A Case of X-Linked Moesin-Associated Immune Deficiency in a Pediatric Patient

Background: X-Linked Moesin-Associated Immune Deficiency (X-MAID) is a rare severe combined immunodeficiency (SCID) subtype that can present at any age due to its variability. Depending on severity, patients demonstrate failure to thrive, recurrent bacterial and viral infections, and increased susceptibility to varicella zoster. It has been characterized by marked lymphopenia with hypogammaglobulinemia and impaired T-cell migration and proliferation. Case Presentation: This is a report of a Cuban 7-year-old male with poor weight gain and facial dysmorphia. He had a history of recurrent bacterial gastrointestinal infections and pneumonia beginning at 4 months of age. He additionally had 4-6 upper respiratory tract and ear infections annually. While still living in Cuba, he was admitted for a profound EBV infection in the setting of significant leukopenia. A bone marrow biopsy confirmed no malignancy. After he moved to the United States, his laboratory work-up revealed marked leukopenia with low absolute neutrophil and lymphocyte count with low T and B cells, very low immunoglobulin levels IgG, IgA, and IgM, and poor vaccination responses to streptococcus pneumonia, varicella zoster, and SARS-CoV-2. Genetic testing revealed a missense pathogenic variant c.511C>T (p.Arg171Trp) in the moesin (MSN) gene associated with X-MAID. He was managed with Bactrim and acyclovir prophylaxis, and immunoglobulin replacement therapy, and considered for hematopoietic stem cell transplantation. Discussion(s): Diagnosis of X-MAID should be considered in patients with recurrent infections and profound lymphopenia. As with SCID, early diagnosis and intervention is of utmost importance to prevent morbidity and mortality. This case demonstrates the importance of genetic testing in identifying this disease as it may prompt an immunologist to consider HSCT if conservative management is suboptimal. In the current literature, HSCT appears promising, but the long-term outcomes have yet to be described.Copyright © 2023 Elsevier Inc.

A Case of a Relapsing Remitting Macrophage Activating Syndrome After Covid-19 Vaccine In a Teenager with UNC13D Heterozygous Variant of Uncertain Significance

Introduction: Macrophage activation syndrome (MAS) is a severe hyper inflammatory condition caused by the over-activation and proliferation of T cells, NK cells and macrophages. It is often associated with complications of rheumatic/immune diseases. We present a case of a 15-year-old female who experiences recurrent episodes of MAS without any known definitive underlying etiology. Case Presentation: A 15-year-old previously healthy female developed fatigue, fevers, myalgia, chest pain, splenomegaly and lymphadenopathy 10 days after receiving her first Pfizer COVID-19 vaccine. Her symptoms recurred 10 days after receiving the second dose. Her myocarditis, MIS-C, and infectious work up was negative except for positive EBV IgG. Laboratory studies revealed anemia, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. She initially responded to decadron;however, her symptoms recurred with steroid taper. Bone marrow biopsy revealed hemophagocytosis. Whole exome sequencing (WES) revealed a heterozygous variant of uncertain significance in UNC13D c.962C>A (p.Thr321Asn). She had multiple re-admissions with significantly elevated inflammatory markers, including extremely high IL2-R, IL-18 and CXCL9. Each episode was complicated by an acute viral infection. She responds to high dose steroids, anti-IL-1, and JAK inhibitors. Nonetheless, it has been difficult to wean decadron without triggering a flare. She continues to require increasing doses of baricitinib. Discussion(s): MAS may be seen as a complication of rheumatic diseases, as well as inborn errors of immunity. However, none of these conditions have been diagnosed in this patient despite extensive testing, including WES. The degree of her immune dysregulation has been very severe making her disease process unpredictable and extremely difficult to control. She has frequent flares precipitated by viral infections or attempts at adjusting her immunomodulators. Weaning her medications has been challenging as she continues to require increasing doses of baricitinib and corticosteroids. The UNC13D gene is associated with autosomal recessive familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Our patient is heterozygous for an UNC13D variant of uncertain significance. Additional genetic inquiries with whole genome sequencing to help elucidate the underlying etiology of her severe condition is being conducted. We hypothesize she developed MAS due to a combination of genetic predisposition, prior EBV infection, and immune stress associated with the COVID-19 vaccine. [Formula presented] [Formula presented] [Formula presented]Copyright © 2023 Elsevier Inc.

Disseminated Mucormycosis in a patient on long term immunosuppression: Severe fungal infections as multi-system disorders

Introduction: Mucormycosis is a rare, severe fungal infection with an incidence of 0.005 to 0.17 per million.1 but incidence has risen recently, particularly in the Asian subcontinent, due to use of immunosuppression for Covid19.2 Presentations can vary and are classified into: rhino-orbito-cerebral, pulmonary, cutaneous, disseminated, renal and gastrointestinal. Risk factors include diabetes, immunosuppression, iron overload, malnutrition, and prematurity.1,3 Although mucormycosis has an extremely high mortality rate and disseminated infection is usually fatal, treatment options exist if diagnosed early and surgical debridement may be curative. Objective(s): We present a case of mucormycois in a female patient in her 40s who was immunosuppressed with methotrexate for rheumatoid disease. This case is discussed to increase awareness of critical illness caused by opportunistic invasive fungal infections in immunosuppressed patients and promote timely identification and management. Method(s): We detail the clinical context and management of a patient with mucormycosis and discuss relevant literature. Result(s): A female patient in her 40s who had been experiencing upper respiratory tract symptoms for several weeks, including cough and brown sputum, was admitted with a presumptive diagnosis of methotrexate toxicity after a full blood count performed by the general practitioner demonstrated pancytopenia. Initially, National Early Warning System 2 score (NEWS2) was 2 but became intensely hypertensive during blood transfusion and then profoundly shocked with an escalating NEWS2. Broad-spectrum antibiotics and fluconazole were commenced for neutropenic sepsis and the patient was referred to critical care in multiple organ failure. Computerised tomography (CT) scan of the chest, abdomen and pelvis showed "left upper lobe consolidation, which with neutropenia might represent an angioinvasive aspergillosis". She had multiple areas of skin discolouration and desquamation. Haematology and Infectious Diseases opinions were sought, and a bone marrow biopsy was performed which showed severe toxic effects consistent with sepsis/life threatening infection. Progressive proptosis was noted, and CT scan of her head was requested. Sadly, she was never stable enough for CT transfer. Beta D Glucan and aspergillus antigen serology was negative. Broncho-alveolar lavage demonstrated Candida albicans and then, later, Rhizopus arrhizus was isolated and anti-fungal treatment changed to voriconazole and then amphotericin B. Upon reviewing the notes in light of the positive culture for Rhizopus, the patient had likely been exhibiting symptomatic Mucormycosis sinus infection for some time prior to this admission with disseminated infection. The patient's condition continued to deteriorate and she sadly died. Conclusion(s): * The Early Warning Score significantly underestimated how unwell the patient was upon arrival in ED, a systems-based assessment would have demonstrated that the patient had multiple system dysfunction and significant potential to deteriorate suddenly despite having stable observations * The methotrexate level has no clinical value in diagnosing or refuting a diagnosis of methotrexate toxicity * A full examination of the immunosuppressed patient including ENT is a necessity when searching for a source of infection * Invasive fungal infections can cause multi-system symptoms and atypical presentations * As a greater proportion of patients have received systemic immunosuppression for Covid-19, vigilance for more unusual pathogens, including Mucormycosis by clinicians is advised.

Anaplastic Large-Cell Lymphoma (ALCL) First Manifested as a Rapidly Progressive Acute Respiratory Failure (RF): Lymph Node Biopsy Negative Presentation Posing a Diagnostic Challenge.

Anaplastic large-cell lymphoma (ALCL) is an aggressive subtype of non-Hodgkin lymphoma. There are two forms of ALCL: primary and secondary. Primary can be systemic, affecting multiple organs, or cutaneous, affecting mainly the skin. A secondary form occurs when another lymphoma undergoes an anaplastic transformation. ALCL rarely presents as initial symptoms of respiratory failure. In most of these situations, the trachea or bronchial involved with an obstruction was present. We present an unusual case of ALCL where the patient rapidly progressed to acute hypoxic respiratory failure with a patent bronchus and trachea. Unfortunately, the patient rapidly deteriorated and died before diagnosis. Only upon at autopsy, it was found that his lung parenchyma was diffusely involved with ALCL. The autopsy report showed that the patient had CD-30 anaplastic lymphoma kinase (ALK)-negative ALCL diffusely involving all lung fields.

Esophageal Mucosal Calcinosis: A Rare Site of Calcium Deposition in End-Stage Renal Disease

Introduction: Calciphylaxis, otherwise known as calcium uremic arteriolopathy, is defined as calcium deposition around blood vessels in skin and fat tissue which occurs in 1-4% of patients with end-stage renal disease (ESRD). Calcium deposition in the esophagus is extremely rare;to date, there have been only 4 cases reported worldwide. We report the fifth case of esophageal mucosal calcinosis occurring in a young male with ESRD. Case Description/Methods: A 37-year-old Thai man with ESRD on peritoneal dialysis since 2005 presented with generalized weakness and odynophagia due to oral ulcers, resulting in poor PO intake. He denied drinking alcohol, illicit drug use, or smoking. On exam his abdomen was soft, non-distended, non-tender, without any guarding. Past medical history included hypertension and COVID-19 in January 2022. Laboratory tests revealed neutropenia and pancytopenia, hyperphosphatemia, and hypocalcemia. EGD revealed distal esophageal esophagitis and hemorrhagic erosive gastropathy. Biopsy showed ulcerative esophagitis with dystrophic calcification, consistent with esophageal mucosal calcinosis .No intestinal metaplasia was noted. Immunohistochemistry was negative for CMV, HSV1, and HSV2. The patient was treated with pantoprazole 40mg IV every 12 hours, Magic Mouthwash 5ml qid, and Carafate 10mg qid. He was transferred to a cancer center where he had a bone marrow biopsy formed which was negative. His symptoms resolved and the patient was discharged to home (Figure). Discussion(s): Esophageal mucosal calcinosis is extremely rare. It is due to a combination of factors involving acidosis and the phenotypic differentiation (and apoptosis) of vascular smooth muscle cells (VSMC) into chondrocytes or osteoblast-like cells. These changes, along with the passive accumulation of calcium and phosphate, induce calcification. Acidosis is well-known to promote inflammation of the arterial walls, releasing cytokines that induce vascular calcification. The benefits of treatment with sodium thiosulfate remain unclear. An ample collection of cases should help devise standardized treatment options and establish management guidelines for this condition.

IgM Multiple Myeloma Presenting With Diarrhea

Introduction: IgM Multiple Myeloma (MM) is a rare subtype of MM consisting of <1% cases of MM. It is distinguished from Waldenstrom Macroglobinemia, which also produces IgM, by the absence of somatic mutation MYD88. We present a patient with a chief complaint of diarrhea which unknowingly led to his hematological diagnosis Case Description/Methods: A 64 year old male with RA-SLE overlap syndrome on steroids, and recent COVID19 pneumonia, had presented with 5 episodes of watery diarrhea every day and 40 Ib weight loss within 2 months. CT revealed small bowel enteritis and stool studies, including C. diff, cultures, ova and parasites were negative. Diarrhea persisted despite antibiotics, therefore an EGD and Colonoscopy were performed which showed duodenal lymphangiectasia and a normal colon. Duodenal biopsy revealed eosinophilic deposits in the villous lamina propria which stained for IgM and stained negative under congo red ruling out amyloidosis. SPEP and a bone marrow biopsy revealed monoclonal IgMspikes and plasma cells in the bone marrow suggesting MMalong with a co-existing population of CLL. Next-generation sequencing was negative forMYD88, supporting IgM MM instead of Waldenstrom. He developed a protein-losing enteropathy with dramatic hypoalbuminemia (albumin 0.9) and lower extremity edema and DVTs. He was started on chemotherapy and frequent albumin infusions. His diarrhea completely resolved, however not in time, as his other medical comorbidities lagged behind and he developed anasarca and continued to deteriorate. Discussion(s): Plasma cell dyscrasias such as IgM MM or more commonly Waldenstrom have rarely been reported to cause GI symptoms. GI involvement can include direct GI infiltration of plasma cells, IgM deposition, or the finding of a plasmacytoma. It has been speculated that IgM deposits can lead to interstitial viscosity and obstructive lymphangiectasia leading to diarrhea and a protein-losing enteropathy as in our patient. Protein loss has led him to have hypoalbuminemia and possibly loss of antithrombotic proteins that have caused DVTs. Few case reports have suggested that treating the underlying cause with chemotherapy stops diarrhea entirely. Although our patient's diarrhea ceased, we believe that it was not in time for him to entirely recover from the later complications of the disease. We hope that this case can help clinicians to attempt prompt treatment of patients when they find GI specimens showing IgM deposits and they suspect a plasma cell dyscrasia.

Acute myeloid leukemia complicated by post COVID-19 multi-system inflammatory syndrome-children

Corona Virus disease 2019 (COVID-19) pandemic has presented a huge challenge to the health care system in terms of magnitude of cases and to pediatric oncology units with varied clinical presentations. Acute myeloid leukemia(AML) is a rare heterogenous cancer of childhood with an induction mortality around 15% in our country due to neutropenic sepsis. Multisystem inflammatory syndrome in children(MIS-C) is an hyperinflammatory syndrome seen 4–6 weeks after COVID-19 infection. COVID infection in some of these children would have gone unnoticed. Here we report a two year eight months old boy diagnosed with AML on induction chemotherapy developed post COVID MIS-C. © 2022

Solid organ graft-versus-host disease in a recipient of a COVID-19 positive liver graft

A 66-year-old male with end-stage liver disease (ESLD) secondary to non-alcoholic fatty liver disease (NAFLD), complicated by hepatocellular carcinoma (HCC), underwent deceased donor liver transplantation from a Coronavirus disease 2019 (COVID-19) positive donor. He presented a month later with fever, diarrhea and pancytopenia which led to hospitalization. The hospital course was notable for respiratory failure, attributed to invasive aspergillosis, as well as a diffuse rash. A bone marrow biopsy revealed hypocellular marrow without specific findings. In the following days, laboratory parameters raised concern for secondary hemophagocytic lymphohistiocytosis (HLH). Clinical concern also grew for solid organ transplant graft-versus-host-disease (SOT-GVHD) based on repeat marrow biopsy with elevated donor-derived CD3+ T cells on chimerism. After, a multidisciplinary discussion, the patient was started on ruxolitinib, in addition to high dose steroids, to address both SOT-GVHD and secondary HLH. Patient developed symptoms concerning for hemorrhagic stroke and was transitioned to comfort care. Although GVHD has been studied extensively in hematopoietic stem cell transplant (HSCT) patients, it is a rare entity in SOT with a lack of guidelines for management. Additionally, whether COVID-19 may play a role in development of SOT-GVDH has not been explored.Copyright © 2023 The Authors

An 81-Year-old Woman With Proximal Weakness

An 81-year-old woman developed progressive proximal weakness and myalgias several months following a COVID-19 infection. She was admitted to her local hospital for progressive weakness, peripheral edema, and exertional dyspnea. Neurology evaluation noted proximal arm and leg weakness. She had creatine kinase 740 U/L, white blood cells 21,000/mL (with abnormal differential), and abnormal antibody serologies. Additional diagnostic testing obtained included a thigh MRI and muscle biopsy. During her COVID-19 admission, a mediastinal mass had been detected, which was increased in size on this current admission. Notably, she had a remote history of an incidentally discovered mediastinal mass, which had been incompletely resected 18 years prior. At neuromuscular follow-up one month later, she reported improvement in peripheral edema and dyspnea but ongoing weakness. Strength exam noted symmetric Medical Research Council grade 4 weakness in neck flexion/extension, shoulder abduction, elbow flexion/extension, wrist extension, hip flexion/abduction/extension, and knee flexion. She had no fatiguability and no facial or bulbar weakness. Remainder of her neuromuscular examination was unremarkable. Her white blood cell count differential remained abnormal but had improved from her initial presentation. Her recent muscle biopsy slides were reviewed again. Bone marrow biopsy and mediastinal mass biopsy were obtained. A unifying diagnosis was made, and she was started on therapy with resolution of her weakness, myalgias, and abnormal cell counts.

Lympho-no: a happy ending to a mediastinal mass

Case Report: Mediastinal masses are rare with an incidence of 1 in 100 000 [1]. While the differential is broad, the risk of malignancy is higher in the pediatric population. Lymphomas account for about 50% of mediastinal masses [2].We present a patient with superior vena cava (SVC) syndrome from a mediastinal mass, concerning for lymphoma. After extensive work up, the mass was determined to be reactive. Case Presentation: A 5-year-old male, presented with one day of left sided face and neck swelling. Review of systemswas positive for a fewweeks of cough but notably negative for night sweats, fatigue, fever, or weight loss. Computed tomography (CT) scan (Figure 1, left) showed a heterogeneous mass, most concerning for lymphoma. Blood work was notable for lymphopenia (640 x 103/uL), elevated lactate dehydrogenase and uric acid (549 U/L and 7.1 mg/dL respectively). He tested positive for SARs- CoV2 RNA on nasopharyngeal PCR. Upon admission, he was started on methylprednisolone and allopurinol. A bone marrow biopsy and a lumbar puncture were unrevealing for immunophenotypic evidence of lymphoid neoplasm. A mediastinal biopsy showed fibrosis with patchy inflammation and inadequate number of viable cells to allow for flow cytometric analysis. A post-biopsy echocardiogram revealed a moderate sized pericardial effusion which eventually resolved. He was discharged with infectious disease and oncology follow up. Later, histoplasma and bartonella antibodies, and T spot were negative. A CT (Figure 1, right), ten days after initial presentation showed significant decrease in size of the mediastinal mass. At one month follow up, he remained clinically well with a normal chest x-ray. [Figure presented] Fig 1: A CT ten days after initial presentation showed significant decrease in size of the mediastinal mass Conclusion(s): This patient presented with SVC syndrome from a mediastinal mass that resolved with 3 days of intravenous steroids. The initial presumed diagnosis of lymphoma was ultimately inconsistent with the extensive workup, and the mass was ultimately deemed reactive. COVID-19 related mediastinal mass is not described in the literature, and although possible, remains unlikely. This case represents the importance of avoiding premature closure and keeping a broad differential diagnosis. 1. Park DR, Vallieres E. The mediastinal mass. Murray and Nadel's Textbook of Respiratory Medicine. 5th edn. Philadelphia, PA: Saunders;2010. pp. 1814-35. 2. Glick R. D., & La Quaglia M. P. (1999). Lymphomas of the anterior mediastinum. Seminars in Pediatric Surgery, 8(2),69-77.Copyright © 2023 Southern Society for Clinical Investigation.

Minor Procedures in Patients with Congenital Bleeding Disorders - One Centre Experience

Introduction: Patients with congenital bleeding disorders (CBD) have an increased bleeding tendency, which varies according to the factor deficiency and severity. In most cases, prolonged bleeding is observed after trauma, surgery and/or invasive procedures. Haemostatic treatment is needed to prevent bleeding complications and allow a good clinical outcome. Our aim is to evaluate the management of patients with CBD in minor procedures. Method(s): Retrospective study of patients with CBD who performed minor procedures over a 7-year period, through review of clinical files. Result(s): Between January 2015 and December 2021, 249 minor procedures were performed in 113 patients with CBD: 42 had diagnosis of Haemophilia A (HA) (15 severe without inhibitors;3 severe with inhibitors;4 moderate and 20 mild);12 had Haemophilia B (HB) (7 severe without inhibitors;2 moderate and 3 mild);5 were carriers of HA and 2 of HB. 35 had von Willebrand disease (VWD);15 had rare bleeding disorders (8 FVII deficiency;6 FXI deficiency;1 FX deficiency) and 2 had diagnosis of inherited platelet glycoprotein deficiencies (1 Glanzmann thrombasthenia and 1 Bernard Soulier syndrome). Most procedures were dental treatments (189);synoviorthesis/ infiltration/mesotherapy (17);endoscopies and colonoscopies (15);skin lesions excision (8);COVID-19 vaccination (5);sebaceous cyst excision (4);cardiac catheterization (3);ureteral stent removal (3);bone marrow biopsy (2);cystoscopy (2) and breast fibroadenoma excision (1). Prophylactic treatment was performed in 237 (95%) of the procedures, respectively FVIII concentrate factor (59);FIX concentrate factor (27);DDAVP (66);von Willebrand factor/factor VIII concentrates (44);bypassing agents (24);platelet (6);inactivated human plasma (9);tranexamic acid (47) and epsilon-aminocaproic acid (161). No side effects were reported. Discussion/Conclusion: Most patients that underwent minor procedures had Haemophilia and VDW(83%). The most common procedure was dental treatment (76%). Patients with CBD require attention and special care in dental practice. The haemostatic prophylactic treatment varies according to the specific haemostatic defect, severity and type of procedure. The treatment performed has been demonstrated safe and effective, with low incidences of haemorrhagic and treatment-related complications. These patients' treatment requires multidisciplinary teams and reference centres.

GATA2 deficiency presenting as fever and rash

Case Report: Our patient is an 8-year-old Caucasian female with a history of choanal atresia, first degree heart block, recurrent urinary tract infections, and recent COVID-19 infection, who initially presented with an episode of syncope and vomiting. By history, she had two weeks of daily fever and an intermittent nonspecific rash. She was diagnosed with a UTI 5 days prior to presentation but had not defervesced despite treatment. Shewas initially found to be in shock with tachycardia and poor perfusion and was treated with fluid resuscitation, antipyretics, and empiric antibiotics. Labs were significant for leukopenia, elevated inflammatory markers, lactic acidosis, coagulopathy, and mildly elevated troponin. Chest x-ray showed abnormal but non-specific widespread infiltrates. She was initially treated with IVIG and pulse steroids for a working diagnosis of MIS-C, however she did not improve and a more extensive infectious, oncologic, and rheumatologic work-up was performed. Her workup revealed a disseminated Mycobacterium abscessus infection. Bone marrow biopsy revealed myelodysplasia with monosomy 7. Her buccal swab testing revealed a heterozygous germline mutation in the GATA2 gene, a variant that is predicted to cause loss of normal protein function. She is presently on multidrug regimen for her mycobacterial infection. Her myelodysplasia evolved into an acute leukemia, and she is undergoing chemotherapy for that at this time. Discussion(s): GATA2 deficiency, first identified in 2011, is a rare immune disorder resulting in a wide variety of clinical presentations. It is caused by a germline mutation of the GATA2 gene that disrupts blood cell differentiation, resulting in decreased or absent monocytes, B cells, NK cells, and dendritic cells1. This case presented multiple challenges due to the broad range of differential diagnoses. This patient was ultimately diagnosed with myelodysplastic syndrome associated with monosomy 7 and GATA2 deficiency, confirmed by FISH testing. Due to the presentation and lab derangements this patient had, there was a delay in targeted treatment while managing her cytopenias and presumed pulmonary infection. GATA2 deficiency carries a high risk of progression from myelodysplastic syndrome to acute myelogenous leukemia. The best long-term treatment for GATA2 deficiency is hematopoietic stem cell transplant, which is the ultimate goal for our patient. Copyright © 2023 Southern Society for Clinical Investigation.

Diamond-blackfan anemia in an adult

Case Report: A 25-year-old woman with history of Diamond-Blackfan anemia (DBA) presented with a 3- week history of weakness and fatigue. The patient was in her usual state of health until 3 weeks prior when she was diagnosed with COVID-19, at which time she experienced cough, congestion, weakness, and fatigue. She reported that the cough and congestion improved after a few days, but the fatigue and weakness progressively worsened. Admission labs were notable for a hemoglobin of 5.5 g/dL with a MCV of 119.3 fL. She received 2 units of packed RBCs with improvement in hemoglobin to 8.9 g/dL. The patient was diagnosed with DBA at birth via bone marrow biopsy and had been stable on chronic prednisone with a baseline hemoglobin around 8 g/dL. Prior to this admission, she has only required one transfusion at 3 months old. Her outpatient management involved close monitoring of her hemoglobin and increasing/decreasing prednisone based on her trending hemoglobin. She had been stable on 15 mg/day of prednisone for the past few years. Her hematologist was consulted, and the decision was made to increase her dose of prednisone to 20 mg/day resulting in resolution of symptoms and stabilization of her hemoglobin level. Discussion(s): We present a rare case of DBA with worsening anemia in the setting of a recent COVID-19 infection. The literature regarding the risk and complications of COVID-19 in these patients is severely limited, with no current data on disease management, outcomes, or predictors of morbidity. DBA is a rare, congenital erythroid red cell aplasia that typically presents in infancy with an estimated incidence of 5 cases per 1 million births. DBA is characterized by progressive macrocytic anemia, congenital malformations, and increased risk of endocrine dysfunction and malignancies. Glucocorticoids are the first-line therapy for DBA, although the exact mechanism of how they stimulate erythropoiesis in DBA remains unknown. In terms of patient prognosis, approximately 40% are steroid-dependent, 40% are transfusiondependent, and 20% go into remission by age 25 years. Copyright © 2023 Southern Society for Clinical Investigation.

Idiopathic Hypereosinophilic Syndrome Diagnosed in an Infant: A Case Report

Introduction: Idiopathic hypereosinophilic syndrome (IHES) is a rare disorder characterized by persistent eosinophilia (>1.5 x 109/L) for >=6 months, tissue infiltration with end-organ damage, and exclusion of known causes for hypereosinophilia. It is mainly observed in adults, and rarely in children. We report, to our knowledge, the first case report of IHES in an infant. Case Description: A 5-month-old male presented with severe failure to thrive and malnutrition. His hospitalization was complicated by acute kidney injury, pulmonary edema requiring intubation, pseudomonas bacteremia with concomitant tibial osteomyelitis, COVID-19 infection, and bradycardic arrest requiring CPR. Notably, patient had persistent eosinophilia (maximum 11.4 x 109/L) (Table 1). Parasite testing was negative. Immune work-up was normal (Table 1). Primary immunodeficiency panel testing of 407 geneswas negative. Endoscopy revealed eosinophilia in the sigmoid colon and rectum. Bone marrow biopsy revealed a low normocellular bone marrow (70%) with maturing trilineage hematopoiesis and increased eosinophils and eosinophil precursors (approximately 50% of nucleated cells). A FISH panel was negative for PDGRFRA/4q12, PDGRFRB/5q33, FGFR1/8p12, and ETV6/12p13 gene regions. The patient was diagnosed with IHES and started on steroids at 0.5 mg/kg/day. Hydroxyurea was added due to up-trending eosinophil count despite steroid therapy. Three months post-diagnosis, he is doing well off medications, with most recent eosinophil count being 2.1 x 109/L. Discussion(s): Hypereosinophilia in children is most commonly due to secondary causes such as atopic dermatitis, parasitic infections, neoplasms, graft-versus-host disease, sickle cell disease, and immunodeficiency. Once the above diagnoses have been excluded, IHES should be considered, especially in patients with evidence of end-organ damage. Copyright © 2022

Hyperviscosity Syndrome Complicating Igg Myeloma - Cognizance of Early Plasmapheresis Is Crucial

BACKGROUND: Hyperviscosity syndrome (HVS) is an infrequent but life-threatening complication of multiple myeloma (MM) and classically presents with the triad of mucosal bleed neurological and visual disturbances. HVS is typically associated with Immunoglobulin M (IgM) MM and very rarely may complicate IgG MM. Even suspicion of HVS necessitates therapy based on clinical severity rather than the calculated degree of viscosity. While plasmapheresis promptly decreases serum viscosity by 30-50% early initiation of antimyeloma therapy is crucial to prevent rebound phenomena. AIM OF THE STUDY: In this context, we report a case of IgG MM which despite being complicated by HVS had gratifying outcome attributable to early clinical suspicion and consequent prompt therapeutic intervention. METHOD(S): Case report - A 60-year-old lady presented with headache altered sensorium blurring of vision and bleeding from both nostrils of two days duration. She also had breathlessness on exertion and generalized fatigue for one month. Clinical evaluation was remarkable for pallor hypertension (blood pressure - 160/96 mm Hg) tachypnea (respiratory rate - 26/minute) with blood clots in nostrils bleeding from gums dry tongue and skin bruising on the arms. Besides altered mentation neurological evaluation revealed bilateral venous congestion and perivenular flame-shaped hemorrhages on direct ophthalmoscopy. There were no features of heart failure peripheral lymphadenopathy or organomegaly. Her initial blood sampling was difficult as blood was rapidly clogging during sampling itself. After rapid saline infusion, samples could be drawn and processed. Hemogram showed normocytic normochromic anemia (hemoglobin-6.3%g/ dL) thrombocytopenia (platelets -71 000/mm3) and rouleaux formation without hemolysis or blast cells on peripheral blood smear. SARS-CoV-2 PCR was negative. She had reversal of albumin-globulin ratio (total protein -10.6 g/dL;albumin -2.1 g/dL) hypercalcemia (corrected calcium - 14 mg/dL) and raised creatinine of 2.5 mg/dL. Her coagulation profile was essentially normal. Computed tomography images of head chest and abdomen were essentially normal. Further evaluation revealed M-spike (5.3%gm/dL) on serum protein electrophoresis raised IgG (4.69 g/dL) increased kappa light chain (kappa 171 mg/L lambda 24.3 mg/L;ratio -7) on serum-free light chain assay monoclonal band of IgG Kappa on serum immune-fixation electrophoresis. Bone marrow aspiration revealed 60% plasma cells (Figure-1) with sheets of plasma cell on bone marrow biopsy having kappa-restriction on immunohistochemistry thereby confirming multiple myeloma and ruled out remote possibility of lymphoplasmacytic lymphoma-related HVS. In view of presumptive HVS complicating multiple myeloma patient was managed with urgent plasmapheresis and consequently initiated on bortezomib-based anti-myeloma triplet therapy including lenalidomide and dexamethasone (VRd) besides supportive therapy for hypercalcemia and acute kidney injury. After three sessions of plasmapheresis patient showed complete resolution of symptoms of HVS with remarkable change in plasma color (Figure-2). Her acute kidney injury also recovered by day-7, and she went home walking on day-10 of her hospitalization. Two months later she was tolerating her chemotherapy well with complete resolution of hypergammaglobulinemia. Six months later she is in complete remission and is being planned for autologous hematopoietic stem cell transplant. RESULT(S): Discussion - Classical triad of HVS include mucosal bleed, neurological disorders, and visual disturbances.5 Presence of oro-nasal bleed mandates thorough retinal evaluation since hemorrhages may occur without visual symptomatology. Furthermore, clinical signs include hypertension, congestive heart failure5, priapism6, and decreased hearing merit consideration. Structure of protein is an important determinant of viscosity, whereby spherical proteins rotate through plasma and contribute very little and large linear proteins spin end over end and raise viscosity disproportionatel . Likewise, IgM (molecular weight of 950 Kd) has a high axial length-to-width ratio and, therefore, raises plasma viscosity at levels above 5 g/ dL. IgA circulates as a dimer, and results in HVS at levels above 7 g/dL7. HVS complicating IgG MM with IgG circulating as a monomer (molecular weight of 180 Kd) is rare and accounts for less than 5% of cases and requires IgG level usually above 10 g/dL7. Even presumptive suspicion of HVS necessitates therapy based on clinical severity rather than the calculated degree of viscosity as correlation between serum viscosity and clinical manifestation is not precise;nevertheless, symptoms attributable to HVS are rare if serum viscosity is less than 4 centipoise (CP) [normal value -1.5 CP]. With rapid symptomatic relief following plasmapheresis, absence of further therapeutic and prognostic implications and logistic constraints, serum viscosity and Ig G subtyping8 couldn't be estimated in the index case. As IgM is predominantly limited to intravascular space (over 80%), only a single session of plasma exchange (removal of 1-1.5 plasma volume) typically, decrease plasma viscosity by 30% to 50%, and reduce IgM level by 60%9 and is generally sufficient to abate acute symptoms in patients with IgM-related HVS. In contrast, maximum of three sessions of plasmapheresis10 may be needed in IgG-related HVS (due to late and less efficient removal of IgG as it is near equally distributed between the intravascular space and extravascular space) or if the viscosity remains over six CP11. Although International Myeloma Working Group does not specifically identify HVS as myeloma-defining event, clearly its presence warrants Bortezomib-based chemotherapy for rapid decline of Ig levels.5 However, pharmacological treatment should never be considered as an alternative to plasma exchange for immediate hyperviscosity reduction.5 Moreover, patients with HVS tend to have plasma volume expansion;hence, actual anemia may be partially dilutional. Consequential red blood cell transfusion can have negative rheological impact of adding red cells to the circulation and further increase in blood viscosity and worsen HVS.5 Therefore, red blood cell transfusion is recommended only after blood viscosity reduction. Symptomatic HVS consequent to IgG MM with IgG levels below 5 g/dL7 is infrequent and hence reported for its novelty. Moreover, early clinical suspicion of HVS and consequent pre-emptive plasmapheresis (even before completion of work-up of MM) may improve clinical outcome as evident in the index case. CONCLUSION(S): To conclude, neurological dysfunction at presentation of MM with / without mucosal bleed and visual disturbance should caution us toward an albeit infrequent, yet devastating complication of HVS, which is otherwise potentially reversible subject to early clinical suspicion and prompt initiation of appropriate therapy.

CASPR-2 Antibody Associated Autoimmunity in the Setting of COVID-19 (Infection, Vaccination, or Both?) and Chronic Lymphocytic Leukemia: Case Report and Review of the Literature

Objective To report a case of Anti-Contactin-Associated Protein-like2 (CASPR-2) autoimmunity in a patient with low-grade Chronic Lymphocytic Leukemia (CLL) following COVID-19 vaccination and infection. Background Anti-CASPR2 antibody disorder has been associated with neoplastic disorders like thymoma. Recent reports enlist COVID-19 as apotential trigger of CASPR2 autoimmunity. While the clinical presentations are similar, management differs based on the underlying etiology. Design/Methods We review a case of anti-CASPR2-antibody associated disorder with concurrent low grade CLL and recent history of COVID-19 vaccination and infection. Additionally, we review the literature and discuss the therapeutic challenges. Results A 73-years old male presented with five months of progressive fatigue, weight loss, diffuse sweating, muscle cramps, and neuropathic pain. He eventually developed bilateral upper and lower facial weakness. Patient contracted a mild COVID-19 infection two months prior and COVID- 19 vaccination one month prior to his symptom onset. His exam was remarkable for bilateral facial weakness, diffuse fasciculations and sensory neuropathy on his trunk and extremities. His diagnostic work up including bone marrow biopsy was consistent with a chronic lymphocytic leukemia (CLL)-like immunophenotype. Cerebrospinal fluid (CSF) analysis was remarkable for five WBC (lymph-dominant) and protein of 74 mg/dl. Serum paraneoplastic panel revealed positive CASPR2 antibody with a titer of 1:100. Magnetic Resonance Imaging (MRI) of the brain showed enhancement of bilateral cranial nerve VII. After lack of clinical response to IV methylprednisone (1 gram for 5 days), patient was treated with a single cycle of IV immunoglobulin (IVIG). He had complete recovery of his symptoms except for residual facial weakness. He remains stable at his six months post-treatment follow-up. Conclusions Anti-CASPR2 associated autoimmunity following COVID-19 infection or in the setting of CLL has previously been reported. However, cranial neuropathy in association with CASPR2 antibody has never been. A trial of IVIG could be beneficial in patients with viral-spike protein-induced autoimmunity and CLL who do not otherwise meet the criteria for CLL treatment.

Severe Autoimmune Hemolytic Anemia in a Young Child with Active Covid-19 Infection

INTRODUCTION: Autoimmune hematological complications related to COVID-19 are rare. There are only 5 pediatric case reports of autoimmune hemolytic anemia (AIHA) among 14 million pediatric COVID-19 cases in USA. Four were older (13-17 years), two had underlying autoimmune/hematologic conditions. Immunologic analysis varied, with cold, warm & mixed hemolytic anemias described. We present a previously healthy child with COVID-19 associated severe AIHA with peripheral reticulocytopenia. DESCRIPTION: A 3-year-old male presented with lethargy, fever, tachycardia and jaundice 10 days after COVID-19 diagnosis. Pertinent labs include hemoglobin (Hgb) 3.8 g/dL, Hct 9.9%, bilirubin 3.6 mg/dL, platelets 321,000/muL, RBC count 1.2 M/muL, WBC 35,600/muL, MCV 82.5fL. Reticulocyte count (RC) was only 2.8%. Peripheral blood smear showed anisocytosis, poikilocytosis, nucleated RBCs and left shifted granulocytosis. Bone marrow biopsy revealed erythroid hyperplasia without underlying malignancy;myeloid:erythroid ratio of 0.3:1. The outside hospital reported cold C3 agglutination following 4degreeC incubation, while our laboratory identified spontaneous agglutination at room temperature (warm agglutination). IV fluids, O2, and methylprednisolone (4 mg/kg/day) were started and two packed RBC transfusions (total 30 ml/kg) given for symptomatic anemia with Hgb < 4 g/dL. LDH peaked at 2255 U/L on Day 3. Reticulocyte count was low (2.8%-3.8%) Days 1-3, increased to 6.5% on Day 4 and peaked at >30.0% on Day 7. He was changed to oral prednisone 2 mg/kg/day on Day 12 and discharged on Day 13 with Hgb 7.0 g/dL and RC 29.9%. Most recent Hgb is 13.0 g/dL and RC 2.6%. DISCUSSION: COVID-19 associated AIHA is rare, and previously reported mostly in older children. Our patient was previously healthy, and demonstrated a strong bone marrow response with erythroid hyperplasia. Peripheral reticulocytosis was delayed, and correlated with initiation of systemic steroid therapy. Our patient had both cold and warm agglutination supporting extensive autoimmune destruction of early red cell lineage. These findings support immune activation during acute COVID-19 infection and COVID-19 as a trigger for AIHA. Patients developing AIHA may need to be tested for COVID-19 and carefully monitored for complications.

Aplastic Anemia Following SARS-COV-2 Infection

Introduction: COVID 19 is caused by a novel virus SARS-CoV-2.It has become a pandemic as declared by WHO with its first case being reported in China. Among children the intensity is usually mild and without any further impact. Aims & Objectives: Unusual presentation of aplastic anemia following SARS-CoV-2 infection: A rare case report. Material(s) and Method(s): A 6 year old male child presented with complaints of rashes and epistaxis for 2 weeks and also one episode of blood in stools.Two weeks prior to the onset of above complaints, the patient had a history of recovery from COVID -19.Blood investigations revealed pancytopenia with hemoglobin of 5.6 gm/dl,total leukocyte count of 2000/cumm and platelets were 43,000/cumm.The corrected reticulocyte count was 0.3%.Bone marrow examination done showed completely hemodilutedsmears.Bone marrow biopsy revealed a markedly hypocellular marrow with cellularity of 10% and the cellular components being replaced by fat spaces. Result(s): Based on the above findings, and other viral markers being negative a diagnosis of aplastic anaemia following SARS CoV-2 was made. Conclusion(s): COVID-19 being a relatively new disease,it's sequelae in children is not much studied.Aplasticanemia following an infection of SARS-CoV-2 is extremely rare with only two cases reported in literature till date.Hence this entity should be kept in mind by the treating physician encountering a case of pancytopenia following COVID-19.

A Rare Case of T-Cell Chronic Active Ebstein-Barr Virus (Caebv) Complicated by Development of Hemophagocytic Lymphohistiocytosis (Hlh), T Cell Lymphoproliferative Disorder (Lpd) and Ebv Meningitis

Background: T-cell chronic active Epstein-Barr virus infection (CAEBV) is a rare disease in which patients have the Epstein-Barr virus (EBV) present mainly in the T-cells, which infiltrate tissues like the liver, and bone marrow. Patients eventually develop liver failure, hemophagocytic lymph histiocytosis (HLH), coronary artery aneurysms, EBV infiltrating T-cells impairing organ function, or T-cell lymphomas. Prognosis is poor. The current treatment of choice is an allogeneic hematopoietic stem cell transplant. A study by the NIH and Baylor College of Medicine, which reviewed 28 years of data, only found 19 cases of CAEBV. We aim to report a rare case of T-cell chronic active Ebstein-Barr Virus (CAEBV) complicated by the development of HLH and T-Cell LPD. Method(s): A chart review of the CAEBV patient was performed, focusing on disease progression, treatment plans, and complications. Result(s): A 45-year- old Latin American woman from Mexico initially presented with abnormal liver enzymes after taking herbal medications. The patient underwent a liver biopsy and was initiated on prednisone for possible autoimmune hepatitis pending the biopsy report. The liver biopsy showed EBV hepatitis with EBV positive atypical T-cell infiltrate with steatohepatitis and marked steatosis. Prednisone was stopped, and the patient was referred to Hematology. Plasma EBV level was elevated to 3300 IU/mL. The patient was readmitted for sepsis and pancytopenia prior to being seen by Hematology. Bone marrow biopsy showed EBV+T-cell LPD and HLH, and the patient was started on dexamethasone and rituximab. The patient improved, and dexamethasone was weaned off. Subsequently the patient has had numerous hospital admissions for ESBL UTI, CoNS bacteremia, aspiration pneumonia, vocal cord dysfunction, EBV pneumonia, PCP pneumonia, chemotherapy-induced neuropathy, neutropenic fever, chronic respiratory failure and EBV reactivation. The patient underwent multiple rounds of chemotherapy with rituximab and R-CHOP regimen for persistent HLH. In spite of the treatment, the patient developed EBV encephalitis, further complicated by COVID -19 infection. Her family opted for comfort care, and the patient passed away in the hospital. Conclusion(s): Approximately 95% of adults are infected with EBV at some point in their lives and are asymptomatic in most cases. Very rarely do patients develop CAEBV -a life-threatening disease. Allogeneic stem cell transplant should be considered early on in the disease. Unfortunately, our patient had social factors such as lack of insurance and social support that prevented her from getting a timely stem cell transplant. (Figure Presented).

A Case of Renal Amyloidosis (AD) Presented as Orthostatic Hypotension

Introduction: Neurogenic hypotension can happen in the context of immunoglobulin light chain AD. The most serious feature is autonomic nervous system impairment, mainly characterized by severe refractory orthostatic hypotension. Amyloid deposition may be found in many organs and the patient can presents with cardiac, gastrointestinal, renal, and neurological symptoms, but rarely hypotension only. Here we describing a patient who presented with sever orthostatic hypotension, found to have renal AD. Case Description: 67 year old male with past medical history of type 2 diabetes, chronic kidney disease, coronary artery disease, colon cancer, and history of COVID-19 infection who presents to nephrology clinic after being referred by primary care provider for elevated Creatinine to 2.5 mg/dl (baseline around 1.2 mg/dl). on clinic visit found to have severe orthostatic hypotension. blood pressure (BP) supine 121/80 mmHg, heart rate (HR) 87 beat per minute (BPM) ;sitting 106/70 mmHg, HR-92 BPM;standing: 92/59 mmHg, HR-100 BPM, no other abnormalities on physical examination. and was admitted to the hospital for evaluation. upon admission to the hospital, pateint received IV fluid, found to have 11 gram protein on 24 hour urine collection laboratory work up showed positive ANA, immunofixation was positive for lambda chain. Fat pad biopsy without signs of AD. Bone marrow biopsy results were inconclusive. Renal biopsy was performed, findings consistent with AL AD. pateint to start treatment with hematology Discussion: The amyloidoses are a group of disorders in which soluble proteins deposit extracellularly in tissues as insoluble fibrils, causing organ dysfunction that is usually progressive. Renal amyloid is a major source of morbidity in affected individuals. When the kidney is involved, renal insufficiency is common, accounting for 47% of cases in a study. Proteinuria has been reported with full nephrotic syndrome in 25-68%. it usually progress to end stage renal disease if left untreated. in our case we are describing an unusual presentation of renal AD, in which the symptoms were orthostatic hypotension. renal function was below baseline but was improving with volume replacement, pateint was felt to have prerenal acute kidney injury. the significant amount of proteinuria prompted further testing. We feel that nephrotic syndrome from amyloid should be considered when patient presented with orthostatic hypotension.