of our studied patients were females. This is in accordance with female predominance in autoimmune diseases [1],[11] . Infants constituted 34% of all cases, with more than half of the cases younger than 6 years of age, suggesting predominance of the disease in young children [12] . An association between AIHA and concurrent infection was shown as the onset of AIHA was associated with nonspecific febrile illness in 34% of cases. In addition, specific viral infection, detected by viral serology against the Epstein-Barr virus, cytomegalovirus, or mycoplasma, was found in 37.5% of tested cases. It has been shown that infection is unlikely to be a direct cause of AIHA, but rather a causative factor [12],[15],[16] . Reticulocytosis and positive DAT were not consistent findings on initial presentation of AIHA. Reticulocytopenia was present in 12% of cases. A higher figure of 39% was reported in the French national study [12] . Postulated mechanisms include concomitant parvovirus infection, transient sideration of erythropoiesis, or associated autoimmune mechanism destroying erythroid progenitors [1] . For DAT, it was negative in 6% of cases, which is comparable with other reports [1] . We included cases as AIHA even if DAT was negative, if there were features of hemolysis, in order not to miss cases with negative DAT.

For the evaluation of treatment response and disease outcome, we used the CEREVANCE criteria for disease remission at 1 and 12 months in addition to assessment of CCR at last follow-up [12] . In addition, we included disease remission assessment at 3 months because we considered the similarities between AIHA and childhood ITP, and the possibility of progression of each to one another during the course of the diseases [17] . According to updated panel consensus, newly diagnosed ITP was defined as disease duration less than 3 months from diagnosis because of the high rate of disease remission during this period [13] . CR was achieved in nearly half of the patients at 1 month, with a strong correlation with disease remission at 3 and 12 months and with survival in CCR. This is very important as it indicates the prognostic value of disease outcome at 1 month on overall outcome. These figures are in agreement with those of the French national study (CR at 1 month in 58% and CCR at last follow-up in 39%) [12] . The validity of this prognostic value of disease remission at 1 month should be studied further until a consensus is reached on the definition and outcome criteria similar to those of ITP [13] .

Fifty percent (16 patients) of our patients' cohort had ES according to concomitant or subsequent immune hemolysis and thrombocytopenia [4],[14] . Previous reports ranged between 13 and 73% [4],[7],[12] . Six patients developed thrombocytopenia within 18 months after AIHA. Previous reports showed that second cytopenia may appear up to 10 years after the first one even after apparent remission or cure [14],[18] . Disease outcome was significantly less favorable in ES patients at 1, 3, and 12 months with nonachieved CCR at last follow-up. Patients who developed ES were significantly older on presentation, were predominantly females, and had significantly higher prevalence of HSM. This finding in the context of a less favorable remission rate in patients with ES indicates the generalized immune dysregulation, broader spectrum, and more likely resistance to therapy in those with combined cytopenia and/or lymphoid hyperplasia [17] . Previous studies showed that combined cytopenias are frequently associated with generalized autoimmune diseases such as SLE, autoimmune lymphoproliferative syndrome (ALPS), or primary immune deficiency syndrome [19] . Two of our ES patients developed SLE. A recent retrospective study on children with ES showed that 47% were diagnosed with ALPS [20] . It is worth noting, however, that detailed immunological studies of our ES patients are beyond the scope of this retrospective, primarily epidemiological study and we will present it separately. Significantly longer follow-up in ES patients further reflects the more chronic and indolent nature of this syndrome, which requires closer follow-up and treatment modification. This is very important especially in the context of overlap with ALPS when there is a need for steroid sparing, targeted therapy. For ALPS, mycophenolate mofetil [21] and sirolimus [22] have been used successfully, whereas both splenectomy and rituximab are not favored because of the risk of hypogammaglobulinemia and severe sepsis [23] .

  Conclusion Top

CR of AIHA at 1 month was highly predictive of subsequent CR. ES was important concordant with AIHA, which is associated with significantly less favorable outcome. There is a need for consensus on standardization of the outcome criteria in this relatively uncommon disease similar to that of ITP.

  Acknowledgements Top

  References Top

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13.Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 2009; 113 :2386-2393.  Back to cited text no. 13
14.Michel M, Chanet V, Dechartres A, Morin AS, Piette JC, Cirasino L, et al. The spectrum of Evans' syndrome in adults: new insight into the disease based on the analysis of 68 cases. Blood 2009; 114 :3167-3172.  Back to cited text no. 14
15.Sokol RJ, Hewitt S, Stamps BK, Hitchen PA. Autoimmune haemolysis in childhood and adolescence. Acta Haematol 1984; 72 :245-257.  Back to cited text no. 15
16.Zuelzer WW, Mastrangelo R, Stulberg CS, Poulik MD, Page RH, Thompson RI. Autoimmune hemolytic anemia. Natural history and viral-immunologic interactions in childhood. Am J Med 1970; 49 :80-93.  Back to cited text no. 16
17.Savaºan S, Warrier I, Ravindranath Y. The spectrum of Evans' syndrome. Arch Dis Child 1997; 77 :245-248.  Back to cited text no. 17
18.Price V. Autoimmune lymphoproliferative disorder and other secondary immune thrombocytopenias in childhood. Peditr Blood Cancer 2012; 60 :S12-S14.  Back to cited text no. 18
19.Teachey DT, Manno CS, Axsom KM, Andrews T, Choi JK, Greenbaum BH, et al. Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS). Blood 2005; 105 :2443-2448.  Back to cited text no. 19
20.Seif AE, Manno CS, Sheen C, Grupp SA, Teachey DT. Identifying autoimmune lymphoproliferative syndrome in children with Evans syndrome: a multi-institutional study. Blood 2010; 115 :2142-2145.  Back to cited text no. 20
21.Rao VK, Dugan F, Dale JK, Davis J, Tretler J, Hurley JK, et al. Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome. Br J Haematol 2005; 129 :534-538.  Back to cited text no. 21
22.Teachey DT, Greiner R, Seif A, Attiyeh E, Bleesing J, Choi J, et al. Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome. Br J Haematol 2009; 145 :101-106.  Back to cited text no. 22
23.Teachey DT, Seif AE, Grupp SA. Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS). Br J Haematol 2010; 148 :205-216.  Back to cited text no. 23


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]

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