Severe relapse of Evans syndrome in an adult patient with treatment resistance and fatal outcome: A case report

Abstract

Evans syndrome is an uncommon autoimmune disorder characterized by autoimmune hemolytic anemia and immune thrombocytopenia. It can follow a relapsing course in adults and may be challenging to treat. A woman in her 50s, diagnosed with Evans syndrome 2 years ago and on 10 mg prednisolone once daily, presented with worsening symptoms, lymphadenopathy, and abnormal uterine bleeding. Lymph node biopsies revealed caseating and noncaseating granulomas, and infections and systemic autoimmune diseases were ruled out. She required intensive care unit admission and treatment with high-dose corticosteroids and rituximab. Plasmapheresis was attempted as the last-line therapy; however, it resulted in hemodynamic instability. This case reflects the clinical challenges involved in managing relapsed Evans syndrome in the absence of a clear secondary cause. The presence of granulomatous inflammation raises questions about lesser-known immune features of the disease. The use of plasmapheresis in unstable patients should be approached with caution.

Background

Evans syndrome (ES) is a rare autoimmune disorder first described in 1951, characterized by the coexistence of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), and less commonly, neutropenia.^1,2 It accounts for approximately 7% of AIHA and 2% of ITP cases. ² A recent study estimated the annual incidence of ES between 2000 and 2016 to be 1.84/10,00,000, ³ with a higher rate reported in female patients, accounting for 60%–70% of ES cases. ⁴ ES is subclassified into primary (idiopathic) and secondary forms, with the latter being associated with underlying conditions such as lymphoproliferative disorders, autoimmune diseases, and infections, often resulting in worse outcomes. ³

The pathophysiology of ES is characterized by substantial immune dysregulation, including the generation of autoantibodies against erythrocytes, platelets, and, in some cases, neutrophils. In AIHA, warm immunoglobulin G (IgG) autoantibodies bind to red blood cells, resulting in their destruction through Fc receptor–mediated phagocytosis in the spleen or complement activation. In ITP, antibodies mediate peripheral platelet destruction and impair megakaryocyte function in the bone marrow. ⁵ In addition to humoral immunity, T-cell dysregulation contributes to disease pathogenesis; patients with ES often show expansion of T-follicular helper (Tfh) cells and reduced regulatory T-cell (Treg) function, allowing ongoing autoantibody production. ⁶

This case report highlights the diagnostic and therapeutic challenges associated with managing ES, particularly in the context of unusual histological findings and a fatal outcome following escalation of care.

Case presentation

A female patient in her 50s presented to a tertiary medical center with jaundice, fatigue, and dark urine. Initial investigations revealed a low RBC count (2.3 × 10¹²/L), thrombocytopenia (platelet count, 42 × 10⁹/L), and reticulocytosis. Additional investigations showed elevated unconjugated bilirubin level, low haptoglobin level, and a positive direct Coombs test. Immune markers were negative. Bone marrow aspiration and biopsy were performed and showed no evidence of malignancy or myelodysplasia. Based on laboratory investigations that confirmed the coexistence of AIHA and ITP, a diagnosis of ES was established. The patient was started on 50 mg prednisolone once daily, which was tapered to 10 mg daily over time. She had a history of multiple supportive blood transfusions when her hemoglobin level had dropped to 6–7 g/dL.

Two years later, the patient was admitted to the internal medicine department after experiencing an acute exacerbation triggered by increased psychological stress and nonadherence to steroid therapy. She presented with generalized weakness and heavy vaginal bleeding and was referred to the Obstetrics and Gynecology clinic; however, no identifiable gynecological source was identified upon examination. At presentation, she appeared ill but was conscious, cooperative, and well oriented to time, place, and person with a Glasgow Coma Scale (GCS) score of 15/15. Lymphadenopathy was detected above and below the diaphragm. General and systemic examination revealed no other significant findings. Her vital signs were stable. A true cut biopsy followed by an excisional biopsy revealed caseating and noncaseating granulomas. A comprehensive workup was performed to exclude other identifiable systemic diseases. Infectious workup, including viral serologies (human immunodeficiency virus (HIV) as well as hepatitis B and C), fungal stains (periodic acid‐Schiff stain (PAS) and Gomori methenamine–silver stain (GMS)), tuberculin skin test, and chest X-ray, was negative. Epstein–Barr virus (EBV) and cytomegalovirus (CMV) serologies were not performed given the absence of clinical features suggestive of an active infection. Autoimmune testing, including antinuclear antibody (ANA), anti-double-stranded (ds) DNA antibody, antineutrophil cytoplasmic antibody (ANCA), and rheumatoid factor, was negative. According to the established diagnostic criteria, these findings excluded infectious, autoimmune, and lymphoproliferative causes, supporting the diagnosis of ES. Subsequently, she was hospitalized in the adult internal medicine ward, and 50 mg oral prednisolone once daily was initiated.

Her hemoglobin level rapidly declined from 11 g/dL to 3.5 g/dL within 3 days of her stay in the ward, necessitating transfer to the intensive care unit (ICU) for tachycardia and hemodynamic instability. Detailed laboratory results during her ICU stay are presented in Figure 1. Electrocardiogram (ECG) revealed sinus tachycardia. Complete laboratory investigations (Table 1) revealed the following: lactate dehydrogenase (LDH), 493 U/L; reticulocyte count, 4.5%; and progressive anemia indicated by a hemoglobin level of 3.0 g/dL. She received a total of 13 units of leukocyte-depleted red blood cells, raising her hemoglobin level to 8.6 g/dL, and platelet transfusions for platelet counts ranging between 41 and 74 × 10⁹/L. After 7 days, her direct bilirubin level was 44 µmol/L and indirect bilirubin level was 19 µmol/L, reflecting ongoing hemolysis.

Figure 1.

Detailed laboratory results during ICU stay. ICU: intensive care unit.

Table 1.

Laboratory results on the first day of ICU admission.

Test	Result	Reference range
Hemoglobin (Hb)	5.5 g/dL	11.7–15.5 g/dL
Red blood cell (RBC) count	1.7 × 10¹²/L	3.8 × 10¹²–5.1 × 10¹²/L
Platelet count	79 × 10⁹/L	150 × 109–400 × 10⁹/L
White blood cell (WBC) count	5.9 × 10⁹/L	4.0 × 109–11.0 × 10⁹/L
Reticulocyte count	4.5%	0.2%–2.0%
Lactate dehydrogenase (LDH)	493 U/L	135–214 U/L
Total bilirubin	63 µmol/L	5–21 µmol/L
Direct bilirubin	44 µmol/L	0–7 µmol/L
Indirect bilirubin	19 µmol/L	<17 µmol/L
Haptoglobin	low	30–200 mg/dL
Direct Coombs test	positive	negative
INR	1.02	0.8–1.1
PT	11.3 s	11–13.5 s
Prothrombin concentration	93.0%	70%–120%

ICU: intensive care unit; INR: internalized normalized ratio; PT: prothrombin time.

Intravenous methylprednisolone (500 mg/day for 5 days) was initiated followed by rituximab (600 mg, with weekly infusions planned). Plasmapheresis was initiated as a last resort for refractory thrombocytopenia; however, during the first session, she developed hemodynamic shock necessitating emergency reintubation. Despite aggressive supportive care, she died in the ICU. Table 2 outlines the timing of major therapeutic interventions with hemoglobin levels and platelet counts. The patient was managed at Kafr Elsheikh University Hospital in Kafr Elsheikh, Egypt in mid-2025. The reporting of this study conforms to the Case Report (CARE) guidelines. ⁷ We have deidentified all patient details. Written informed consent for treatment was received from the patient.

Table 2.

Clinical course and follow up during Intensive Care Unit (ICU) stay.

ICU days	Hemoglobin (g/dL)	Platelet count (/mm³)	Key treatments/Events
Pre-ICU (ward)	11.0 → 3.5	90,000	Oral prednisolone (50 mg) started. Progressive hemolysis with hemodynamic instability → transfer to the ICU
Days 1–3	5.5 → 5.9	79,000 → 104,000	Pulse therapy: IV methylprednisolone (500 mg/day) started (planned 5-day course); patient was hemodynamically unstable but managed with fluids and pressors
Days 4–6	↑ to 8.6 → 6.4	110,000–80,000	Completion of steroid pulses (day 5); 600 mg rituximab (first dose for planned weekly protocol, which could not be completed); first intubation for tachypnea and respiratory fatigue; subsequently, the patient self-extubated
Days 7–10	7.0 → 5.2	67,000–43,000	Ongoing severe hemolysis; supportive ICU care
Days 11–13	5.0 (preplasmapheresis)	74,000 (preplasmapheresis)	Plasmapheresis attempted as salvage therapy; hemodynamic shock during first session → second intubation; patient remained unstable
Outcome	8.0	–	Death in the ICU despite maximal supportive measures and administration of 13 units of leukoreduced packed RBCs

ICU: intensive care unit; IV: intravenous; RBC: red blood cell; IV: intravenous.

Discussion

ES remains a diagnostic and therapeutic challenge, particularly in adult patients, in whom secondary causes must be carefully excluded. The diagnostic process requires ruling out autoimmune diseases (e.g. systemic lupus erythematosus and antiphospholipid syndrome), lymphoproliferative disorders, and infections, each of which can drive immune dysregulation and secondary ES.^1,8 In our patient, extensive workup, including autoimmune serologies and infectious screening, comprising ANA testing and tuberculosis (TB) polymerase chain reaction (PCR), failed to identify an underlying cause, thereby supporting the diagnosis of idiopathic ES.

A unique aspect of this case was the presence of caseating and noncaseating granulomas on lymph node biopsy. Such histological findings usually raise suspicion for noninfectious conditions such as sarcoidosis, granulomatous lymphomas, drug-induced granulomatous inflammation, or infectious diseases such as TB or fungal infections. However, a thorough workup that included autoimmune serology and chest X-ray showed no signs of any secondary illness. Granulomas are extremely rare and poorly described in the literature in association with ES.^4,9 These findings pose a diagnostic dilemma: should the granulomas be regarded as a nonspecific inflammatory variable, an early sign of a developing systemic illness, or an immunologic consequence of ES itself that has not yet been identified? This aspect distinguishes our case and may represent a previously underreported immunopathological variant.

More than 70% of adult patients with ES require at least two lines of medication during the disease, and approximately one-third experience several relapses despite initial treatment. ¹⁰ Currently, high-dose corticosteroids (typically 1–2 mg/kg/day prednisolone) and, in severe cases, intravenous immunoglobulin (IVIG) are a part of first-line therapy. Durable remissions are rare; according to studies, approximately 20%–30% of adult patients can maintain durable remission with steroids alone, indicating the need for second-line treatments. Our patient was treated with high-dose corticosteroids (500 mg prednisolone once daily for 5 days), followed by rituximab (600 mg) due to poor response. Rituximab, which targets CD20 on B cells, has demonstrated response rates of up to 82% in ES, although clinical improvement may take weeks. ⁴ Plasmapheresis was employed as a last-resort therapy, based on case reports suggesting possible benefit in severe disease, although evidence remains limited and it is not a part of standard guidelines.^11,12 The patient developed shock during the first session and later died despite receiving full supportive care. We cannot confirm direct causality between the initiation of plasmapheresis and hemodynamic instability as the patient was critically ill, anemic, and already at high risk of circulatory collapse, independent of the procedure. ¹³

The hallmark of ES is a chronically relapsing clinical course of disease that is often resistant to standard therapies, frequently necessitating escalation to intensified lines of immunosuppression and transfusion support. This is attributable to the interaction of autoantibody-driven cytopenias, T- and B-cell dysregulation, and genetic predispositions. ⁸ As a result of this long-term therapeutic approach, along with persistent or relapsing cytopenias, patients with ES are at increased risk of systemic complications, particularly thromboembolic events and serious infections. ¹⁴ Studies have reported that infections are a common and serious complication of ES, affecting approximately one-third of adult patients following diagnosis, with approximately 77% of these being grade-3 or -4 events. ⁹ Such risks contribute significantly to the syndrome’s overall morbidity and mortality rates.

The patient’s rapid deterioration, refractoriness to standard therapy, and hemodynamic collapse following plasmapheresis highlight the clinical challenges in managing relapsed ES, particularly in the presence of atypical immune features.

The absence of a postmortem examination limits definitive conclusions regarding the cause of the granulomatous lymphadenopathy and other potential contributors to clinical decline. In the absence of further histological analysis, the immune-mediated hypothesis remains speculative.

Conclusion

This case highlights the complexity of managing severe ES, especially in cases of relapse. It demonstrates the need for early identification of treatment resistance and timely use of second-line therapies such as rituximab. The unexpected finding of granulomatous lymphadenopathy in the absence of infection or malignancy raises important questions about the underlying immune mechanisms associated with ES. Based on the rapid clinical deterioration in our patient, we recommend proactive planning for second-line therapies in addition to close monitoring of the hemolytic and hemodynamic statuses throughout treatment. Ultimately, this case underscores the need for caution when using plasmapheresis in unstable patients. A multidisciplinary approach and further study of the immune features of adult ES are needed to guide safer and more effective management strategies.