Evans Syndrome

Race

• Of 42 patients reported in a national survey, 29 were white, 7 were black, and 6 had other racial backgrounds.¹⁰ This distribution could suggest a preponderance among whites or a reporting bias.
• As individual conditions, AIHA and immune thrombocytopenia have no racial predilection.

Sex

• No predilection is known in Evans syndrome; AIHA affects boys more frequently than girls at a ratio of 1.4:1.
• Among adults, AIHA affects women more often than men. In one study from Genty et al, 67% of cases occurred in women.¹¹

Age

Evans syndrome occurs in individuals of all ages.

• In a 1997 survey of North American pediatric hematologists, the median reported age at diagnosis was 7.7 years (range 0.2-26.6 y).¹⁰ This late presentation age may indicate the disease was undiagnosed until the second presentation of cytopenia, which was usually months to years after the first presentation.
• Evans syndrome in adults has been anecdotally reported.

Clinical

History

• In a national survey, thrombocytopenia was the presenting feature in 76% of patients with Evans syndrome, and anemia was the presenting feature in 67% of these patients.¹⁰
• In addition, 24% of patients had neutropenia, and 14% had pancytopenia.

Physical

Evans syndrome is a diagnosis of exclusion. Confounding disorders, such as infections, rheumatologic diseases, and malignancies can present with autoimmune cytopenias, must be ruled out.

• Signs of thrombocytopenia include purpura, petechiae, and ecchymoses.
• Signs of anemia include pallor, fatigue, and light-headedness.
• Jaundice may indicate hemolysis.
• A case report described a patient with visceral leishmaniasis who had common variable immunodeficiency and Evans syndrome.¹²

Causes

The etiology of Evans syndrome remains unknown .

• Autoantibodies are directed against antigens specific to red cells, platelets, or neutrophils, but these autoantibodies do not cross-react.
• Many patients have associated disorders (eg, systemic lupus erythematosus [SLE] and other autoimmune diseases, chronic lymphadenopathy, hypogammaglobulinemia).
• Acquired cytopenias occur in association with sex-linked agammaglobulinemia, common variable immunodeficiency, and IgA deficiency.
• Evans syndrome has been diagnosed in one child with insulin-dependent diabetes mellitus,¹³  in another after an autologous bone marrow transplant for recurrent Hodgkin disease,¹⁴ and in one child with Celiac disease.¹⁵
• Most patients with Evans syndrome have decreased levels of serum IgG, IgM, and IgA and decreased in vitro synthesis of IgG and/or IgM.
• Decreased T-helper lymphocyte populations and increased T-suppressor lymphocyte populations that are similar to levels found in congenital hypoplastic anemia and amegakaryocytic thrombocytopenia have been observed. This finding has led to speculation that the cytopenias in Evans syndrome may relate to T-cell abnormalities.
• Teachey et al demonstrated that numerous patients with Evans syndrome may have autoimmune lymphoproliferative syndrome.⁵
• The role of childhood immunizations in the development of Evans syndrome has been investigated, but specific associations have not been reported. However, case reports suggest that immunizations may trigger the development of this disease in susceptible individuals.

Differential Diagnoses

Thrombocytopenia-Absent Radius Syndrome

Other Problems to Be Considered

Evans syndrome is a diagnosis of exclusion. Other causes of immune cytopenias should be excluded, such as:

SLE
IgA deficiency
Common variable immune deficiency
Acquired immune deficiency syndrome
Autoimmune lymphoproliferative syndrome
Paroxysmal nocturnal hemoglobinuria
Thrombotic thrombocytopenic purpura
Hemolytic-uremic syndrome
Kasabach-Merritt syndrome
Hypersplenism
Rosai Dorfman Disease (may be associated with autoimmune lymphoproliferative syndrome)

Workup

Laboratory Studies

• The CBC count and reticulocyte count reveal anemia, thrombocytopenia, neutropenia, or combined cytopenias in patients with Evans syndrome; the reticulocyte count increases if the patient has anemia. Features of hemolysis include a raised reticulocyte count, increase in unconjugated bilirubin, and decreased haptoglobins.
• In Evans syndrome, the direct antiglobulin result (ie, Coombs test result) is almost invariably positive (often weakly) and may be positive for IgG, complement, or both. Indirect antiglobulin test findings may also be positive in 52-83% of patients.
• Prudent studies include measurement of serum immunoglobulins to rule out such differential diagnoses as common variable immunodeficiency and IgA deficiency; serum markers for conditions such as systemic lupus erythematosus (SLE), measuring antinuclear antibody, double-stranded DNA; and peripheral blood T-cell subsets using flow cytometry to rule out autoimmune lymphoproliferative syndrome and bone marrow examination to rule out infiltrative disorders.
• Various antibodies directed against RBCs and platelets (eg, antierythrocyte, antineutrophil, antiplatelet antibodies) occur in association with Evans syndrome.
  • In a study by Fagiolo of 32 adults, as many as 91% had antiplatelet antibodies demonstrated using thromboagglutination and indirect antiglobulin consumption tests.¹⁶ About 81% had leukocyte antibodies detected using cytotoxicity testing. However, variable intervals were reported between the detection of antibodies and the demonstration of leukopenia or thrombocytopenia. No relationship was shown between the leukocyte antibodies and platelet antibodies (alone or in combination) and the type of RBC antibodies.
  • Kakaiya et al reported that the antibodies directed against RBCs and platelets were different.¹⁷ Pegels et al confirmed this finding.¹⁸ In absorption and elution experiments, they found that the autoantibodies were directed against specific antigens on RBCs, platelets, and white cells, and that the autoantibodies did not cross-react. These findings lead to questions about the clinical usefulness of these tests. Pui et al found platelet antibodies in only 2 of 6 children tested.⁷ Antineutrophil antibodies were positive in 3 of 4 patients with neutropenia. Therefore, positive antibody results are useful, but negative results provide little clinical information.

Other Tests

• Lupus antibody (Lupuslike inhibitor) and antinuclear antibody tests are used to detect SLE.
• Perform T-cell and B-cell function tests for quantitative immunoglobulins to evaluate for hypogammaglobulinemia and perturbations in T-cell numbers.
• Bone marrow aspiration helps reveal aplastic anemia or an infiltrative disorder. Bone marrow aspiration may be indicated when patients initially present with pancytopenia.
• Flow cytometry of blood samples is indicated to look for double negatives.
• Gene mutation studies are used to detect known condition such as autoimmune lymphoproliferative syndrome.

Procedures

• Blood tests are typically used to determine the CBC count and reticulocyte count and to perform the Coombs test.
• Bone marrow aspiration helps in evaluating the morphology and is usually indicated in patients who present with pancytopenia to exclude infiltrative processes.
• Bone marrow examination is usually not indicated in classic cases when patients present with AIHA or immune thrombocytopenia.

Histologic Findings

• Bone marrow studies may reveal erythroid hyperplasia and, occasionally, hypoplasia if autoimmune hemolytic anemia (AIHA) is the predominant finding.
• Normal levels or increased numbers of megakaryocytes confirm that thrombocytopenia is caused by increased destruction in the blood.

Treatment

Medical Care

• The management of Evans syndrome is challenging. Although almost all patients require therapy at some time during the course of the disease, the search for a consistent, effective, and nontoxic therapy continues. Medical therapy continues to be the mainstay. Response to therapy varies even within the same individual, and the disease is characterized by periods of remission and exacerbation. No randomized trials have been conducted in patients with Evans syndrome, and the evidence for treatment is based on case reports, case series, and retrospective studies.
• Prednisone therapy, the most commonly used first-line therapy, often effectively controls acute episodes, although relapses may be frequent when patients are weaned off prednisone.
• Intravenous immunoglobulin (IVIG) may help patients who depend on steroids.^19,20
• Other therapies effective in small series include danazol, cyclosporine, azathioprine, cyclophosphamide, and vincristine.
• Recently, rituximab (a chimeric human/mouse monoclonal antibody which targets CD20 on B lymphocytes) has been used in the management of refractory patients.^{21,22,23,24,25,26}  Responses have varied. Norton and Roberts recently reviewed the use of rituximab in 18 patients (aged 0.3-65 y).²⁷ The results were encouraging, with sustained complete remission of as long as 17 months. In a recent pediatric prospective series by Rao et al, 2 patients with Evans syndrome were treated with rituximab; one had a partial response, and one had no response.²⁶ Complications associated with rituximab in these studies have been minimal; the most common is infusion-associated reaction.
• In an acute setting, blood transfusions and/or platelet transfusions may be required to alleviate symptoms, although their use should be minimized.
• Additional therapies include splenectomy, alemtuzumab administration, and hematopoietic stem cell transplantation.
  • The role of splenectomy is not clearly established, but it may improve blood counts and reduce steroid dependence; relapses are common and, in most cases, occur within 1-2 months postsplenectomy.
  • Children with Evans syndrome appear to have a higher risk of postsplenectomy sepsis, especially children with pancytopenia.
  • Autologous and allogeneic stem cell transplantation have been used in a small number of patients (14 patients aged 5-52 y), with mixed results.²⁸
  • Alemtuzumab is a humanized IgG monoclonal antibody specific for the CD52 antigen present on T cells and B cells. Willis et al reported its use in 3 patients with Evans syndrome; although a response was seen in 2 patients, both relapsed in 3 months.²⁹

Surgical Care

Consider splenectomy in refractory cases.

• Splenectomy may improve CBC counts and decrease the steroid requirement, although relapses are common.
• According to a national survey, splenectomy provided a reported duration of response that ranged from 1 week to 5 years; however, the median response duration was just one month.¹⁰
• The risk of infection after splenectomy appears to be increased in children with pancytopenia.

Consultations

• Pediatric hematologist
• Pediatric oncologist
• Rheumatologist
• Immunologist

Diet

• Dietary restrictions are not usually required.
• Patients receiving steroid therapy should have some restrictions on their salt, sugar, and fluid intake to prevent excessive fluid retention.

Activity

• Restrict activities based on patient tolerance and the degree of anemia and bruising.

Medication

Prednisone (eg, 1-2 mg/kg dose, usually divided twice or three times daily) often effectively controls acute episodes of Evans syndrome. Although some patients are successfully weaned off steroids, relapses may occur when prednisone is tapered or stopped. Use an alternate-day steroid therapy, if possible.

Patients with persistent immune cytopenia and those who require prolonged or high doses of steroids may benefit from intravenous immunoglobulin (IVIG), at doses such as 1-2 g/kg/d for 1-2 days. Their thrombocytopenia is more likely than their hemolysis to respond. Long-term control of thrombocytopenia is reportedly achieved with interval doses of IVIG.

Other therapies reported in a national survey by Mathew et al included immunomodulating agents (eg, cyclosporine, danazol, azathioprine, cyclophosphamide, vincristine).¹⁰ Plasmapheresis was performed in 3 patients. One patient had transient responses, at best, to receiving the immunosuppressive agent tacrolimus (Prograf, FK506), protein A-Sepharose column plasmapheresis, whole blood exchange transfusion, and total nodal irradiation. Another patient showed some response to treatment with a combination of Rh D immunoglobulin (anti-D), methotrexate, prednisone, and folic acid (responses to these agents varied).

One pilot study showed that a multiagent approach may be effective in patients with Evans syndrome³⁰ . Transfusions of RBCs and platelets were also used as adjuncts to treatment.

One of the newer agents that has been tried in refractory Evans syndrome is rituximab. However, recent reports suggest that it is being used as a second-line therapy. Rituximab is approved for the treatment of relapsed and refractory B-cell non-Hodgkin lymphoma. Binding of rituximab to cells expressing CD20 results in cell death by means of a combination of mechanisms, including antibody-dependent cell cytotoxicity, complement activation and apoptosis. Hence, it has been used in the treatment of various autoimmune disorders mediated by autoantibodies.

Galor et al reported the successful use of rituximab in a patient with Evans syndrome.²¹ Mantadakis et al reported its successful use in a patient with long-lasting Evans syndrome refractory to standard treatments; the patient responded well to Rituximab and then responded again when relapse occurred 7 months later.²² In contrast, Grossi et al treated 2 patients with rituximab without success.³¹ In fact, the patients had a worsening of their anemia. Zecca et al described the weekly use of rituximab in 5 children with Evans syndrome, all of whom were successfully treated.²³ In a retrospective review of patients at the Mayo Clinic, Shanafelt reported responses in one of the cytopenias among 3 patients with Evans syndrome, but not both.²⁴

Glucocorticoids

Initial therapy for Evans syndrome. Elicits anti-inflammatory properties and cause profound and varied metabolic effects. They modify the immune response of the body to diverse stimuli.

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

Commonly used steroid medication that interferes with macrophage Fc gamma and C3b receptors responsible for destruction of red cells and platelets; may work by decreasing abnormal IgG antibody production that may be responsible for destruction of the cells; can increase vascular stability and ameliorate endothelial abnormalities associated with thrombocytopenia; also helps decrease clearance of opsonized platelets.

Dosing

Adult

Up to 60-80 mg/d PO divided bid/tid (or equivalent IV form)

Pediatric

1-2 mg/kg/d PO divided bid/tid (or equivalent IV form)

Interactions

Coadministration with estrogens may decrease prednisone clearance; concurrent digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, or rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; serious infections (excluding meningitis and septic shock), fungal or varicella infections

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Administer with meals to decrease GI upset; early onset adverse effects include glucose intolerance, hypertension, agitation, indigestion; long-term use, usually more than a month, may cause growth retardation, osteoporosis, pseudotumor cerebri, cataracts, hypertension, fluid retention, psychosis, acne, and cushingoid facies; abrupt discontinuation of glucocorticoids may cause adrenal crisis

Immune Globulin

This is a purified preparation of gamma globulin. It is derived from large pools of human plasma and is composed of 4 subclasses of antibodies, approximating the distribution of human serum.

Immune globulin intravenous (Carimune NF, Gammar-P, Gammagard, Iveegam EN)

Neutralizes circulating myelin antibodies through antiidiotypic antibodies; down regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase CSF IgG (10%).

Dosing

Adult

1-2 g/kg/d IV for 1-2 d

Pediatric

Administer as in adults

Interactions

May cause live virus vaccines (eg, MMR) to not replicate successfully, thus, decreasing immune response

Contraindications

Documented hypersensitivity; anti-IgE/IgG antibodies

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Acquire low IgA-titer product for IgA deficient patients; slowly increase infusion rate to prevent infusion related adverse effects (eg, hypotension, fever); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d)
Increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; laboratory test result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

Follow-up

Further Inpatient Care

• Patients admitted for severe anemia or thrombocytopenia should have respiratory and cardiovascular functions stabilized first; receive blood transfusions, if needed, after consultation with a pediatric hematologist; and then be started on therapy with either intravenous immunoglobulin (IVIG) or steroids.
• In classic cases (ie, patients who present with either autoimmune hemolytic anemia [AIHA] or immune thrombocytopenia), bone marrow aspiration is not indicated.
  • When a patient has pancytopenia at presentation, or when diagnosis of immune thrombocytopenia is unconfirmed, bone marrow aspiration findings may help exclude an infiltrative pathology or an aplastic marrow.
  • Bone marrow examination may be indicated in unusual cases, in cases refractory to treatment, or in cases when a peripheral blood smear suggests immature myeloid cells.
• A patient may be discharged if clinically stable (eg, with rising blood counts).

Further Outpatient Care

• Weekly follow-up is recommended with blood counts and physical examinations until counts become stable or return to reference ranges.
• Subsequent follow-up care may be arranged at intervals of 2-4 weeks.
• More frequent follow-up care may be indicated for patients with clinical or laboratory signs of recurrence (eg, when steroids are tapered).

Complications

• A risk of hemorrhage with severe thrombocytopenia is noted.
  • The national survey reported hemorrhage in 29% of patients.¹⁰
  • This study reported 2 patient deaths from severe GI bleeding and a third death from an acute intracranial bleed.
• Patients with neutropenia also risk serious infection.
  • The national survey showed invasive infections in 29% of patients, including pneumonia, sepsis, and meningitis with Streptococcus pneumoniae, localized abscess, and osteomyelitis.
  • One patient died from presumed sepsis and liver failure 9 years after splenectomy.

Prognosis

• The characteristic clinical course of Evans syndrome has periods of remission and exacerbation, with variable and often disappointing responses to therapy.
• Recurrences of thrombocytopenia and anemia are common, as are episodes of hemorrhage and serious infections. Evans syndrome sometimes is fatal.
• Treatment occasionally provides complete resolution. In the national study on Evans syndrome, after a median follow-up of 3 years (range, 4 mo to 18.9 y), 48% had active disease and continued to be treated, 12% had persistent disease but were receiving no treatment, and 33% had no evidence of disease for periods ranging from 1.5-5 years (median, 1 y).¹⁰ Long-term survival data are limited. In patients followed for a median range of 3-8 years, the mortality ranged from 7-36%. Causes of death were mainly due to hemorrhage or sepsis. None of these patients developed any malignancy. 
• Patients rarely do well without treatment.
  • In the national survey, each patient received a median of 5 (range, 1-12) treatment modalities, either in combination or sequentially.¹⁰
  • Only one patient received no treatment; this patient's hemoglobin levels were 9-13.2 g/dL and platelet counts were 9-208,000/µL during follow-up examinations over 11 years.

Patient Education

• Educate patients and their families about the chronic nature of this condition, which can include periods of remission and exacerbation.
• Explain potential adverse effects of medications, especially long-term steroids, each time a steroid is used to treat an exacerbation.

Miscellaneous

Medicolegal Pitfalls

• Evans syndrome may not be apparent when a child presents with an isolated cytopenia. Therefore, diagnosis may be delayed until a second episode of cytopenia manifests.

References

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15. Yarali, Nese; Demirceken, Fulya; Kondolat, Meda; Ozkasap, Serdar; Kara, Abdurrahman; Tunc, et al. A Rare Condition Associated With Celiac Disease: Evans Syndrome. Journal of Pediatric Hematology/Oncology. September 2007;29 (9):633-635.

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17. Kakaiya RM, Sherman LA, Miller WV, Katz AJ. Nature of platelet antibody in Evans syndrome: a case report. Ann Clin Lab Sci. Nov-Dec 1981;11(6):511-5. [Medline].

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25. Maloney DG, Grillo-Lopez AJ, White CA, et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood. Sep 15 1997;90(6):2188-95. [Medline].

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38. Sneller MC, Wang J, Dale JK, et al. Clincal, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood. Feb 15 1997;89(4):1341-8. [Medline].

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Keywords

Evans syndrome, ES, autoimmune hemolytic anemia, AIHA, idiopathic thrombocytopenia, ITP, Evans syndrome, autoimmune lymphoproliferative syndrome, ALPS, common variable immunodeficiency, IgA deficiency, diabetes mellitus, Hodgkin disease, Celiac disease, treatment, diagnosis, symptoms

Contributor Information and Disclosures

Author

Prasad Mathew, MBBS, DCh, Director, Hemostasis and Hematology Program, Professor of Pediatrics, University of New Mexico
Prasad Mathew, MBBS, DCh is a member of the following medical societies: American Society of Hematology
Disclosure: Nothing to disclose.

Medical Editor

Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories
Gary R Jones, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Gary D Crouch, MD, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Associate Professor, Uniformed Services University of the Health Sciences
Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Hematology
Disclosure: Nothing to disclose.

CME Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine
Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

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