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.

Acute pancreatitis associated with diabetic ketoacidosis in a child with COVID-19 infection.

BACKGROUND: There is a mutual influence between COVID-19, diabetes ketoacidosis, and acute pancreatitis, with clinical manifestations overlapping each other, which can lead to misdiagnosis and delayed treatment that could aggravate the condition and affect the prognosis. COVID-19-induced diabetes ketoacidosis and acute pancreatitis are extremely rare, with only four case reports in adults and no cases yet reported in children. CASE PRESENTATION: We reported a case of acute pancreatitis associated with diabetic ketoacidosis in a 12-year-old female child post novel coronavirus infection. The patient presented with vomiting, abdominal pain, shortness of breath, and confusion. Laboratory findings showed elevated levels of inflammatory markers, hypertriglyceridemia, and high blood glucose. The patient was treated with fluid resuscitation, insulin, anti-infection treatments, somatostatin, omeprazole, low-molecular-weight heparin, and nutritional support. Blood purification was administered to remove inflammatory mediators. The patient's symptoms improved, and blood glucose levels stabilized after 20 days of admission. CONCLUSION: The case highlights the need for greater awareness and understanding of the interrelated and mutually promoting conditions of COVID-19, diabetes ketoacidosis, and acute pancreatitis among clinicians, to reduce misdiagnosis and missed diagnoses.

Clinical Features, Laboratory Findings Outcomes in Multisystem Inflammatory Syndrome (Mis-C) Following Covid-19 Infection - a Multicenter, Observational, Ambidirectional Cohort Study in Rio De Janeiro State, Brazil

Objectives: As of March 5th, 2022, around 1.585 cases of MIS-C and 98 deaths (6,4%) were reported in Brazil. The state of Rio de Janeiro State (RJ) having 94 cases (5,9%) and 4 deaths (4,2%)1.Our aim was to evaluate clinical and laboratory features, and management of MIS-C in seven pediatric hospitals in RJ, Brazil. Method(s): Multicenter, observational, ambidirectional cohort study in seven tertiary hospitals in RJ(Brazil), assessing medical charts of pediatric inpatients (0-18 years) diagnosed with MIS-C according to WHO/CDC criteria, from August, 2020 to February, 2022. Descriptive statistics were used to analyze distributions of continuous variables, frequencies, and proportions. Result(s): A total of 112 cases of MIS-C were enrolled. The mean age was 4.2 years and thre was male predominance (59,8%). All cases had a SARS-CoV-2 contact (29.5% close contact;31.3%:positive PCR;serology:43.8%).Only 12.5% had comorbidities. Length of stay (LOS) was 7 days.Median duration of fever was 8 days. Most common symptoms were: rash(67%);gastrointestinal (67%);conjunctivitis (42%);neurological(39.6%);cardiovascular(37.5%);cervical lymphadenopathy (36.6%), and shock/hypotension(28.6%).Co-infection occurred in 3 patients. Forty-four patients fulfilled criteria for Kawasaki disease. Most patients were admitted to PICU(12;62,5%) for amedian of 2 days. Respiratory distress was seen in 18,7%;hypotension:28,6%, and shock in 23,2%. Main laboratory findings were: high C-reactive protein in 95%;D-dimer:77%, anemia:77%, thrombocytosis:63%;transaminitis:43.8%, lymphopenia:38%;hypoalbuminemia:34%;thrombocytopenia: 29%;hypertriglyceridemia:28%, and high pro-BNP in 27%. Echocardiogram was performed in 91/112 patients;abnormal in 70,3%;exhibiting myocardial dysfunction( 25%);pericardial effusion(21%);coronary dilation/aneurysms(11%) and, valvulitis (14.5%). IVIG+corticosteroids (CTC) were administered in 59.8%(67/ 112);18.6%(18/112) IVIG only;10.7%(12/112) CTC only;3.4%(4/112)biologics, and 15(13.3%) received no treatment. ASA low dose in 77.7% (87/112) and moderate/high dose in 34.8%. Oxygen support was needed in 27,7%;vasoactive amines:18,7%;dialysis:5,3%, and transfusion:18,7%.One patient died from a cytokine storm syndrome. Conclusion(s): Our study reports a higher number of MIS-C cases in RJ than the number reported to Brazilian authorities, highlighting underreporting. Our patients were younger, had fewer comorbidities, cardiovascular/gastrointestinal/renal involvement, shortest LOS in ICU, and a higher frequency of myopericarditis.

Covid-19 Infection Presenting as Acute Pancreatitis

Purpose of study Introduction COVID-19 emerged at the end of 2019 as an epidemic of respiratory disease in Wuhan, China that later spread globally and was declared as pandemic. The common clinical manifestations of COVID-19 infection include fever, cough, myalgias, headache, sore throat, anosmia, nasal congestion, fatigue and chest pain. The most serious complications include bilateral multifocal pneumonia and acute respiratory distress syndrome. Acute pancreatitis is rarely reported in association with COVID-19 infection. We report a case of acute pancreatitis secondary to COVID-19 infection. Case Report: A 69-year-old man with past medical history of hyperlipidemia and seizure disorder presented with two days of epigastric pain radiating to back. The patient reported fever, malaise and dry cough for the last 3 days. Home medication included atorvastatin and carbamazepine for 10 and 15 years respectively. The patient denied smoking and alcohol use. COVID- 19 PCR was positive. Labs showed WBC of 3800/muL, hgb 11.8 g/dL, calcium 8.4 mg/dL , lipase 426 U/L, D-Dimer 179 ng/ml DDU, High sensitivity C-reactive protein 27.5 mg/L (normal <5 mg/L) ALT 26 U/L, AST 31 U/L, alkaline phosphatase 103 U/L and total bilirubin 0.3 mg/dL. Ultrasound of the right upper quadrant and CT abdomen showed normal pancreas, common bile duct and gallbladder with no evidence of gallstones. Triglyceride level was 70 mg/dL (<149 mg/dL) on the lipid panel. The patient was diagnosed with acute pancreatitis and received treatment with IV fluids and pain medication. The symptoms improved gradually and the patient was discharged home with resumption of home medications. Methods used Case Report Summary of results The common differentials for acute pancreatitis include alcohol use, gallstones, hypertriglyceridemia, viral infections like mumps and measles, hypercalcemia and medication-related, etc. Normal AST, ALT, alkaline phosphatase and total bilirubin along with absence of gallstones and normal common bile duct ruled out alcoholic and biliary pancreatitis. Normal calcium level and triglyceride level rule out hypercalcemia and hypertriglyceridemia as the cause of pancreatitis. Carbamazepine has rarely been reported to cause acute pancreatitis typically soon after the initiating the therapy or with increase in the dose. The use of carbamazepine for more than 15 years without any recent dose change makes this unlikely as the cause of pancreatitis. The onset of acute pancreatitis during the timeline of COVID-19 constitutional symptoms and absence of other risk factors suggests that COVID-19 infection is responsible for acute pancreatitis in our patient. Conclusions We report a case of acute pancreatitis secondary to COVID-19 infection. Further studies are warranted to better understand the etiology and the pathophysiology of acute pancreatitis secondary to COVID-19 infection.

The Complexities of Managing Hypertriglyceridemia-Induced Pancreatitis in a Critically-Ill COVID-19 Patient

Introduction: Hypertriglyceridemia-induced pancreatitis (HTP) is a variant of pancreatitis requiring unique management. The complications of COVID-19 and its treatments can make HTP therapy more nuanced. This case describes a patient who presented in diabetic ketoacidosis (DKA) with HTP, and COVID-19. The patient developed renal and respiratory failure, necessitating hemodialysis (HD) and extracorporeal membrane oxygenation (ECMO), complicating an otherwise straightforward medical management plan. Case Description: A morbidly obese (BMI 38.9 kg/m2) 43-year-old male presented to an outside hospital with abdominal pain, and vomiting, and was found to have HTP with triglycerides (TG) >2000 mg/dL (<149 mg/dL) and presumed new-onset type 2 Diabetes (HbA1c 10.9%) with DKA. Treatment with fluids, intravenous (IV) insulin infusion and plasmapheresis were initiated. He developed hypoxia after receiving over 17 liters of fluids and was intubated, subsequently developing renal failure and was transferred to our tertiary center for HD and ECMO. On admission, he tested positive for COVID-19, rhabdomyolysis [creatinine kinase 5600 U/L (30-200 U/L)], HTP [TG 783 mg/dL (<149 mg/dL), lipase 461 U/l (7-60 U/L)], glucose 269 mg/dL (not in DKA), transaminitis [AST 184 U/L (4-40 U/L), ALT 61 U/L (4-41 U/L)] and renal failure (GFR 10 ml/min/1.73m2). IV insulin infusion was initiated for hyperglycemia worsened by COVID-19 dexamethasone treatment. Plasmapheresis was performed twice with minimal effect at maintaining a low TG. Fenofibrate was not initiated due to renal failure;Lovaza could not be given via oral gastric tube;Atorvastatin was attempted once rhabdomyolysis resolved, with subsequent worsening of liver function tests. Heparin infusion was initiated for deep vein thrombosis treatment and HTP but was stopped after development of heparin induced thrombocytopenia. The patient developed worsening hypoglycemia requiring cessation of IV insulin, hypotension requiring maximum pressor support, and worsening sepsis leading to his death. Discussion(s): This case illustrates the challenges of managing a patient with HTP and COVID-19. It demonstrates how a normally straightforward treatment algorithm can become increasingly complex when factoring the patient's comorbid conditions. The case highlights the importance of knowing both treatment indications and contraindications for HTP. In this case, HTP may have been the initial diagnosis, straightforward for most endocrinologists, but its treatments and comorbid conditions ultimately made the landscape more challenging, limiting effective management and ultimately leading to this patient's demise.Copyright © 2023

Essential fatty acid and lipoprotein status in pediatric cystic fibrosis: Impact of cystic fibrosis transmembrane conductance regulator modulators

Background: Dyslipidemias and essential fatty acid deficiencies (EFADs) are well established complications of cystic fibrosis (CF). In the general population, a diet high in saturated fat is associated with hyperlipidemia and greater risk of cardiovascular disease and type 2 diabetes. Increasing life expectancy in CF brings concern about the risks of the "legacy" high-fat CF diet. The impact of CFTR modulators on CF-related dyslipidemia and EFAD is not known. Previous studies reported dyslipidemia in people with CF (PwCF) using traditional lipid measures. This study aimed to evaluate the lipoprotein and fatty acid profiles in children and adolescents with CF and to correlate biochemical results with clinical and molecular findings. Plasma and red blood cell (RBC) samples were studied to compare the ability of each method to identify EFAD markers. Method(s): Blood samples (n = 171) were obtained from 142 (78 female) children with CF aged 9.8 +/- 4.7 (range 4 months to 18 years) during routine laboratory draws at pediatric CF center clinic visits. Pancreatic insufficiency was present in 92% and glucose intolerance or diabetes in 14%. Body mass index percentile (BMI%ile) for age z-scorewas 0.23 +/- 0.89 (range -2.4-2.6). F508del mutation was homozygous for 56% and heterozygous for 41%. CFTR modulator therapy had been initiated 3 or more months before for 62% of samples. Sample collection began in September 2019, paused during the COVID-19 pandemic, and resumed in July 2021. An accredited, regional laboratory with expertise in fatty acid analysis processed all samples. Serum was separated and refrigerated for lipoprotein analysis, plasmawas separated and frozen, and RBCs were washed and frozen for fatty acid analysis. Nuclear magnetic resonance lipoprotein assayswere conducted to determine particle number and size of lipoprotein classes. Triglyceride, total cholesterol, and high-density lipoprotein cholesterol (HDL-C) were measured directly (Roche). Low-density lipoprotein cholesterol (LDL-C) and very low-density lipoprotein cholesterol (VLDL-C) were calculated. To correlate laboratory results with clinical findings, medical records were reviewed, and a CF clinic dietitian conducted 24-hour dietary recalls concurrent with study labs. Result(s): Of PwCF homozygous F508del/F508del, 43% tested positive for EFAD biomarkers (RBC linoleic acid, RBC mead acid, RBC triene/tetraene ratio), compared with 13% of PwCF heterozygous F508del ( p <=0.01) (Figure 1). There was no significant difference in concentrations of fatty acid and EFAD biomarkers between those who had or had not initiated CFTR modulator therapy. Lipoprotein abnormalities were identified in 69% of samples with low HDL-C and 39% with large HDL-C, 87% with large VLDL-C particle size and 52% with large VLDL-C particle number, and 5% with high LDL-C or small LDL-C particle numbers. High total cholesterol was found in 15% and high triglycerides in 17%. HDL-C was low in 24%, and 3% had high LDL-C. (Figure Presented) Figure 1. Differences in concentrations of red blood cell (RBC) linoleic and mead acids and triene/tetraene (T/T) ratio between F508del homozygous and F508del heterozygous individuals Conclusion(s): Despite clinical advances and use of CFTR modulator therapy, EFAD remains prevalent and underrecognized in the pediatric CF population. Of PwCF, those homozygous for f508del may have a higher risk of EFAD. Limitations of this study (four different CFTR modulator therapies and small sample sizes in each group) may have precluded significant findings for EFAD and lipid profiles, but PwCF receiving modulator therapy appear to have healthier lipid profiles than those not receiving therapy. Lipids and fatty acid are not routinely evaluated in PwCF, but evaluation should be included in the standard of care for timely dietary interventionsCopyright © 2022, European Cystic Fibrosis Society. All rights reserved

44th Annual Conference of the Association of Clinical Biochemists in Ireland, ACBI 2022

The proceedings contain 16 papers. The topics discussed include: false identification of icterus by eye in a complex patient with severe neutropenic sepsis;an unusual cause of Hypertriglyceridemia in an Infant;a confectionary cause of biochemical mimic for fructose-1,6-bisphosphatase (FBP1) deficiency;forward thinking for reverse PseudoHyperKalaemia;an unexpected follow-up of increased leucine on newborn blood spot screening;'that's gas!' - evaluation of the Abbott Alinity carbon dioxide assay;calcium verification with a difference?;changes in diagnosis of gestational diabetes mellitus during the Covid-19 pandemic at a large maternity hospital in Southwest Ireland;NT-proBNP in primary care. What's the indication and can it be interpreted? and elevated serum neurofilament light chain (NfL) as a potential biomarker in neuropsychiatric disorders.

Prevalence of metabolic syndrome criteria among adults post COVID pandemic situation and steps towards prevention

Metabolic Syndrome (MetS) is one among the Non-Communicable Diseases (NCDs) which might occur due to genetic, environmental, physiological and behavioural factors. MetS is increasing alarmingly in the population. Addressing the modifiable factors to reduce the risk is of prime importance. The current study is intended to observe the prevalence of Metabolic Syndrome criteria with respect to its relation to lifestyle factors among subjects post pandemic situation and the MetS incidence to understand how the disease can be prevented and the means to improve the public health. Random sampling method was used to enrol 20-50 year old (male and female) urban adults of Bengaluru into the study. Type-I-diabetics, lactating and pregnant women, post-cardiac surgery/ pre-post-transplant/ covid-19 recovered patients were excluded. Height, weight, Waist-Circumference (WC) and hip-circumference were measured. BMI and Waist-Hip Ratio (WHR) were calculated. Fasting Blood Glucose (FBS), Triglycerides (TG), HDL, Blood Pressure (BP) values were analysed and recorded. Diet recall was captured and calories consumed per day was estimated. The habits of exercise routine, smoking, tobacco chewing and alcohol were observed. IDF (International Diabetes Federation, 2006) criteria was used to categorise MetS. The data was analysed using relevant statistical tools. A total of 1211 adults (females 486 and males 725) were assessed. High WC indicating central obesity was observed in 55%. High FBS was observed in 29%. Hyper-triglyceridemia was more in males (36%) than females (19%). Low HDL was observed in 65% females against 43% males. High BP was observed among 10% in males and 8% in females. Lack of exercise was observed among 81% of the adults. Due to pandemic situation 10.7% stopped doing exercise. Moderate activity in 5.6% and vigorous activity in 2.8% was recorded;68% of the subjects were consuming >2000 calories/day on an average;18.6% were alcoholic. MetS was observed in 10.6% and MetS-2 criteria in 33.4% and MetS-1criteria in 24.5% before pandemic situation and post pandemic there was an increase. MetS was observed in 12.2% and MetS-2criteria in 49.7% and MetS-1criteria in 27.9% post pandemic. The lack of exercise and high-calorie consumption had a significant correlation with altered lipid values and central obesity. High WC had significant relation to High BMI. WHR had very significant correlation with high FBS and TG. Women had significantly high WC compared to men. The alcohol habit had a significant correlation with hypertriglyceridemia in males. Increased calorie consumption had a moderate correlation with raised FBS and WHR. MetS was significantly observed in those who had lack of exercise, high calorie consumption and alcohol habit. Findings suggest that MetS is in rise in 31-50 year age group. Central obesity, dyslipidemia and high FBS were predominant in 31-40 year group. High BP was observed in 45-50 years age group. Identifying and educating the young adults to correct their life style is the need of the hour to reduce increase of MetS in community.

Dyslipidemia and SARS-CoV-2 spike antibody titres after the second and third doses of the BNT162b2 vaccine among healthcare workers in Japan.

OBJECTIVE: This study aimed to examine the sex-associated differences in the relationship between dyslipidemia and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike immunoglobulin (Ig)G antibodies among BNT162b2 vaccine recipients. METHODS: Participants were staff members (aged 21-75 years) of a medical and research institution who underwent an anti-SARS-CoV-2 spike IgG antibody test after the second (n = 1872) and third doses (n = 1075) of the BNT162b2 vaccine. Dyslipidemia was defined as triglyceride level ≥150 mg/dl, high-density lipoprotein-cholesterol level <40 mg/dl, low-density lipoprotein-cholesterol level ≥140 mg/dl, or lipid-lowering medication use. Multivariable linear regression was used to calculate the ratio of means for SARS-CoV-2 spike IgG titre according to dyslipidemia status. RESULTS: The prevalence of dyslipidemia was 38.0% in men and 19.6% in women. The relationship between dyslipidemia and SARS-CoV-2 spike IgG titres after the second dose differed markedly by sex (P for interaction <0.001). In men, dyslipidemia was associated with significantly lower IgG titres: the ratio of means (95% confidence interval) was 0.82 (0.72-0.93). However, this association disappeared after the third dose (0.96 [0.78-1.18]). Of the dyslipidemia components, hypertriglyceridemia was inversely associated with SARS-CoV-2 spike IgG antibody titre after both the second and third doses (ratio of means: 0.82 [0.70-0.95] and 0.73 [0.56-0.95], respectively). In women, IgG titres did not differ according to dyslipidemia or hypertriglyceridemia status after either dose. CONCLUSIONS: These results suggest a detrimental role of hypertriglyceridemia in the humoral immune response to the BNT162b2 vaccine for COVID-19 in men but not in women.

Propofol-Related Hypertriglyceridemia as a Risk Factor for Pancreatitis in Patients with Covid-19

INTRODUCTION: Hypertriglyceridemia is a known complication of propofol infusion, and higher levels of triglycerides are known to be associated with pancreatitis. Patients with severe COVID-19 pneumonia often require prolonged mechanical ventilatory support and often undergo prolonged sedation with medications such as propofol. In our study we looked to identify safe cut offs for triglyceride levels as well as cumulative dosing of propofol in order to minimize the risk of developing pancreatitis. METHOD(S): Utilizing our COVID-19 database from hospitals in the Steward Health Care Network we conducted a retrospective multi-center review to evaluate the instances of pancreatitis in critically ill patients with COVID-19 pneumonia who received propofol for sedation while intubated. We chart reviewed each patient and collected data regarding the number of days over which propofol was administered, cumulative doses of propofol, peak triglyceride levels, lipase levels, symptoms of pancreatitis and abdominal CT imaging consistent with pancreatitis. For the data analysis we used ROC analysis in conjunction with Youden's index to identify the optimal thresholds for propofol administration parameters and triglyceride levels that would offer maximal sensitivity and specificity for predicting pancreatitis. RESULT(S): We reviewed 499 cases of COVID-19 pneumonia and found 154 patients that were on propofol for sedation for a sufficient period of time. Among these we identified 6 cases of suspected pancreatitis. Using the ROC analysis and Youden's index we identified optimal cut-offs for peak triglyceride levels (688 mg/dl), number of days on propofol (4.5 days), Average daily propofol dose (3007 mg/ day), cumulative propofol dose (24,113 mg) to indicate low risk of pancreatitis. The NPVs for suspected pancreatitis for these cut-offs were found to be from 0.98 to 1. CONCLUSION(S): Our study suggests that patients who have triglyceride levels less than 688 mg/dl, have been on propofol for less than 4.5 days, received less than 3007 mg of propofol per day or have received less than 24113 mg in total of propofol may have a lower risk of developing pancreatitis. While these results are encouraging, larger prospective studies with more confirmed cases of pancreatitis are still necessary.

The correlations among racial/ethnic groups, hypertriglyceridemia, thrombosis, and mortality in hospitalized patients with COVID-19.

Reports of racial and ethnic disparities regarding both rates of infection of the SARS-CoV-2 virus and morbidity of the coronavirus disease-19 (COVID-19) contain profound differences depending on the population. Our previous study has shown that patients with COVID-19 who developed hypertriglyceridemia during hospitalization have a 2.3 times higher mortality rate. However, whether the correlation between hypertriglyceridemia and mortality has disparity among different racial and ethnic groups is unknown. In this study, we investigated the impact of race/ethnicity on the correlation between hypertriglyceridemia and mortality in hospitalized patients with COVID-19. De-identified information from 904 hospitalized patients diagnosed with COVID-19 between March 2020 and June 2021 were extracted from the Medical College of Wisconsin Clinical Data Warehouse. A multivariable regression analysis suggested that the Asians and non-White Hispanics had 4 or 3.9 times higher mortality rate, respectively, after adjusting for age, morbid obesity (BMI ≥40), and gender. The hypertriglyceridemia (≥150 mg/dL) was associated with higher mortality, after adjusting for age, gender, and morbid obesity. The baseline hypertriglyceridemia occurrence had relevantly more consistent percentages among all racial/ethnic groups. However, non-White Hispanic and Asian patients had the highest frequencies of peak hypertriglyceridemia occurrence during hospitalization. The peak hypertriglyceridemia developed during hospitalization correlates with the incidence of thrombosis after adjusting for morbid obesity, age, and sex. In summary, in this retrospective study of 904 hospitalized COVID-19 patients, Asians and non-White Hispanics had a greater likelihood of developing hypertriglyceridemia during hospitalization and mortality than White patients.

LPL Gene Mutation in Type 1 Familial Triglyceridemia Presenting as Recurrent Pancreatitis and Complicated by COVID19

A 7-year-old girl with recurrent episodes of pancreatitis with risk factor of poorly controlled hyperglyceridemia presented with an acute episode of pancreatitis. She was managed conservatively and underwent whole exome sequencing which showed a likely pathogenic LPL gene mutation. Incidentally, she was diagnosed with COVID-19 on screening, which we hypothesize to have triggered the recent episode. On further examination, she was found to have bilateral cataracts. Her hypercholesterolemia was effectively managed with dietary therapy, high dose omega 3, and gemfibrozil. Our case report sensitizes the clinician to use a modern diagnostic tool such as whole exome sequencing in children with recurrent pancreatitis where hypertriglyceridemia is a known risk factor. This child is the first case of LPL mutation reported in India.

COVID-19 treatment: A potential cause of acute pancreatitis.

Remdesivir can precipitate fatal acute necrotizing pancreatitis especially in patients who previously suffer from hypertriglyceridemia.

Therapeutic delivery: industry update covering January 2022

This industry update covers the period from January 1 through January 31, 2022, and is based on information sourced from company press releases, scientific literature, patents and news websites. January 2022 saw Janssen and Midatech expand their collaboration on bioresorbable polymer microsphere technology for drug delivery. Takeda announced its plans to acquire UK-based Adaptate Biotherapeutics and Gandeeva raised further investment funds to support its drug discovery and development platform focused on the evaluation of protein-drug interactions. Biogen announced that it will sell its stake in a biosimilars joint venture and ABL Bio and Sanofi announced a collaboration around a novel treatment for Parkinson's disease. New regulatory announcements this month included US FDA approvals of a new insomnia treatment for Idorsia and a treatment for atopic dermatitis developed by Pfizer. Insulet gained FDA clearance for a closed-loop insulin pump and Ascendis Pharma followed up its United States approval last year for a once-weekly treatment for growth hormone deficiency with European approval. Pfizer and Ionis announced the discontinuation of the clinical development of a novel cardiovascular drug. In terms of collaborations, Novartis and Alnylam announced they will work together to explore targeted therapies to restore liver function;Scorpion Therapeutics partnered with AstraZeneca to develop novel cancer treatments and Nutriband Inc. and Kindeva Drug Delivery will work together to develop a transdermal fentanyl patch. Collaborations were also announced between Century Therapeutics and Bristol Myers Squibb and Lilly and Entos Pharmaceuticals in the areas of stem cell therapies for cancer treatment and neurology, respectively. A team from the Massachusetts Institute of Technology reported progress in developing oral mRNA treatments and West Pharmaceutical Services published a blog describing the development of a proof-of-principle system for a closed-loop feedback system targeting opioid overdose. A report on the BBC website highlighted the benefits of more sustainable inhalers.

A PROBABLE CASE OF IGG4-RELATED LUNG DISEASE MIMICKING PNEUMOCONIOSIS

SESSION TITLE: Autoimmune Diseases Gone Wild: Rare Cases of Pulmonary Manifestations SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 01:35 pm - 02:35 pm INTRODUCTION: Immunoglobulin G4-related disease (IgG4-RD) is a complex entity related to autoimmune dysfunction and inflammation that can cause mass-like lesions and fibrosis of a variety of organs, including pancreas and/or lungs. IgG4-RD in the lung can have diverse clinical and radiographic presentations. We present a case of suspected IgG4-RD that manifested as idiopathic pancreatitis and interstitial lung disease that mimicked coal workers' pneumoconiosis. CASE PRESENTATION: A 72 year-old male with a decades-long coal mining history and a presumptive diagnosis of coal-worker's pneumoconiosis was admitted to the hospital for necrotizing pancreatitis. There was no evidence of gallstones, elevated triglycerides, history of alcohol use or medication known to precipitate pancreatitis. Two years prior, a presumptive diagnosis of coal-worker's pneumoconiosis had been reached largely on the basis of history and chest imaging (Figure 1) showing a progressive massive pulmonary fibrosis pattern. His hospital course was protracted and complicated by nosocomial COVID-19 treated with remdesivir and a 10-day course of dexamethasone. He then had persistent hypoxemia that worsened after dexamethasone was discontinued. Empiric high-dose methylprednisolone was given and the hypoxemia improved dramatically. However, the hypoxemia and pancreatitis repeatedly worsened with significant dose decrease. Inpatient CT chest showed worsening interstitial reticulation and ground-glass opacities superimposed on prior fibrosis (Figure 2). Serum IgG subclass levels were checked;IgG4 and IgG4:IgG ratio were mildly elevated at 93mg/dL and 0.09, respectively. In the setting of idiopathic pancreatitis, pulmonary fibrosis, and steroid-sensitive hypoxemia, he was diagnosed with probable IgG4-RD involving pancreas and lungs. An association between inhaled occupational exposures and development of IgG4-RD has been observed. To confirm the diagnosis of pulmonary IgG4-RD, a tissue biopsy will be necessary. He is now discharged from hospital on a long steroid taper. DISCUSSION: A serum IgG4 level >125mg/dL or an IgG4:total IgG ratio >0.08 support the diagnosis, as does clinical response to steroids. However, these criteria are nonspecific and will be in the normal range in a substantial minority of cases. Lymphocytes and a predominance of IgG4-positive plasma cells infiltrating fibrotic tissue in involved organs are pathologic hallmarks of IgG4-RD. Lung involvement in patients with pancreatitis due to IgG4-RD is common and likely under recognized. CONCLUSIONS: Pulmonary involvement in IgG4-RD can show a wide array of radiographic patterns, but that seen in this case with pseudotumor and fibrosis is among the most commonly reported. Given the overlap in risk factors and radiographic appearance between IgG4-RD and pneumoconiosis, vigilance for IgG4-RD is warranted. Reference #1: Hirano K., Kawabe T., Komatsu Y., et al. High-rate pulmonary involvement in autoimmune pancreatitis. Internal Medicine Journal. 2006;36(1):58–61. doi: 10.1111/j.1445-5994.2006.01009.x Reference #2: Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet. 2015 Apr 11;385(9976):1460-71. doi: 10.1016/S0140-6736(14)60720-0. Epub 2014 Dec 4. PMID: 25481618. Reference #3: de Buy Wenniger, L. J., Culver, E. L., & Beuers, U. (2014). Exposure to occupational antigens might predispose to IgG4-related disease. Hepatology (Baltimore, Md.), 60(4), 1453–1454. https://doi.org/10.1002/hep.26999 DISCLOSURES: No relevant relationships by Jordan Minish, source=Web Response No relevant relationships by Robert Ousley, source=Web Response No relevant relationships by Meagan Reif, source=Web Response No relevant relationships by Derek Russell, source=Web Response

PLASMAPHERESIS FOR HYPERTRIGLYCERIDEMIA-INDUCED PANCREATITIS

SESSION TITLE: Critical Renal and Endocrine Disorders Case Report Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: About 7% of acute pancreatitis (AP) cases are caused by hypertriglyceridemia (HTG). In such cases bowel rest, IV fluids, symptomatic therapy, and triglyceride (TG) lowering interventions are initiated. Plasmapheresis is one of the treatment options, but it has specific indications. We present a case of severe hypertriglyceridemia-induced pancreatitis that required plasmapheresis. CASE PRESENTATION: A 30 y/o man with type 2 diabetes, hyperlipidemia, multiple previous admissions for HTG-AP, presented with severe abdominal pain, nausea, and vomiting x 1 day. On admission, he was tachycardic, hypotensive, afebrile, SpO2 > 96% on RA. Labs: Glu 491 mg/dL, TG > 1000 mg/dL, Cholesterol 509 mg/dL, Lipase 987 U/L, Cr/BUN 2.4 mg/dL /20 mg/dL, VBG pH 7.25/PCO2 36.2 mmHg/PO2 19.4 mmHg/Ca 0.8/lactate 5.6;WBC 13.07 K/cm;COVID PCR positive. CXR: diffuse patchy opacities. CTAP with contrast was deferred because of AKI. He was admitted to the ICU and started on insulin drip with no improvement over 24hrs. He was still acidotic, Ca persistently low, TG still >1000, and kidney function worsened. Plasmapheresis was initiated. After one session his TG lowered to 700. He was restarted on insulin drip and in the next 24hr TG decreased to < 500 and metabolic acidosis resolved. Once AKI resolved, CT abdomen/pelvis with contrast confirmed acute pancreatitis, with focal hypodensities within the uncinate process and the proximal body, concerning infarcts as well as large phlegmon surrounding the pancreas, but no evidence of necrotizing or hemorrhagic pancreatitis. His hospital course was complicated with sepsis and DVT, which resolved with therapy. He was discharged home with TG lowering agents, Apixaban, and his previous T2DM regimen. DISCUSSION: Plasmapheresis is indicated in patients with severe HTG (>1000- 2000 mg/dl), severe HTG-AP, and when standard treatment options are inadequate. It lowers the lipid levels and removes proinflammatory markers and cytokines stopping further inflammation and damage to the pancreas and other organs faster compared to conservative therapy. Most patients need only one session which lowers TG level by 50-80%, as seen in our patient. CONCLUSIONS: Plasmapheresis should be considered in cases of HTGP with worrisome features such as lactic acidosis, hypocalcemia, worsening inflammation, and multi organ failure. Reference #1: Rajat Garg, Tarun Rustagi, "Management of Hypertriglyceridemia Induced Acute Pancreatitis", BioMed Research International, vol. 2018, Article ID 4721357, 12 pages, 2018. https://doi.org/10.1155/2018/4721357 Reference #2: Pothoulakis I, Paragomi P, Tuft M, Lahooti A, Archibugi L, Capurso G, Papachristou GI. Association of Serum Triglyceride Levels with Severity in Acute Pancreatitis: Results from an International, Multicenter Cohort Study. Digestion. 2021;102(5):809-813. doi: 10.1159/000512682. Epub 2021 Jan 21. PMID: 33477149. Reference #3: Gavva C, Sarode R, Agrawal D, Burner J. Therapeutic plasma exchange for hypertriglyceridemia induced pancreatitis: A rapid and practical approach. Transfus Apher Sci. 2016 Feb;54(1):99-102. doi: 10.1016/j.transci.2016.02.001. Epub 2016 Feb 20. PMID: 26947356. DISCLOSURES: No relevant relationships by Adam Adam No relevant relationships by Moses Bachan No relevant relationships by Chen Chao No relevant relationships by Vaishali Geedigunta No relevant relationships by Zinobia Khan No relevant relationships by Jelena Stojsavljevic

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

Triglyceride levels in COVID-19 patients during admission in intensive care correlate with disease severity and mortality

Introduction: It has been established that plasma triglyceride levels are raised during infection and inflammation, due to increased adipose tissue lipolysis, fatty acid synthesis and suppressed fatty acid oxidation.1 Increased triglycerides have also been linked to the 'cytokine storm' underlying the pathophysiology of coronavirus disease 2019 (COVID-19).2 Severe outcomes in COVID-19 patients have been found to be associated with higher triglyceride levels before the infection.3 Another study found triglycerides to be significantly higher after recovery than during the acute phase of infection.4 There is limited data on the trajectory of triglyceride levels in COVID-19 patients during admission in intensive care. Investigating whether triglyceride levels are a useful predictor of disease severity and mortality would enable earlier detection of high-risk patients. While triglyceride levels in COVID-19 patients with mild or severe infections were found to be elevated, this was not the case in those with critical illness which included respiratory or multiple organ failure and septic shock.5 The differences in lipid metabolism between COVID-19 patients and patients with critical illness are yet to be elucidated. Objectives: In this study, triglyceride levels of COVID-19 patients during admission in the general intensive care (GICU) were examined in relation to disease severity and mortality. Triglyceride levels at the beginning of hospitalisation were compared between GICU patients with COVID-19, acute respiratory distress syndrome (ARDS) and critical illness, and healthy controls. Methods: Data was obtained from medical records of 93 patients with COVID-19 admitted to GICU at University Hospital Southampton, between March 2020 and May 2020. Triglyceride levels were recorded for each day of hospitalisation. Data was also obtained from medical records of 8 critically ill patients, 10 patients with ARDS and 10 healthy volunteers. Results: The trajectory of triglyceride levels in this cohort of COVID-19 patients started low, then increased over the course of admission (Figure 1). Increased average triglyceride levels correlated with increased risk for severe disease outcome, as indicated by the Sequential Organ Failure Assessment (SOFA) score calculated at the beginning of GICU admission (p<0.05) (Figure 2). Increased triglyceride levels in the first week of GICU admission also correlated with mortality (p<0.05). When compared with healthy controls and patients admitted to GICU with ARDS, patients with COVID-19 and critical illness had raised triglycerides (Figure 3). Conclusions: Increased triglyceride levels in COVID-19 patients over the duration of GICU admission are associated with worse disease outcomes and increased mortality. This provides further evidence for the role of dyslipidaemia in the progression of COVID-19.

Prescribing practices in a UK Intensive Care Unit during the first wave of the COVID-19 pandemic

Introduction: Comparatively little is known about drug requirements in patients admitted to ICU with COVID-19 pneumonitis. We analysed drug usage for patients admitted during the first wave of the pandemic, comparing these with a retrospective cohort admitted with Influenza pneumonia. Methods: Forty-nine ventilated patients with COVID-19 pneumonitis were identified through ICNARC, ten were excluded as duration of stay < 7 days or not needing ventilation. Further three were excluded due to missing data and one due to ECMO escalation. Results: The median age was 61 years;length of stay 22 days and 68% survived ICU. Table 1 describes the use of Infusions and enteral medications. Discussion: Propofol was used in most (43% patient-hours in ICU/median duration = 234 hours). All patients received opiate infusions (mainly morphine or alfentanil in similar proportions) and 91% received muscle relaxants, for prolonged periods. Over half received Midazolam (median 106 hours) as an adjunct or substitute to Propofol as patients were difficult to sedate, required longer ventilation, paralysis and concerns with Propofol associated hypertriglyceridemia. Over two-third received alpha agonist infusions (median 68.5 hours) as adjunctive sedation or delirium management. Three quarters of patients received a furosemide infusion (median 90 hours), the evidence extrapolated from studies such as FACTT.1 Around three quarters received Human Albumin (median 100 grams over 3 days). Nearly a quarter received nebulized Prostacyclin for refractory hypoxia, often associated with saturation of HME filters and ventilatory difficulties.2 Over half of patients received Carbocisteine (median 13 days). Clonidine and Risperidone to manage delirium were used in a third (median 10.5 and 11 days respectively), as was Acetazolamide to restore pH and aid weaning. Over a third were prescribed enteral opiates and nearly a quarter received benzodiazepines to manage withdrawal symptoms. Just under a half of patients received Melatonin. Antibiotic usage was high with a median of 3 Antibiotics used (median duration 15 days/61% of patient days). Diagnosing superadded infection such as VAP was challenging3 and we did not routinely monitor serum Procalcitonin levels. We also compared prescribing habits with 12 influenza patients (11 survivors) identified using similar inclusion criteria and found patients with COVID-19 were older (61 versus 51 years ) with longer ICU stays (median 22 versus 20 days). They were also more likely to receive enteral Carbocisteine, Clonidine, Acetazolamide, Morphine and Diazepam. Conclusion: We were able to generate valuable data on prescribing in ventilated patients with COVID-19 pneumonitis during the first wave. Through this, we are able to use drug usage as a surrogate for issues such as delirium, drug withdrawal, antibiotic prescribing and nursing workload in general.