EBV Serology Research Articles

One-year follow-up of young people with ME/CFS following infectious mononucleosis by Epstein-Barr virus.

Infectious mononucleosis after primary infection with Epstein-Barr virus (EBV-IM) has been linked to the development of myalgic encephalomyelitis/chronic fatigue-syndrome (ME/CFS) in children, adolescents, and young adults. Here, we present clinical phenotypes and follow-up data from a first German cohort of young people with ME/CFS following EBV-IM. 12 adolescents and 13 young adults were diagnosed with IM-triggered ME/CFS at our specialized tertiary outpatient service by clinical criteria requiring post-exertional malaise (PEM) and a history of confirmed EBV primary infection as triggering event. Demographic information, laboratory findings, frequency and severity of symptoms, physical functioning, and health-related quality of life (HRQoL) were assessed and re-evaluated 6 and 12 months later. Young adults displayed more severe symptoms as well as worsening of fatigue, physical and mental functioning, and HRQoL throughout the study, compared to adolescents. After one year, 6/12 (54%) adolescents no longer met the diagnostic criteria for ME/CFS while all young adults continued to fulfill the Canadian consensus criteria. Improvement in adolescents was evident in physical functioning, symptom frequency and severity, and HRQoL, while young adults showed little improvement. EBV serology and EBV DNA load did not correlate with distinct clinical features of ME/CFS, and clinical chemistry showed no evidence of inflammation. Remarkably, the median time from symptom onset to ME/CFS diagnosis was 13.8 (IQR: 9.1-34.9) months. ME/CFS following EBV-IM is a severely debilitating disease often diagnosed late and with limited responses to conventional medical care, especially in adults. Although adolescents may have a better prognosis, their condition can fluctuate and significantly impact their HRQoL. Our data emphasize that biomarkers and effective therapeutic options are also urgently needed to improve medical care and pave the way to recovery.

Evaluating the diagnostic performance of Liaison® chemiluminescence assay as screening tool for detection of acute Epstein-Barr infection: A comparative study

The present investigation assessed the Liaison® diagnostic performance in detecting Epstein-Barr (EBV) IgM-VCA in a large patient cohort, considering age and symptomatology. VIDAS® were employed as a benchmark for acute EBV infection. The study also probed other coexisting conditions and potential cross-reactivity for error sources. A total of 1311 samples were analyzed, with notable associations found only among paediatric (kappa=0.75) and young adult (kappa=0.58) populations with compatible symptoms. ROC analysis revealed varying optimal cutoff values based on age and symptom categorizations. Logistic regression models identified age and patients from Oncology or Infectious Disease as significant factors for false positives. Potential interferences emerged with RF, ANCA, cytomegalovirus-IgM and VHS-IgM. Notably, Liaison® couldn´t distinguish EBV patients from Oncology, Haemathology or Internal Medicine. This study provides valuable insights, such as implementing ageand symptom-specific thresholds or reviewing test requests, for optimizing EBV serology in microbiology laboratories, leading to faster and more reliable responses.

1219 A Rare Case of EBV Infection Presenting as Acute Appendicitis with Septic Shock - a Case Report and Review of the Literature

Abstract 18yo male presented to the emergency department (ED) with a 2-week history of progressive lower abdominal pain, weight loss of 8kg & diarrhoea. On examination he looked dehydrated, was tachycardic and had a large, tender, palpable mass in his lower abdomen up to the umbilicus. Blood investigations of note were white cell count (WCC) 29.7 and CRP 187. Computerized tomography (CT) reported an extremely large abscess occupying the lower abdomen and pelvis resulting in bilateral hydronephrosis and hydroureter. The appendix was not visualised. On the night of admission, the patient went into septic shock on the ward and was taken to theatre from emergency laparotomy. 4 litres of a large abscess were evacuated, the appendix was identified with an inflamed appearance and an appendicetomy performed. His post operative course was complicated by an ileus and slow resolving, inter-loop abscesses that required multiple courses of antibiotics and eventual return to theatre for further washout. During his early admission, EBV serology was recommended by the microbiology team on foot of a positive monospot test. Serology was also positive for EBV. Histopathological results of the appendix and lymph nodes showed EBV associated changes. Acute appendicitis can be considered a complication of EBV infection with the proposed mechanism being obstruction of the appendiceal lumen due to swollen lymphoid tissue, this most commonly occurs in the acute phase of EBV infection. In this case it has been shown that EBV and subsequent Infectious mononucleosis can cause acute appendicitis and may be its initial presentation.

XMEN DISEASE: MAGT1 MUTATION IN A CHILD WITH HYPOGAMMAGLOBULINEMIA

<h3>Introduction</h3> X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN) disease is a rare disorder caused by mutations in the MAGT1 gene, which codes for a magnesium transporter important in CD8+ T cells and their response. These cells are not activated efficiently in the setting of EBV infection, increasing the likelihood of developing lymphoma. <h3>Case Description</h3> A 9-month-old was evaluated at the hospital due to upper respiratory symptoms. Patient was born at 39 weeks and spent 16 days in NICU due to thrombocytopenia. Physical exam was remarkable for low weight. Laboratories revealed anemia, thrombocytopenia, and hypogammaglobulinemia. Lymphocyte subset panel was normal. Genetic testing showed a pathogenic hemizygous mutation in MAGT1, associated with XMEN disease. Patient was started on intravenous immunoglobulin replacement which he tolerated well. Since then, no other infections have been reported. At 3 years old, patient developed transaminitis. Abdominal ultrasound, hepatitis serology and inflammatory markers were normal. He is being evaluated by Gastroenterology. <h3>Discussion</h3> Regardless of EBV serological status, the cellular and clinical phenotype of XMEN patients is similar, implying that the virus is not responsible for the pathogenesis. Management is based on the individual clinical manifestations. Some patients may require immunoglobulin replacement or prophylactic antibiotic therapy. Recommendations include routine EBV serologies and viral load assessment and malignancy surveillance. A small, controlled trial evaluating the role of magnesium supplementation found no benefit in these patients. Given its rarity and broad spectrum of clinical presentations, there is need to increase awareness of this disease and further investigate possible therapies for these patients.

X-LINKED LYMPHOPROLIFERATIVE DISEASE: DIAGNOSTIC CHALLENGE IN A MIDDLE-AGED MALE

<h3>Introduction</h3> X-Linked Lymphoproliferative Disease Type 1 (XLP1) is a rare disease of males caused by mutation in the gene <i>SH2D1A</i> and is characterized by vulnerability to EBV infection, lymphoma and dysgammaglobulinemia. Fulminant infectious mononucleosis in early childhood is the most common clinical manifestation, but on rare occasions XLP1 does not present until adulthood. <h3>Case Description</h3> We present a 43-year-old male with a history of recurrent sinusitis and bronchitis and leukopenia since childhood. He had EBV infection when he was 18 years old complicated by jaundice and hepatitis that required treatment with corticosteroids. At the age of 42, he developed ITP and was found to have mild splenomegaly. Serum immunoglobulins were mildly abnormal with IgG of 575, IgM of 762 and IgA of 145 mg/dL. Lymphocyte immunophenotyping was within normal limits and serum protein electrophoresis and serum free light chains were normal. Bone marrow biopsy was unremarkable. Invitate PID panel was performed, which revealed a pathogenic variant in SH2D1A gene (c.2T>C). SAP expression by flow cytometry revealed absence in NK cells but present in 17% of CD8+ T cell population suggestive of a somatic reversion in this population. He had mildly decreased NK cell function and positive EBV serology. <h3>Discussion</h3> We present a case of XLP1 diagnosis in adulthood with a history of EBV infection of moderate severity and mild initial immunologic abnormalities. In patients with somatic reversion in CD8+ T cells, milder disease may be more common and genetic testing should be considered early. The management options including bone marrow transplant should be carefully considered.

UNIQUE CASE OF ISOLATED CONGESTIVE SPLENOMEGALY DUE TO ALCOHOLIC CARDIOMYOPATHY RESULTING IN PANCYTOPENIA

UNIQUE CASE OF ISOLATED CONGESTIVE SPLENOMEGALY DUE TO ALCOHOLIC CARDIOMYOPATHY RESULTING IN PANCYTOPENIA

S3157 Respiratory Syncytial Virus-Associated Hepatitis in Pregnancy

Introduction: Respiratory syncytial virus (RSV) predominantly affects children and typically manifests as an upper respiratory tract infection. Primary RSV infection in immunosuppressed adults may increase risks of disseminated infection manifesting as RSV hepatitis. RSV hepatitis may present with fever, abdominal pain, nausea, vomiting, jaundice, coagulopathy, and elevation of transaminases. Case Description/Methods: A 29-year-old woman with 10 weeks of pregnancy, history of anemia and vitamin B12 deficiency was admitted to the hospital for fatigue, intractable nausea, vomiting and inability to tolerate oral intake. She denied respiratory symptoms. She was taking prenatal multivitamins but denied starting new medications or supplements. At presentation, her vital signs and clinical exam were unremarkable with uterine fundus palpable just above the pubic bone. Initial laboratory work up revealed elevated liver enzymes with AST 497 U/L, ALT 712 U/L, normal total bilirubin and ALP. Abdominal ultrasound (US) demonstrated cholelithiasis without evidence of cholecystitis or common bile duct dilation. Subsequent workup including an acute hepatitis panel; CMV, EBV serology; stool H. pylori testing; and autoimmune workup was negative. HSV IgM serology was indeterminant. A respiratory viral molecular panel by PCR was positive for RSV. Abdominal US with doppler showed normal hepatic and portal vessel blood flow and magnetic resonance cholangiopancreatography was negative for choledocholithiasis. She was treated supportively with intravenous fluids, antiemetics and close fetal monitoring. Her liver enzymes peaked on hospital day 4 with AST 863 U/L, ALT 1214 U/L, total bilirubin 1.1 mg/dL. By hospital day 5, her symptoms improved, and she was discharged. At 5 week follow up, AST and ALT improved to 62 U/L and 82 U/L, respectively. Her elective laparoscopic cholecystectomy was deferred until after delivery due to symptom resolution and absence of acute cholecystitis. Discussion: Disseminated RSV a rare manifestation in immunocompromised individuals. Clinical presentation may be atypical, creating diagnostic challenges. Liver biopsy is rarely required to establish the diagnosis. RSV hepatitis is typically self-limited and can be treated with supportive care as antiviral agents have no proven efficacy. A high index of suspicion is required for early identification of RSV hepatitis as timely supportive care may prevent progression to acute liver failure. Table 1. - Laboratory Testing Done to Investigate Emesis Etiology Caption Laboratory Test Reference Range and Units Results Liver Function Tests Alanine aminotransferase (ALT) 0-34 U/L 990 (H) Aspartate aminotransferase (AST) 15-46 U/L 750 (H) Alkaline phosphatase (ALP) 38-126 U/L 89 (N) Total bilirubin 0.2-1.3 mg/dL 1.4 (H) Total Protein 6.3-8.2 g/dL 6.4 (N) Albumin 3.5-5.0 g/dL 3.6 (N) Coagulation Studies Prothrombin time (PT) 9.0-12.0 10.9 (N) International normalized ratio (INR) 0.9-1.1 1.0 (N) Viral Serologies Hepatitis A, IgM Non-reactive Non-reactive Hepatitis B, core IgM Non-reactive Non-reactive Hepatitis B, surface antigen Non-reactive Non-reactive Hepatitis C antibody Non-reactive Non-reactive Hepatitis E antibody Non-reactive Non-reactive Human immunodeficiency virus 1 and 2 antibody/antigen Non-reactive Non-reactive Herpes simplex virus 1 and 2 IgM < =0.89 0.96 (intermediate) Cytomegalovirus quantitative PCR Non-reactive Not detected Epstein Barr virus, IgM Not detected Not detected Influenza A, antigen Not detected Not detected Influenza B, antigen Not detected Not detected Respiratory Syncytial Virus Not detected Detected Autoimmune liver disease panel Liver-Kidney Microsome-1 Antibody IgG (Anti-LMK) 0.0 - 24.9 U 0.8 (N) Antinuclear antibody (ANA) titer < 1:80 < 1:80 (N) Anti-smooth muscle antibody (ASMA) 0-19 Units 6 (N) Antimitochondrial antibody (AMA) 0.0-24.9 Units 2.4 (N) Miscellaneous Rapid plasma regain (RPR) Negative Negative Total Creatinine Kinase (CK) 30-170 U/L < 20 (L) H. pylori antigen Negative Negative - H: High; N: Normal; L: Low.

S3207 Vanishing Tacrolimus Syndrome

Introduction: Cellular rejection is common and therapeutic IS levels are needed to minimize this risk. This case stresses the need to fully explore, and potentially reexplore common causes of subtherapeutic IS levels. Case Description/Methods: A 38-year-old man with history of alcohol related cirrhosis and liver transplant in 2019. followed by 2 episodes of acute rejection, presented with significantly abnormal liver tests. Tacrolimus levels were undetectable and liver biopsy showed moderate rejection. After a course of IV steroid, he was started on prednisone, sirolimus, and increased doses of tacrolimus. Tacrolimus levels remained undetectable despite escalating doses, and addition of fluconazole– used for cytochrome (CYP) inhibition. Liver tests worsened after initial improvements, and repeat biopsy showed changes of chronic rejection. He was treated with a 5-day course of anti-thymocyte globulin, steroids, and maintained on increased immunosuppression (IS). Drug levels for tacrolimus, sirolimus, and mycophenolate were undetectable. He reported medication adherence, and undetectable tacrolimus levels were thought to be due to CYP metabolism. With this concern, he was started on azathioprine and belatacept infusions for IS. He was readmitted with abdominal pain and chronic 10-15 stools daily. Physical exam was notable for abdominal pain, no jaundice or asterixis. Labs showed WBC 5.7, INR 1.03, total bilirubin 11.9, AST 784, ALT 714, Alkaline phosphatase 538, albumin 3.5, negative serology for EBV, CMV, and HSV, and tacrolimus level < 1.0. Lab testing for diarrhea was negative for viral and bacterial causes. With concern for malabsorption, IV tacrolimus was started. EGD and colonoscopy with biopsies were negative for malabsorptive pathology. He was started on pancreatic enzymes for concerns of pancreatic insufficiency, and fecal elastase obtained after was elevated. After 24 hours of IV tacrolimus, serum level was 22.7, and continued to rise even after reduction of dosing suggesting malabsorption as cause of subtherapeutic IS. Discussion: Therapeutic IS levels are vital for transplant success, with an understanding that this needs effective absorption and metabolism. Our patient failed to have therapeutic levels since shortly after his transplant– despite previous negative lab and endoscopic evaluations for malabsorption. We used tactics focused on abnormal metabolism, however, resultant drug levels after IV tacrolimus shows the importance of considering malabsorption as barriers to achieving therapeutic IS.

#19 Viral DNAemia and Viral Seropositivity are Associated with Mortality in Pediatric Patients with Severe Sepsis

Abstract Background Sepsis remains the leading cause of pediatric mortality worldwide. While sepsis recognition campaigns have improved early mortality, current contributors to mortality are unclear. Little attention has been paid to the incidence of latent viral infection in septic pediatric patients, but resultant immune remodeling may affect future host response to acute illness. We report a large multi-center study of viral DNAemia and viral seropositivity in pediatric patients with severe sepsis. Method 401 patients from 9 Pediatric Intensive Care Units (PICUs) in the Eunice Kennedy Shriver National Institutes of Child Health and Human Development Collaborative Pediatric Critical Care Research Network were enrolled. Enrollment criteria included severe sepsis, indwelling central venous or arterial catheter, and age between 44 weeks gestation and 18 years. Blood samples were collected twice per week up to 28 days of admission or until death or PICU discharge. Viral DNAemia was defined by qPCR detection of EBV, CMV, HSV, adenovirus, TTV, HHV6, and/or parvovirus B19. CMV, EBV, HSV and HHV6 serologies (IgG) were performed on one sample from each subject. Infection status was defined as uninfected (serologically negative without detectable DNAemia), acute infection (serologically negative with DNAemia), reactivated infection (serologically positive with DNAemia), or latent infection (serologically positive without DNAemia). Results Of 401 pediatric patients with severe sepsis, 55% were male, 39% previously healthy, and 27% immunocompromised. 44 subjects (11%) died in the PICU. 56% of subjects had documented infection(s) on enrollment (63% bacterial, 50% viral, and 2% fungal). Viral DNAemia, excluding TTV, was detected in 57% of immunocompromised patients and 44% of non-immunocompromised patients. Among patients with viral DNAemia, detection was due to reactivation in 91% of subjects with EBV DNAemia, 63% of those with CMV, and 100% of subjects with HSV and HHV-6. After adjusting for age, PRISM, previously healthy and immunosuppressed status, higher mortality was observed in patients with viral DNAemia due to CMV (OR 3.29 [1.46,7.21], p=0.005), adenovirus (3.55 [1.45,8.38] p=0.006), and HHV-6 (2.29 [1.11,4.63] p=0.025). DNAemia with multiple viruses, excluding TTV, during ICU admission was also independently associated with increased mortality in both immunocompromised (OR 5.51 [1.61,22.6] p=0.001) and non-immunocompromised subjects (OR 3.93 [1.36,11.5] p=0.015). Seropositivity was common (HSV 33%, CMV 42%, EBV 61%, HHV6 98%). Mortality was significantly higher in subjects who were seropositive for EBV (OR 11.5 [2.24, 211.2], p&amp;lt;0.001) and HSV (OR 2.65, [1.03, 7.21], p=0.004). Mortality was increased if more than one virus antibody was detected (OR 6.89 [1.98, 43.5], p&amp;lt;0.001) and highest when all four virus antibodies were detected. With HHV6, DNAemia increased mortality associated with seropositivity (18% vs. 7%, p=0.024). Conclusion In this study, viral DNAemia was common in pediatric patients with severe sepsis and was associated with mortality. Detection of multiple viruses during ICU admission increased risk of mortality, even in patients without preexisting immunosuppression. CMV and adenovirus reactivation were most strongly associated with mortality. Viral seropositivity was also strongly associated with ICU mortality independent of the presence of viral DNAemia. Future analyses will investigate mechanisms by which viral DNAemia and seropositivity contribute to pediatric sepsis mortality.

Coeliac Disease Presenting as Chronic Neutropenia and Leukopenia in a 14‐Year‐Old

Coeliac disease (CD) is an immune-mediated multisystem disorder due to gluten hypersensitivity. Common findings of CD include chronic diarrhoea, weight loss, short stature, iron and folate deficiency and delayed puberty.1, 2 Leukopenia and neutropenia are rare presenting features of CD.3, 4 We report a 14-year-old girl with neutropenia probably caused by CD resolving on a gluten-free diet (GFD). A previously healthy 14-year-old girl presented to her general practitioner with lethargy. Investigations revealed a normal haemoglobin and platelets, leukopenia (WCC 3.2 × 109/L), neutropenia (1.33 × 109/L) and low ferritin (18 μg/L). She was commenced on iron supplements. Repeat full blood count (FBC) in 4 months showed persistent leukopenia and neutropenia prompting a referral to a paediatric clinic in regional New South Wales. Further evaluation in clinic found no history of a viral infection or medications and no family history of a haematological disorder. Physical examination was unremarkable with no lymphadenopathy or hepatosplenomegaly; and the weight and height were at 25th and 75th percentiles. Subsequent FBCs, 8 and 11 months later demonstrated persistent leukopenia (3.6 and 3.1 × 109/L) and neutropenia (1.2 and 1.2 × 109/L). Blood picture, vitamin B12, folate, EBV and CMV serology, anti-neutrophil antibodies, ferritin and copper levels were normal. A presumptive diagnosis of benign chronic neutropenia was made, and in view of previous low ferritin coeliac serology was performed. Serum tTG IgA (>100 U/mL), anti-deamidated Gliadin IgG (80 U), anti-endomysial IgA (positive) were high. A duodenal biopsy revealed prominent villous atrophy with blunting and multiple intraepithelial lymphocytes (more than 30 lymphocytes per 100 enterocytes) suggestive of Marsh 3b type of CD. She was commenced on a GFD. An FBC 6 months after commencement of GFD revealed normal leukocyte and neutrophil counts and the coeliac antibodies were negligible. The causes of chronic neutropenia in children include congenital, cyclic, viral, medications, autoimmune, B12, folate, copper and zinc deficiency, and benign chronic. Neutropenia and leukopenia are uncommon manifestations in CD with only a few cases reported in literature.3, 4 Neutropenia in CD could be caused by deficiency of B12, folate, zinc and copper due to malabsorption of nutrients or else it could be due to autoimmunity. In our patient, B12, folate and copper levels were normal and zinc levels were not done. CD is an immune-mediated disease. In the absence of a nutritional deficiency, we postulate that an autoimmune reaction targeting clones of neutrophils or its precursors is the most likely cause of isolated leukopenia and neutropenia in our patient.4 Our case highlights that coeliac serology could be an important second-line investigation of children with persistent neutropenia. It also reiterates the famous medical maxim: uncommon presentations of common disease are more common than common presentations of uncommon disease.

Hydroa vacciniforme associated with EBV infection in a Moroccan child

Hydroa vacciniforme (HV) is a very rare photosensitivity disorder of childhood characterized by pruritic or painful vesicles in photo-distributed areas. We report a case of a seven-year-old male presenting with recurrent scars on the face with significant impact on psychological health. The history of the patient’s disease went back to when he was five years old and began to show eruptions on the face and forearms associated with a burning sensation, evolving recurrently with each exposure to the sun. Later, these lesions became confluent and crusted, then detached, leaving residual scars. A clinical examination revealed varioliform scars on the face, with scaly and crusted lesions on the nose and auricle (Figs. 1a – 1c). The rest of the examination revealed no adenopathy or organomegaly. Blood count, lymphocyte circulating levels, and immunophenotyping were normal and EBV serology was positive, with IgG+ and IgM-. The child refused to have a skin biopsy performed and did not return for another consultation.

Rituximab‐induced mild encephalopathy with a reversible splenial lesion syndrome (MERS): An adverse effect to add to the list

Mild encephalopathy with a reversible splenial lesion syndrome (MERS) is a rare clinico-radiological entity. Rituximab (RTX)-induced MERS has never been described before. Herein, we report the case of a 33-year-old patient diagnosed since 2017, with an IgG4-related disease (IgG4-RD). This diagnosis was retained in the face of a prolonged fever, sicca syndrome, hepatic damage and renal pseudotumour associated to a high level of IGg4 at 2.8g/L with suggestive renal histology. The patient was treated with corticosteroid therapy with persistence of renal impairment and nephrotic syndrome indicating RTX therapy. The patient received his first dose of RTX and presented neurological and respiratory impairments a few hours afterwards. An infectious investigation comprising a SARS CoV-2 PCR and viral PCRs (VZV, herpes and CMV) on cerebrospinal fluid (CSF) were negative. The HBV, HCV, HIV, Parvo B19, CMV, EBV, herpes, mycoplasma and syphilis serologies as well as Legionella antigenuria were also negative. The patient had received intravenous immunoglobulins (IVIG) and methylprednisone, associated with sodium valproate with favourable outcome. The diagnosis of MERS induced by RTX was retained in our patient according to clinical and radiological features. We herein report the first case of MERS following RTX in a patient treated for IgG4-RD.

Seropositivity for cytomegalovirus and PCR-EBV monitoring: Protective factors for posttransplant lymphoproliferative disorder in pediatric liver transplant.

PTLD is a clinical condition with high mortality. Monitoring EBV replication can be a useful tool to avoid the development of PTLD. This was a retrospective analysis of 428 pediatric patients who underwent liver transplantation between 1989 and 2016. The patients were divided into 2groups (transplanted before 2006, when PCR-EBV was not monitored, and after 2006, when PCR-EBV monitoring was started). Patients with continuous PCR measurements for EBV were evaluated for the impact of a reduction in immunosuppression or a change in immunosuppressants on the number of viral copies. A logistic regression model was applied to evaluate factors related to PTLD. The prevalence of PTLD was 4.2%. After monitoring patients with PCR for EBV levels, a predominance of the most severe, monomorphic form of lymphoproliferative disorder was observed (p=.009). The PTLD mortality was 5%. There was a change in the PCR level after tacrolimus reduction (p=.002) and after tacrolimus exchange for mTOR (p=.008). The number of EBV copies was significantly higher (p=.029) in patients who developed PTLD. In the multiple regression model, seropositivity for CMV was an independent protective factor for lymphoproliferative disorder (OR=0.09; 95% CI 0.02-0.42), reducing the chance of having PTLD adjusted by serology for EBV by 91%. Monitoring the EBV viral load by PCR seems to prevent the emergence of milder forms of lymphoproliferative disorder. Pretransplant seropositivity for CMV is a protective factor for PTLD.

Mononeuritis multiplex associated with primary EBV infection

• Neurologic complications can follow primary EBV infection, although these are rare. • EBV should be considered as a precipitant of unexplained mononeuritis multiplex. • EBV serology requires repeating and careful interpretation to demonstrate evolution of antibody responses and to confirm the diagnosis. A 20 year old lady presented to the acute medical unit with new neurological deficits. She described gastrointestinal symptoms in the preceding 24 hours. Her case was discussed with infectious diseases and neurology overnight, both of whom were resident at a hospital on the other side of the city. The infectious diseases team were concerned enough to discuss the case with Public Health England for consideration of botulism antitoxin. When this diagnosis was discounted on the basis of asymmetric neurological deficits, the patient was admitted under the care of the neurologists. Mononeuritis multiplex of unclear aetiology was diagnosed. A subsequent infectious diseases review resulted in a diagnosis of primary EBV infection, the likely trigger of the symptoms. Whilst neurologic deficits resolved, neuropathic pain continues. Learning points include the importance of an early, accurate description of neurologic deficits and the need to consider EBV as an infectious trigger of mononeuritis multiplex. Collaboration between neurology and infectious disease physicians was key in managing this patient and disentangling the broad array of infectious and non-infectious differential diagnoses.

Clinical Case of a Child with Optic Neuritis, Associated with Epstein-Barr Virus

We present a clinical case of a child with bilateral papillitis, associated with EBV-infection in a 5-year-old female child, who was diagnosed and treated at the Aleksandrovska University Hospital. The initial reason for the eye-exam was a new-onset squint. On admission, she had discrete Eidon confocal scan, decreased visual acuity and bilateral edema and hyperemia of the optic disks. MRI of brain and orbits was evaluated on emergency to rule out a demyelinating or intracranial process. The child had persistent lymphadenopathy and laboratory abnormalities and tested positive for EBV serology. She was treated with intravenous corticosteroid pulse therapy and visual acuity was restored to 100%. Papillitis in children is frequently bilateral, with viral genesis and has a good prognosis. Isolated papillitis (without inflammation of other eye structures) is difficult to distinguish clinically from papilledema. When papilledema is suspected, urgent MRI has to be carried out.

P086 Kawasaki syndrome and Epstein Barr virus: a case report (again!)

Abstract Background Kawasaki disease (kDa), also known as mucocutaneous lymph node syndrome, is always updating. We present the case of a toddler boy with concomitant positive EBV serology. Material The infant is referred to the pediatric ward for stomatitis with cheilitis, fever&amp;gt; 40 ° C, asthenia, irritability evolving for 4–5 days. In addition, clinical examination revealed multiple, small cervical lymph nodes, &amp;lt; 1 cm. There is no conjunctivitis, no skin rash, nor reactivation of the BCG scar. Biology reveals hyperleukocytosis with very high ESR and CRP. ECG and Echo-heart, requested for suspicion of Kawasaki syndrome, are normal. Results Empirical treatment with Aciclovir—Cefalexin with topical care was started. Viral serologies return HSV (-), CMV (-), but EBV (+). Clinical improvement was noted within 36 h. However, inflammatory markers improve within 2–3 days. At 15 days, the child presents with typical convalescent peeling of the fingers and toes; associated with marked thrombocytosis. The diagnosis of Kawasaki Syndrome is definitively confirmed. Discussion The exact aetiology of Kawasaki syndrome remains unclear. Among the factors frequently encountered, the Epstein Barr Virus is reported for almost 30 years. The syndrome frequency is highest before the age of 5 years; similar to Infectious Mono-Nucleosis (due to EBV…). Our case depicts a concomitant Kawaski syndrome and positive EBV serology; without any detectable coronary artery abnormality. Conclusion Kawasaki syndrome is a real “chameleon” condition with possible cardiovascular complications. The viral aetiology springs up through “an old friend”: the Epstein Barr Virus ...Even without any aneurysm (also associated with EBV), the American Heart Association recommends long-term monitoring for all Kawasaki syndromes.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome Associated with Enoxaparin Therapy in a Pediatric Patient

Introduction: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a rare drug hypersensitivity reaction characterized by diffuse skin eruption with systemic symptoms (fever, lymphadenopathy, elevated transaminases, leukocytosis with eosinophilia and atypical lymphocytes) which develops 2-6 weeks after exposure to inciting medications. Clinical presentation is variable and nonspecific. DRESS syndrome is more common in adults, can be life threatening, and is most commonly seen with antibiotics, antiepileptic drugs, and allopurinol. An inciting drug is identified in the majority of cases. DRESS syndrome has been described rarely in association with Vitamin K antagonists and direct oral anticoagulants. In an in-depth examination of existing literature, there are only two reported cases of DRESS syndrome associated with enoxaparin therapy, both in adult patients and no reports of pediatric DRESS syndrome secondary to anticoagulants. We present a case of a pediatric patient with DRESS syndrome associated with enoxaparin therapy.Case Report: A previously healthy 11-year-old female was admitted with sepsis secondary to osteomyelitis and periosteal abscess of the left lower extremity, as well as MRSA bacteremia. The patient was initiated on clindamycin and vancomycin for treatment of underlying infections. A left lower extremity ultrasound with doppler was obtained due to lower extremity swelling and demonstrated an acute deep venous thrombus of the left popliteal vein. She was initiated on a heparin drip and subsequently transitioned to enoxaparin one week later. Several weeks into her hospital course (two weeks after initiation of enoxaparin), she developed facial swelling, a generalized morbilliform rash, and diffuse lymphadenopathy both on exam and abdominal imaging. She continued to have persistent fevers despite multiple washouts of the extremity, appropriate antimicrobial coverage, and negative blood cultures. Liver enzymes concurrently increased (AST 362 IU/L (normal 5-60 IU/L), ALT 371IU/L (normal <35 IU/L) at peak) with development of clinical symptoms. Eosinophilia was not present on initial CBC, though she subsequently developed mild eosinophilia (1.1 K/ul at peak). HHV6, CMV, and EBV serologies were all negative. Skin biopsy was performed and was consistent with a drug eruption. Using the RegiSCAR criteria for DRESS syndrome, this constellation of labs and symptoms indicate a definite case of DRESS syndrome with a score of 6 (final score >5 is needed for a definite case). The patient was started on treatment with high-dose steroids. Clindamycin and vancomycin were both discontinued due to their known association with DRESS syndrome. She was transitioned to doxycycline, however, no improvement in rash, fevers, or liver enzymes was seen over the course of five days. Given this, enoxaparin was transitioned to apixaban. The patient improved with resolution of rash, fevers, and improvement of liver enzymes and eosinophilia within a few days of the discontinuation of enoxaparin.Conclusion: The diagnosis of DRESS syndrome can be challenging due to its nonspecific presentation, particularly in pediatric patients where symptoms can overlap with common viral syndromes and Kawasaki disease, and therefore requires a high index of suspicion. Though children with DRESS syndrome have a better prognosis than adults, prompt recognition and treatment is required to limit morbidity and mortality. In pediatric patients receiving treatment with enoxaparin, DRESS syndrome should be included on the differential for those who develop persistent fevers, lymphadenopathy, rash, transaminitis and/or eosinophilia, and discontinuation of enoxaparin should be considered. DisclosuresWeyand: Takeda: Consultancy; Genentech: Consultancy; Novo Nordisk: Research Funding; Sanofi: Consultancy, Research Funding.

S3675 Azithromycin-Induced Acute Liver Injury

Introduction: Idiosyncratic drug-induced liver injury (DILI) is a subtype of drug-induced liver injury that is typically variable in presentation and independent of medication dose or duration. A great number of commonly used medications and herbal supplements have been associated with idiosyncratic drug-induced liver injury. DILI is of clinical significance due to the potential for progression to chronic liver disease or acute liver failure, and may be caused by drugs not commonly associated with liver injury. Case Description/Methods: A 60 year old female was admitted after presenting with sore throat, fever, cough, diarrhea, rash and generalized malaise for 4 days prior to admission. Her past medical history was significant for mixed connective tissue disease, rheumatoid arthritis, and a remote history of alcohol abuse. She was on day two of an outpatient Azithromycin course prescribed for community acquired pneumonia. Physical exam showed diffuse, blanching, maculopapular rash along chest wall and dorsum of her upper extremities. Hepatic panel showed AST 64, ALT 42, Total bilirubin 1.1, and alkaline phosphatase of 68. Liver chemistries peaked during admission to AST 607, ALT 936, Total Bilirubin 20.8, ALP 739. MRCP demonstrated gallbladder adenomyomatosis and multiple simple hepatic cysts. Azithromycin was discontinued, and patient was started on N-acetylcysteine infusion. Workup for viral hepatitis was negative, as were EBV, CMV, HSV and HIV serologies. Immunologic workup showed positive ANA with chromatin of 6.5, SMRNP >8, and RNP of 8. AMA and ASMA were < 1:20. Given rising liver chemistries and history of autoimmune disease, a liver biopsy was obtained and revealed mild chronic hepatitis with minimal periportal activity, moderate bile duct injury with marked cholestasis, pseudoxanthomatous degeneration, and mild anisonucleosis consistent with DILI. Liver chemistries began improving on day 11 of admission. Patient’s maculopapular rash was largely cleared prior to discharge. Discussion: Azithromycin is recognized as a common agent in DILI. In this case, Azithromycin was recognized early as a potential cause of the patient’s worsening liver chemistries. Cessation of the offending agent will resolve most cases of DILI. This case demonstrates how a commonly prescribed medication may cause DILI with risk of progression to acute liver failure. Medications not typically associated with hepatic injury should be assessed when considering DILI.Figure 1.: Portal area with reactive atypia in bile ducts consistent with cholestasis. Mixed inflammatory infiltrate surrounding portal area.

SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN A CHILD WITH CONCOMITANT EBSTEIN BARR VIRUS AND SCRUB TYPHUS INFECTION – A RARE ENTITY

Scrub typhus is a life threatening zoonosis caused by Orientia tsutsugamushi organisms that are transmitted by the larvae of trombiculid mites. It is endemic to a geographically distinct region, the so called Tsutsugamushi triangle, which includes Japan, China and South Korea. The disease is more prevalent in southern and northern India.It is characterised by focal or disseminated vasculitis and perivasculitis involving the lungs, liver, spleen and central nervous system. We report our experience with pediatric scrub typhus at a hospital in eastern India with EBV positive and secondary HLH. An 8 year old boy with fever, maculopapular rash, hepatosplenomegaly and lymphadenopathy was admitted in our institution and diagnosed with Scrub typhus. Physical and laboratory data showed hepatosplenomegaly, bicytopenia, hyperferritinemia, and hypobrinogenemia. Secondary HLH was diagnosed and the child was managed with IVIG and steroids. In view of rash followed by lymphadenopathy and hepatosplenomegaly EBV serology was also sent as a cause of HLH. Surprisingly, EBV panel was also positive. We therefore concluded that the most probable explanation was EBV triggered HPS following scrub typhus infection. Another possible explanation is EBV can be reactivated in critically ill patients. To our knowledge this is the rst such case in the pediatric population reported till date.

Acquired Amegakaryocytic Thrombocytopenic Purpura Associated with a Paroxysmal Nocturnal Hemoglobinuria Clone: A Case Report and Review of the Literature

Background: Acquired amegakaryocytic thrombocytopenic purpura (AATP) is a rare bone marrow disorder characterized by a marked reduction in megakaryocytes with otherwise normal hematopoiesis. Both humoral and cell-mediated suppression of megakaryocytopoeisis have been postulated as mechanisms causing AATP. Herein we report a case of a 67-year-old man diagnosed with AATP with a co-existent paroxysmal nocturnal hemoglobinuria (PNH) clone and review the literature on AATP, focusing on proposed etiologies for this rare condition. Case: A 67-year-old man presented to clinic with a 1-week history easy bruising, petechiae and a platelet count of 6 x 109/L. He had a history of left elbow bursitis caused by S. pyogenes, treated with antibiotics 6-months prior to his presentation. His CBC was normal at that time. On assessment, HIV, HBV, HCV, and H. pylori serologies were negative; CMV and EBV serologies were positive for IgG and negative for IgM. ANA and RF were negative, and vitamin B12 level was normal. There was no hepatosplenomegaly on ultrasound. Bone marrow aspirate and biopsy demonstrated a normocellular marrow with severe megakaryocytic hypoplasia. Cytogenetics demonstrated normal male karyotype with loss of Y chromosome in 9/20 metaphases. Flow cytometry revealed a population of 3.99% GPI-deficient neutrophils by FLAER assay. Molecular testing for myeloid mutations and T-cell gene rearrangement is pending. The patient was initially treated with corticosteroids and IVIG, and showed no response with persistent isolated thrombocytopenia. He was managed with platelet transfusions which resulted in a normal platelet increment of 35 x 109/L 1-hour post-transfusion. A diagnosis of AATP was established and he was admitted for immunosuppressive therapy (IST) with ATG and cyclosporine. Methods: We conducted a narrative review of the literature on AATP, searching MEDLINE and EMBASE for articles on AATP published in English between 1946 and 2020. Reference lists of selected articles were reviewed to identify additional cases. We extracted data on presentation, bone marrow findings (including cytogenetics, molecular genetics, and flow cytometry), treatment regimens and outcomes. Results: We identified 47 cases of adult patients with thrombocytopenia attributed to AATP reported in the literature (Table 1). Three main mechanisms were proposed: (i) cell-mediated autoimmunity, (ii) humoral autoimmunity, and (iii) intrinsic stem cell defect. All three mechanisms were supported by in vitro studies, which demonstrated suppression of colony forming unit-megakaryocytes (CFU-M) by patients' T-lymphocytes (Gerwitz et al. 1986; Colovic et al. 2004) and serum (Hoffman et al. 1982) found to contain IgG antibodies inhibiting CFU-M formation, as well as intrinsic defects in CFU-M progenitor proliferation. Few studies reported cytogenetic abnormalities and only one documented molecular genetic testing. Response to IST was reported in several cases, most commonly ATG and cyclosporine. Four recent cases demonstrated remission following treatment with TPO agonists eltrombopag and romiplostim. Six cases progressed to aplastic anemia and 4 to myelodysplastic syndrome (MDS). Flow cytometry results were not reported in the majority of cases, and only 1 case reported coexistence of a PNH clone, identified in a pregnant patient with AATP (Zimmerman et al. 2019). Discussion: AATP is defined as severe thrombocytopenia with bone marrow showing marked decrease or absence of megakaryocytes with preservation of other cell lineages. This broad definition encompasses a range of causes, and our review of the literature highlights the heterogenous nature of AATP which has several proposed mechanisms and a number of therapeutic options. The best evidence suggests that AATP is often secondary to T-cell-mediated suppression of megakaryocytopoeisis, which has been demonstrated by in vitro studies, and is supported in vivo by a case of AATP following PD-1 inhibition (Iyama et al. 2020), and frequent response of AATP to T-cell-directed IST. The co-existence of a PNH clone in our case lends further support to a T-cell-mediated autoimmune process, analogous to the mechanism described in aplastic anemia and hypoproliferative MDS. The application of molecular diagnostics may help to further elucidate the role of clonal hematopoiesis and intrinsic stem cell defects versus humoral and cell-mediated autoimmunity in AATP. Disclosures No relevant conflicts of interest to declare.