Evans syndrome in the course of COVID-19 infection, essentials and approaches

Redundant studies proved coronavirus infection results from a defect in a suitable immune response that may exacerbate immune-inflammatory reactions like cytokine storm and autoimmunity. Evans syndrome (ES) is a rare chronic autoimmune disease that distinguishes it from autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP). Reports have shown significant differences in immune cells and laboratory parameters in Evans syndrome/COVID-19 co-infected patients. Also, the contribution between autoimmune diseases and SARS-CoV-2 infection could result in immune response disequilibrium that considers a possible mechanism for ES development. Moreover, we will briefly explain the double-edged sword role of immunosuppressive drugs in Evans syndrome/ COVID-19 co-infected patients. Generally, the pathophysiology of SARS-CoV-2 in hematologic autoimmune disorders progression, particularly ES, remains unclear, but some investigations explain the COVID-19 infection mechanism in the mentioned disorders development. The purpose of the current study is to look at the coronavirus effects on Evans syndrome aggravation, the immune cells and laboratory markers alterations in Evans syndrome/COVID-19 co-infected patients, the coronavirus effects on Evans syndrome patients during their pregnancy, and the Evans syndrome / COVID-19 co-infected patient management. Copyright © 2022, Iranian Pediatric Hematology and Oncology Society. All rights reserved.

COVID-19-INDUCED EVANS SYNDROME: UNUSUAL COMPLICATION OF THE NEW USUAL

SESSION TITLE: Management of COVID-19-Induced Complications SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Evans syndrome (ES) is a rare autoimmune disorder characterized by the combination of two or more cytopenias with an incidence of 0.8-3.7%.Here we present a case of COVID-19 pneumonia complicated by the development of ES. CASE PRESENTATION: A 75-year-old female with the past medical history of 50 pack-year smoking, recent asymptomatic COVID-19 Pneumonia 2 week ago came to the emergency room (ER) with shortness of breath. Her vitals and physical exam were unremarkable. Labs were significant for leukocytosis of 11.66 and D-dimer of 3.32. CT pulmonary angiogram showed bilateral pulmonary embolism along with a COVID-19 pattern of pneumonia. She was started on heparin drip and was eventually discharged on Warfarin with Prednisone taper. After 3 weeks, she presented to the ER with worsening shortness of breath. She was found to have platelet count of 4k and Hb of 6.6 gm%(compared to 370k and 13.1 gm% on last discharge) and was started on transfusions which could not be completed due to development of mid-transfusion fever. She received Dexamethasone and IVIG. All forms of active bleeding were ruled out by bronchoscopy, CT scans and EGD. Flow cytometry was negative for ADAMTS13 ruling out thrombotic thrombocytopenic purpura. Bone marrow biopsy was unremarkable. She was positive for IgG warm agglutinin hemolytic anemia. She was discharged on long-term Prednisone taper. In the clinic she was given intermittent IVIG and Romiplostim to improve her counts. Due to multiple failed attempts to wean her off steroids, she was started on Rituximab with an excellent response of platelets increment to 450k and Hb to 8.5 gm%. Rituximab will be given for a total of 8 weeks. DISCUSSION: ES is considered to be caused by immune system dysregulation. ES in COVID-19 is a diagnostic dilemma as the thrombocytopenia is usually misdiagnosed as COVID-19 sequelae and leads to delay in diagnosis. The treatment of ES is usually with steroids 1 mg/kg/day but they only provide short term improvement. Rituximab, plasma exchange, IVIG, and splenectomy are second-line treatments for relapsing/refractory ES. Our patient had an acceptable response to steroids but it was transient,demonstrating the limited role of steroids in the long term and was eventually treated successfully with Rituximab. A review of limited published cases of ES caused by COVID-19 suggests that diagnosis, treatments, and prognosis are usually individualized according to patient characteristics, presenting symptoms, physician preference, and disease complications. CONCLUSIONS: ES is a very rare syndrome although it requires prompt treatment. It is important to be mindful about immunological causes when a COVID-19 patient presents with cytopenia, as delay in treatment can cause poor outcomes. Reference #1: Turgutkaya A, Bolaman AZ, Yavaşoğlu Í. COVID-19-associated Evans syndrome: A case report and review of the literature. Transfus Apher Sci. 2021 Dec 7:103339. doi: 10.1016/j.transci.2021.103339. Epub ahead of print. PMID: 34896007;PMCID: PMC8655821. DISCLOSURES: No relevant relationships by Nitesh Jain No relevant relationships by Kashyap Kela No relevant relationships by Princy Shah No relevant relationships by namita sharma No relevant relationships by AMIT SHARMA

A CASE OF REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA INDUCED IMMUNE THROMBOCYTOPENIC PURPURA SUCCESSFULLY TREATED WITH VENETOCLAX

Background: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. Approximately 2% of patients with CLL develop immune thrombocytopenic purpura (ITP) during the course of the disease. When resistant to steroids, this constitutes as indication for treatment of the CLL. Here we report a patient with refractory ITP secondary to CLL successfully treated with venetoclax. Aims: To present an interesting case with CLL related refractory ITP treated successfully with novel agent venetoclax. Methods: Patient data was taken from the patient herself and Hospital records. Informed consent to publish the case is obtained from patient. Permission for off-label venetoclax and eltrombopag was obtained from Ministry of Health of Turkey. Results: 46-year-old female patient presented with lumps on her neck that were present for the last 9 months in November 2020. She has a history of frequent pneumonia and otitis but no constitutional symptoms. Her physical examination reveals multiple 2cm lymphadenopathies on her neck and no organomegaly or other pathological features. Blood work shows mild lymphocytosis (6800/mm3) with no serious cytopenias. Peripheral blood smear, flow cytometry and bone marrow biopsy were all compatible with CLL. She was classified as Binet A CLL and was followed up with no treatment after appropriate vaccinations against capsulated pathogens. In July and August 2021 she received two doses of mRNA vaccination against COVID-19. On 1st November 2021 she experienced excessive menstrual bleeding and blood work showed platelet count of 23000/mm3, she was started on steroids (1 mg/kg/day) and after 4 days platelet count has risen to 55000/mm3, she discontinued steroids on her own against medical advice. On 13th of November she presented with extensive petechiae and purpura and was again started on steroids and was given the courses of intravenous immunoglobulins (IVIG) without any sustained response. She was refractory to platelet transfusions too. She was transferred to our clinic. She was found to have del11q and del13q. She refused bone marrow examination. She was treated with rituximab, steroids, vincristine, IVIG and eltrombopag for ITP without success (Fig. 1). She had a minimal response to IVIG only. She received two courses of bendamustine (90 mg/kg for two days) also without success. Three courses of plasmapheresis yielded no response either. After mild success with immunadsorbtion apharesis she was started on venetoclax plus rituximab with ramp-up. Sustained response was achieved within the first week of venetoclax therapy. (Figure Presented ) Summary/Conclusion: Gordon et al. reported 2 CLL cases one with ITP and other with Evans syndrome successfully treated with venetoclax. We think, this treatment should be considered in patients with refractory immune cytopenias secondary to CLL and assessed with prospective clinical trials.

MANAGEMENT OF AUTOIMMUNE HAEMOLYTIC ANAEMIA DURING PREGNANCY OR POST-PARTUM: AN INTERNATIONAL MULTI-CENTRE EXPERIENCE

Background: Autoimmune haemolytic anaemia (AIHA) during pregnancy is a rare finding, and few is known about maternal and foetal outcomes. AIHA may either develop or relapse during gestation and postpartum or be an issue in a patient on active therapy who becomes pregnant. AIHA management during pregnancy and lactation is not standardized and drug use is often limited by safety concerns. Aims: We studied AIHA impact on pregnancy focusing on disease severity, treatment need and maternal/foetal outcome. Methods: Through a multicentric retrospective cohort study, we identified 38 pregnancies occurred in 28 women from 1997 to 2021 in 10 European centres in Italy, Denmark, France, the Netherlands, USA, and Spain. All included patients had a previous AIHA history or developed/exacerbated AIHA during gestation or postpartum. AIHA was classified according to the direct antiglobulin test. Results: We registered 18 warm AIHA (10 IgG;8 IgG+C3d), 2 cold agglutinin disease, 3 mixed and 5 atypical forms (Table 1). Evans syndrome (i.e., association of AIHA and immune thrombocytopenia or neutropenia) was present in 4. Mean age at AIHA diagnosis was 27 (3-39) and at pregnancy 32 (21-41) years. AIHA diagnosis predated pregnancy in 15 women and had required at least 1 therapy line in all of them, and >2 lines in 12 (rituximab, N=7;cytotoxic immunosuppressants, N=6;splenectomy, N=5). Among these 15 patients, 6 had a relapse during pregnancy, 3 during postpartum and 9 were on active treatment at the time of pregnancy (steroids, N=8;cyclosporine, N=1;azathioprine, N=1;the latter stopped after positive pregnancy test). A patient with a previous AIHA, relapsed as immune thrombocytopenic purpura during pregnancy. Further 8 patients had an AIHA onset during gestation and 2 postpartum. A patient had AIHA onset during the postpartum of the 1st pregnancy and relapsed during the 2nd one. In the 20 women experiencing AIHA during pregnancy/postpartum, median Hb and LDH levels were 6,4 g/dL (3,1 - 8,7) and 588 UI/L (269-1631), respectively. Management consisted in blood transfusions (N=10) and prompt establishment of steroid therapy+/-IVIG (N=20), all with response (complete N=13, partial N=7). After delivery, rituximab was necessary in 4 patients and cyclosporine was added in one. Anti-thrombotic prophylaxis was given in 7 patients. Overall, we registered 10 obstetric complications (10/38, 26%), including 4 early miscarriages, a premature rupture of membranes, a placental detachment, 2 preeclampsia, a postpartum infection and a biliary colic. Apart from the case of biliary colic and one of the two cases of preeclampsia, 8/10 complications occurred during active haemolysis and treatment for AIHA. Nine foetal adverse events (9/38, 24%) were reported: a transitory respiratory distress of the new-born in a mother with active AIHA, 3 cases of foetal growth restriction, a preterm birth, an infant reporting neurologic sequelae, a case of AIHA of the new-born requiring intravenous immunoglobulins, blood transfusions and plasma exchange, and 2 perinatal deaths. The latter both occurred in women on active AIHA therapy and were secondary to a massive placental detachment and a symptomatic SARS-CoV-2 infection. (Figure Presented ) Summary/Conclusion: AIHA developing/reactivating during pregnancy or postpartum is rare (about 5%) but mainly severe requiring steroid therapy and transfusions. Importantly, severe maternal and foetal complications may occur in up to 26% of cases mostly associated with active disease, pinpointing the importance of maintaining a high level of awareness. Passive maternal autoantibodies transfer to the foetus seems a rare event.

Unexpected Thrombocytopenia in a Parturient With Evans Syndrome Complicated by COVID-19 Infection.

We report the case of a 23-year-old parturient who received epidural analgesia and was subsequently diagnosed with Evans syndrome (ES). The diagnosis was made after a complete blood count (CBC) resulted in severe anemia and a platelet count of less than 10K/µL. To further complicate this case, the patient developed post-delivery pleuritic chest pain and pulmonary emboli (PE), and a chest computed tomography (CT) scan showed bilateral ground-glass lung opacities. This prompted a COVID-19 testing and ultimately confirmed infection.

COVID-19 Vaccines and Autoimmune Hematologic Disorders.

Worldwide vaccination against SARS-CoV-2 has allowed the detection of hematologic autoimmune complications. Adverse events (AEs) of this nature had been previously observed in association with other vaccines. The underlying mechanisms are not totally understood, although mimicry between viral and self-antigens plays a relevant role. It is important to remark that, although the incidence of these AEs is extremely low, their evolution may lead to life-threatening scenarios if treatment is not readily initiated. Hematologic autoimmune AEs have been associated with both mRNA and adenoviral vector-based SARS-CoV-2 vaccines. The main reported entities are secondary immune thrombocytopenia, immune thrombotic thrombocytopenic purpura, autoimmune hemolytic anemia, Evans syndrome, and a newly described disorder, so-called vaccine-induced immune thrombotic thrombocytopenia (VITT). The hallmark of VITT is the presence of anti-platelet factor 4 autoantibodies able to trigger platelet activation. Patients with VITT present with thrombocytopenia and may develop thrombosis in unusual locations such as cerebral beds. The management of hematologic autoimmune AEs does not differ significantly from that of these disorders in a non-vaccine context, thus addressing autoantibody production and bleeding/thromboembolic risk. This means that clinicians must be aware of their distinctive signs in order to diagnose them and initiate treatment as soon as possible.

Evans Syndrome Presenting as an Atypical Complication of SARS-CoV-2 Vaccination.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has drastically affected our daily lives, causing millions of deaths worldwide. The early and late complications of this infection are being increasingly revealed on a regular basis; however, an important brake on the spread and especially the lethality of the disease has been guaranteed by the introduction of mRNA-based and viral vector-based COVID-19 Vaccines. Also, an increasing number of adverse effects of the vaccination have been reported to specific pharmacovigilance boards, most of them totally non-serious events that are resolved within one to three days after the administration of the vaccine. In this report, we present a case of Evans syndrome (ES) secondary to SARS-CoV-2 vaccination in an 85-year-old male patient. To the best of our knowledge, this is the first case of ES caused by the COVID-19 vaccination to be reported in the literature.

A rare case of calvarial tuberculosis in post-COVID-19 scenario.

Isolated calvarial involvement with tuberculosis (TB) is a very rare entity, with the incidence of only 0.01% of all patients with mycobacterial infections. The factors attributable could be malnutrition, poor socioeconomic conditions, and immunodeficiency syndromes. We hereby present the case of a 35-year-old male who had recently recovered from coronavirus disease 2019 and a diagnosed case of Evan's syndrome with secondary hemophagocytic lymphohistiocytosis who presented with a scalp swelling on the right frontotemporal region. He presented to the emergency department with acute-onset generalized tonic - clonic seizures with high-grade fever. Clinically, the swelling appeared like a cystic swelling of the scalp. On evaluation, there was a collection present below the scalp communicating with the extradural space, involving the underlying skull bone. The patient was operated with drainage of the abscess plus excision of the pathological underlying skull bone. The pus revealed florid amount of acid-fast bacillus on Ziehl-Neelsen staining. The patient was started on four drugs Category 1 antitubercular regimen. The patient responded well to the combined surgical and medical treatment. It should be emphasized that TB can involve any part of the body. It should be kept as differential diagnosis of any chronic inflammatory lesion involving the bony skeleton, especially in endemic countries where combined surgical and medical treatment is usually sufficient to provide a cure.

Identifying systemic lupus erythematosus presenting as hemorrhagic oral bullae in a covid positive pediatric patient

Case Report A previously healthy 13 year-old female presented with painful, oral mucosal bullae filled with sanguinous fluid. She was initially (mis)diagnosed with angina bullosa haemorrhagica (ABH) and was provided symptomatic treatment. After a CBC demonstrated severe thrombocytopenia, anemia, and leukopenia, the patient was admitted for further workup including Coombs and COVID-19 PCR, which were both positive. Given a remote family history of Lupus and increasing right knee pain, further diagnostic testing was ordered. These results demonstrated a positive ANA, anti-Smith, anti-chromatin, anti-RNP, increased dsDNA and increased SM/RMP, confirming Lupus as the etiology of this patient's presentation. A form of Blistering Systemic Lupus Erythematosus (BSLE) was likely responsible for the patient's oral manifestations. The patient was discharged on Prednisone 30 mg twice per day after receiving 60 g IVIG and 3 days of high dose pulse corticosteroids. Discussion This outlines the case of a thirteen yearold girl with SLE with an initial presentation of blood-filled oral mucosal lesions. The patient's COVID-19 positive status, young age, and atypical presentation added to the intricacy of her case. After presenting with blood-filled bullae in the oral cavity, the patient was initially suspected of having Angina Bullosa Haemorrhagica (ABH). ABH is a rare condition that presents with painful or painless blood-filled oral vesicles or bullae that rupture spontaneously and heal without scarring. The patient's abnormal CBC ruled out ABH and suggested a diagnosis of Evan's syndrome, a disorder in which cytopenias are present in two or more cell lines. Before SLE was determined to be the cause of the patient's cytopenias, the etiology of her Evan's syndrome was attributed to her COVID-19 positive status. Rarely, Lupus has been reported to present with vesicles and bullae in a syndrome known as BSLE. Upon an extensive review of the literature, only four articles mentioned oral bullae in a pediatric patient with SLE and not a single article mentioned hemorrhagic bullae in pediatric SLE patients. Conclusion A deeper understanding of the variety of cutaneous manifestations of SLE is essential for disease diagnosis and management. The present study details the first ever reported case of SLE presenting with blood-filled oral bullae in a pediatric patient. Novel presentations of SLE such as this reinforce the need for a collaborative, inter-specialty approach to diagnosis and treatment of autoimmune disease. This case reinforces the utility of a centralized database for recording unique autoimmune manifestations in order to aid in physicians' diagnosis and expediency of treatment. Lastly, this case should support an increase in a clinician's degree of suspicion for underlying autoimmune disease when dealing with unique cutaneous presentations of autoimmune diseases like SLE.

Autoimmune Cytopenias and Covid-19 Vaccination: Relapse and Suggested Treatment

Introduction: There are “de novo” and relapsed autoimmune diseases in patients with COVID-19 that includes autoimmune thrombocytopenia, Evans syndrome and autoimmune hemolytic anemia among others (Hematology 2021;26:225-239 and Curr Rheumatol Rev 2021;17:193-204). There is scanty material about relapse of autoimmune hematological diseases after vaccination for COVID-19 (Blood Adv 2021;13:2794-2798). Material and methods: Adult patients 18 years or older with autoimmune thrombocytopenia, Evans syndrome and autoimmune hemolytic anemia who completed SARS-Cov2 vaccination. Results: Between December 2020 and June 2021 there were identified 53 patients with autoimmune hematological disease that completed SARS-Cov2 vaccination. Thirty-six with autoimmune thrombocytopenia, all were preexisting. Twelve with autoimmune hemolytic anemia, 5 secondaries to previous COVID-19 and 7 preexisting. Five with Evans syndrome, all preexisting. Twenty-three patients with autoimmune thrombocytopenia did not develop any fall in the platelet count. Ten patients had a fall of 50 % from basal counts and recovered spontaneously. Three patients developed counts below 30,000 with purpuric symptoms and needed treatment that consisted in two courses of dexamethasone 40 mg daily for four days every three weeks;all patients reached complete remission without any further treatment. All patients with Evans syndrome developed hemolysis and low platelet counts. Two patients maintained Hb levels above 10 and platelet counts above 50,000;both patients had spontaneously recovery. Three patients developed Hb levels below 7 with anemic syndrome and platelets below 50,000 but without purpuric syndrome;they received the same treatment as patients with autoimmune thrombocytopenia and reached complete remission too. All five patients with autoimmune hemolytic anemia secondary to COVID-19 developed Hb levels below 7 with anemic symptoms and needed treatment as described. The remaining 7 patients with preexisting autoimmune anemia developed hemolysis;five with Hb levels above 7 and recovery without any treatment;two had Hb levels below 7 and received the same treatment with full recovery and complete remission. Conclusions: Autoimmune cytopenias can be trigger by vaccines and viral infections by involving molecular mimicry and circulating immune complexes, including SARS-Cov2. The viral protein spike from SARS-Cov2 has mimicry between the Ankyrin-1 in the erythrocyte surface, and has been linked as one of the pathogenesis pathways of autoimmune hemolytic anemia secondary to COVID-19 (Br J Haematol 2020;190:e92-e93 and Blood 2020;136:suppl8,138001). Relapse of autoimmune cytopenias after vaccination with SARS-Cov2 involves stimulation of autoantibodies production from preexisting B cells. Although relapses were observed in the three kinds of patients, all with hemolytic component developed a drop in the hemoglobin levels, most of them needed treatment. It is important to notice that patients with hemolytic autoimmune anemia secondary COVID-19 had severe relapse, event that support the mimicry mentioned lines above. It is important to follow up closely this kind of patients after SARS-CoV2 vaccination, we suggest weekly complete blood counts, and a short courses of high dose dexamethasone can induce curable responses if treatment is advised. Disclosures: No relevant conflicts of interest to declare.

A full-term pregnant woman with secondary Evans syndrome caused by severe coronavirus disease 2019: a case report.

BACKGROUND: In this report, we describe a very challenging case of a patient with secondary Evans syndrome caused by severe coronavirus disease 2019 infection in a pregnant full-term woman. CASE PRESENTATION: A 29-year-old full-term pregnant Indonesian woman presented with gross hematuria, dry cough, fever, dyspnea, nausea, anosmia, and fatigue 5 days after confirmation of coronavirus disease 2019 infection. Laboratory examinations showed very severe thrombocytopenia, increased indirect bilirubin, and a positive direct Coombs' test. From peripheral blood, there was an increased number of spherocytes, which indicated an autoimmune hemolytic process. Antinuclear antibody and anti-double-stranded DNA test results were negative, and her virology serological markers are also negative for human immunodeficiency virus, cytomegalovirus, and hepatitis B and C. Despite aggressive treatment with platelet transfusion, high-dose steroid, and thrombopoietin receptor agonists, the platelet count did not recover, and a speculative cesarean delivery had to be done with a very low platelet count.

New-onset Evans syndrome associated with systemic lupus erythematosus after BNT162b2 mRNA COVID-19 vaccination.

Evans syndrome presents as concurrent autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). Systemic lupus erythematosus (SLE) is the most frequent autoimmune disorder associated with Evans syndrome. We herein report a case of new-onset Evans syndrome associated with SLE after BNT162b2 mRNA coronavirus disease 2019 (COVID-19) vaccination in a 53-year-old woman. Blood examination at diagnosis showed hemolytic anemia with a positive Coombs test and thrombocytopenia. Hypocomplementemia and the presence of lupus anticoagulant indicated a strong association with SLE. Prednisolone administration rapidly restored hemoglobin level and platelet count. This case suggests that mRNA COVID-19 vaccination may cause an autoimmune disorder. Physicians should be aware of this adverse reaction by mRNA COVID-19 vaccination and should consider the benefits and risks of vaccination for each recipient.

ADEM post-Sars-CoV-2 infection in a pediatric patient with Fisher-Evans syndrome.

INTRODUCTION: Sars-CoV-2 is a single-strained RNA virus belonging to Coronaviridae's family. In pediatric age, the majority of patients is asymptomatic; however, several neurological manifestations associated with Sars-CoV-2 infection have been detected in a percentage of cases ranging from 17.3 to 36.4%. Acute disseminated encephalomyelitis (ADEM) has been recently included among the potential complications of Sars-Cov2 infection. The available data regarding pediatric patient show only one case. CASE REPORT: We present a case regarding a 6-year-old patient suffering from Fisher-Evans syndrome who was given sirolimus and thalidomide therapy. After 10 days since the first positive nasopharyngeal swab for Sars-CoV-2, in which he had no symptoms, he presented an episode of generalized tonic-clonic seizure with spontaneous resolution. The patient underwent MRI which showed the typical picture of acute disseminated encephalomyelitis. His clinical course was favorable, with a good response to cortisone therapy and a progressive improvement of the neuroradiological and electroencephalographic picture. CONCLUSIONS: According to our knowledge, this is the second case of an acute disseminated encephalomyelitis following SARS-CoV-2 infection in a pediatric patient, characterized by monosymptomatic onset, in which the immunosuppressive therapy practiced for the Fisher-Evans syndrome has probably contributed to a favorable evolution of ADEM, in contrast to other case described in the literature.

Immune dysregulation and multisystem inflammatory syndrome in children (MIS-C) in individuals with haploinsufficiency of SOCS1.

BACKGROUND: We studied 2 unrelated patients with immune thrombocytopenia and autoimmune hemolytic anemia in the setting of acute infections. One patient developed multisystem inflammatory syndrome in children in the setting of a severe acute respiratory syndrome coronavirus 2 infection. OBJECTIVES: We sought to identify the mechanisms underlying the development of infection-driven autoimmune cytopenias. METHODS: Whole-exome sequencing was performed on both patients, and the impact of the identified variants was validated by functional assays using the patients' PBMCs. RESULTS: Each patient was found to have a unique heterozygous truncation variant in suppressor of cytokine signaling 1 (SOCS1). SOCS1 is an essential negative regulator of type I and type II IFN signaling. The patients' PBMCs showed increased levels of signal transducer and activator of transcription 1 phosphorylation and a transcriptional signature characterized by increased expression of type I and type II IFN-stimulated genes and proapoptotic genes. The enhanced IFN signature exhibited by the patients' unstimulated PBMCs parallels the hyperinflammatory state associated with multisystem inflammatory syndrome in children, suggesting the contributions of SOCS1 in regulating the inflammatory response characteristic of multisystem inflammatory syndrome in children. CONCLUSIONS: Heterozygous loss-of-function SOCS1 mutations are associated with enhanced IFN signaling and increased immune cell activation, thereby predisposing to infection-associated autoimmune cytopenias.