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.

Lymphoproliferation- a clue towards an underlying monogenic disorder of immune dysregulation- a retrospective analysis from a single center in India

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.

Clinical profile and outcomes of COVID-19 infection during the first wave in children with hematological illnesses and cancer: An observational study from a tertiary care center in North India

Background: Patients with cancer are at a higher risk of getting infected with the severe acute respiratory syndrome coronavirus 2 owing to their immunocompromised state. Providing care to these patients amidst the first wave of the coronavirus disease-2019 (COVID-19) pandemic was extremely challenging. Objective(s): This study was aimed at evaluating the clinical profile and disease-related outcomes of pediatric patients with hematological illnesses and cancer. Material(s) and Method(s): This retrospective study was conducted at a tertiary care center in North India during the first wave of the pandemic from March 2020 to December 2020. Children aged up to 18 years, who were treated for a hematological illness or malignancy or underwent hematopoietic stem cell transplantation (HSCT) and tested positive for COVID-19 regardless of symptoms were included in the study. Baseline demographic data related to the age, diagnosis, treatment status, and chemotherapy protocol used were collected. Outcomes including the cure rates, comorbidities, and sequelae were recorded. Result(s): A total of 650 tests for COVID-19 were performed for 181 children;22 patients were found to be COVID-19 positive. The most common diagnosis was acute leukemia (63.6%). None of the patients developed COVID-19 pneumonia. The majority of patients had asymptomatic infection and were managed at home. Among those with a symptomatic infection, the most common symptoms were fever and cough. A total of 3 (13.6%) patients needed oxygen therapy, one developed multisystem inflammatory syndrome of children leading to cardiogenic shock. Three patients required intensive care or respiratory support;all the patients had favorable clinical outcomes. The median time from the onset of COVID-19 to a negative result on the reverse transcription-polymerase chain reaction test was 21.3 days. Cancer treatment was modified in 15 patients (68.2%). Conclusion(s): Our results suggest that children with hemato-oncological illnesses rarely experience severe COVID-19 disease. The impact of the first wave of COVID-19 primarily manifested as disruptions in the logistic planning and administration of essential treatment to these children rather than COVID-19 sequelae.Copyright © 2021 Cancer Research, Statistics, and Treatment Published by Wolters Kluwer - Medknow.

Fatal COVID-19 in an infant prompted an early diagnosis of ZNFX1 deficiency in a sibling

Background: NFX1-type zinc finger-containing 1 (ZNFX1) is an interferon-stimulated double-stranded RNA sensor that restricts the replication of RNA viruses in mice. ZNFX1 deficiency in humans is very rare;to date, only fifteen cases have been reported by Vavassori S et al. (10.1016/j.jaci.2021.03.045). The disease presented in all cases as severe viral infections complicated by multisystem inflammation evolved to multiorgan failure with a high mortality rate. Pediatric Allergy and Immunology Section at Queen Rania Children's Hospital in Jordan had confirmed the diagnosis of ZNFX1 deficiency in an infant at his first presentation with severe viral illness based on the positive family history of one sibling death caused by complicated COVID-19 infection. Case presentation: A 12-month-old boy was born to consanguineous parents, full-term, with no NICU admission. He was doing well till the age of four months when he was admitted to the hospital with fever, hypoactivity, and maculopapular skin rash. On admission, he was ill, hypoactive, and febrile, and a physical exam showed hepatosplenomegaly and maculopapular skin rash. His lab showed thrombocytopenia, elevated transaminases, hyperferritinemia, and high CRP;he was treated with broad-spectrum antibiotics, but he continued to deteriorate, and his infectious workup was unrevealing, including COVID-19 PCR. His older sibling died at eight months in 2020 when she got a COVID-19 infection, deceased after rapid deterioration evolved to multiorgan failure. Unfortunately, she had no stored DNA, as she was treated at a peripheral hospital. Based on this presentation and the fatal COVID-19 infection, pediatric immunology service got consulted;we did an immunological workup, which showed normal lymphocyte subsets, Immunoglobulins, and bacterial antibodies. Whole exome sequencing showed a homozygous frameshift mutation in the ZNFX1 gene, protein change defect had detected;p.Tyr555MetfsTer6, and nucleotide change variant: c.1663_1665delTACinsAT. Family screening showed heterozygous for the same variant in both parents and a healthy sibling. The patient was diagnosed with the hemophagocytic lymphohistiocytosis-like disease and treated with steroids, intravenous immunoglobulin, and antimicrobials, he showed complete recovery, and we are going to do bone marrow transplantation as his brother is 8/8 HLA matched.Copyright © 2023 Elsevier Inc.

Incidence and Clinical Outcomes of Newonset Autoimmune Connective Tissue Diseases after Covid-19 Infection- a Systematic Literature Review

Background/Aims Cases of new autoimmune and autoinflammatory conditions have been reported among COVID-19 survivors. A literature review on newonset autoimmune connective tissue diseases (ACTDs) following infection with COVID-19 is lacking.This systematic literature review aimed to evaluate the potential association between COVID-19 infection and the development of new-onset ACTDs in adults. Methods Articles published until September 2022, investigating the association between COVID-19 infection and new-onset ACTDs were included. The ''population'' searched was patients with disease terms for autoimmune connective tissue diseases, including (but not limited to) systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic sclerosis (SSc), any idiopathic inflammatory myositis (IIM), antisynthetase syndrome, mixed CTD and undifferentiated CTD (and related MeSH terms), with ''intervention'' as COVID-19 and related terms. For terms for COVID-19, a dedicated search strategy developed by the National Institute for Clinical Excellence was used.Medline, Embase, and Cochrane databases were searched, restricted to English-language articles only. Eligible articles were: case reports and series (of any sample size), observational studies, qualitative studies and randomised controlled trials. Patients developing ACTDs without prior COVID-19 or reporting flares of existing ACTDs were excluded. Information was extracted on patient demographics, new ACTDs' onset time, clinical characteristics, COVID-19 and ACTD treatment, and COVID-19 and ACTDs outcomes. The protocol was registered in PROSPERO (CRD42022358750). Results After deduplication, 2239 articles were identified. After screening title and , 2196 papers were excluded, with 43 proceeding to fulltext screening. Ultimately, 28 articles (all single case reports) were included. Of the 28 included patients, 64.3% were female. The mean age was 51.1 years (range 20-89 years). The USA reported the most cases (9/28). ACTD diagnoses comprised: 11 (39.3%) IIM (including 4 cases of dermatomyositis);7 (25%) SLE;4 (14.3%) anti-synthetase syndrome;4 (14.3%) SSc;2 (7.1%) other ACTD (one diagnosed with lupus/MCTD overlap). Of eight, four (14.3%) patients (including that with lupus/MCTD) were diagnosed with lupus nephritis. The average onset time from COVID-19 infection to ACTD diagnosis was 23.7days. A third of the patients were admitted to critical care, one for ACTD treatment for SLE with haemophagocytic lymphohistiocytosis (14 sessions of plasmapheresis, rituximab and intravenous corticosteroids) and nine due to COVID-19. The majority (80%) of patients went into remission of ACTD following treatment, while two (10%) patients died- one due to macrophage activation syndrome associated with anti-synthetase syndrome and two from unreported causes. Conclusion Our results suggest a potential association between COVID-19 infection and new-onset ACTDs, predominantly in young females, reflective of wider CTD epidemiology. The aetiology and mechanisms by which ACTDs arise following COVID-19 infection remain unknown and require more robust epidemiological data.

Activated CD8 T-cell hepatitis in children: a single institution experience

Background: Pediatric acute liver failure is a rare and serious life-threatening situation, principally for the 30 to 50% of children in whom the etiology of their liver failure is unclear or indeterminate. Treating these patients is challenging, requiring constant assessment over time with regular evaluation for possible liver transplantation. Children with pediatric acute liver failure of undetermined etiology have lower spontaneous survival and higher rates of transplantation and death than other diagnostic groups. Emerging evidence suggests that a subgroup of patients with indeterminate pediatric acute liver failure have clinical, laboratory, and liver biopsy features of immune dysregulation with a dense infiltration of CD8 T cells. Method(s): In 2022, we received percutaneous liver biopsies from three children with acute hepatic dysfunction that showed an increased number of lymphocytes including CD8 T cells. For each case, routine H&E stains with levels, special stains and immunostains were performed. The first biopsy was from an 18-month-old male who presented with COVID infection, pancytopenia, elevated transaminases, and synthetic liver dysfunction (elevated INR). The second was from a 9-year-old female with a history of elevated liver enzymes with no clear cause. The third case was from a 2-year-old male with elevated liver enzymes, coagulopathy, and cholestasis. Result(s): The three cases showed similar histopathologic findings;an acute liver injury pattern with lobular architectural disarray, giant cell formation, reactive changes, single cell necrosis, cholestasis and marked mixed lymphocytic infiltrates. The infiltrates were predominantly composed of CD8-positive T-lymphocytes with scattered neutrophils, eosinophils and rare plasma cells. Portal areas were mildly expanded with mild bile ductular proliferation and mild to moderate lymphocytic infiltrates. Immunostains for CD8 demonstrated that the infiltrates were predominantly composed of CD8-positive T-lymphocytes. All three patients received steroids and responded to treatment evidenced by normalization of liver enzymes and function. Conclusion(s): Dense hepatic CD8 T-cell infiltration is a major finding inactivated CD8 T-cell hepatitis. However, the percentage distribution of lymphocyte subtypes in the setting of hepatitis is not well established, and CD8 T-cell infiltration has also been described in cases of drug-induced hypersensitivity reactions, viral hepatitis, hemophagocytic lymphohistiocytosis, and macrophage activation syndrome, as well as autoimmune hepatitis. Further investigation is needed to better understand the diagnostic criteria in this disease.

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

The clinical utility of CD163 in viral diseases.

Macrophage activation and hypercytokinemia are notable presentations in certain viral infections leading to severe disease and poor prognosis. Viral infections can cause macrophage polarization into the pro-inflammatory M1 or anti-inflammatory M2 phenotype. Activated M1 macrophages usually restrict viral replication whereas activated M2 macrophages suppress inflammation and promote tissue repair. In response to inflammatory stimuli, macrophages polarize to the M2 phenotype expressing hemoglobin scavenger CD163 surface receptor. The CD163 receptor is shed as the soluble form, sCD163, into plasma or tissue fluids. sCD163 causes detoxification of pro-oxidative hemoglobin which produces anti-inflammatory metabolites that promote the resolution of inflammation. Hence, increased CD163 expression in tissues and elevated circulatory levels of sCD163 have been associated with acute and chronic inflammatory diseases. CD163 and other macrophage activation markers have been commonly included in the investigation of disease pathogenesis and progression. This review provides an overview of the involvement of CD163 in viral diseases. The clinical utility of CD163 in viral disease diagnosis, progression, prognosis and treatment evaluation is discussed.

X-Linked Inhibitor of Apoptosis (XIAP) deficiency presenting as hemophagocytic lymphohistiocytosis triggered by drug allergy

X-linked inhibitor of apoptosis (XIAP) deficiency is a primary immunodeficiency associated with recurrent hemophagocytic lymphohistiocytosis (HLH) episodes. The clinical phenotypes of XIAP deficiency vary, ranging from splenomegaly to life-threatening inflammation. We report a case of XIAP deficiency with unusual late-onset HLH presentation likely triggered by a drug allergy. A previously healthy adolescent boy presented to the hospital with fever and rash seven days after starting antibiotics for a neck abscess. Laboratory evaluation demonstrated cytopenias, elevated liver enzymes, and increased inflammatory markers. Initially, antibiotics were discontinued due to concern for drug rash. He continued to deteriorate clinically and became hypotensive. Additional testing revealed decreased NK cell function, as well as elevated ferritin, triglycerides, and soluble IL-2 receptor. SLAM-Associated Protein (SAP) and XIAP evaluation by flow cytometry demonstrated decreased XIAP expression. Subsequently, genetic testing revealed a known pathogenic mutation in BIRC4 (c.421_422del), confirming the diagnosis of XIAP deficiency.Copyright © 2023

AZD1222 (ChAdOx1 nCoV-19) Vaccine: Hurdles and Visions

ChAdOx1 nCoV-19 (AZD1222) is a replication-deficient chimpanzee adenovirus vectored vaccine developed by Oxford and AstraZeneca for a disease we all know as Coronavirus, or COVID-19. Ongoing clinical studies reveal that the ChAdOx1 nCoV-19 vaccine has a tolerable safety profile and is effective against symptomatic COVID-19. This vaccine may prove crucial in boosting herd immunity, averting life threatening illness, and relieving the current pandemic. In this mini review, we performed a thorough literature search through PubMed and Google Scholar and reported various case reports associated with complications of the adenovirus-vectored COVID-19 vaccine. Various adverse effects of the ChAdOx1 nCoV-19 vaccine were reported around the globe, which were often serious but rare and developed into life-threatening pathologies such as GBS, thrombocytopenia, demyelinating neuropathies, progressive dementia, cerebral infarction, IgA vasculitis, hemophagocytic lymphohistiocytosis, herpes zoster, cutaneous reactions, and vein thrombosis. These worldwide reported complications, which are usually rare and severe, will aid clinicians in understanding and managing unforeseen situations. There is a need for more research to find out more about these complications and their etiopathogenesis. However, the benefits of these vaccinations for stopping the spread of the outbreak and lowering the fatality rate outweigh the potential risk of the uncommon complications.Copyright © The Author(s) 2023.

Thrombocytopenia, anasarca, and renal insufficiency as severe and rare complications of Hodgkin lymphoma: a case report.

BACKGROUND: Patients with Hodgkin lymphoma exhibit various clinical presentations. Needle biopsy of the lymph nodes is a minimally invasive procedure and a useful diagnostic method for malignant lymphomas. However, at times it is difficult to differentiate malignant lymphomas from reactive lymph node changes using a small amount of biopsy material. CASE PRESENTATION: A 77-year-old Japanese man was referred to the emergency department of our hospital owing to high fever and disturbance of consciousness. We diagnosed sepsis due to an acute biliary tract infection because he presented with Charcot's triad-fever, jaundice, and right-sided abdominal pain. However, he did not respond well to antimicrobial therapy and his high fever persisted. Considering the swelling of the right cervical, mediastinal, and intraperitoneal lymph nodes and splenomegaly detected on computed tomography, a differential diagnosis of malignant lymphoma was needed. Hence, we performed a needle biopsy of the right cervical lymph node; however, the amount of sample obtained was insufficient in establishing a definitive diagnosis of malignant lymphoma. Furthermore, during hospitalization, the patient developed thrombocytopenia, anasarca, and renal insufficiency. These symptoms seemed to be the typical signs of the thrombocytopenia, anasarca, fever, reticulin fibrosis or renal insufficiency, and organomegaly syndrome. Next, an external incisional mass biopsy of the right cervical lymph node was performed, which helped identify Hodgkin and Reed-Sternberg cells. Collectively, we established a definitive diagnosis of Hodgkin lymphoma with lymphoma-associated hemophagocytic syndrome. CONCLUSIONS: This case highlights the importance of performing an external incisional mass biopsy of the lymph nodes for the early diagnosis and treatment, if malignant lymphoma is strongly suspected.

A case of hemophagocytic lymphohistiocytosis in a hemodialysis patient with coronavirus disease 2019.

During the treatment of a patient on hemodialysis with severe coronavirus disease 2019 (COVID-19), the patient was weaned from extracorporeal membrane oxygenation, which was used to treat severe COVID-19 pneumonia. However, the patient's condition worsened after the peak infection phase of COVID-19 because of acute respiratory distress syndrome with suspected hemophagocytic lymphohistiocytosis (HLH). After a bone marrow biopsy confirmed the diagnosis, methylprednisolone pulse therapy, followed by combination therapy (including oral prednisolone and cyclosporine) was immediately administered, and the patient survived. Because HLH can occur a month or more after the onset of COVID-19, even if the viral load is reduced to the point of being undetectable by reverse transcriptase-polymerase chain reaction, it can be considered to correspond to the "post-acute COVID-19 syndrome," which has recently been proposed. Early intervention is necessary, because HLH can be fatal. Therefore, it is important to know that HLH can occur at any stage of COVID-19 and to pay attention to the patient's progress over time, including checking the HScore.

The First Case of Haemophagocytic Lymphohistiocytosis Triggered by the Booster Dose of Anti-SARS-CoV-2 Vaccine in a Patient with β-Thalassemia

Background: Haemophagocytic lymphohistiocytosis (HLH) is a rare and potentially life-threatening systemic hyperinflammatory disease, which can have several aetiologies. Clinical case: a 48-year-old woman affected by a transfusion-dependent β-thalassemia was hospitalized in our haematology unit presenting with intermittent fever, haepatosplenomegaly and pancytopenia, which developed a few days after the booster dose of anti-SARS-CoV-2 mRNA vaccine. The investigations performed during hospitalization led to a diagnosis of HLH and steroid therapy where IV dexam-ethasone was initiated and provided benefits. Conclusions: the severity of HLH mandates early treatment, but the management of patients with post-vaccine HLH is still challenging and requires further study. No cases of HLH in patients with thalassemia were previously described.

New development and flares of pre-existing autoimmune diseases following COVID-19 vaccination

Background/Purpose: Covid-19 vaccine is one of the most effective strategies to control coronavirus disease 2019 (COVID-19) pandemic. However, safety data of these vaccines among patients with autoimmune diseases is limited. We report case series of patients who developed new-onset or flares of autoimmune disease after COVID-19 vaccination. Method(s): We conducted a retrospective chart review of patients treated by rheumatologists for new-onset or flares of autoimmune diseases after COVID-19 vaccination between March 2021-July 2022. Patients who had COVID-19 infection or other explainable causes were excluded. According to World Health Organization's Adverse Event Following Immunization causality assessment, we use 30-day cut off. Patients were divided into 2 groups. The first group had symptom onset within 30 days after vaccination whereas the second group had symptom onset 31-90 days post-vaccination. Patient's demographics, clinical manifestations and laboratory data were collected. Result(s): We identified 18 (46%) patients with new-onset autoimmune diseases, and 21 (54%) patients with autoimmune disease flares after COVID-19 vaccination. Four patients had recurrent flares following subsequent vaccination. The median age was 45 years and 66.7% were females. The median duration from last vaccination to symptom onset was 16 days. Twenty-two (56.4%) of patients developed symptoms within 30 days post-vaccination. Symptoms occurred mostly after the 2nd (44.2%) dose. The most common diagnosis was systemic lupus erythematosus (SLE) (32.6%) with modified Systemic Lupus Erythematosus Disease Activity Index-2000 ranging from 1-21 at diagnosis. Among patients with disease flares, 4 patients had undiagnosed autoimmune diseases before vaccination, 4 patients stopped immunosuppressive medications months prior to disease flares, 5 patients stopped immunosuppressive medications 1 week after vaccination, and 7 patients continued immunosuppressive medications. Fourteen (35.8%) cases required hospitalization, four of which were treated in intensive care units. The remaining patients were treated at outpatient clinic. Seven patients required initiation or adjustment of biologic disease modifying anti-rheumatic drugs, 19 patients received intravenous cyclophosphamide and/or intravenous methylprednisolone, 3 patients received intravenous immunoglobulin, and 5 patients underwent plasmapheresis. One patient improved without intervention. Three (7.9%) patients with new-onset autoimmune diseases died: 2 patients with SLE, and 1 patient with Hemophagocytic lymphohistiocytosis. Conclusion(s): There are cases of patients with new-onset or flare of autoimmune diseases occurring after COVID-19 vaccination. Although previously undiagnosed autoimmune disease or prior discontinuation of immunosuppressive medications partly contributed to disease flares, some cases occurred without other precipitating factors and were severe. Disease awareness and early detection are needed to improve patient outcomes. (Figure Presented).

Prolonged fever and inflammation in a young child in the midst of the pandemic - it's not always MIS-C

Case Report: Prolonged fever in children is a symptom that is seen in many different diseases, infections, malignancies, and autoimmune conditions. This can, at times, make the correct diagnosis challenging. A previously healthy 10-year-old male was transferred to our institution with one week history of fever, fatigue, abdominal pain, and vomiting. Laboratory studies demonstrated pancytopenia, transaminitis, electrolyte abnormalities, elevated pro-inflammatory markers & D-Dimer, and hypoalbuminemia. COVID-19 IgG was reactive. Due to the severity in presentation the patient was transferred to the ICU with a presumptive diagnosis of MIS-C. Hewas started on IVIG as well as a five-day course of high-dose methylprednisolone per protocol. Aspirin was added, but later discontinued, due to worsening thrombocytopenia. CT imaging with contrast showed small bilateral pleural effusions & periportal edema, mild splenomegaly, and echocardiogram showed diffuse dilation of the left main and left anterior descending arteries. Given the laboratory findings the differential diagnosis was expanded, Ehrlichia caffeensis serology was sent and empiric Doxycycline started. EBV Nuclear Antigen IgG antibody and EBV Viral Capsid Antigen IgM Antibody resulted as positive suggesting recent or reactivated infection. Respiratory viral PCR with COVID-19, Cytomegalovirus and Parvovirus PCR were negative. Despite initial treatment, the patient continued to have persistent fever, severe pancytopenia, and high ferritin up to 24 426 ng/mL, raising suspicion for Haemophagocytic Lymphohistiocytosis (HLH). Soluble interleukin-2 level was elevated & his presentation was then considered to be more consistent with HLH given that he met 6/8 criteria. Screening for primary HLH including CD107a, perforin and granzyme B, SAP, and XIAP resulted in the latter three being normal but CD107a was abnormal. Next generation sequencing for primary criteria was negative. E. Chaffeensis resulted positive: IgM 1:80, IgG 1:256. MIS-C and HLH have overlapping features but differ in some clinical manifestations. Timely recognition and management is paramount as the management differs. This case illustrates the importance of performing a broad search for potential causes, allowing for appropriate and timely treatment. COVID-19 serology alone should not be the basis for diagnosis of MIS-C in a patient with fever and inflammation. This is important as SARS-CoV2 becomes endemic. Infections such as EBV and Ehrlichiosis should be on the differential particularly in endemic areas and during seasons of higher prevalence for the latter, as these have been well documented to cause HLH. Copyright © 2023 Southern Society for Clinical Investigation.

Using HScore for the evaluation of the signs of hemophagocytosis in multisystem inflammatory syndrome associated with covid-19 in children

Background/Purpose: Multisystem inflammatory syndrome associated with COVID-19 in children (MIS-C) is a rare but severe disease associated with coronavirus infection, in which various systems and organs are affected, including the heart, lungs, kidneys, brain, skin, eyes and gastrointestinal tract. One of the most severe features of this disease can be hemophagocytosis. The aim of this study is to assess the features of hemophagocytosis in MIS-C. Method(s): The retrospective study included 166 children (99 male, 67 female), aged from 4 months to 17 years (median 8.2 years), who met the WHO criteria for MIS-C. The analysis of the obtained data was performed using the STATISTICA software package, version 10.0 (StatSoft Inc., USA). Result(s): To study the signs of hemophagocytosis in patients with MIS-C they were divided into 2 equal groups: with HScore<=91 (n = 79) and with a HScore value >91 (n = 79). This division was done, since this value was associated with the severe life-threatening course of MIS-C and need in ICU admission (70.9% vs. 32.3%, P = 0.000002). Patients with HScore > 91 were more likely to have symptoms such as cervical lymphadenopathy (80.6% vs 54.1%, P = 0.0007), red dry cracked lips (63% vs 34.3%, P = 0.0007), face swelling (66.7% vs 34.7%, P = 0.001), hepatomegaly (84.2% vs 43.1%, P = 0.000000), splenomegaly (54.7% vs 43.1%, P = 0.0003), hypotension/shock (63.3% vs 25.3%, P = 0.000002), had higher levels of ESR (47 mm/h vs 34 mm/h, P = 0.0001), CRP (175.5 mg/L vs 125.8 mg/L, P = 0.01), D-dimer (2135 ng/mL vs. 1079 ng/mL, P = 0.0003), but lower levels of fibrinogen (3.1 g/L vs 5.6 g/L, P = 0.000002) erythrocytes (3.6 x 1012/L vs 4.0 x 1012/L, P = 0.000005), hemoglobin (98 g/L vs 112 g/L, P = 0.000000), and a tendency to thrombocytopenia (110 x 109/l vs 192 x 109/L, P = 0.0002) in 63.3% of patients. According to EchoCG data, signs of myocardial (45.5% vs 15.6%, P = 0.00006) and pericardial (45.5% vs 14.3%, P = 0.00002) lesions were more common in patients with HScore > 91. Patients with HScore > 91 more often needed treatment with IVIG (66.2% vs 24%, P = 0.000000), acetylsalicylic acid (65.7% vs. 47.1%, P = 0.027) and biological drugs (9.1% vs. 1.6%, P = 0.061). The average duration of hospitalization was also much longer in patients with HScore > 91 (23 days vs 14 days, P = 0.000000). Also, the identification of clinical and laboratory signs that were more common in the group of patients with HScore > 91 was performed using sensitivity and specificity analysis, and calculation of odds ratio. Results are presented in Table 1. Conclusion(s): Hemophagocytic syndrome is one of the most severe manifestations of MIS-C occuring in 35.4% of patients. It was found that HScore > 91 is associated with such a severe signs of MIS-C as myocarditis, pericarditis, hypotension/shock, and ICU admission. HScore is a simple tool that can also be used to assess the severity of MIS-C and dynamic monitoring.

Reduced Incidence of Hemophagocytic Lymphohistiocytosis in Japan during the Covid-19 Pandemic

Purpose: Various infectious diseases have dramatically decreased during the COVID-19 pandemic. In Japan, the most frequent cause of HLH in children and adolescents and young adults was infection. In this study, we assessed the incidence of six hematological diseases including HLH, before and during the COVID-19 pandemic Methods:We analyzed the public dataset from the Blood Disease Registration maintained by the Japanese Society of Hematology. From 2016 to 2019, the mean number of patients registered was 42,406 +/- 5,046. In 2020, this figure was 46,471. To analyze changes in annual incidence, we calculated the mean and standard deviation for the 2016-2019 data, and compared this to the annual incidence of each disease in 2020 Results: The total incidence of HLH decreased to 73.7%, compared with the 2016-2019 mean incidence of HLH (152.0 vs. 206.3+/-10.2) Furthermore, HLH incidence in 2020 decreased by 77.5% in those less than 20 years old, and 77.9% in those over 20 years old. Similarly the incidence of IM and aITP decreased by 91.5% and 78.4% in 2020, compared to the respective mean incidences of IMand aITP from 2016 to 2019. The decrease in the number of IM and aITP patients was larger among those less than 20 years of age, compared to those 20 years of age or older (IM: 84.8% vs. 96.6%, and aITP: 52.6% vs 106.5%). On the other hand, the incidences of LCH, ALL, and B-NHL did not decrease in 2020 (LCH, 109.9%;ALL, 102.9%;and B-NHL 111.9%). CONCLUSION(S): The incidence of HLH decreased during the COVID-19 pandemic. Lifestyle changes may be implemented during theCOVID-19 pandemic, specifically social distancing, wearing of facemasks alcohol disinfection, and school closure, effectively reduced contact and droplet transmission.

Plasma Protein Profiles Correlate Hemophagocytic Lymphohistiocytosis (Hlh) Signature with More Severe Pediatric Covid-19

Purpose: In general, children have less severe disease with SARSCoV2 infection than adults. However, some children do experience life-threatening sequelae from infection. In order to analyze inflammatory responses to SARS-CoV2 and clinical outcomes, this study evaluates the plasma protein profiles of pediatric COVID19 patients compared to HLH, severe sepsis, Kawasaki disease, febrile viral illness and healthy controls Methods: The Luminex platform measured 150 analytes in 108 patients with pediatric COVID19, 32 of which developed MIS-C, 16 with HLH, 14 with severe sepsis, 25 with Kawasaki disease, 21 with febrile viral illness, and 20 health controls. The results were tested for significant proteins with a p<=0.05 and those that pasted with an FDR cut off of 0.1 and 80% confidence. Semi-supervised learning using protein analyte profiles of inflammatory disease were used to predict COVID19 similarities and clinical outcomes were compared Results: Analyte comparison COVID19 patients revealed increase in CXCL9 in patients with MIS-C. Semi-supervised predictions revealed HLH as the most common predictor and showed that an HLH plasma signature in pediatric patients with COVID19 was associated with higher instances of MIS-C, longer hospital stay, and higher instances of respiratory failure Conclusion(s): This evaluation of plasma proteins demonstrated that pediatric patients with SARS-Cov2 infection with inflammatory plasma profile similar to an HLH signature experienced more severe disease These results reflect complex range of immune responses in children with COVID19, and they support potential for prospective risk stratification using plasma biomarkers.

Evaluation of Outcome in Patients With Moderate and Severe COVID-19 Via H-Score

Background: Due to uncontrolled lymphocyte reaction, the overproduction of cytokines in COVID-19 patients can cause sepsis-like symptoms, suggesting sepsis, cytokine release syndrome (CRS), and secondary hemophagocytic lymphohistiocytosis (sHLH). Since different therapeutic approaches are used for each diagnosis, differentiation is essential. This study aims to use H-score as a possible prognostic tool in COVID-19 patients. Method(s): A sample of 64 moderate and severe COVID-19 patients was enrolled in this study. Clinical and laboratory findings were assessed. H-score was initially calculated and reevaluated among severe cases 72 hours later and among moderate cases showing severe features of COVID-19. Result(s): Mortality of 31.3% was reported. Laboratory findings, including triglycerides (TG), ferritin, and aspartate aminotransferase (AST) showed significantly higher initial and follow-up laboratory assessment levels in severe cases than in moderate cases. Moreover, fibrinogen was significantly higher among severe cases than moderate cases at the initial assessment, but no significant difference was reported in the second fibrinogen assessment. Conclusion(s): In this study, H-score was useful as a predictive tool for the initial evaluation of severe cases of COVID-19. H-score is much lower in these patients than in non-COVID-19 HLH patients may be due to the different underlying immunologic pathophysiology of COVID-19;thus, each H-score criterion must be evaluated for sensitivity and specificity in COVID-19 patients. The H-score cut-offs, H-score may be useful for diagnosing immune overreaction and determining the need for more exclusive immunomodulatory treatments. Copyright © 2022 Shahid Beheshti University of Medical Sciences. All rights reserved.