| Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access |
| Article copyright, the authors; Journal compilation copyright, J Hematol and Elmer Press Inc |
| Journal website https://jh.elmerpub.com |
Review
Volume 000, Number 000, May 2025, pages 000-000
Evans Syndrome and COVID-19 Infection or Vaccination: A Systematic Review of Case Reports
Figure
Tables
| Author | Number of patients | Country of report | Patient age/sex | Comorbidities and medical history |
|---|---|---|---|---|
| CBC: complete blood count; cITP: chronic immune thrombocytopenia purpura; COVID-19: coronavirus disease 2019; DAT: direct antiglobulin test; DVT: deep vein thrombosis; ES: Evans syndrome; HELLP: hemolysis, elevated liver enzymes and low platelets; SLE: systemic lupus erythematosus. | ||||
| Demir et al, 2021 [24] | 1 | Turkey | 22/M | None. |
| Georgy et al, 2021 [30] | 1 | India | 33/M | None. |
| Ghariani et al, 2023 [29] | 1 | Tunisia | 27/F | None. |
| Li et al, 2020 [23] | 1 | United States | 39/M | None. |
| Mohammadien et al, 2022 [26] | 1 | Egypt | 54/M | Diabetic and Goza smoker. |
| Santosa et al, 2021 [25] | 1 | Indonesia | 29/F | Gravida 2, para 1, abortus 0, presenting at 39 weeks of gestation. No history of prior illnesses or complications during the previous pregnancy. HELLP syndrome was ruled out on admission. |
| Shah et al, 2022 [22] | 1 | United States | 75/F | 50 pack-year smoking. |
| Turgutkaya et al, 2022 [21] | 1 | Turkey | 63/F | Bilateral pulmonary embolism on admission. |
| Wahlster et al, 2020 [27] | 1 | United States | 17/M | Refractory cITP was well controlled on eltrombopag and mycophenolate. Previously negative DAT testing without signs of anemia or hemolysis. |
| Zama et al, 2022 [28] | 1 | Italy | 15/M | Not reported. |
| Zarza et al, 2020 [20] | 1 | Paraguay | 30/F | Diagnosed with DVT at age 11. Denied any family history of thrombosis. The most recent CBC, performed one year ago, was within normal limits. On admission, the patient was diagnosed with SLE with anti-phospholipid antibodies, concurrently with ES. |
| Author | Number of patients | Country of report | Patient age/sex | Comorbidities and medical history |
|---|---|---|---|---|
| COVID-19: coronavirus disease 2019; ES: Evans syndrome; LS: localized scleroderma; SLE: systemic lupus erythematosus. | ||||
| Cvetkovic et al, 2023 [35] | 1 | Italy | 85/M | Atrial fibrillation and hypertension, being treated with edoxaban, furosemide, bisoprolol, and canrenone. No history of thrombocytopenia. Unremarkable blood test parameters before receiving the vaccine except lymphocytopenia at 790 cells/µL. |
| De Felice et al, 2022 [32] | 1 | Germany | 56/F | No history of easily bruising or abnormal bleeding prior to receiving the vaccine. No evidence for hematological conditions. No family history of autoimmune disorders. On admission, diagnosis of LS was made. |
| Gambichler et al, 2022 [33] | 1 | Japan | 53/F | History of bronchial asthma, Vogt-Koyanagi-Harada disease, and Hashimoto disease. Anemia and thrombocytopenia not observed 3 months before admission. On admission, diagnosed with SLE. |
| Hidaka et al, 2022 [31] | 1 | Singapore | 43/F | History of SLE in 2-year remission on azathioprine, hydroxychloroquine, and prednisolone. |
| Ng et al, 2023 [34] | 1 | Serbia | 47/M | Splenectomized in April 2017, complete remission of ES. |
| Author | Patient presentation (signs and symptoms) | COVID-19 infection relationship (temporality) | Hematological parameters of ES | Verbatim diagnosis | Therapies administered | Response to treatment and outcome |
|---|---|---|---|---|---|---|
| Each case report which presented the findings of one patient was analyzed to collect the following: patient signs and symptoms, the temporal relationship between ES and COVID-19, hematological parameters and workup, the verbatim diagnosis provided, the therapy administered, the response to the therapy, and the outcome. AIHA: autoimmune hemolytic anemia; COVID-19: coronavirus disease 2019; DVT: deep vein thrombosis; ES: Evans syndrome; HRCT: high-resolution computed tomography; ITP: immune thrombocytopenia; IVIG: intravenous immunoglobulin; LDH: lactic dehydrogenase; PCR: polymerase chain reaction; RBC: red blood cell; SARS-CoV-2: severe acute respiratory syndrome coronavirus-2. | ||||||
| Demir et al, 2021 [24] | Jaundice, weakness, shortness of breath, fever, icteric sclerae, conjunctivae pale | On admission: CT findings consistent with COVID-19 pneumonia. 5 days following admission: rapid antibody test positive for IgM and IgG against SARS-CoV-2 | Hemoglobin 3.9 g/dL, platelet count 86 × 109/L, direct Coombs test: positive IgG 4(+), C3d, 4(+), LDH 792 U/L, indirect bilirubin 7.6 mg/dL, reticulocyte ratio 36%, corrected reticulocyte ratio 10.4%, reticulocyte count 352,000 cells/µL, no blasts or schistocytes | “SARS-CoV-2-associated ES due to AIHA and grade IV thrombocytopenia” | Hydroxychloroquine, moxifloxacin, favipiravir, methylprednisolone, intermittent subcutaneous enoxaparin, erythrocyte suspension, IVIG, plasmaphereses | On discharge: AIHA - partial response, ITP - partial response. Patient recovered |
| Georgy et al, 2021 [30] | 3 weeks of gum bleeding, black tarry stools, reddish spots on the skin, petechial lesions over the chest, legs, oral mucosa | On admission: nasopharyngeal swab RT-PCR for SARS-CoV-2 was positive | Hemoglobin 7.5 g/dL, platelet count 6 × 109/L, direct Coombs test: positive (2+), LDH 1,953 U/L, reticulocyte count 13.73%, smear: poikilocytosis, ovalocytes, and polychromatic cells with no schistocytes | “Evans syndrome induced by immune destruction” | Pulse dexamethasone, platelet transfusions, IVIG | AIHA - no response, ITP - no response. Patient expired on day 3 of admission |
| Ghariani et al, 2023 [29] | 4 days of epistaxis and gum bleeding, fever, cough, arthralgia, myalgia, asthenia, darkened urine color, itching, petechiae, bruises in lower limbs | On admission: a PCR COVID-19 test was positive | Hemoglobin 7.5 g/dL, platelet count 20 × 109/L, direct Coombs test: positive (4+) type IgG + C3d, LDH 749 U/L, reticulocyte count 200 G/L, indirect bilirubin 62 µmol/L, blood smear: spherocytes | “The comparison of clinical and biological data (jaundice, dark urine, petechial purpura, ecchymosis, combination of anemia and thrombocytopenia, positive TCD (IgG + C3d)) led to the diagnosis of ES secondary to infection with COVID-19” | IVIG, methylprednisolone, prednisone | On discharge: AIHA - partial response, ITP - partial response. Patient recovered |
| Li et al, 2020 [23] | One day of hemoptysis and epistaxis, 1 week of sore throat, productive cough, fever, chills and dyspnea, dried blood in the oropharynx, nares, and mouth. Second admission (10 days following initial admission): weakness, fatigue, intermittent fever, cough | About 7 days from COVID-19 symptoms to initial ES symptoms. During initial admission: positive rapid PCR assay for COVID-19 | Hemoglobin 15.6 to 6.4 g/dL, platelet count 3 × 109/L, no schistocytes nor microspherocytes on peripheral blood smear. Second admission (10 days following initial admission): hemoglobin 6.0 g/dL, direct Coombs test: positive (3+), reticulocyte count 22%, LDH 947 U/L, smear: microspherocytes, nucleated RBCs, and reticulocytes | “Clinical picture raised concern for ES versus immune hemolytic anemia secondary to IVIG.” | IVIG, therapeutic heparin for DVT complication | On discharge: AIHA - no response, ITP - complete response. Patient recovered |
| Mohammadien et al, 2022 [26] | Fever (39 °C), arthralgia, myalgia, fatigue, dark color of urine, pallor and jaundice. Second admission (6 days following initial admission): dyspnea, cough, progressive fatigue, jaundice | Second admission: HRCT chest revealed bilateral glass opacities in lungs, RT-PCR detected SARS-CoV-2 in nasopharyngeal swab. | Initial admission: hemoglobin 6.1 g/dL, platelet count 185 × 109/L, RBCs 2.23 × 1003/µL, indirect bilirubin 4.6 mg. 5 days following initial admission: hemoglobin 5.4 g/dL, platelet count 117 × 109/L, RBC 1.6 × 1003/µL, hematocrit 15.1%, reticulocyte count 12.5%, LDH 947 U/L, smear: anisopoikilocytosis, spherocytes. 6 days following initial admission: direct Coombs test: positive for immunoglobulin G and C3d | “At 6 days, combination of AIHA, ITP, and a positive direct Coombs test to IgG and C3d concluded the diagnosis of Evans syndrome secondary to SARS-CoV-2 infection (COVID-19)” | Packed RBCs, favipiravir, ivermectin, dexamethasone, prednisone, ceftriaxone, moxifloxacin, enoxaparin, and rivaroxaban. Supplemental O2 | On discharge: AIHA - partial response, ITP - partial response. Patient recovered |
| Santosa et al, 2021 [25] | Gross hematuria, dry cough, fever, dyspnea, nausea, anosmia, fatigue | Confirmed COVID-19 for 5 days on admission. On admission: chest X-ray showing bilateral bronchopneumonia | Hemoglobin 10 g/dL, platelet count 2 × 109/L, direct Coombs test: positive, blood smear: spherocytes, indirect bilirubin 2.9 mg/dL, reticulocyte count 1.9% | “Secondary Evans syndrome” | Remdesivir, moxifloxacin, dexamethasone, eltrombopag, methylprednisolone, cyclosporin, hydroxychloroquine, 2 units of platelet concentrate, 16 units of platelet, 5 units of leukodepleted packed red cells, 4 units of fresh frozen plasma, 2 units of convalescent plasma, supplemental O2 | On discharge: AIHA - partial response, ITP - partial response. Patient recovered |
| Shah et al, 2022 [22] | Shortness of breath. Second admission (3 weeks following initial admission): worsening shortness of breath | Asymptomatic COVID-19 pneumonia 2 weeks prior to initial admission | Initial admission discharge: hemoglobin 13.1 g/dL, platelet count 370 × 109/L. Second admission: hemoglobin 6.6 g/dL, platelet count 4 × 109/L, direct Coombs test: positive for IgG warm agglutinin | “COVID-19 pneumonia complicated by the development of ES” | Blood cell transfusions, dexamethasone, rituximab, IVIG, romiplostim, prednisone | On discharge: AIHA - no response, ITP - partial response. Patient recovered |
| Turgutkaya et al, 2022 [21] | Cough, high fever over several days | On admission: positive PCR, CT detected bilateral lung infiltrates indicative of COVID-19. 7 days following initial admission: increased weakness and petechiae in the legs | Hemoglobin 6.5 g/dL, platelet count 2 × 109/L, direct Coombs test: positive +4 for both IgG and C3 warm, LDH 426 U/L, absolute reticulocyte count 316,000/µL | “COVID-19-induced Evans syndrome” | IVIG, methylprednisolone, azathioprine | On discharge: AIHA - no response, ITP - partial response. Patient recovered |
| Wahlster et al, 2020 [27] | Progressive jaundice, pallor, fatigue, 4 days of emesis, diarrhea and fever, febrile, tachycardia, tachypnea, hypoxia, pallor, jaundice, increased work of breathing | On admission: PCR nasopharyngeal swab testing for SARS-CoV-2 was positive and negative for other respiratory viruses | Hemoglobin 2.5 g/dL, platelet count 94 × 109 cells/L, direct Coombs test: positive (IgG 2+, C3 2+), hematocrit 7.2%, reticulocyte count 0.61%, absolute reticulocytes 0.005 M cells/µL, indirect bilirubin 7.9 mg/dL, LDH 1,501 U/L, smear: microspherocytes, hypochromic microcytic red blood cells and large platelets | “Evans syndrome with warm autoimmune hemolytic anemia (AIHA)” | Intravenous corticosteroids, oxygen supplementation, red blood cell transfusion. | Inconclusive - numerical data post-treatment not provided, only: hemolysis and hemoglobin stabilized and bilirubin and LDH decreased within 48 h of corticosteroids. Patient recovered |
| Zama et al, 2022 [28] | Nausea, vomiting, asthenia, febrile, tachycardia, tachypnea, hepatosplenomegaly | On admission: A nasopharyngeal swab resulted in a positive SARS-CoV2 result | Hemoglobin 3.7 g/dL, platelet count 77 × 109/L with anti-platelet antibodies, direct Coombs test: positive with high title cold agglutinins (IgG+/C3d+), hematocrit 7.4%, bilirubin 3.51 mg/dL, LDH 425 U/L, smear: severe anisocytosis and aggregates of red blood cells | “Evans syndrome” | Red blood concentrates, intravenous prednisone, IVIG, prednisone | On discharge: AIHA - partial response, ITP - partial response. Patient recovered |
| Zarza et al, 2020 [20] | 9 days of upper respiratory symptoms, nasal congestion, a cough, loss of her taste and smell, a few days of sore throat, 1 day of gingivorrhagia. Second admission (4 days following initial admission): epistaxis, petechiae | 9 days from COVID-19 symptoms to initial ES symptoms. RT-PCR returned a positive COVID- 19 test 7 days following initial admission (3 days following second admission) | Initial admission: hemoglobin 8 g/dL Platelet count 2 × 109/L. 4 days later: hemoglobin 8.9 g/dL, platelet count 34 × 109/L, direct Coombs test: positive, C4 = 8 mg/dL, hematocrit 25%, reticulocyte count 7% | “SARS-CoV-2 infection, SLE with associated antiphospholipid antibodies and Evans syndrome” | IV methylprednisolone, azithromycin, hydroxychloroquine, enoxaparin, prednisone, ceftriaxone. Treatment with IVIG was not performed due to patient improvement | On discharge: AIHA - no response, ITP - partial response. Patient recovered |
| Author | Patient presentation (signs and symptoms) | COVID-19 vaccination relationship (temporality) | Hematological parameters of ES | Verbatim diagnosis | Therapies administered | Response to treatment and outcome |
|---|---|---|---|---|---|---|
| Each case report which presented the findings of one patient, was analyzed to collect the following: patient signs and symptoms, the temporal relationship between ES and COVID-19, hematological parameters and workup, the verbatim diagnosis provided, the therapy administered, the response to the therapy, and the outcome. AIHA: autoimmune hemolytic anemia; COVID-19: coronavirus disease 2019; ES: Evans syndrome; ITP: immune thrombocytopenia; IVIG: intravenous immunoglobulin; LDH: lactic dehydrogenase; PCR: polymerase chain reaction; RBC: red blood cell; SARS-CoV-2: severe acute respiratory syndrome coronavirus-2. | ||||||
| Cvetkovic et al, 2023 [35] | Initial admission (day 8 post-vaccination): ecchymoses on extremities and oral bleeding. Second admission (day 28 after vaccination): sudden weakness, jaundice, dark brown urine, pallor, and icteric | Eight days after the second dose of BNT162b2 (Pfizer- BioNTech) COVID-19 vaccine | Initial admission: hemoglobin 15.3 g/dL, platelet count 8 × 109/L. Second admission: hemoglobin of 4.5 g/dL, platelet count of 27 ×109/L, direct Coombs test (anti-IgG antibody +++, anti-C3 antibody -) positive, reticulocytes of 10.4%, indirect bilirubin 86.8 µmol/L, LDH 633 U/L | “Relapsing ES that occurred after the second dose of BNT162b2 (Pfizer- BioNTech) mRNA COVID-19 vaccine” | Prednisone, azathioprine, two doses dexamethasone, IVIGs were introduced, 10 units of packed red blood cells | On discharge: AIHA - partial response, ITP - complete response. Patient recovered |
| De Felice et al, 2022 [32] | Large hematoma in right shoulder area, widespread ecchymosis, icteric scleras, pale conjunctivas | Vaccine administered: Comirnaty® SARS-CoV-2 (Pfizer-BioNTech). Local ecchymosis 48 h after vaccine and admitted after 7 days. No infiltrate on CXR and PCR for COVID-19 was negative | Hemoglobin 10 g/dL, platelet count 8 × 109/L, direct Coombs test: positive 3+, LDH 400 U/L, indirect bilirubin 1.2 mg/dL, reticulocytes 10% | “A diagnosis of post- vaccination ES was made based on the hematological findings which also included a bone marrow biopsy” | Methylprednisolone, five IVIG administrations, rituximab, eltrombopag, prednisone | On discharge: AIHA - partial response, ITP - complete response. Patient recovered |
| Gambichler et al, 2022 [33] | Bruising after minor trauma, brownish urine, 3-day history of oral, nasal, genital, and intestinal bleedings, petechiae on extremities, hemorrhagic bullae of the tongue, oral and genital mucosa, yellowish sclera, large bruise on foot | 2 weeks after receiving first dose of ChAdOx1 nCoV-19 (AstraZeneca) vaccine. Viral serology was negative for SARS-CoV-2 | Hemoglobin 9.9 g/dL, platelet count 1 × 109/L, fell to 0/L within 24 h of admittance, direct Coombs test: positive for warm anti-IgG antisera with panreactive specificity, erythrocytes 2.8/µL, hematocrit 28.3%, reticulocytes 25%, LDH 248 U/L, smear: mild anisocytosis, polychromasia, absence of thrombocytes | “Based on these clinical and laboratory findings, we diagnosed the patient with COVID-19 vaccine induced Evans’ syndrome preceded by a new onset of LS.” | High-dose prednisolone, dexamethasone, IVIG | On 3 months after admission: AIHA - no response, ITP - partial response. Patient recovered |
| Hidaka et al, 2022 [31] | Shortness of breath, yellowing skin, bulbar conjunctiva, anemic palpebral conjunctiva, wheezing at inspiration | Received two doses of BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech) at 5 and 2 weeks before admission.. After the first dose, transient (few days) purpura in her extremities and wheezing, after the second dose, thrombocytopenia with mild anemia | Hemoglobin 6.9 g/dL, platelet count 39 × 109/L, direct Coombs test: positive, RBCs 180 × 104/µL, reticulocytes 36.54 × 104/µL, indirect bilirubin 6.1 mg/dL, LDH 771 U/L | “Development of Evans syndrome associated with SLE and exacerbation of bronchial asthma following mRNA COVID-19 vaccination.” | Prednisolone, RBC transfusion | 2 weeks after admission: AIHA - partial response, ITP - partial response. Patient recovered |
| Ng et al, 2023 [34] | Initial admission: 1 week of lethargy, headache, exertional dyspnea, near syncope, and few days of gum bleeding and bruising. Physical exam: pale and lethargic looking | 1 week after second dose of SARS-CoV2 BNT162b2 (Pfizer-BioNTech) mRNA vaccine | Hemoglobin 5.8 g/dL, platelet count 7 × 109/L, direct Coombs test: positive, LDH 2,226 U/L, reticulocytes 125.9 × 109/L | “The new-onset autoimmune hemolytic anemia and immune thrombocytopenia were consistent with Evans syndrome (ES), which signified a major SLE flare” | Pulse intravenous methylprednisolone, IVIG, and rituximab | 2 weeks after admission: AIHA - partial response, ITP - complete response. Patient recovered |