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Background: Lymphoproliferation is the persistent proliferation of lymphoid cells and it's incidence in inborn errors of immunity varies from 0.7 to 18%. Material(s) and Method(s): This is a retrospective analysis of patients referred to the department of Immunology, B. J. Wadia Hospital for Children, Mumbai between March 2017 to December 2022. Inclusion criteria consisted of 3 months duration of significant lymphadenopathy and/or splenomegaly or history of lymphoma. The clinical characteristics, laboratory and molecular findings of the included patients were analyzed. Result(s): A total of 66 patients were included. There was a male preponderance with male:female ratio of 25:8. Median age of onset of lymphoproliferation was 4.75 years(Range 1 year to 60 years). Splenomegaly was seen in 75%. Infections included recurrent pneumonia (14/66), recurrent ear infections(5/66), COVID(4/66), one episode of pneumonia(6/66), herpes zoster(3/66), recurrent subcutaneous abscess (3/66), abdominal koch(3/66), chronic sinusitis(2/66), dermatophytosis(2/66), esophageal candidiasis(2/66), recurrent malaria(1/66), recurrent varicella(1/66), cryptococcal meningitis(1/66), gram negative sepsis(1/66), BCG adenitis(1/66), pseudomonas osteomyelitis(1/66), impetigo (1/66), pseudomonas urinary tract infection (1/66), chicken pox(1/66), herpes keratitis(1/66), dengue(1/66), Other manifestations included Evans plus phenotype(10/66), Evans phenotype(8/66), Autoimmune hemolytic anemia(5/66), bronchiectasis(5/66), Type 1 diabetes(3/66), hyper reactive airway disease(2/66), inflammatory bowel disease(4/66), autoimmune thrombocytopenia(2/66), stroke(3/66), hemophagocytic lymphohistiocytosis(2/66), hypertriglyceridemia(2/66), hypothyroidism(2/66), celiac disease(1/66), Type 2 diabetes(1/66), autoimmune encephalitis(1/66), autoimmune hepatitis(2/66), anti-parietal cell antibody(1/66), arthritis(1/66), autoimmune enteropathy(1/66), systemic lupus erythromatosus(1/66), primary biliary cirrhosis requiring liver transplant(1/66), nephrotic syndrome(1/66), lymphoedema(1/66), hypersplenism(1/66), recurrent oral ulcers(1/66), gout(1/66), dermatitis(1/66), ovarian teratoma(1/66), alopecia areata(1/66). Hodgkin's lymphoma(HL) was the most common malignancy(9/66), followed by non Hodgkin lymphoma(NHL)(6/66), transformation from NHL to HL(1/66), Burkitt to T-cell lymphoma(1/66), HL to DLBCL(1/66), HL to anaplastic T-cell lymphoma(1/66). EBV driven lymphoproliferation was seen in biopsy of21/66. Genetic testing showed mutations in LRBA(11/66), PIK3CD(5/66), CTLA4(3/66), TET2(2/66), IL2RA (1/66), IL12RB1(1/66), BACH2(1/66), PRKCD(1/66), TNFSFR13B(1/66), TNFAIP3(1/66), FAS(2/66), FASL(1/66), Caspase8(1/66), CARD11(1/66), RTEL1(1/66), AICD(1/66), PIK3R1(1/66), IKBKB(1/66). Treatment included IVIG, chemotherapy, rituximab, sirolimus, abatacept, HSCT. Conclusion(s): All children with persistent lymphoproliferation, with or without autoimmunity and/or infections should be worked up for an underlying monogenic disorder of immune dysregulation. Lymphomas presenting at abnormal site and/or age, relapse and EBV driven lymphomas require further evaluation. Presence of monogenic cause helps in providing targeted therapy.Copyright © 2023 Elsevier Inc.
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Case Report: A 26-year-old woman with a history of warm autoimmune hemolytic anemia, immune thrombocytopenia, triple positive antiphospholipid syndrome, and chronic migraine presented to the emergency department with worsening generalized fatigue for one week associated with headache, dyspnea on exertion, nausea, vomiting and lightheadedness. Of note, she had received her second dose of mRNA COVID-19 vaccine 4 days prior to presentation. On admission, patient was found to be severely anemic with a hemoglobin of 4.3g/dL which is decreased from her baseline hemoglobin of 9-10.5g/dL;however, W-AIHA precluded the administration of blood product until adequate blood with the appropriate antibodies could be acquired. During the hospitalization, hemoglobin decreased to 3.3g/dL. Patient was then administered the most compatible blood product which she tolerated well. Hematology was consulted who started the patient on hydroxychloroquine, high dose methylprednisolone, and Intravenous Immunoglobulin (IVIG). Throughout the admission, the patient remained asymptomatic. After 2 days of IVIG, three days of high dose glucocorticoids, and one unit of packed red blood cells, the patient's hemoglobin increased to 7.2g/dL. Patient was discharged home on prednisone taper and hydroxychloroquine. Conclusion(s): Episodes of hemolytic anemia after either the first or second dose of mRNA COVID vaccines are rare and have occurred in patients with known hematological pathology as well as patients without any history of hematologic or immunologic disorders. When taking the history of patients presenting with hemolytic anemia, it is important to query recent vaccinations as, while rare, mRNA COVID vaccine may well be the etiology. While this ultimately will likely not change patient management, this information would be beneficial for further study.
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Background: Covid-19 infection has caused a global pandemic in the recent years and although initially it was considered mainly a respiratory ailment it has proven over time to cause a constellation of complications across various systems such as hematological, immune, cardiovascular, gastrointestinal, and neurological. Method(s): We report a case of a lupus patient with Covid-19 infection who presented initially with fever and gum bleeding with a negative dengue serology and negative HIV serology. Result(s): A 45-year- old lady with a 30-year history of SLE was admitted to our hospital with Covid 19 infection. She had relatively stable disease over the past few years but was admitted to the hospital with complaints of fever, gum bleeding and shortness of breath with no chest x-ray changes. Her oxygen saturations were 95% under room air and her vital signs were stable. Laboratory examinations revealed raised white cell count (11.63) with neutrophilia and elevated C-reactive protein (2.84mg/dl). Her platelet count was low at 113 when compared to her baseline of 549. An urgent peripheral blood film showed an incidental finding of Stomato-ovalocytosis with mild anaemia however there was no features of haemolysis. She was initially treated as acquired Immune thrombocytopenia provoked by Covid-19 infection and was started on IV hydrocortisone. She had a lack of response as evident of a further decline in her platelet counts and the following day, she developed rapid decline in her renal function wherein her creatinine increased from 83 to 207. An urgent ultrasound doppler of the kidneys to rule out acute renal vein thrombosis was organised however it showed normal patent renal vessels. Peripheral blood films were repeated which showed minimal schistocytes and the diagnosis was clinched with the Adamst13 activity levels being less than 0.2%. She was started on 20g IVIG per day with plasma exchange however succumbed to the illness. Conclusion(s): The diagnosis of TTP classically involves the recognition of the pentad of fever, microangiopathic hemolytic anemia, thrombocytopenia, acute renal failure, and neurological abnormalities however 60% of patients do not fulfil the pentad. It is essential to recognize that Covid-19 is an acquired cause of TTP, and a high index of suspicion must be maintained for early treatment institution.
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Background. Immune dysregulation associated with COVID-19 includes immune cell activation, inflammatory cytokine release, and neutrophil extracellular trap release (NETosis), which are mediated by spleen tyrosine kinase (SYK) (Fig 1). Fostamatinib, an oral spleen tyrosine kinase (SYK) inhibitor, was approved for immune thrombocytopenia (ITP) in 2018, and the Phase 3 trials showed a lower than expected rate of thrombosis.1 Clinical studies showed a reduction in IL-6 in patients with rheumatoid arthritis.2 The active metabolite of fostamatinib (R406) protected against LPS-induced acute lung injury and thrombosis in mice3,4 and reduced MUC1 in a mouse model of ALI.5 Fostamatinib demonstrated abrogation of the hyperimmune response caused by anti-spike IgG,6 including reduction in hyperactivation of platelets7 and NETosis in neutrophils8 in in vitro studies using plasma from patients with severe COVID-19. A phase 2 study (NCT04579393) evaluated fostamatinib vs. placebo (all received standard of care [SOC]) in 59 hospitalized patients with COVID-19 and demonstrated reduction in mortality, ordinal scale scores, and number of days in the intensive care unit (ICU) as well as meeting the primary endpoint of safety.9 A phase 3 clinical study (NCT04629703) of fostamatinib for the treatment of COVID-19 is underway. (Figure Presented) Methods. A Phase 3, randomized, double-blind, placebo-controlled, adaptive design, multi-center study (NCT04629703) is underway to evaluate fostamatinib in 308 adult patients hospitalized with COVID-19 and on oxygen without intubation (Fig 2). Patients will receive fostamatinib 150 mg BID or placebo for 14 days;both arms receive SOC. At baseline, the clinical status score (8-point ordinal scale) had to be 5 or 6. Patients >= 65 years had to have >= 1 risk factor for severe disease and adults < 65 had to have >= 3. The primary outcome is days on oxygen (Day 1 to 29). Other endpoints include change in clinical status score, days in the ICU, time to hospital discharge, all-cause mortality, oxygen-free status and safety. Fostamatinib is investigational for COVID-19. Results. Blinded data from this trial in progress are as of 2 December 2021. See Fig 3. Conclusion. Final results of this Phase 3 trial are anticipated in 2022.
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Objective: To describe 2 cases of autoimmune neutropenia (AIN) patients infected with Sars-Cov-2. Design/Method: Two subjects case report. Result(s): Case report 1: A girl with primary AIN since 1 year and 10 months old, maintaining severe neutropenia and mild recurrent infections. Presented to the emergency department in June/2020, at 3 years and 8 months old, with flu-like symptoms, afebrile, in good general condition. Physical examination was normal. The absolute neutrophil count (ANC) was 0.279 x 109/L. At hospital admission, Sars-Cov-2 (RT-PCR) tested positive and filgrastim (G-CSF) 5 mug/kg/day was initiated. Chest X-ray was also normal and blood culture resulted negative. She remained in great general condition, afebrile, and was discharged on the 2nd day of hospitalization, with clarithromycin (15 mg/kg/day). After G-CSF, ANC: 0.494 x 109/L (1st dose), 1.431 x 109/L (2nd dose). On outpatient follow-up, she had no long-term complications from Covid-19. Case Report 2: A man with chronic immune thrombocytopenia purpura (ITP) since 2008, autoimmune hemolytic anemia since 2013, evolved with AIN on May/2020, at 42 years old, with ANC lower than 0.5 x 109/L. On 6/1/2020, he had ANC 0.170 x 109/L. On 6/25/2020, he started flu-like symptoms, had ANC of 5.118 x 109/L, and tested positive for Sars-Cov-2 (RT-PCR). He kept high fever (102,2degreeF) and was hospitalized for 10 days without use of G-CSF. After discharge, on outpatient follow-up, he had no long-term complications from Covid-19, and presented ANC 0.338 x 109/L (Aug/2020). Discussion(s): At beginning of Covid-19 pandemic, severity infection in children was unknown. Today is known that most of them have milder clinical course, regardless of chronic diseases. In adults, in contrast, the inflammatory response tends to exacerbation, with more severe clinical conditions. Furthermore, many case reports of patients infected by SARS-CoV-2 with comorbidities literature are published. However, to date there are no reports on the impact of COVID-19 in AIN patients. Increased neutrophil counts during infectious episodes are common in AIN, which appears to be related to the benign course of most infections. We reported 2 cases of AIN patients diagnosed with Covid-19, both with favorable clinical outcomes despite heterogenic clinical course. On the first case, she presented few symptoms and ANC increased only after using G-CSF. On the second reported patient, there was a spontaneous increase of ANC and greater inflammatory response than the first case. It could suggest a correlation between inflammatory response to COVID-19 and ANC in cases of autoimmune neutropenia. Conclusion(s): In the reported cases, clinical course of disease and neutrophil count were different between adult and pediatric patients. It is not possible to state whether this difference is due to age group, individual response to infection or other variables. It is important to assess other cases of AIN infected by COVID 19 to better understand correlation between severity of infection and neutrophil count response. Copyright © 2022
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Background: Immune thrombocytopenia (IT) is a complication described within COVID-19, probably secondary to the immunological storm produced during the acute infection. It usually responds to first-line treatment (corticosteroids, immunoglobulins), with the use of thrombopoietin (TPO) agonists being somewhat infrequent. Aim(s): The objective is to present these cases of eltrombopag-dependent immune thrombocytopenia secondary to severe COVID-19 infection within a probable context of persistent COVID syndrome . Method(s): Unicentric, descriptive study that describes our experience with two patients who presented severe forms of COVID-19 (need to stay in intensive care) during the first wave (March 2020) and who to date have depended on eltrombopag to maintain hematological response. Result(s): Two patients (women aged 67 and 65 years) with no relevant medical history, diagnosed in March and April 2020, respectively, with bibasal pneumonia secondary to severe COVID-19. On discharge they had severe IT associated with skin bleeding events, initially treated with oral prednisone mg/kg/day plus unspecific IVIg g/kg/day (no hematologic response in both cases) and dexamethasone 40 mg for 4 days plus unspecific IVIg g/kg/day every 15 days (3 cycles), without response. Second-line treatment was started with TPO analogues (oral eltrombopag 50 mg/day, with dose escalation to 75 mg/day), obtaining hematological response on day +7 of start and complete remission on day +21 of treatment. After 18 months of treatment at high doses, it was decided to de-escalate the dose, with loss of symptomatic hematological response, for which it was decided to return to the previous dose in both patients, with platelet count recovery 5-14 days later. Conclusion(s): The fact that IT is refractory to corticosteroids and, furthermore, dependent on high doses of eltrombopag (with no possibility of reduction) after almost two years of treatment, gives us an idea that the process of immune dysregulation secondary to COVID -19 persists in time, as well as its long-term consequences.
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Background: Case reports of autoimmune hematological diseases secondary to COVID-19 infection or vaccination are emerging. However, there are limited case series that analyze patterns of presentation, treatment patterns and responses. Most reports have limited follow-up duration, occurred prior to the incorporation of corticosteroid in COVID-19 treatment, and did not report on vaccine re-challenge. Aim(s): To characterize case presentations, severity, treatment courses and response of immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA) and thrombotic thrombocytopenic purpura (TTP) associated with COVID-19 infection, or vaccination. Method(s): In this multi-centre case series, adults (>18) diagnosed with de novo or relapsed ITP, AIHA and TTP associated with COVID-19 infection or vaccination (January-December 2021) were recruited from hematologists at two academic hospitals in Edmonton, Alberta (population 1.5 million). The Brighton Collaboration criteria was used to adjudicate diagnostic certainty. Research ethics approval and informed consent were obtained. Result(s): Thirteen patients presented with 14 autoimmune hematological complications (Tables 1-2). Following the BNT162b2 (n = 7) or mRNA-1273 (n = 2) vaccine, we diagnosed 6 cases of ITP (5 de novo) and 3 AIHA (1 de novo). A greater proportion of hematological disorders developed after second-doses of vaccine compared to first (66 vs 33%). Three individuals received subsequent doses of COVID-19 vaccine without disease relapse. In addition, 5 patients developed ITP (3), AIHA (1) and relapsed TTP (1) precipitated by COVID-19 infection. Among 8 patients with de novo autoimmune hematological disorders, the majority (75%) achieved complete or partial response at a median follow-up of 4.6 months, only three individuals had relapses requiring subsequent treatment. All patients were managed with glucocorticoids, 3 received IVIG and 4 required second-line therapy. Conclusion(s): Autoimmune hematological conditions due to COVID-19 infection or vaccination present, and are successfully managed similarly to cases unrelated to COVID-19. Among vaccine-associated hematological disorders, repeat doses of vaccine may be safely administered.
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Background: The SARS-CoV- 2 pandemic has led to changes in the way we manage autoimmune disease such as immune thrombocytopenia (ITP). Immunosuppression is a risk factor for severe COVID-19 and also leads to reduced vaccine responses. Medical therapy for ITP is broadly divided into immunosuppressive or that which stimulates megakaryopoeisis. Aim(s): To assess changes in medical therapy for ITP during the SARS-CoV- 2 pandemic using data from the UK adult ITP registry Methods: The UK registry of primary adult ITP (https://www.qmul. ac.uk/itpre gistr y/), one of the largest internationally, produces annual treatment reports on therapy use, trends and to identify cohorts for study. We reviewed data from annual reports to assess treatment changes. Result(s): At the time of analysis, there were 4503 patients in the registry: 224 diagnosed with ITP in 2019, 105 in 2020 and 97 in 2021 (median age 57y, 59y and 55y respectively). Table 1 shows changes in treatment 2019-2021. Most patients still received steroids as part of the treatment for ITP acutely. IVIG use remained static between 2019 and 2021. For diagnoses made between 2019 and 2021 all patients received at least 1 treatment. Immunosuppressive therapy use reduced from pre-2019 levels (data not tabulated) where almost 23% patients received rituximab and 18% MMF to 0% and 3% respectively by 2021. Use of TPO-RA increased, from 33% in 2019 to 43% in 2021. Median time to starting TPO-RA was 3.76 months (IQR 1.317,9.225) in 2019 reducing to 0.985 months (IQR 0.58,1.465) in 2021. Platelet response criteria will undergo analysis once additional data entry has taken place. Conclusion(s): Steroids continue to be used acutely for most ITP patients but TPO-RA are being used ahead of other immunosuppressive therapy in line with interim NHSE pandemic policy. Most patients entered received at least one line of treatment -likely reflecting those frequently attending sites to access healthcare.
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Background: There is emerging data on immune thrombocytopenia (ITP) exacerbation after initial Covid-19 vaccination. The rate of ITP exacerbation after booster vaccines is unknown. Aim(s): Explore rates of ITP exacerbation after first, second and booster Pfizer-BioNTech COVID-19 vaccines in adult ITP patients. Method(s): Retrospective study of ITP patients, receiving 1-3 doses of Pfizer-BioNTech vaccine. The primary outcome was clinical ITP exacerbation defined as platelet count decrease requiring initiation or escalation of ITP treatment and/or a new medical attention due to bleeding, within 3 months. Secondary outcome was any clinically-relevant platelet decrease during the 3 months post-vaccination compared to pre-vaccine count, defined as platelet decrease to <=30x109/L or thrombocytopenia with >50% decrease from baseline. Result(s): The study included 93 ITP patients (83 with chronic ITP) receiving 1 (n = 2), 2 (n = 22) or 3 (n = 69) vaccine doses. ITP exacerbation occurred in 2/93 (2.2%) patients following first/second dose, and 3/69 (4.3%) following booster dose. Clinically-relevant platelet decreases after initial doses occurred in 8/72 (11.1%) patients with platelet counts available, and in 8/39 (20.5%) after the booster, within a median 18 and 20 days. Table 1 shows clinical data and platelet counts in patients experiencing primary or secondary outcomes. Clinical ITP exacerbation after booster doses was preceded by a clinically-relevant platelet decrease after the initial doses in 1 of 3 patients, but not by clinical exacerbations. Four of 8 patients (50%) with clinically-relevant platelet decreases after booster doses also had clinically-relevant decreases following initial vaccination. Conclusion(s): Clinical ITP exacerbation in chronic ITP patients is infrequent following Pfizer-BioNTech COVID-19 vaccine. Clinical exacerbation after booster doses was not preceded by clinical exacerbation after initial doses in this study. Clinically-relevant platelet decreases after booster doses occur frequently in patients with clinically relevant decreases after initial doses. This suggests monitoring of platelet counts in ITP patients receiving COVID-19 vaccines.
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Background: Immune thrombocytopenia (ITP) has been reported following COVID-19 vaccination. From a population of over 20 million eligible vaccine recipients in Australia, over 32 million doses have been administered: 19,600,000 Pfizer BNT162b2 (BNT), 12,600,000 AstraZeneca ChAdOx1 nCoV-19 (ChAd), and 397,000 Moderna mRNA-1273. Aim(s): Describe a comprehensive series of ITP after vaccination with clinical outcomes. Method(s): After obtaining IRB approval (2021/ETH00723), we collected data on all ITP cases diagnosed by haematologists in Australia within six weeks of any COVID-19 vaccination. We analysed their outcomes using international consensus definitions of responses and WHO bleeding. Result(s): Demographics (n = 50), treatments, and platelet outcomes (Figures A and B). Bleeding was mostly minor: 35/50 (70%) WHO score <2. Compared to relapses of prior ITP, new presentations of ITP were significantly associated with ChAd over BNT (OR 7.1: 95% CI 1.7 to 25.7, p = 0.0124*). Most patients responded quickly and deeply: Median TTR 4 days (IQR 2-7), median TTCR 7 days (IQR 4-19), overall RR 45/47 (96%), and CR 40/45 (89%). Gender, age, antecedent influenza vaccination and severity of thrombocytopenia had no significant impact on: Bleeding at presentation, response rates, relapse rates, time to response, or the need for ongoing treatments at day 90. No patients presented with thrombosis. PF4 ELISA was positive in one of 18 cases after ChAd (functional testing was negative). Conclusion(s): We diagnosed ITP more frequently after ChAd than BNT vaccination, occurring de novo after 1st doses. Ascertainment bias cannot be excluded due to greater scrutiny for platelet related complications, but almost all patients in this cohort needed treatment. Standard first-line treatments for ITP are highly effective for both de novo and prior ITP (96%), but second-line therapies are often required (34%). Our data reaffirms the safety of vaccinating patients with pre-existing ITP, as bleeding is mild (92% WHO < 2) and platelets respond quickly (TTCR 5 days).
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SESSION TITLE: COVID-Related Critical Care Cases SESSION TYPE: Case Reports PRESENTED ON: 10/19/2022 11:15 am - 12:15 pm INTRODUCTION: We present a case of diffuse alveolar hemorrhage (DAH) secondary to Immune Thrombocytopenia (ITP) temporally related to SARS-CoV-2 (CoV) vaccine. CASE PRESENTATION: An 80-year-old female presented with dyspnea, hemoptysis, diffuse petechiae, and ecchymosis;no focal neurological deficits or hepatosplenomegaly. She had no history of bleeding or autoimmune disorders;no recent respiratory or gastrointestinal infections;but received Moderna CoV vaccine 4 weeks prior to presentation. Chest X-ray (CXR) and CTA of chest demonstrated multifocal bilateral patchy airspace opacities. Initial platelet was 1 x 109/L with normal morphology of platelet and WBC, and no schistocytes. Coagulation panel, LDH, haptoglobin, and bilirubin were all normal. CoV NAAT was negative. Dexamethasone and IVIG for high suspicion of ITP was initiated. Supportive care including platelet transfusion and oxygen via nasal cannula was maintained. Platelets were severely consumed in spite of treatment with platelets undetectable at nadir and rapid decrease of hemoglobin, approximately 6 g/dL, within 24 hours of admission. IgM and IgG plasma platelet autoantibodies returned positive, confirming ITP diagnosis. Additional workup was unremarkable for infections, rheumatologic disorders, and malignancy. Respiratory state rapidly declined with worsening hemoptysis and significant increase of bilateral airspace opacities on repeat CXR, indicative of DAH. Lung protective mechanical ventilation protocol was initiated on day 2 with medically induced deep sedation and paralysis to minimize hemorrhage exacerbation. Rituximab, romiplostim, and nebulized tranexamic acid were added for severe and refractory ITP, which eventually slowed platelet consumption, reduced pulmonary hemorrhage, and stabilized hemoglobin. Platelets recovered above 30 x 109/L on day 9, and subsequent bronchoscopy showed persistent blood on bronchoalveolar lavage. She was successfully extubated after prolonged 14-day intubation. Platelet normalized before discharge. DISCUSSION: Incidence of ITP related to CoV vaccine is approximately 0.8-0.9 case per million vaccinated. Most cases present with superficial bleeding and respond to first-line agents with rapid recovery. GI bleeding and intracranial hemorrhage, but not DAH, have been reported in several cases, requiring third-line agents to promote platelets recovery and achieve hemostasis. We report a case of DAH secondary to ITP following CoV vaccine. Temporal relationship and severe presentation are consistent with other reports of ITP with life-threatening internal bleeding probably secondary to CoV vaccine. CONCLUSIONS: When DAH is suspected, rapid escalation of treatment to include third-line agents is desired. If intubated, lung protective ventilation with paralysis is preferred to minimize further lung injury due to DAH. Reference #1: Lee EJ, Cines DB, Gernsheimer T, et al. Thrombocytopenia following Pfizer and Moderna SARS-CoV-2 vaccination. Am J Hematol. 2021;96(5):534-537. doi:10.1002/ajh.26132 doi:10.1016/J.VACCINE.2021.04.054 Reference #2: Welsh KJ, Baumblatt J, Chege W, Goud R, Nair N. Thrombocytopenia including immune thrombocytopenia after receipt of mRNA COVID-19 vaccines reported to the Vaccine Adverse Event Reporting System (VAERS). Vaccine. 2021;39(25):3329-3332. Reference #3: Tarawneh O, Tarawneh H. Immune thrombocytopenia in a 22-year-old post Covid-19 vaccine. Am J Hematol. 2021;96(5):E133-E134. doi:10.1002/ajh.26106 DISCLOSURES: No relevant relationships by Timothy Barreiro No relevant relationships by Tiewei Cheng No relevant relationships by Zeina El Amil No relevant relationships by Jin Huang No relevant relationships by Sanaullah Khalid
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Several vaccine strategies are in use against the SARS-CoV2 virus which causes COVID-19. There are three major approaches to vaccine development: Using the whole virus (live virus, inactivated virus, or viral vector vaccines), using immunogenic parts of the virus, or using the genetic material of the virus. As of April 29, 2022, 10 vaccines with different mechanisms of action have received EUL by WHO.1 In the United States, 3 vaccines have received either emergency use authorization or FDA approval.2 The timing and number of injections in the primary series and timing and need for booster doses of these vaccines depend on the age of the person, underlying immunocompromised status.4 The vaccines have overall been demonstrated to be safe and effective in preventing COVID-19 infection and also in preventing serious COVID-19 infection. However they are rarely associated with some serious side effects. Thrombosis with thrombocytopenia syndrome (TTS) after Johnson & Johnson/ Janssen adenoviral vector vaccine is a rare complication that appears to affect women between the ages of 30 and 49 years. It has also been described with the Oxford/Astra Zeneca vaccine. Based on the available data there is no increased risk for TTS after mRNA vaccination, although cases of immune thrombocytopenia have bene reported after the Pfizer/ BioNTech and Moderna vaccines.3,4 An increased risk of Guillain-Barré syndrome has also been associated with this the Janssen vaccine.3 Myocarditis and pericarditis, particularly in male adolescents and young adults have been associated with the Pfizer and Moderna mRNA vaccines.5 Currently, antibody testing either post infection or post vaccination are not recommended for various reasons.6, 7 Preexposure prophylaxis with a combination of 2 long-acting antibodies, tixagevimab-cilgavimab target the receptor binding domain of the SARS-CoV-2 spike protein and inhibit virus attachment. In December 2021, the US FDA provided emergency use authorization for preexposure prophylaxis of COVID- 19 in patients 12 years or older weighing at least 40 kg, not currently infected with COVID-19 or have a known recent exposure and either have moderate to severe immunocompromise due to a medical condition or receipt of immunosuppressive treatments and may not mount an adequate immune response to COVID-19 vaccines, or in whom available vaccines are not recommended due to prior severe adverse reaction.8 This consists of 2 consecutive intramuscular injections at the same visit and the effi cacy appears to last for up to 6 months. It was granted marketing authorization in the EU in March 2022.
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Background: Rituximab is one of the second-line treatments for ITP. At present, there are few studies on low-dose rituximab, lacking of a large number of prospective and randomized trials to support the efficacy and safety of lowdose rituximab, especially in children's ITP. Influenced by COVID-19, we used two low-dose rituximab regimens before and after March 2020 for second-line treatment of children's ITP. Aims: To compare the efficacy and safety of two different regimens for low-dose rituximab of children patients with chronic /refractory ITP, so as to provide basis for clinical treatment. Methods: 83 children patients were enrolled in this study and non-randomly assigned to receive 100mg/200mg (body weight 30kg) rituximab weekly for 4 weeks (group A, 53 cases) or a single dose of 375mg / m2 rituximab (group B, 30cases). The study was follow-up for at least half a year. Results: The baseline data of group A and B were the same. For group A: Overall and complete response (OR and CR) rates were 35.8% and 15%, respectively;the side effects rate is 3.8%. In responders, the median time to response was 4 (1 -12) weeks, with a median follow-up time of 12 (6 ∼ 36) months, 6 of 19 responders (31.6%) relapsed. For group B: OR and CR rates were 36.7% and 23%, respectively;the side effects rate is 10%. In responders, the median time to response was 1 (1 ∼ 4) weeks, with a median follow-up time of 11.5 (6 ∼ 17) months, 4 of 11 responders (36.4%) relapsed. No significant difference in the OR, NR, relapse free survival and incidence of side effects was observed in patients between the two groups. Image: Summary/Conclusion: The two low-dose rituximab regimens in the treatment of ITP in children both are safe and effective;The single-agent scheme is more recommended because of easier use and not increasing safety events.
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CASE: A 25-year-old female with no medical history presented with progressive petechial rash at the chest, trunk, bilateral forearms, and thighs. Patient had the COVID-19 vaccine three weeks prior. However, denied recent travel or tick bites. No home medications nor recent hospitalizations, other than a tooth extraction a month earlier. On physical exam, the patient's vitals were unremarkable and had non-blanching petechial rash noted on her torso and bilateral extremities. Labs were significant of platelet count 1,000/mcL, hemoglobin 12.9 mg/dL, WBC 7.52 x103 /mcL, absolute lymphocytes 3.33x103 /mcL. Patient was administered two units of platelets followed by intravenous immunoglobulin (IVIG) and dexamethasone. No bleeding or hemodynamic instability was identified. Platelet count improved to 100,000/mcL over the next 24 hours. Further work-up revealed a positive HIV-1 antibody, absolute CD4 256 cells/mcL, viral load 27,300 copies/mcL. Once starting antiretroviral therapy (ART);bictegravir, emtricitabine, and tenofovir alafenamide, platelet count increased within a month to more than 200,000/mcL. IMPACT/DISCUSSION: Thrombocytopenia is defined as platelet count below 150,000/mcL. HIV-induced cytopenias are common, mainly neutropenia. However, sentinel events of thrombocytopenia are very rare in otherwise healthy individuals. A review of 5,290 HIV patients at the University of British Columbia from 1996 to 2012 revealed only 0.6% incidence of severe thrombocytopenia which they defined as platelet count <20,000/mcL. The exact pathophysiology is not clearly understood, but it is possible that antibodies against HIV cross-react with platelets or possible immune alteration. This is suggested by the prompt resolution of thrombocytopenia once ART is initiated. Immune thrombocytopenia (ITP) is a diagnosis of exclusion typically presenting with thrombocytopenia while other cell lines are normal. The greatest concern is when platelet counts drop less than 20,000/mcL due to fears of intracranial bleeding. Literature is not decisive in a correlation between platelet counts and risk of bleeding, yet it is suggested that circulating platelets are younger and more effective to maintain hematopoiesis in ITP when compared to other causes of thrombocytopenia. Treatment approach for ITP depends on the bleeding risk. In the presence of bleeding, urgent platelet transfusion, glucocorticoids, and IVIG are the mainstay of treatment. In absence of bleeding, individualized assessment of the condition is recommended to either monitor or treat. Platelet counts below 20,000-30,000/mcL require steroids or IVIG. In our case, she surprisingly presented only with minor petechial bleeding. Prompt initiation of ART, close monitoring of platelet response and CD4 count, as well as identifying resistant thrombocytopenia is indicated once patient is medically stable. CONCLUSION: Sole presentation of ITP due to HIV infection is rare. Risks of critical bleeding and further management are crucial to prevent fatal outcomes.
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CASE: 54-year-old female presented with 1 week of generalized weakness, headache, congestion, cough with dark- colored phlegm, and several days of decreased smell and taste. She was unvaccinated and had positive sick contacts. Patient tested positive for Covid and found to have severe thrombocytopenia with platelets of 5K/uL, very rare schistocytes on smear, and no other notable abnormalities. She received platelet transfusion and was treated for presumed immune thrombocytopenia with IVIG and dexamethasone. The patient had no petechiae, bleeding, or other symptoms concerning for secondary TMA, notably TTP. The platelet count was 93 K/uL by day 5 and she was discharged home. Later that day her ADAMTS13 test resulted at <2% and the ADAMTS13 antibody was elevated. The patient was asked to return to the hospital for monitoring of TTP symptoms. She reported improvement in her weakness. Her thrombocytopenia and oxygen saturation remained normal. Bilateral lower extremity ultrasound showed no lower extremity VTE. On the day of discharge, 10 days after her original thrombocytopenia identified, she had a platelet count of 373 K/uL and repeated ADAMTS13 of 14.8%. IMPACT/DISCUSSION: ADAMTS13 is known as von Willebrand factor (VWF) protease as it cleaves prothrombotic and highly adhesive to platelets ultra-large multimers of VWF into smaller multimers, thus modulating VWF activity and regulating the adhesive function. A severe deficiency of ADAMTS13 characterizes TTP, a rare but potentially fatal disorder associated with thrombosis due to accumulation of prothrombotic ultra-large VWF multimers. There are literature reports of TTP and TTP-like syndromes in Covid-19. It is speculated that in COVID-19, the excess of VWF released in response to endothelial activation likely exhausts the available reserves of ADAMTS13, which may then propagate formation of microthrombi in different organs. We report an extreme thrombocytopenia, marked decrease of ADAMTS 13 and elevated ADAMTS13 antibodies, which would be confirmative evidence of TTP should our patient have clinical features of it. Our patient did not have fever, neurologic abnormalities, renal dysfunction, or active hemolysis. She was followed in outpatient clinic after the discharge. The platelet count recovered and ADAMTS 13 trended up without need for plasmapheresis. Our case is a good example of a fortunate outcome without any complications despite threatening presenting criteria. CONCLUSION: Covid-19 associated endothelial stimulation and damage could mimic a life-threatening disorder without expected fatal complications. On the other hand, it can ultimately lead to the most severe form of thrombotic microangiopathy, TTP, for which the mortality rate is close to 90%. It is hard to know which outcome to expect in different circumstances. Therefore, it is crucial for physicians to promptly recognize clinical picture of TTP as treatment is lifesaving.
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Introduction: The development of vaccines against SARS-CoV-2, along with the observation of immune thrombocytopenia (ITP) following COVID-19, raised the concern about ITP triggered by COVID-19 vaccines. We here describe the cases of de novo ITP and ITP relapses-induced COVID-19 vaccines reported to the French Pharmacovigilance Network. Material and methods: All cases reported up to August 15, 2021, with the terms "thrombocytopenia", "immune thrombocytopenia", "purpura", "thrombocytopenic purpura" were reviewed to detect potential cases of ITP. De novo ITP were subsequently classified by certain ITP and probable ITP. Descriptive analyses were conducted overall and by vaccines. The incidence of reporting of ITP-induced COVID-19 vaccines were also estimated. Results: About 106 cases of De novo ITP are registered during this period mostly reported with Comirnaty∗(n = 58) and Vaxzevria∗(n = 45). Only 2 cases were reported with Spikevax∗and 1 with Janssen∗. Median age was 67 years (min-max: 16-96) and 54.7% of patients were women. The median time from vaccination (first dose: 71.8%) to ITP onset was 11 days (min-max: 1-40). Three positive (with Comirnaty∗) and 4 negative (1 with Comirnaty∗and 3 with Vaxzevria∗) rechallenges were described. The median time from vaccination (first dose: 70.6%) was 5 days for cases of relapse of ITP (n = 17). The outcome was favorable with (72.7%) or without (27.3%) treatment. The estimated incidence of reporting of ITP was: 1.22 (0,97-1.54) for Comirnaty∗, 6.12 (4.63-8.04) for Vaxzevria∗, 0,72 (0,30-15,60) for Spikevax∗and 1,19 (0,02-0,67) for Janssen∗. Discussion/Conclusion: The rate of reported ITP was the highest with Vaxzevria∗. We identified very few cases reported after Spikevax∗and Janssen∗and our results regarding these vaccines should be interpreted with caution. These series of ITP provide important clinical insights for knowledge of this very rare event, with good response to usual management of ITP and an unpredictable effect of rechallenge.
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Introduction: Since the beginning of vaccination against COVID-19 in 2020, the occurrence of adverse events of special interest (AESI) after the 1st dose of vaccine raises the question of the potential risk associated with the following injections. Real-life vaccine data collected in pharmacovigilance databases can provide information about the safety of a rechallenge with COVID-19 vaccines. In order to help physicians to decide whether another injection is at risk, we analyzed the cases reported in the WHO pharmacovigilance database, Vigibase®. Material and methods: We identified AESI with major concerns about the safety of a rechallenge with COVID-19 vaccines: facial paralysis, immune thrombocytopenia, herpes viral infections, hypertension, hearing loss, Guillain-Barré syndrome (GBS), convulsions, myelitis, encephalitis, myocarditis, pericarditis and acute pancreatitis. We extracted cases with rechallenge of these AESI from VigiBase®, whether the AESI recurred or not, until 24 November 2021. The rate of recurrence of the initial AESI according to the vaccine platform was calculated. Results: 676 cases of AESI with COVID-19 vaccines reported information of recurrence after rechallenge, 320 with positive recurrence and 356 with no recurrence. Facial paralysis, herpes viral infection, GBS and myocarditis mostly did not reccur whatever the vaccine type. Whereas hypertension, hearing loss, convulsion and pericarditis seemed to reoccur only after rechallenge of mRNA vaccines, compared to others vaccines. There were few data for immune thrombocytopenia, encephalitis, myelitis and acute pancreatitis. Discussion/Conclusion: This study provided information about the safety of rechallenge of COVID-19 vaccines after first occurrence of AESI. Such information is of great importance considering that several booster shots are being proposed to populations to improve protection against COVID-19 variants. In case of AESI after COVID-19 vaccine, the decision to maintain the following dose must take into account the patient's individual risk benefit balance as well as his history. Although limited, our results provide clinical elements that may help decision-making.
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Explain what has changed the practice: As part of the Covid-19 vaccination campaign, the ANSM and all the 31 regional pharmacovigilance centers have been mobilised in an exceptional reinforced surveillance program. The aim of this national system is not to be exhaustive nor to compare vaccines but to detect safety signals in addition to European and international pharmacovigilance actions. It is based on the daily analysis of adverse reactions cases reported in the national pharmacovigilance database by experts in charge of the surveillance of each Covid-19 vaccines. As for other Covid vaccines, the number of administered doses of Astrazeneca Covid-19 vaccine (ChAdOx1-S vaccine) has been collected via the VACSI platform and spontaneous reports were extracted from the French Pharmacovigilance Database on 12/30/2021 and reviewed. On 30/12/2021, 7 832 223 doses of ChAdOx1-S vaccine were administered in France with 28 313 notifications corresponding to 53 389 adverse events, of among which one fifth were considered serious according to WHO criteria. The first pharmacovigilance signal, which appeared after the first injections, was unexpectedly severe flulike syndromes, according to the SPC. It was quickly followed by a more serious problem that would have a major impact on the vaccination campaign at both national and European level: Immune thrombotic thrombocytopenia (ITT). Subsequently, other signals highlighted during pharmacovigilance monitoring, such as Guillain-Barré syndromes, facial paralysis, capillary leak syndromes, urticaria and angioedema, and more recently, immune thrombocytopenia and cerebral venous thrombosis all of which remind the importance of post-authorisation monitoring. All those signals were transmitted to the European authorities, some of which led to the updating of the VaxZevria SPC. Today, the AstraZeneca vaccine has only a marginal place in the national vaccination strategy, but pharmacovigilance monitoring is still ongoing.
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Introduction Immune thrombocytopenia (ITP) is an acquired thrombocytopenia due to autoantibodies. Eltrombopag is a thrombopoietin receptor agonist (TPO-RA) used as a second-line agent in the setting of persistent or chronic ITP. Potential severe adverse effects include hepatotoxicity, thromboembolism, and increased risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Upper respiratory infections and pharyngitis have also been described, but to our knowledge, no known cases of eltrombopag-induced pneumonitis have been reported to date. Case Presentation We present a 68-year-old male with a history of recent onset ITP, stage IV mantle cell lymphoma (in remission), and Pneumocystis pneumonia who was initiated on eltrombopag 11 days prior to admission for ITP refractory to corticosteroid therapy. Three weeks prior to admission, the patient underwent a bone marrow biopsy without evidence of monoclonal B cells or immunophenotypically abnormal T cell populations. Following initiation of eltrombopag, the patient had progressive dyspnea on exertion associated with subjective fevers and chills requiring hospitalization. Oxygen saturation was 88% on room air with exam notable for coarse crackles to the bilateral lung bases. CT angiogram of the chest revealed bilateral pulmonary emphysema, ground glass opacities, and bilateral bronchiectasis most pronounced in the lower lobes (Figure 1). No pulmonary embolism or mediastinal adenopathy was identified. Cytomegalovirus DNA, aspergillus antigen, and COVID-19 NAAT testing were negative. A respiratory viral panel was positive for Rhinovirus. Bronchoalveolar lavage (BAL) and right middle lobe lung parenchymal biopsy were subsequently performed. Pathology demonstrated focal intra-alveolar organization and fibroblast plugs, interstitial fibrosis, pneumocyte hyperplasia, and mixed (predominantly chronic) inflammatory infiltrate (Figure 2a & 2b). BAL was negative for malignant cells. Pneumocystis jirovecii DNA was detected, but < 250 copies/mL were identified and thus was thought to be less likely contributing to the disease process.Given the suspicion for eltrombopag-induced pneumonitis, the patient was initiated on high-dose corticosteroid therapy with a slow taper over the span of several weeks. Following initiation of corticosteroids, the patient was noted to have gradual improvement in his respiratory status. The patient was ultimately discharged on room air 1 month later due to other hematologic complications necessitating a prolonged hospital stay. Discussion The exact mechanism of eltrombopag-induced pneumonitis is unclear, although we postulate that it is related to an exaggerated immune response involving T-cell homeostasis resulting in alveolarcapillary permeability, inflammation, and fibrosis. Suspicion for eltrombopag-induced pneumonitis should prompt initiation of early corticosteroid therapy to prevent acute and chronic complications of pneumonitis. (Figure Presented).
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Objective: To present a single-health system retrospective analysis of post-mRNA-based COVID-19 vaccination CNS autoimmunity conducted in the greater New York City area. Background: There have been rare reports associating mRNA-based COVID-19 vaccines with central nervous system (CNS) inflammation. We report a case series of five patients with newonset neurological disorders of immunological origin temporally associated with these vaccines. Design/Methods: Case-series. Results: Five cases of post-vaccination CNS disorders of immune origin were observed within two weeks of inoculation with either the first or second dose of mRNA-based COVID-19 vaccines (Moderna = 3, Pfizer = 2). This includes: Fatal ADEM (n = 1), new-onset NMO (n = 2), new-onset fulminant MS (n = 1), and meningoencephalitis (n = 1). The age of our patients ranged from 27 to 81, and three were female. None of the patients had pre-existing neurological illnesses and one had a pre-existing autoimmune condition (immune thrombocytopenia purpura). New-onset focal neurological symptoms were present in all five patients, including quadriparesis, numbness, diplopia, and encephalopathy. CSF pleocytosis was present in all patients, and three had elevated protein. All but one patient (meningoencephalitis) had contrastenhancing lesions involving either the cerebrum or spinal cord. Both NMO patients had longitudinally extensive transverse lesions involving the central thoracic cord. Aquaporin-4 serum antibody was present in one NMO patients and aquaporin-4 CSF antibody present in the other. All but one patient (fatal ADEM) clinically improved with pulse steroids or plasmapheresis. Conclusions: These are among the emerging cases of CNS immunological events temporally associated with mRNA-based COVID-19 vaccines. These findings should be interpreted with great caution as they neither prove a link nor imply a potential long-term increased risk in postvaccination CNS autoimmunity. Larger prospective studies are needed. The mRNA-based SARS-CoV-2 vaccines should continue to be strongly encouraged given their high efficacy in overcoming this pandemic.