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.

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.

Cytokine Release Syndrome and Treatment in COVID-19

The emergent outbreak of coronavirus disease 2019 (COVID-19) is a global health problem and has been recognized as a pandemic. Although COVID-19 leads to mild flu-like symptoms in most patients, the disease may cause frequently fatal, severe complications, such as acute respiratory distress syndrome and cytokine release syndrome. In these patients, defects in lymphocytic cytolytic activity trigger the proinflammatory cytokine cascade, and then "cytokine storm” begins. As a result, it leads to uncontrolled active macrophage entry into the tissues and hemophagocytosis. Here, the responses of host cells, cytokine release syndrome and the therapeutic approaches to alleviate the cytokine storm in COVID-19 will be reviewed.

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.

COVID-19: A CONFOUNDING MIMICKER OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

SESSION TITLE: Challenging Cases of Hemophagocytic Lymphohistiocytosis SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome involving pathologic immune activation that is often fatal. The link between the cytokine storm related to COVID-19 and development of HLH has been reported since the onset of the pandemic, but little is known about clinical manifestations of HLH, thereby delaying treatment. CASE PRESENTATION: A 50 year-old male presented with a several day history of progressive weakness in the setting of missed dialysis session. Medical history was significant for ESRD on dialysis and diastolic heart failure (EF 35%). Initial vitals were unremarkable. Physical exam was notable for peripheral edema bilaterally. Laboratory studies were consistent with hyperkalemia, elevated ferritin (28,383) and elevated liver function tests. COVID-19 PCR was positive upon admission. Chest x-ray, CTA chest and a right upper quadrant ultrasound were unremarkable. He was admitted to the medical ICU for emergent dialysis. Soon after arrival to the ICU, he became lethargic and confused with increasing oxygen requirements and a subsequent a code blue was called. Cardiopulmonary resuscitation was immediately initiated, with a first rhythm consistent with ventricular fibrillation. He was shocked and placed on an amiodarone infusion with return of spontaneous circulation. TTE revealed a severely reduced EF <10%. Despite initiation of advanced COVID-19 therapies with Solu-Medrol and tocilizumab he remained ventilator dependent. Due to hemodynamic instability and persistent metabolic acidosis, he was transitioned to continuous renal replacement. Further blood work showed worsening inflammatory markers (ferritin 33,500, LDH 6981). Because of the significantly elevated ferritin, there were concerns for possible HLH. Triglycerides and IL-2 receptor were 395 mg/dL and 9300 pg/mL respectively. Total NK cells were decreased to 1.2%. He remained persistently unstable despite aggressive measures. He suffered a second cardiopulmonary arrest, which was unable to achieve return of spontaneous circulation and he ultimately passed away. DISCUSSION: HLH is characterized by uncontrolled activation and proliferation of benign macrophages in reticuloendothelial organs. This results in histiocytic hemophagocytosis, worsening peripheral blood cytopenia(s), cytokine storm, and cytokine mediated biochemical alteration ultimately culminating in multiorgan dysfunction and disseminated intravascular coagulation. Although a distinctive constellation of features has been described for HLH, diagnosis remains challenging as patients have diverse presentations associated with a variety of triggers. CONCLUSIONS: As HLH is a medical emergency with poor prognosis, prompt recognition and early treatment is crucial for improving clinical outcomes. We hope this case will create increased awareness and timely diagnosis of cytokine storm syndromes in patients with severe COVID-19 infection. Reference #1: Meazza Prina M, Martini F, Bracchi F, Di Mauro D, Fargnoli A, Motta M, Giussani C, Gobbin G, Taverna M, D'Alessio A. Hemophagocytic syndrome secondary to SARS-Cov-2 infection: a case report. BMC Infect Dis. 2021 Aug 13;21(1):811. doi: 10.1186/s12879-021-06532-7. PMID: 34388982;PMCID: PMC8361241. Reference #2: Schnaubelt, Sebastian MDa,*;Tihanyi, Daniel MDb;Strassl, Robert MDc;Schmidt, Ralf MDc;Anders, Sonja MDb;Laggner, Anton N. MDa;Agis, Hermine MDd;Domanovits, Hans MDa Hemophagocytic lymphohistiocytosis in COVID-19, Medicine: March 26, 2021 - Volume 100 - Issue 12 - p e25170 doi: 10.1097/MD.0000000000025170 DISCLOSURES: No relevant relationships by Garrett Fiscus No relevant relationships by Niala Moallem No relevant relationships by Resham Pawar

SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN A PATIENT WITH COVID-19 AND HERPES SIMPLEX VIRUS (HSV): A CASE REPORT

SESSION TITLE: Unique Inflammatory and Autoimmune Complications of COVID-19 Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Hemophagocytic Lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome caused by severe, dysregulated hypercytokinemia. This can be associated with genetic defects or immunologic triggers such as infection, malignancy or autoimmune disorder. The clinical picture consists of multi-organ failure including fever, hepatosplenomegaly, cytopenia,hypertriglyceridemia, hemophagocytosis, high ferritin and IL-2 levels, neurological and liver dysfunction. We present a case of a patient with HLH in the setting of Herpes Simplex Virus (HSV) and SARS-CoV-2 co-infection. CASE PRESENTATION: A 39-year-old male presented to the ER with dyspnea and was found to have COVID-19 pneumonia. He had worsening hypoxemia and was admitted to ICU. He rapidly developed multi-system organ failure (MSOF)including severe hepatitis with AST 13,950 U/L and ALT 10,000 U/L, pancytopenia (Hb 12.9 g/dL, WBC 1.7 K/uL, platelet 15,000 K/uL), acute kidney injury (Cr 6.61 mg/dL), and severe ARDS requiring mechanical ventilation. Abdominal ultrasonography showed splenomegaly. Blood HSV1 DNA PCR was positive with liver biopsy revealing viral inclusions consistent with HSV hepatitis. He had elevated ferritin > 100,000 ug/L and LDH > 2500 U/L. Bone marrow biopsy demonstrated hemophagocytosis and trilineage hematopoiesis. He met 6 of 8 diagnostic criteria for HLH per the HLH-2004 protocol. He received dexamethasone. Risks and benefits of HLH-specific therapy were considered in the setting of liver dysfunction and the decision was made to withhold etoposide and administer anakinra. He died of refractory septic shock and disseminated intravascular coagulopathy. DISCUSSION: Diagnosis of HLH can be challenging due to its rarity and the clinical picture may be initially attributed to sepsis in the presence of infection, as in our patient who had COVID-19 infection and HSV hepatitis. However, a ferritin level >10,000 ng/mL is 90% sensitive and 96 % specific for HLH, with very minimal overlap with sepsis, infections, and liver failure. Additionally, infection is a known trigger of HLH. Despite high mortality without therapy, survival can be significantly increased with HLH-specific therapy, such as etoposide. Treatment with etoposide in the setting of severe liver disease can raise concern because it is metabolized by the liver but it is an essential component of optimal therapy and can be considered in patients with hepatic dysfunction with dose reduction. CONCLUSIONS: Our case highlights the importance of maintaining a high index of suspicion for HLH in critically ill patients with MSOF and liver failure, despite an apparent infectious etiology. This may allow timely diagnosis, early referral to a specialist center and consideration of HLH-specific therapy such as etoposide despite liver dysfunction, to prevent high morbidity and mortality in this potentially fatal disease. Reference #1: Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology Am Soc Hematol Educ Program 2009;:127. DISCLOSURES: No relevant relationships by Abdul Khan No relevant relationships by Nehan Sher No relevant relationships by yuttiwat vorakunthada

A CHALLENGING CASE OF MYCOBACTERIUM TB-INDUCED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

SESSION TITLE: Challenging Cases of Hemophagocytic Lymphohistiocytosis SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune activation in response to a variety of insults including malignant, autoimmune and infectious processes. The most common infectious trigger is a viral infection, but other pathogens have also been implicated including Mycobacterium tuberculosis (MTB) CASE PRESENTATION: 62-year-old male from Bangladesh presented due to lethargy, weakness, and anorexia for several weeks. He also reported fevers, diarrhea, and unintentional weight loss. On examination, he appeared acutely ill with diffuse bibasilar crackles on lung exam. Labs showed platelets of 132, ESR 45 mm/hr, CRP 9.6mg/dL, ferritin 1,765ng/mL and transaminitis. A viral panel was positive for Rhinovirus. Computed tomography (CT) of the chest showed diffuse bilateral ground-glass opacities and he was started on antibiotics for pneumonia. On day 3, his respiratory status worsened and he was emergently intubated. He underwent bronchoscopy and bronchoalveolar lavage (BAL) and started on high-dose steroids for possible hypersensitivity pneumonitis. On day 5, he was extubated to nasal cannula, however, his condition worsened despite treatment. Extensive infectious workup, including HIV, Covid and P jirovecii PCR, sputum, and blood cultures, and preliminary AFB smear were negative. Subsequent labs noted rising ferritin levels (4,164 ng/mL), high triglycerides, pancytopenia and transaminitis. Calculated H score was 211 which gave a 93-96% probability of HLH. Initiation of Etoposide was discussed but family deferred. He was later transferred to another facility. On follow-up, IL-2 receptor antibodies were elevated, bone marrow biopsy showed hemophagocytosis and necrotizing granulomas. He was intubated for worsening hypoxemia. Repeat bronchoscopy and BAL analysis showed many acid-fast bacilli. Anti TB treatment (ATT) was deferred due to his critical state. He further declined and eventually expired. DISCUSSION: The exact mechanism for which MTB triggers HLH is unclear, however, it is thought that MTB serves as an obligate intracellular pathogen after phagocytosis by phagocytic cells to induce TH1-mediated cytotoxicity, activating macrophages and NK cells, further releasing a large quantity of cytokines and chemokines. The lack of specific clinical signs, low sensitivity for acid-fast staining, and time-consuming culture make the diagnosis of TB-HLH difficult. However, the use of NAATs has improved the yield of sputum testing. Exceedingly high ferritin levels should serve as a red flag in cases of undetermined diagnosis. Moreso, Cytopenias, elevated LFTs, and coagulation dysfunction are other clues that a diagnosis of HLH should be on the differential. It is believed that early and effective ATT is the key to preventing HLH in TB patients. CONCLUSIONS: It is paramount to both recognize the features of TB as well as HLH as early diagnosis and treatment favor better outcomes. Reference #1: Padhi S, Ravichandran K, Sahoo J, Varghese RG, Basheer A. Hemophagocytic Lymphohistiocytosis: An Unusual Complication in Disseminated Mycobacterium Tuberculosis. Lung India (2015) 32(6):593–601. doi: 10.4103/0970-2113.168100 Reference #2: Dalugama, C., Gawarammana, I.B. Fever with pancytopenia: unusual presentation of extrapulmonary tuberculosis: a case report. J Med Case Reports 12, 58 (2018). https://doi.org/10.1186/s13256-018-1596-0 Reference #3: O M P Jolobe, Timely recognition of hematophagocytosis attributable to coexistence of lymphoma and tuberculosis, QJM: An International Journal of Medicine, Volume 112, Issue 4, April 2019, Page 315, https://doi.org/10.1093/qjmed/hcy198 DISCLOSURES: No relevant relationships by Katherine Acosta No relevant relationships by Chika Winifred Akabusi No relevant relationships by Uma Medapati No relevant relationships by Hector Ojeda-Martinez No relevant relationships by Busala Oke No relevant relationships by Mar o Torres

EVALUATION OF BONE MARROW & PERIPHERAL BLOOD SMEAR FINDINGS IN SARS-COV-2 PATIENTS, CENTRAL INDIA

This study was done to assess the morphological changes in peripheral blood smears during COVID-19 infection .We aimed to examine the characteristics of the cells detected in the peripheral blood smear and bone marrow at the time of diagnosis in COVID-19 patients. Clinical features, laboratory data, peripheral blood smear of 35patients diagnosed with COVID-19 by PCR was evaluated at diagnosis. Peripheral smear samples of the patients were compared with the age and sex-matched 35 healthy controls. The relationship between the laboratory values of all patients and the duration of hospitalization was analyzed. Peripheral smear shows neutrophilic leucocytosis, lymphopenia and thrombocytopenia while Bone marrows were normocellular to hypercellular, most showing maturing trilineage hematopoiesis with myeloid left shift. In 09 out of 35 evaluable bone marrows, hemophagocytic histiocytes were identified.

LATE ONSET PRIMARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS in AN INDIAN ADOLESCENT BOY during A PEAK of POST COVID-19 MULTISYSTEM INFLAMMATORY SYNDROME

Background: Familial Hemophagocytic lymphohistiocytosis (fHLH) categorized as FHL2 (PRF1), FHL3 (UNC13D), FHL4 (STX11), and FHL5 (STXBP2) encoding for Perforin, Munc13-4, Syntaxin11, and Syntaxin binding protein 2, respectively. There is limited information available about the clinical and mutational spectrum of FHL patients in Indian population. Objectives: To delineate clinical and laboratory features of late onset familial Hemophagocytic Lymphohistiocytosis. Methods: A 12-years-old well nourished sick looking boy, born to a non-consanguineous parents with normal birth, development and immunization history with uneventful past presented to us with 6 days history of high fever, cough, breathing difficulty and severe headache. He had occasional vomiting, abdominal pain, polyarthragia & chest pain from last 10 days. Mother also had given history of throat pain, backache & some non-specifc papular rashes over face before the onset of fever. His vitals were normal. Examination revealed faint diffuse fxed erythematous rash all over the body, pallor, icterus and hepatos-plenomegaly. Musculoskeletal examination was unremarkable. Lab evaluation revealed HB 8.9gm%, TLC 4700/cumm with neutrophils 40% and lymphocytes 56% with 8-9% activated lympocytes. Further evaluation showed low ESR 6mm/hr, fbrinogen 97mg% and albumin 2.2 gm% with elevated CRP 40mg/L, ferritin 2000ng/ml, LDH 658IU/L, SGPT 110IU/L, SGOT 221 IU/L, total bilirubin 6mg%, D-dimer 4355 ng:EFU/ml and Triglycerides 441mg%. His blood, urine, CSF and bone marrow cultures were sterile for endemic bacterial and viral infections in our area. His EBV PCR, CoVID RT PCR and CoVID antibody (Total & IgG) test were negative. His immunoglobulin leves were normal. HRCT Chest showed bilateral mild-moderate plural effusions, mild interstitial thickening in both the lower lobes, few fbrotic opacities & old areas of consolidation bilaterally. 2D echo showed mild pericardial effusion. Bone marrow examination showed Hypercellular marrow with iron depletion and occasional hemophagocytosis with CD8 T lymphocytes proliferation (55.2%) and double positive CD4 & CD8 (1.2%). He was initially commenced on supportive therapy, oxygen & intravenous antibiotics. In view of most probable non-infectious, non-malignant hemophagocytic lymphohistiocytosis, he was fnally given intravenous immunoglobulin (2gm/kg) and intravenous pulse methylprednisolone (30mg/kg). He responded well to above regimen within 3 days. He was discharged with tapering steroids over few weeks. Clinical exome by NGS revealed Homozygous Mutation in STXBP2 gene Intron 14, c.1280-1G>C (3' Splice Site) His parents has been counselled for hematopoietic stem cell transplantation and their decision is still pending. Results: We compared our patietnt with a reference to the largest Indian series of pediatric HLH1. Conclusion: Primary HLH type 5 can present frst time during childhood and adolescence. Any child presenting with unexplained HLH features should undergo genetic analysis irrespective of person's past and family history.

Coronavirus-2019 Disease with Pancytopenia with Leptospirosis and Herpes Simplex Virus Co-infection

Aim and background: COVID-19 pandemic has affected the whole world. Besides COVID, many infections may emerge during the course of the disease. Lymphopenia, use of immunosuppressants underlying comorbidities, and immune dysregulation secondary to SARS-CoV-2 could be the likely cause of the emergence such infections. We hereby describe a case of COVID-19 disease which presented with pancytopenia and was found to have Leptospirosis and Herpes Simplex Virus co-infection. Case summary: A 23-yearold postpartum female with no comorbidities and uneventful obstetric history was referred to our hospital 2 weeks after a full-term normal vaginal delivery. She developed generalized convulsive status epilepticus on the 10th day of her delivery, which was managed elsewhere with anti-epileptic drugs (AEDs). During her hospital stay, RTPCR for COVID-19 turned out to be positive but she remained asymptomatic throughout the course of her illness and seizures remained well-controlled on AEDs. On admission to our hospital, she was fully conscious, alert with no focal neurological deficits. Notable findings on evaluation were pancytopenia with megaloblastic features, bilateral pedal edema, and hepatosplenomegaly. NCCT brain was done which was suggestive of subarachnoid hemorrhage (SAH) along bilateral parietooccipital region for which conservative management was planned. 2D echocardiography was normal. Ultrasonography of abdomen revealed gross splenomegaly and mild hepatomegaly with mesenteric lymphadenopathy. NCCT thorax and abdomen were unremarkable apart from hepatosplenomegaly. In the panel sent for pancytopenia workup, IgM anti-HSV 1 antibodies turned out to be positive in blood. In addition, tropical workup was suggestive of Leptospirosis (IgM antibodies were positive). Workup for tuberculosis was negative. Bone marrow workup revealed features of trilineage hematopoiesis with micronormoblastic maturation consistent with iron deficiency anemia with no evidence of hemophagocytosis. Subsequently, IV acyclovir, IV doxycycline, and iron replacement were added. She improved clinically after these therapies and was subsequently discharged in a stable condition. MRI brain with MR angiography and venography done before discharge showed T1 sulcal hyperintensities along bilateral parietooccipital regions suggestive of SAH which was not progressing (as compared to NCCT brain scan done at admission). On day 60 of telephonic follow-up, patient was doing well and leading normal life without any persistence or emergence of symptoms.

Hemophagocytic Lymphohistiocytosis after COVID-19 Vaccination: A Case Report

Aim and background: Cases of thrombotic thrombocytopenia induced by coronavirus disease 2019 (COVID-19) vaccines have been reported recently. Herein, we describe hemophagocytic lymphohistiocytosis (HLH) following COVID-19 vaccination. Case report: A 35-year-old male, chronic alcoholic, 3 years into abstinence received first dose Covishield vaccine. He started developing a fever, testicular pain, diminished sensorium requiring invasive ventilation, and decreased urine output 4 days after getting vaccinated. Initial workup for NCCT brain and HRCT chest was normal, tropical fever panel was negative, cultures for blood and endotracheal aspirate were sterile, liver and renal functions showed mild derangement, CSF study was normal. Ultrasound examination of the abdomen revealed mild hepatosplenomegaly, mild testicular swelling, and suprainguinal lymphadenopathy, with no focus of infection. Subsequently, he developed bicytopenia with haemoglobin 9.0 g/dL and platelet counts 50 × 109/L, ferritin 2130 μg/L, triglyceride 353 mg/dL, and decreased fibrinogen 1.41 g/L. Bone marrow as well as lymph node biopsy showed haemophagocytosis with engulfment of neutrophils, lymphocytes, and normoblasts making HLH a likely diagnosis. Soluble CD25 and NK cell function could not be performed. Extensive evaluation was done to look into the etiology of HLH. SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR) test was negative. RT-PCR test for Epstein-Barr virus (EBV), influenza A (H1N1, H3N2), influenza B, cytomegalovirus (CMV) performed from endotracheal aspirate (ETA) was negative. Similarly, the RT-PCR test from serum samples for EBV, Parvo B-19, CMV, and from CSF sample for EBV, Parvo B-19, CMV, and HSV-1 was negative. Hepatitis B, C, and HIV serologies were negative. Culture and sensitivity repeated from blood, ETA and urine was sterile. Autoimmune panel including complements levels were negative. Peripheral smear, bone marrow, and lymph node biopsy were normal and did not reveal abnormal or malignant cells. He had persistent fevers to 38.6°C during the first 6 days of his admission, with a rise in his ferritin to 1950 μg/L. The patient received steroids but not etoposide. By the 8th day, his fevers resolved, with improvement in his lethargy and malaise. Two weeks later, his ferritin had reduced to 510 μg/L, platelet count rose to 180 × 109/L, and repeat ultrasound abdomen demonstrated resolution of his splenomegaly. In our patient, there was no clear precipitant of HLH other than the Covishield vaccine. There was no evidence of an infection or malignancy. Due to our patient's clinical stability, resolution of symptoms, and improvement of HLH parameters he did not require HLH specific therapy. It is unclear if he had a pre-existing genetic predisposition to HLH as genetic testing is pending, however, it is unlikely as he has reached the age of 35 and suffered from previous viral infections without developing HLH.

A Case Report of Novel Coronavirus-2019 (COVID-19) Disease and Cytomegalovirus (CMV) Co-Infection: A Lethal Combination

Aim and background: The novel coronavirus-2019 (COVID-19) pandemic is raging all across the world. As we are delving more into the management of COVID-19, many new challenges are emerging, which may pose additional threats. One of these is the emergence or re-activation of concomitant viral infections owing to lymphopenia, use of immunosuppressants, underlying comorbidities, and immune dysregulation. Although we have come across the threat of fungal infections and resistant bacterial infections, experience regarding reactivation or co-infection with other viral infections is still limited. We hereby describe a case of COVID-19 disease with cytomegalovirus (CMV) co-infection. Case summary: COVID-19 with Cytomegalovirus (CMV) Co-infection. A 55-year-old male, COVID unvaccinated, chronic smoker, overweight, and hypertensive patient was admitted to our ICU with a 1-week history of fever, cough, and breathlessness. SARSCoV- 2 reverse transcriptase-polymerase chain reaction (RT-PCR) test was positive. At admission, he had hypoxaemia (SpO2 86% on room air), respiratory rate (RR) 35-40/minute, and ground-glass opacities in chest X-ray involving 50% of bilateral lung parenchyma suggestive of severe COVID-19 pneumonia. He was managed with lung-protective invasive mechanical ventilation, restrictive fluid strategy, 16-18 hour/day proning sessions (4-5), intravenous (IV) remdesivir, IV dexamethasone 6 mg 12 hourly, and enoxaparin thromboprophylaxis. After 2 weeks of ICU stay, weaning was attempted but the weaning attempts failed due to underlying neuromuscular weakness. On examination, bilateral (B/L) cranial nerve palsies, areflexia, and motor power 0/5 in bilateral upper and lower limbs were noticed. A possibility of Guillain-Barre Syndrome (GBS) was kept and IV immunoglobulin therapy was empirically administered for 5 days with some improvement in power up to 1/5 in upper limbs. On day 35 of hospitalization, he developed pancytopenia along with features of deranged liver function and gut dysfunction (in the form of paralytic ileus and abdominal distension). In evaluation, polymerase chain reaction (PCR) for CMV turned out to be positive in blood with a very high viral load.Bone marrow aspiration and biopsy showed hemopoiesis with viral inclusion bodies and haemophagocytosis (HLH). Histological evidence of CMV inclusion bodies was present in the bone marrow besides viremia (detected by PCR for CMV), which confirmed the diagnosis of CMV co-infection. IV ganciclovir was initiated along with steroids in view of HLH. There was a decrease in CMV viral load after initiation of IV gancyclovir with subtle clinical recovery. However, the patient continued to deteriorate and succumbed to his illness in the 8th week of the ICU stay.

A Case Report of Coronavirus (COVID-19) Disease and Herpesviridae Viral Co-Infections: A Lethal Combination? ABS0138)

Introduction: COVID-19 pandemic has affected the whole world. Besides COVID, other viral infections may emerge during the course of the disease owing to lymphopenia, use of immunosuppressants, underlying comorbidities, and immune dysregulation, which may pose additional threats.1 We hereby describe two cases of COVID- 19 with viral co-infections belonging to the Herpesviridae family with undulating clinical course. Case 1: Cytomegalovirus (CMV) Co-infection: A 55-year-old male, COVID unvaccinated, chronic smoker, overweight and hypertensive was admitted to our ICU with a 1-week history of fever, cough, and breathlessness. SARSCoV- 2 reverse transcriptase-polymerase chain reaction (RT-PCR) test was positive. At admission, he had hypoxaemia (SpO2 86%on room air), respiratory rate 35-40/minute, and ground-glass opacities in chest X-ray involving 50% of bilateral lung parenchyma suggestive of severe COVID-19 pneumonia. He was managed with lung-protective invasive mechanical ventilation, restrictive fluid strategy, 16-18 hour/day proning sessions (4-5), intravenous (IV) remdesivir, IV dexamethasone 6 mg 12 hourly, and enoxaparin thromboprophylaxis. After 2 weeks of ICU stay, weaning was attempted but the weaning attempts failed due to underlying neuromuscular weakness. On examination, bilateral (B/L) cranial nerve palsies, areflexia, and motor power 0/5 in bilateral upper and lower limbs were noticed. possibility of Guillain-Barre syndrome (GBS) was kept and IV immunoglobulin therapy was empirically administered for 5 days with some improvement in power up to 1/5 in upper limbs. On day 35 of hospitalization, he developed pancytopenia along with features of deranged liver function and gut dysfunction. In evaluation, PCR for CMV turned out to be positive in blood. Bone marrow aspiration and biopsy showed hemopoiesis with viral inclusion bodies and hemophagocytosis (HLH) [Figs 1 and 2]. A diagnosis of secondary HLH related to CMV was contemplated and IV ganciclovir was initiated along with steroids. Histological evidence of CMV co-infection was present and moreover, the quantitative viral load of CMV showed a decreasing trend after initiating IV gancyclovir. However, the patient continued to deteriorate and succumbed to his illness in the 8th week of the ICU stay. Case 2: Herpes Simplex Virus (HSV) Co-infection: Twenty-three years postpartum female with no comorbidities and uneventful obstetric history was referred to our hospital two weeks after a full-term normal vaginal delivery. She developed generalized status epilepticus on the 10th day of delivery, which was managed with anti-epileptic drugs (AEDs). During the hospital stay, RTPCR for COVID-19 turned out to be positive but she remained asymptomatic and seizures were well-controlled on AEDs. On admission to our hospital, she was fully conscious and alert with no neurological deficits. Notable findings were pancytopenia with megaloblastic features, B/L pedal edema, and hepatosplenomegaly. NCCT brain revealed mild subarachnoid hemorrhage (SAH) along the bilateral parietooccipital region for which conservative management was planned. 2D echocardiography was normal. Ultrasonography of the abdomen showed gross splenomegaly and mild hepatomegaly with mesenteric lymphadenopathy. NCCT thorax and abdomen were unremarkable apart from hepatosplenomegaly. In pancytopenia workup, IgM anti-HSV-1 antibodies turned out to be positive in blood. In addition, tropical workup was suggestive of Leptospirosis (IgM antibodies positive). Serological evidence was suggestive of acute HSV-1 infection (based on antibody titers). Bone marrow workup had features of trilineage hematopoiesis with micronormoblastic maturation consistent with iron deficiency anemia without any evidence of hemophagocytosis. IV acyclovir, IV doxycycline, and iron replacement were added, after which she improved clinically and was discharged in stable condition. Tables 1 and 2 show a detailed description of these cases. Discussion: Herpesviridae family is the most important group of viruses responsible for persistent vi al infections in humans, of which CMV contributes to 60-90% of infections in adults, especially in developing countries.2 In healthy individuals, these viruses are kept dormant by the body's immune mechanisms but in an immunocompromised population, reactivation from the latent state can occur. SARS-CoV-2 infection predisposes patients to concomitant viral co-infections, owing to T-cell lymphopenia, decreased NK cell number, and use of immunosuppressive medications.3,4 The first case of CMV co-infection was first reported by D'Ardes and co-workers in 2020.5 Since then, many studies have been emerging in this area. In an observational study from France, 38 COVID-19 patients on >7 days of MV were studied for HSV and CMV pulmonary co-infections (by quantitative real-time PCR in tracheal samples) out of which 47% of patients had one of these infections (24% HSV, 5% CMV, 18% both).6 Another study looking for HSV-1 in patients on invasive MV found HSV-1 reactivation between days 11 and 40, which correlated with immunological markers of decreased innate immunity.7 A case series looking for CMV infection (by PCR in plasma or BAL) in COVID-19, also found CMV reactivation between day 7 and 45 of illness. Most of these patients were above 60 years of age and immunosuppressed (HIV, diabetes mellitus, medications).8 Although immunocompromised individuals are more vulnerable, healthy immunocompetent adults who are critically ill or on prolonged MV may also be susceptible to these infections.9-12 This may be explained by a state of immunoparalysis inherent to prolonged critical illness. In case 1, an ICU stay of around 9 weeks complicated with recurrent nosocomial infections, multiple blood product transfusions, and steroid usage could have the likely triggers. Whether viral co-infections are merely bystanders or truly pathogenic is difficult to comment but timely management is essential to avoid end-organ damage (EOD) which may occur directly (by enhanced viral load secondary to compromised host immunity) or indirectly (by inflammatory changes consequent to prolonged cell-mediated immunity required to maintain viral dormancy).2-4,13 It also seems imperative to study if a viral co-infection has a proclivity to develop more severe hematological anomalies (besides the inherent risk of HLH with COVID) as was seen in case 1, in which the patient had a downward spiral of illness with multiorgan dysfunction.14-15 Limitations: Dynamics of PCR trends and virology studies of samples from trachea, gut, and urine could not be analysed in our patients. Conclusion: Viral co-infections can occur in COVID-19 disease as these patients are often immunocompromised and critically ill. A high index of suspicion and prompt management is needed to improve the outcome of patients. Patients with organ dysfunctions especially hematologic abnormalities with bone marrow involvement should be worked up in detail to look for concomitant viral co-infections. In the future, large-scale research is needed to better elucidate the relationship between SARS-CoV-2 and other viral co-infections.

AN UNUSUAL CASE OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ASSOCIATED WITH M.CHIMAERA OR LARGE CELL NEUROENDOCRINE CARCINOMA

CASE: 56-year-old Caucasian male presented to the hospital with worsening weakness, exertional dyspnea, dry and nonproductive cough, and a 5-pound weight loss in 2 weeks associated with loss of appetite. He has a significant medical history of mitral valve repair in July 2014, status post bioprosthetic mitral valve replacement in August 2019- culture-negative treated with ceftriaxone, vancomycin, and doxycycline for 6 weeks complicated with CVA, atrial flutter, tobacco abuse, alcohol abuse. His shortness of breath worsened quickly with O2 saturations dropping to 85% and had to be placed on BiPAP followed by high flow nasal cannula/ noninvasive ventilation and became febrile. He was then transferred to ICU for acute hypoxemic respiratory failure. Differentials could be very broad ranging from infections like visceral leishmaniasis, atypical/tuberculous mycobacteria, histoplasmosis, Ehrlichia, Bartonella, Brucella, adeno, disseminated HSV, hematological like Langerhans cell histiocytosis, multicentric Castleman disease. In this patient, differentials included hemophagocytic lymphohistiocytosis, COVID-19. Covid was negative x2. His lab abnormalities as well as diagnostic testing revealed hemophagocytic lymphohistiocytosis. He was empirically started on antibiotics and dexamethasone 20 mg to be continued for 2 weeks then taper if the patient has continued improvement. Dexamethasone was tapered over 8 weeks. On later admissions, Carious test was positive for M. chimaera, and core biopsy of the lung nodule showed large cell neuroendocrine carcinoma. IMPACT/DISCUSSION: Hemophagocytic lymphohistiocytosis (HLH) is a rare but very dangerous condition, characterized by abnormal activation of the immune system, causing hemophagocytosis, inflammation, and potentially widespread organ damage. The primary (genetic) form, caused by mutations affecting lymphocyte cytotoxicity, is most commonly seen in children. Secondary HLH is commonly associated with infections or malignancies. Most current information on diagnosis and treatment is based on pediatric populations. The HLH-2004 diagnostic criteria are the most commonly used diagnostic criteria and were developed for children;but used in adults as commonly as in children, although there is a gap in the knowledge. The HLH-2004 diagnosis criteria state that diagnosis of HLH can be established if either a molecular diagnosis is made consistent with HLH or diagnostic criteria for HLH is fulfilled, which includes meeting 5 of 8 criteria. These are lab and clinical findings including fever, splenomegaly, significant cytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow/spleen or lymph nodes, low or no NK cell activity, ferritin >500 ug/L or sCD25 >2400 U/mL. CONCLUSION: HLH is a disease that needs to be diagnosed and treated promptly, it is fatal otherwise. Treatment is mostly tailored to the patient's root cause, treat the cause, and symptomatic treatment with dexamethasone and etoposide.

A case of hemophagocytic lymphohistiocytosis in COVID-19

Introduction: Haemophagocytic Lymphohistiocytosis (HLH) is a rare immune disorder with progressive systemic inflammatory desease. Diagnostic criteria includes: fever;hepato-splenomegaly;cytopenias affecting at least 2 of 3 lineage (HB, PLT, N);hypertriglycerideamia;haemophagocytosis in bone marrow, spleen, lymph nodes or liver;low NK cell activity;elevated ferritin;elevated sCD25. Description: A 67-years-old man was admitted in sept 2021 for melena and fever. Blood exams showed bicytopenia (hb: 8,3 g/dl, PLT: 22.000/mmc, PT, aPTT, fibrinogen normal, ALT 106 U/L, PCR 125.7 mg/L). Covid buffer was positive with a mild interstitial pneumonia. We started therapy with methylprednisolone 40 mg/die. A bone marrow aspiration showed haemophagocytosis however in few days hematological disorder resolved and patient was discharged. After 30 days he returned for headache. There was again bicytopenia, elevated PCR, increased transaminases, triglyceride: 302 mg/dl, ferritin: 10280 ug/L. A second bone marrow biopsy confirmed haemohphagocytosis. A PET and a CT were normal. This time there was hemolysis and we started methylprednisolone 1 mg/kg. After 10 days exams get worse and we increased steroid to 2 mg/kg/die without benefit. In suspected secondary HLH to covid infection we started intravenous immune globulin (IVIG) 1 gr/kg for 2 days. After 2 weeks emolytic signs and bycitopenia resolved. Conclusions: COVID-19 infection is correlated to a rare syndrome like HLH. In this case in strong suspect of HLH, after steroid failure, IGEV resolved the disorder.

Erythrophagocytosis in Peripheral Blood Smear of a Patient with Urinary Tract Infection

Erythrophagocytosis refers to the removal of old and damaged red blood cells by leukocytes and macrophages. Observation of erythrophagocytosis in peripheral blood smear is a rare phenomenon that is mostly observed in paroxysmal cold hemoglobinuria and sporadically in some other pathological conditions. Here, we report a case of erythrophagocytosis by monocyte in peripheral blood of a patient with urinary tract infection.

Hemophagocytic lymphohistiocytosis sans triggers

Case Report Hemophagocytic Lymphohistiocytosis (HLH) is an hyperinflammatory state due to hyperactivation of macrophages and T-cells which rarely affects adults. It can be familial or sporadic. Triggers are infections, auto-immune diseases, malignancies, and immune checkpoint inhibitors. HLH diagnostic criteria are fever, splenomegaly, bicytopenia, hypertriglyceridemia, hemophagocytosis, low/absent NK-cellactivity, elevated ferritin, and high-soluble interleukin-2-receptor (IL-2R). Five out of eight criteria are required for diagnosis. A 54-year-old female was noted to have leukopenia during a routine visit with her family physician. Follow up labs revealed worsening leukopenia, anemia and a normal platelet count. She received Amoxicillin/Clavulanic acid for a presumed upper respiratory infection and developed nausea, diarrhea and decreased appetite. She was referred to Hematology Oncology for leukopenia. During workup she developed fatigue, night sweats and high fevers. Workup revealed WBC 2400 mcL, microcytic anemia, transaminitis with lactate dehydrogenase of 1725 U/L and ferritin of >15000 ng/ mL . Peripheral blood smear showed leukopenia without immature cells or blasts and mild microcytic erythrocytes. Further tests detected CXCL-9 of 125050 pg/mL, D-dimer of >5000 ng/mL and interleukin-2-receptor of 20604 pg/ mL. EBV, CMV, HSV, HHV-6, parvovirus, bartonella, leishmaniasis, bacteria and COVID-19 were negative. Computed tomography of the chest, abdomen and pelvis did not reveal lymphadenopathy. Brain imaging showed no abnormalities. Cerebrospinal fluid cytology was unremarkable. Bone marrow biopsy (BMBX) showed prominent histiocytic phagocytosis of erythroid precursors and platelets. HLH-94 treatment protocol including weekly steroid and etoposide initiated. Patient's fever, night sweats and leukopenia resolved during hospitalization, with subsequent down trending of ferritin to 103 ng/ml, CXCL-2 to 2663 pg/mL and interleukin-2-receptor to 2,265 pg/mL. Repeat BMBX revealed significant improvement. HLH is a rare life-threatening diagnosis. This patient with nonspecific symptoms was diagnosed with HLH (fever, bicytopenia, elevated ferritin, high-soluble IL-2R and hemophagocytic lymphohistiocytosis on BMBX). Several HLH gene mutations were tested including PRF1, UNC13D, STXBP2, although none was mutated. No infectious, rheumatologic or oncologic triggers were detected. Early diagnosis and treatment are critical. Without treatment, survival is measured in months due to multiorgan failure. This syndrome rarely presents in the absence of triggers which may cause delay in diagnosis and successful treatment. 5-year overall survival with HLH 94 protocol is 54% as opposed to 0% prior to the advent of this protocol. Etoposide and steroids are the mainstay of HLH-94. Cyclosporine can be added in the maintenance phase and hematopoietic stem cell transplant is reserved for familial or relapsed HLH.

Anaplastic large cell lymphoma presenting as hemophagocytic lymphohistiocytosis

INTRODUCTION: HLH is a rare syndrome with an incidence of 1.2 cases per 1,000,000 individuals per year. Diagnosis of HLH is challenging given its varied presentation and strict diagnostic criteria. DESCRIPTION: A 40 year-old female with no medical history presented with two weeks of shortness of breath and cervical lymphadenopathy. She was evaluated in the ED on two separate occasions with workup significant for CT chest findings of mediastinal and axillary lymphadenopathy, pulmonary nodules and a left pleural effusion. Within one week, she presented a third time with worsening shortness of breath, fatigue and fevers. She was febrile, tachycardic, hypoxemic, leukopenic and thrombocytopenic. A repeat CT chest revealed increased lymphadenopathy and pleural effusion. She was started on empiric broad spectrum antibiotics and admitted to the hospital. Infectious workup, pleural fluid cytology and peripheral blood flow cytometry were negative. Bone marrow biopsy had markedly increased histiocytes and hemophagocytosis, but no evidence of malignancy. She developed progressive hypoxemia requiring intubation, shock requiring vasopressors and multiorgan failure. Fevers persisted with worsening pancytopenia, DIC, and markedly elevated inflammatory markers, notably a ferritin >33000. Further workup revealed positive Covid antibodies, elevated parvovirus IgG, elevated fungal markers and Candida in respiratory cultures. Secondary HLH due to sepsis or following COVID infection in the setting of malignancy was suspected. A course of antifungals and high dose steroids was given without improvement. Etoposide was considered, but avoided given possible sepsis, multiorgan failure and pancytopenia. A lymph node biopsy was performed with evidence of hemophagocytosis and ALK-positive anaplastic large cell lymphoma. Despite aggressive treatment, she developed progressive multiorgan failure resulting in death. Autopsy confirmed anaplastic large cell lymphoma with metastasis to the lymph nodes, lungs, epicardium and stomach. DISCUSSION: Malignancy is a known etiology of HLH in adults, however, few cases of ALK-positive anaplastic large cell lymphoma presenting as HLH have been reported. The rapid progression of HLH in this case stresses the importance of early diagnosis and treatment of HLH while pursuing an aggressive malignancy workup.

Fatal MIS-C in a child with palliated single-ventricle physiology

INTRODUCTION: We report a case of MIS-C, confirmed on autopsy, in a toddler with hypoplastic left heart syndrome (HLHS). DESCRIPTION: The patient was a 15 month-old male with HLHS (aortic and mitral atresia) with a superior cavopulmonary anastomosis, and complete heart block with a pacemaker, admitted for respiratory distress. He had known exposure to multiple COVID+ family members, a positive SARS-COV-2 RT-PCR, fevers, elevated inflammatory markers, skin and mucosal changes, and multi-system organ dysfunction, evolving into severe, irreversible multiple organ failure. He met laboratory and clinical criteria for MIS-C. He was treated with high-dose Methylprednisolone, IVIG, Anakinra, and convalescent plasma, but continued to clinically deteriorate. Upon death, the family elected for autopsy. Significant autopsy findings included: acute ischemia of the papillary muscles;peripheral lung infarcts and hemophagocytosis in the bone marrow. The hemophagocytosis in the bone marrow has been noted on several of the small number of autopsies performed on children with fatal MIS-C. DISCUSSION: The patient met WHO and CDC criteria for MIS-C during his hospital stay. Both criteria require fever, elevated inflammatory markers without alternative cause, evidence of prior COVID-19 infection/exposure, and multi-organ involvement. While the pathophysiology of MIS-C remains unknown, the syndrome clinically and immunologically overlaps with other hyperferritinemic syndromes, such as hemophagocytic lymphohistiocytosis and macrophage activating syndrome, where immune-mediated multi-organ injury results from a dysregulated innate immune response-related cytokine storm. The finding of marrow hemophagocytosis on this patient's autopsy adds to the small body of literature on autopsies of children with fatal MIS-C, which also note hemophagocytosis in the marrow and/or spleen. The immune profile and pathology of patients with MIS-C suggests that Macrophages have a significant role in MIS-C. This case thus adds additional credence to this important role of Macrophages, which in turn can further direct studies into its management, to prevent similar deaths.

A rare disease in the community hospital: Hemophagocytic lymphohistiocytosis (HLH) needs immediate local attention for early recognition and individualized treatment

Purpose: HLH is a severe hyperinflammatory syndrome characterized by highly active cytotoxic T-cells, NK-cells, and macrophages. If undiagnosed, HLH can lead to multiorgan damage and death. Conditions triggering HLH are infections, malignancies and autoimmune/-inflammatory (MAS-HLH) disorders. Immunosuppressive patients are prone to develop infection triggered HLH. The incidence in the European community hospital is unknown, as is the number of unrecorded cases. HLH-patients, diagnosed at a single communal hospital with an adjacent catchment area of 500,000 citizens, were reviewed in the context of national and international guidelines. Methods: From 08/2016 to 11/2020, 13 HLH patients were analysed retrospectively. Both HLH-2004 criteria and the web-based Hscore were used to diagnose HLH. The collected data depicts clinical presentation, underlying disease, laboratory findings, and treatment. Results: This Study includes 13 HLH-patients (10 male). Median age at diagnosis was 53, ranging from 27-80 years. Most common triggers in our cohort were infections (n=7) and malignancies(n=4). MAS-HLH (n=1) was seen in a Still's disease patient. HLH-related gene mutation was identified (n=1) with a heterozygote mutation in Perforin (PrfA91). Lymphomas of B-as well as T-cell origin (n=2) and AML (n=3) represented main cause in malignancy associated HLH. Viral infections i.e., COVID-19(n=1), RSV (n=1) and EBV (n=1), also bacterial infections like M. tuberculosis (n=1), and the attenuated strain BCG (n=2) were seen in infection associated HLH. Most patients presented with fever (n=9) and splenomegaly (n=4). HLH patients show pancytopenia, peak ferritin levels ranging 1352-185000 ng/ml (median=21600), peak soluble IL-2 receptor levels ranging 2571-21660 U/ml (median=6606), and peak triglyceride levels ranging 175-610 mg/ml (median=227). Hemophagocytosis in bone marrow was found in 6 patients. First line therapy was glucocorticoids (n=12) combined with polyvalent immunoglobulins. Etoposide (n=5) and chemotherapy (n=4) were given to malignancy triggered HLH. Rituximab was applied in EBV-triggered HLH. Anakinra (n=3) and Ruxolitinib (n=4) was given to selected patients. Two patients received cytokine-depletion using adsorption columns Cytosorb®. Multiorgan failure (n=5) was the most common cause of death. Conclusion: This data provides incidence estimation of HLH in adult patients. Institutional and national measures will be presented to prevent death due to HLH.