Fulminant Clinical Course Research Articles

Inefficient tissue immune response against MPXV in an immunocompromised mpox patient.

The recent outbreak of monkeypox virus (MPXV) was unprecedented in its size and distribution. Those living with uncontrolled HIV and low CD4 T cell counts might develop a fulminant clinical mpox course with increased mortality, secondary infections, and necrotizing lesions. Fatal cases display a high and widespread MPXV tissue burden. The underlying pathomechanisms are not fully understood. We report here the pathological findings of an MPXV-driven abscess in gastrocnemius muscle requiring surgery in an immunocompromised patient with severe mpox. Presence of virus particles and infectivity were confirmed by electron microscopy, expansion microscopy, and virus culture, respectively. MPXV tissue distribution by immunohistochemistry (IHC) showed a necrotic core with infection of different cell types. In contrast, at the lesion rim fibroblasts were mainly infected. Immune cells were almost absent in the necrotic core, but were abundant at the infection rim and predominantly macrophages. Further, we detected high amounts of alternatively activated GPNMB+-macrophages at the lesion border. Of note, macrophages only rarely colocalized with virus-infected cells. Insufficient clearance of infected cells and infection of lesion-associated fibroblasts sustained by the abundance of profibrotic macrophages might lead to the coalescing of lesions and the severe and persistent clinical mpox course observed in immunocompromised patients.

Amino acid influx via LAT1 regulates iron demand and sensitivity to PPMX-T003 of aggressive natural killer cell leukemia

Aggressive natural killer cell leukemia (ANKL) is a rare hematological malignancy with a fulminant clinical course. Our previous study revealed that ANKL cells proliferate predominantly in the liver sinusoids and strongly depend on transferrin supplementation. In addition, we demonstrated that liver-resident ANKL cells are sensitive to PPMX-T003, an anti-human transferrin receptor 1 inhibitory antibody, whereas spleen-resident ANKL cells are resistant to transferrin receptor 1 inhibition. However, the microenvironmental factors that regulate the iron dependency of ANKL cells remain unclear. In this study, we first revealed that the anti-neoplastic effect of PPMX-T003 was characterized by DNA double-strand breaks in a DNA replication-dependent manner, similar to conventional cytotoxic agents. We also found that the influx of extracellular amino acids via LAT1 stimulated sensitivity to PPMX-T003. Taken together, we discovered that the amount of extracellular amino acid influx through LAT1 was the key environmental factor determining the iron dependency of ANKL cells via adjustment of their mTOR/Myc activity, which provides a good explanation for the different sensitivity to PPMX-T003 between liver- and spleen-resident ANKL cells, as the liver sinusoid contains abundant amino acids absorbed from the gut.

Fulminant hemorrhagic course of a thalamic H3 K27-altered diffuse midline glioma in an adult patient: illustrative case.

H3 K27-altered diffuse midline gliomas (DMGs) are rare tumors, which are, regardless of their histological appearance, classified as World Health Organization grade 4 tumors. They are characterized by a diffuse growth pattern, midline anatomical location, and poor prognosis. Although DMGs occur predominantly in childhood, these tumors can also be found in young adults. The authors present a case of a 29-year-old patient who was found unconscious with a Glasgow Coma Scale score of 4, along with abnormal extensor movements and bilateral middilated nonreactive pupils. Computed tomography revealed obstructive hydrocephalus due to an acute hemorrhage in a right thalamic lesion. To drain the hydrocephalus and relieve the ongoing central herniation, emergent placement of a right-sided, and later a left-sided, extraventricular drain was performed. Despite the postoperative resolution of hydrocephalus, the patient died shortly after because of the central brain herniation that had occurred. Brain autopsy revealed a H3 K27-altered DMG in the right thalamus. Although typically described in the pediatric population and located in the pons, H3 K27-altered DMG should also be considered in young adult patients with midline lesions, particularly if they are located in the thalamus or brainstem. In rare cases, H3 K27-altered DMG may present with an acute tumor-related hemorrhage, leading to a fulminant clinical course.

The clinical characteristics and therapeutic outcomes of adult patients with community-acquired spontaneous bacterial meningitis with a fulminant clinical course in Taiwan

PurposeTo examine the clinical characteristics of adult patients with community-acquired spontaneous bacterial meningitis (CASBM) with a fulminant clinical course.Materials and methodsThe clinical features and therapeutic outcomes of 127 adult CASBM patients were analyzed. The patients were divided into two groups as those with and without a fulminant clinical course. Fulminant clinical course was defined as meningitis presenting initially with marked consciousness disturbance (Glasgow Coma Scale score < 8) or a rapid deterioration in consciousness level within 48 h of hospitalization.ResultsAmong the 127 enrolled patients, 69 had a fulminant clinical course (47 men and 22 women) and 58 did not. The patients with a fulminant clinical course had a significantly higher incidence of end-stage renal disease (ESRD), severe clinical manifestations and higher mortality rate, and the survivors had significantly worse therapeutic outcomes. Klebsiella (K.) pneumoniae (50 strains) was the most important pathogen for the development of a fulminant clinical course, and all strains were susceptible to ceftriaxone and ceftazidime. With treatment, 50.7% (35/69) of the patients with a fulminant clinical course died, and the presence of K. pneumoniae infection was significant prognostic factor.ConclusionsThe presence of ESRD, initial presentation of altered consciousness, septic shock, seizures and CSF total protein level and K. pneumoniae infection were significantly associated with a fulminant clinical course of adult CASBM, and patients with this specific infectious syndrome had high mortality and morbidity rates. The presence of K. pneumoniae infection is a significant prognostic factor.

Initial skin necrosis presentation at emergency room was associated with fulminant clinical course and mortality in patients with Vibrio necrotizing fasciitis

Necrotizing fasciitis (NF) is a life-threatening infection. Skin necrosis is an important skin sign of NF. The purposes of this study was to investigate the initial skin conditions of Vibrio NF patients between emergency room (ER) to preoperative status, to compare the clinical and laboratory risk indicators of the skin necrosis group and non-skin necrosis group when they arrived at ER, and to evaluate whether initial cutaneous necrosis related to fulminant course and higher fatalities. From 2015 to 2019, seventy-two Vibrio NF patients with surgical confirmation were enrolled. We identified 25 patients for inclusion in the skin necrosis group and 47 patients for inclusion in the non-skin necrosis group due to the appearance of skin lesion at ER. Seven patients died, resulting in a mortality rate of 9.7%. Six patients of skin necrosis group and one patient of non-skin necrosis group died, which revealed the skin necrosis group had a significantly higher mortality rate than the non-skin necrosis group. All the patients in the skin necrosis group and 30 patients of non-skin necrosis group developed serous or hemorrhagic bullous lesions before operation (p = 0.0003). The skin necrosis group had a significantly higher incidence of APACHE score, postoperative intubation, Intensive care unit stay, septic shock, leukopenia, higher counts of banded leukocytes, elevated C-reactive protein (CRP), and lower serum albumin level. Vibrio NF patients presenting skin necrosis at ER were significantly associated with fulminant clinical courses and higher mortality. Physicians should alert the appearance of skin necrosis at ER to early suspect NF and treat aggressively by those clinical and laboratory risk indicators, such as elevated APACHE score, shock, leukopenia, higher banded leukocytes, elevated CRP, and hypoalbuminia.

Outcomes After Decompressive Surgery for Severe Cerebral Venous Sinus Thrombosis Associated or Not Associated with Vaccine-Induced Immune Thrombosis with Thrombocytopenia: A Multicenter Cohort Study

BackgroundClinical observations indicated that vaccine-induced immune thrombosis with thrombocytopenia (VITT)-associated cerebral venous sinus thrombosis (CVST) often has a space-occupying effect and thus necessitates decompressive surgery (DS). While comparing with non-VITT CVST, this study explored whether VITT-associated CVST exhibits a more fulminant clinical course, different perioperative and intensive care unit management, and worse long-term outcome.MethodsThis multicenter, retrospective cohort study collected patient data from 12 tertiary centers to address priorly formulated hypotheses concerning the clinical course, the perioperative management with related complications, extracerebral complications, and the functional outcome (modified Rankin Scale) in patients with VITT-associated and non-VITT CVST, both with DS.ResultsBoth groups, each with 16 patients, were balanced regarding demographics, kind of clinical symptoms, and radiological findings at hospital admission. Severity of neurological symptoms, assessed with the National Institute of Health Stroke Scale, was similar between groups at admission and before surgery, whereas more patients with VITT-associated CVST showed a relevant midline shift (≥ 4 mm) before surgery (100% vs. 68.8%, p = 0.043). Patients with VITT-associated CVST tended to undergo DS early, i.e., ≤ 24 h after hospital admission (p = 0.077). Patients with VITT-associated CVST more frequently received platelet transfusion, tranexamic acid, and fibrinogen perioperatively. The postoperative management was comparable, and complications were evenly distributed. More patients with VITT-associated CVST achieved a favorable outcome (modified Rankin Scale ≤ 3) at 3 months (p = 0.043).ConclusionsAlthough the prediction of individual courses remains challenging, DS should be considered early in VITT-associated CVST because an overall favorable outcome appears achievable in these patients.

Dual Antibody Treatment for Simultaneous Acute Cellular Rejection and Antibody-Mediated Rejection After Liver Transplantation: A Case Report

Antibody-mediated rejection (AMR) after liver transplantation is uncommon but sometimes has a grave prognosis. We herein describe a 40-year-old man who developed simultaneous acute cellular rejection and acute AMR due to de novo donor-specific anti-human leukocyte antigen antibodies after living donor liver transplantation. He underwent living donor liver transplantation with his brother-in-law as the donor. Hepatic function deteriorated on postoperative day 6, and a liver biopsy revealed histologic findings of typical acute cellular rejection. However, steroid pulse therapy and thymoglobulin did not produce a clinical response, and his liver function dramatically deteriorated on postoperative day 13 (aspartate aminotransferase, 2787 IU/L; total bilirubin, 14.1 mg/dL). We diagnosed acute AMR based on positive immunohistochemical staining for C4d in portal areas and added plasma exchange and high-dose intravenous immunoglobulin after rituximab. The patient's clinical state improved and ultimately resolved. To our knowledge, this is the first report of dual antibody treatment for simultaneous acute cellular rejection and acute AMR induced by de novo donor-specific anti-human leukocyte antigen antibodies. Despite his fulminant clinical course, we successfully rescued the recipient with immediate anti-humoral therapy. The rapid treatment decision and adequate understanding of the mechanisms of anti-humoral therapy were crucial to overcoming acute AMR in this case.

Balo’s Concentric Sclerosis presenting as Sensorineural Hearing Loss (P14-3.007)

<h3>Objective:</h3> Multiple sclerosis (MS) can affect other cranial nerves apart from optic nerve. We report an interesting case of Balo’s concentric sclerosis (BCS) that presented with sensorineural hearing loss (SNHL). <h3>Background:</h3> BCS is a rare variant of MS. It derives its name from the concentric pattern of demyelination alternating with preserved myelin seen on magnetic resonance imaging (MRI). It typically has a fulminant monophasic clinical course with a fatal outcome although there has been an increasing number of cases reported with a benign clinical course. <h3>Design/Methods:</h3> NA <h3>Results:</h3> 48-year-old presented to our neuro-immunology clinic for evaluation of abnormal MRI which revealed non-enhancing T2 hyperintensities in juxta-cortical, peri-ventricular and infratentorial cerebellar lesions concerning for demyelination. He had tinnitus and SNHL of right ear ongoing for 3–4 months prior to presentation. Extensive workup was pursued to rule out MS mimics including nutritional, autoimmune, and infectious etiologies. LP revealed no evidence of oligoclonal bands. He was originally diagnosed with radiologically isolated syndrome with plans to monitor with MRI brain annually for surveillance. Repeat MRI brain a year later revealed new non-enhancing concentric juxta-cortical lesion along the right frontal operculum exhibiting a laminated appearance with surrounding perilesional edema consistent with BCS. He had no new neurological symptoms in the interim. On re-evaluation, his auditory symptoms were deemed as a clinical event, and he was diagnosed with MS with subsequent initiation of disease modifying therapy. <h3>Conclusions:</h3> BCS may occur simultaneously with MS like lesions or may herald the onset of MS. SNHL is a rare manifestation of MS with demyelinating lesion along the course of vestibulocochlear nerve or nucleus in brain stem. MRI brain can fail to reveal signs of demyelination either due to timing of MRI brain from symptom onset or sub-optimal diagnostic accuracy as vestibular evoked myogenic potentials have detected demyelinating lesions which are invisible on MRI brain. <b>Disclosure:</b> Dr. Potluri has nothing to disclose. Dr. Samaniego has nothing to disclose. Dr. Lannen has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Genentech. Dr. Lannen has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for TG Therapeutics.

The cascade of multiorgan dysfunction in COVID 19 patients. A case presentation.

Introduction: The SARS COV 2 epidemic has caused thousands of deaths due to different mechanisms of organ injury, starting from the respiratory and cardiovascular system and followed with significant involvement of kidneys, liver, pancreas and several metabolic dysfunctions which all caused a rapid progression of disease leading to death within the second week of hospitalization. Method: We present the case of a 67-year-old woman who died within 24 hours of admission due to a rapid deterioration of her clinical condition with several successive complications. Results: The patient developed a fulminant clinical course, starting with flu-like prodromal symptoms proceeding to altered mental status, metabolic acidosis, acute respiratory distress syndrome (ARDS) and renal failure within 3 days. The rapid involvement of several vital organs predicted a poor diagnosis since the first evaluation in admission which resulted to be irreversible. Conclusion: The predictors of poor prognosis and severity may help clinicians to apply therapeutic regimens in order to avoid disease progression to multiorgan damage and potentially death. Key words: Covid-19, multi-organ dysfunction, cascade, case report.

Improving Prognosis of Aggressive Natural Killer Cell Leukemia in Japan

Introduction Aggressive natural killer cell leukemia (ANKL) is a rare leukemic form of mature NK cell neoplasm that is closely associated with the Epstein-Barr virus (EBV). Patients with ANKL show a fulminant clinical course and poor prognosis with a median overall survival (OS) of a few months after diagnosis. L-asparaginase (L-asp)-containing chemotherapies and allogeneic hematopoietic stem cell transplantation (HSCT) are considered as effective therapeutic strategies. However, owing to the rarity of this disease, the characteristics and outcomes of ANKL remain unclear. Methods Data of 103 patients diagnosed with ANKL between 2002 and 2021 from 64 hospitals were retrospectively analyzed. Diagnosis was based on the World Health Organization classification and was verified by two co-authors (AF and RS). Patients registered in our previous ANKL studies were excluded. Results Patient's median age was 50 years (range, 17-90 years), and males accounted for 58%. Twelve patients (12%) had a medical history of chronic active EBV infection (9%), severe mosquito bite allergy (5%), and chronic lymphoproliferative disorder of NK cells (1%). B symptoms were commonly observed at the time of diagnosis (89%). Performance status (PS) was poor (2-4) in more than half of patients (53%). The median percentage of ANKL cells was 20.0% (range, 0-93.4) in bone marrow (BM) and 10.3% (range, 0-89) in peripheral blood (PB). ANKL cells express CD2 (95%), CD7 (53%), CD16 (41%), CD56 (95%), and EBER (86%). Fifty-two patients analyzed (58%) had chromosomal abnormalities by G-banding method, including chromosome 17 abnormalities in 19, deletion of 6q in 11, and isochromosome 7 in 5. Blood tests at diagnosis typically showed pancytopenia with a median white blood cell count of 2,900/μl, hemoglobin level of 10.3g/dl, and platelets 4.3×104/μl. High serum lactate dehydrogenase and soluble interleukin-2 receptor level were also observed (median, 882U/l and 8,475U/dl, respectively). The most common extra-nodal site of involvement was the BM (100%), followed by the spleen (84%), liver (70%), and PB (59%). Median OS of the present cohort was 5.3 months, and 1-year OS was 25.7%. Prognosis was significantly better in patients who underwent HSCT than in those who did not undergo HSCT (P < 0.001). The median OS and 1-year OS were 12.0 months and 52.3% in the former group and 1.7 months and 3.8% in the latter. Eighty-three patients received multi-agents-containing chemotherapy, while the others received single agent or did not receive any anti-lymphoma chemotherapy owing to poor general condition. The most common first-line chemotherapy was the SMILE regimen (39%), followed by anthracycline-based regimens, mainly CHOP (24%), DeVIC (15%) and other L-asp-containing regimens (8%). The response rate was highest in patients treated with SMILE (66%), followed by those who received other L-asp-containing regimens (57%), DeVIC (36%) and anthracycline-based regimens (32%). OS was significantly better in patients who received SMILE than in those who did not receive SMILE (1-year OS 39.3% vs. 12.1%, P < 0.001, Figure). Furthermore, the HSCT rate was significantly higher in patients who received SMILE (68% vs. 26%, P < 0.001). Multivariate analysis using the Cox proportional hazards model showed good PS (0-1) (hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.23-0.91, P = 0.03), administration of SMILE (HR 0.43, 95% CI 0.23-0.80, P = 0.009), and HSCT (HR 0.26, 95% CI 0.12-0.58, P = 0.001) were independent factors associated with favorable OS. Conclusion The present study showed better OS as compared with our previous study. The SMILE chemotherapy and HSCT were suggested to be key components of the therapeutic strategy for ANKL. Further studies are warranted to validate these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Role of Endomyocardial Biopsy in Diagnostics of Myocarditis.

Endomyocardial biopsy as the cornerstone of diagnostics has been re-evaluated throughout the years, leaving unanswered questions on the precedence of it. The reported incidence of myocarditis has increased during the pandemic of coronavirus disease 2019 (COVID-19), reinforcing discussions on appropriate diagnostics of myocarditis. By analysis of evidence-based literature published within the last demi-decade, we aimed to summarize the most recent information in order to evaluate the current role of endomyocardial biopsy in diagnostics and management of myocarditis. For the most part, research published over the last five years showed ongoing uncertainty regarding the use, informativeness, safety and necessity of performing a biopsy. Special circumstances, such as fulminant clinical course or failure to respond to empirical treatment, were reconfirmed as justified indications, with a growing applicability of non-invasive diagnostic approaches for most other cases. We concluded that endomyocardial biopsy, if performed properly and with adjunct diagnostic methods, holds a critical role for treatment correction in specific histological subtypes of myocarditis and for differential diagnosis between immune-mediated myocarditis and secondary infections due to immunosuppressive treatment. A high level of possible misdiagnosing was detected, indicating the need to review terminology used to describe findings of myocardial inflammation that did not meet Dallas criteria.

Diagnosis, management, and outcome of cardiac sarcoidosis and giant cell myocarditis: a Swedish single center experience

BackgroundCardiac sarcoidosis (CS) and giant cell myocarditis (GCM) are rare diseases that share some similarities, but also display different clinical and histopathological features. We aimed to compare the demographics, clinical presentation, and outcome of patients diagnosed with CS or GCM.MethodWe compared the clinical data and outcome of all adult patients with CS (n = 71) or GCM (n = 21) diagnosed at our center between 1991 and 2020.ResultsThe median (interquartile range) follow-up time for patients with CS and GCM was 33.5 [6.5–60.9] and 2.98 [0.6–40.9] months, respectively. In the entire cohort, heart failure (HF) was the most common presenting manifestation (31%), followed by ventricular arrhythmias (25%). At presentation, a left ventricular ejection fraction of < 50% was found in 54% of the CS compared to 86% of the GCM patients (P = 0.014), while corresponding proportions for right ventricular dysfunction were 24% and 52% (P = 0.026), respectively. Advanced HF (NYHA ≥ IIIB) was less common in CS (31%) than in GCM (76%). CS patients displayed significantly lower circulating levels of natriuretic peptides (P < 0.001) and troponins (P = 0.014). Eighteen percent of patients with CS included in the survival analysis reached the composite endpoint of death or heart transplantation (HTx) compared to 68% of patients with GCM (P < 0.001).ConclusionGCM has a more fulminant clinical course than CS with severe biventricular failure, higher levels of circulating biomarkers and an increased need for HTx. The histopathologic diagnosis remained key determinant even after adjustment for markers of cardiac dysfunction.

Unusual presentation of an Epstein barr virus-negative extranodal natural killer/T cell lymphoma: A diagnostic dilemma

Extra-nodal Natural killer/T cell lymphoma (ENKTL) is a well-defined and highly aggressive form of NonHodgkin’s lymphoma with a scarcity of cases reported in literature. The most common primary site of involvement is the nasal cavity followed by skin and the gastrointestinal tract (GIT). Cutaneous involvement is a rarity. More than 95% of cases are usually in association with Epstein Barr Virus (EBV) infection. EBV negative ENKTL can be similar in clinical, pathological, and prognostic characteristics with EBV positive ENKTL. This malignancy is usually characterized by its poor prognosis irrespective of clinical stage and therapy. We describe here, a 58-year-old man presenting with multiple nodular lesions over legs and trunk, had an ileal perforation later, and was diagnosed as ENKTL on the ileal biopsy specimen. This case is being reported in view of the fulminant clinical course of the disease, simultaneous involvement of the GIT and skin without nasal or midline involvement, the usefulness of immunohistochemistry in arriving at a diagnosis, and EBV negativity which is quite rare in the Asian population.

Clinical Course of Mechanically Ventilated COVID-19 Patients With Pneumothoraces.

IntroductionPneumothoraces in mechanically ventilated patients with COVID-19 indicate severe lung damage from inflammatory injury and barotrauma. These patients have a high mortality rate, and additional factors may further alter their clinical course.MethodsWe conducted a retrospective review of patients admitted to 11 public hospitals in New York City between March 6 and April 9, 2020, diagnosed with COVID-19. We identified 39 patients who developed pneumothoraces immediately after intubation or after a period of time on mechanical ventilation. Our study population was divided into various groups using demographic and clinical characteristics. Statistical analyses were conducted using SPSS software (IBM Inc., Armonk, USA) and paired t-tests to compare clinical outcomes between the various groups. P values < 0.05 were considered statistically significant.ResultsOur population was comprised of 28 male (72%) and 11 female patients; 36 out of 39 patients (92.3%) died with a median time of 10 days from admission to death and a median time of 2 days from pneumothorax to death. The remaining three were discharged home or to another facility. Pneumothoraces developed immediately after intubation in 18 patients and after a period of time on mechanical ventilation in 21 patients. Factors associated with a worse clinical course included age greater than 65 years (time from admission to pneumothorax 4.81 vs 8.35 days; p = 0.011) and presence of one or more comorbidities (time from admission to intubation 2.3 days vs 4.8 days; p = 0.041). Other factors that may worsen clinical course include previous smoking (time from admission to pneumothorax 4.4 vs 8.54 days; p = 0.074) and use of positive end-expiratory pressure (PEEP) greater than 15 cm H2O (time from intubation to pneumothorax 3.89 vs 6.42 days; p = 0.14).ConclusionsBased on the findings in our retrospective review, COVID-19 patients who develop pneumothoraces on mechanical ventilation have a mortality rate in excess of 90%. Older patients and those with comorbidities have a more fulminant clinical course.

Allogeneic stem cell transplantation for aggressive NK cell leukemia

Aggressive NK cell leukemia (ANKL) is a rare leukemic form of mature NK cell neoplasms. ANKL presents a fulminant clinical course with a median overall survival (OS) of 2-3 months after diagnosis. Currently, allogeneic stem cell transplantation (allo-HSCT) is the only curative treatment for ANKL patients. Although a few recent reports have evaluated the efficacy of allo-HSCT for ANKL patients, detailed outcomes of allo-HSCT are obscure. We conducted a nationwide retrospective analysis of 59 ANKL patients who underwent first allo-HSCT between 1997 and 2016 in Japan. The median age was 37 years, and 68% were male. The 1- and 5-year OS were 33.9% and 27.3%, respectively; the 1-year cumulative incidence of relapse or progression was 55.5%. The OS was significantly better for patients with complete or partial responses as the time of allo-HSCT, which was equivalent to that for patients who experienced primary induction failure but achieved complete response after allo-HSCT. Patients who underwent cord blood transplantation had significantly better outcomes than those who underwent allo-HSCT from other sources. Therefore, our study demonstrates that allo-HSCT is a promising treatment that can provide a durable response in a subset of ANKL patients. A larger-scale study including unselected ANKL patients is warranted in the future.

Newly Diagnosed Acute Lymphoblastic Leukemia in a Child with COVID-19 Complicated By MIS-C: A Case Report from Kuwait

Introduction:Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a major challenge worldwide. Data reporting manifestations of COVID-19 in pediatric cancer patients are limited. This report describes the presentation and initial management challenges of a newly diagnosed child with acute lymphoblastic leukemia (ALL) with positive (+) SARS-CoV-2 complicated by multisystem inflammatory syndrome in children (MIS-C).Case Description:A previously healthy 9-year-old female had (+)SARS-CoV-2 following a 4-day history of fatigability. This was followed by a day of severe gastroenteritis (GE) necessitating a visit to Jaber Al-Ahamed Hospital (JAH), the designated COVID-19 pandemic center. Examination revealed hypovolemic shock, hepatosplenomegaly (HSM) and cervical lymphadenopathy. Patient also had significant pancytopenia and high inflammatory markers (Table).Bone marrow aspiration (BMA) - done 7 days from diagnosis of SARS-CoV-2 - was consistent with B-ALL. Transfer to National Bank of Kuwait Children's Hospital (NBKCH) - the pediatric cancer center - was delayed for 11 days given her (+)SARS-CoV-2, but once tested negative, transfer was complete. Due to logistical issues, lumbar puncture and repeat BM were delayed. She then developed new fever, abdominal pain and vomiting. Her febrile neutropenia (FN) was managed according to local protocol including antifungal therapy for prolonged FN. Five days into her FN, she developed hematemesis and septic shock. In addition to pancytopenia, she also had disseminated intravascular coagulation with further raise in CRP (Table). She also had a new maculopapular rash (Image). Infectious work-up was negative except for (+)SARS-CoV-2 (after 10 days of negativity), fulfilling criteria of MIS-C. Patient was transferred back to JAH according to local pandemic protocol. Induction chemotherapy as perUK-MRC-ALL 2011 regimen Afor standard risk ALL - with modifications given her MIS-C - was started after 22 days (Figure). On day 5 of chemotherapy, patient was clinically stable with negative SARS-CoV-2, therefore transferred back to NBKCH for continuation of leukemia management.Discussion:Although children tend to have a milder course of COVID-19, this case described a fulminant presentation initially with GE, hypovolemic shock and complicated by MIS-C, lacking any respiratory symptoms throughout her course. Until more data reporting manifestations of SARS-CoV-2 in pediatric cancer patients are available, physicians should keep high index of suspicion for leukemia in presence of pancytopenia and HSM in spite of (+)SARS-CoV-2. Prompt diagnosis of ALL is fundamental to avoid delays in treatment and consequent effects on prognosis. Logistical issues such as lack of optimum COVID-19 isolation measures in our cancer center and paucity of blood products have led to delayed initiation of chemotherapy. These cancer-related challenges have been well described.Another interesting aspect of our case is the seroconversion to (+)SARS-CoV-2 after proved negativity. It is possible that protective antibodies were not well developed as she is immunocompromised, making such patients prone to recurrent SARS-CoV-2 infection. The re-emergence of SARS-CoV-2 has led to the diagnosis of MIS-C after fulfilling other criteria. This phenomenon of negative to (+)SARS-CoV-2 seroconversion has been reported in 20-40% of MIS-C cases.Increased risk of venous thromboembolism (VTE) is linked to the hyperinflammatory state of COVID-19. Chemotherapy is also identified as an independent risk factor for VTE in malignancy. To avoid the collateral effects of these factors, modifications of the planned chemotherapy were implemented in our case to minimize the VTE risk. The high steroid dose with chemotherapy was also planned as a treatment for MIS-C, which is consistent with different modalities of MIS-C treatment offered in literature.Conclusion:Children with B-ALL may suffer from fulminant clinical course when diagnosed with COVID-19 and could be prone to recurrent SARS-CoV-2 infection. Our experience highlights the importance of optimizing isolation measures and raising awareness for need of blood products to avoid treatment delay. Further research can aid in forming recommendations to prevent management pitfalls especially with the anticipation of a second wave of this pandemic.DisclosuresNo relevant conflicts of interest to declare.

A Rare Case of Chronic Lymphoproliferative Disorder of NK Cells with an Unusual Expression of CD57

Abstract Introduction/Objective Natural Killer cells (NK-cells) malignancies are extremely rare and the two NK-cell disorders involving the peripheral blood and bone marrow include chronic lymphoproliferative disorder of NK-cells (CLPDNK) and aggressive NK-cell leukemia (ANKL). ANKL is EBV associated with a prevalence in Asian adults and a fulminant clinical course leading to death within 2 months. Methods A 76-year-old female with a history of iron deficiency anemia presented for evaluation of lymphocytosis (78 TH/mm) and negative EBV with extreme fatigue, weight loss, and worsening weakness from the past 8 months. Results The peripheral and bone marrow aspirate showed an increase in granular lymphocytes with bland nuclei and abundant pale-staining cytoplasm containing fine to coarse azurophilic granules with no evidence of nuclear atypia. Flow cytometry demonstrated an atypical lymphocytic cell population comprising &amp;gt;50% of total marrow and peripheral blood lymphocytes demonstrating loss of CD56 and diminished CD7 expression. The analysis showed atypical lymphocytes with the following immunophenotype: CD2, CD8 (the majority, at least 75%),CD7 (dim), CD38, CD11c (subset) with no expression of CD3, CD5, CD4, CD56, or CD11c. Flow cytometry is important as it helps in the phenotypic detection of aberrancy. A broad panel of immunohistochemical stains revealed scattered positivity for CD3, CD4, CD7, CD8, TIA-1, granzyme, perforin, and tryptase and negative for CD56 and CD57. Our top differential with a similar clinical course included T-cell large granular lymphocytic leukemia which is characterized by a clonal proliferation of mature cytotoxic T cells and also has an indolent course. They show CD3 positivity by flow cytometry along with co-expression of NK cell-associated markers (CD16 and CD57), and variable expression of other pan T cell markers such as CD2, CD5, CD7. It is found incidentally in patients having cytopenias with a persistent increase in circulating mature NK-cells. Of note, the PET scan revealed splenomegaly with no other significant findings.The patient was started on steroids and is currently doing well. Conclusion Thus, overall morphologic, immunophenotypic, and molecular results with negative expression of surface or cytoplasmic CD3 as well as the absence of TCR expression were most consistent with CLPD-NK with an unusual expression of CD57 expression detected in flow cytometry.

LUNG AS THE PRIMARY SOURCE OF INTRAVASCULAR LARGE B CELL LYMPHOMA: A DIAGNOSTIC CHALLENGE

SESSION TITLE: Medical Student/Resident Pulmonary Manifestations of Systemic Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Intravascular large B cell lymphoma (IVLBCL) is a rare form of Non-Hodgkin’s Lymphoma (NHL) that, in most cases, is disseminated at time of diagnosis with majority of manifestations in the central nervous system, cutaneous lesions, or hematologic syndromes. Lung involvement, though not uncommon, is most likely found during autopsy as early diagnosis of IVLBCL has proven to be difficult. CASE PRESENTATION: A 67 year-old male with no known medical history presented with progressive, subacute dyspnea and fatigue. On exam he was hypoxic with fine rales to auscultation and decreased air entry bibasally. Labs revealed moderate anemia, lactic acidosis, acute renal impairment, and transaminitis. CT chest non-contrast showed diffuse ground glass appearance with no acute consolidations or effusions. Peripheral blood smear showed no schistocytes; serum protein electrophoresis and erythrocyte sedimentation rate were unremarkable; ANCA and HIV were negative. Bone marrow biopsy was performed revealing hypercellularity with no evidence of malignancy; bronchoscopy was non-diagnostic. PET scan revealed areas of tracer uptake in the lungs and subsequent VATS with lung biopsy showed nonspecific pneumonitis: hilar membranes, reactive pneumocytes and collapsed vessels, making visualization of intravascular cell invasion difficult. Findings seemed consistent with interstitial lung disease, however, due to unknown origin of lung disease and acute onset of symptoms, the sample was sent for further pathologic review. Subsequent staining of cells revealed positive MUM-1, BCL-6 & BCL-2, CD45, CD20, PAX5, c-myc (20%) and Ki67. CD34 was negative. The final diagnosis was IVLBCL. DISCUSSION: IVLBCL is rare and characterized by the presence of tumor cells within blood vessels. The disease is highly malignant and carries a poor prognosis, as the majority of patients present late in disease course. The lung as a primary source of IVLBCL is a very rare occurrence with only a few cases reported. Although in this case diffuse ground glass appearance was present on chest CT, there was no explanation for pathology findings of interstitial lung disease, which necessitated further testing ultimately revealing a diagnosis. It is apparent that a confirmatory diagnosis of IVLBCL is quite difficult and involves intensive pathologic review. CONCLUSIONS: It is important for physicians to consider a diagnosis of IVLBCL, albeit rare, in patients who present with respiratory symptoms and no apparent cause. Ruling out other possible causes of clinical presentation, as well as adequate pathology samples, are paramount. Reference #1: 1.Yamashita, Hiroyuki, et al. “Intravascular Large B-Cell Lymphoma with Diffuse FDG Uptake in the Lung by 18FDG-PET/CT without Chest CT Findings.” Annals of Nuclear Medicine, vol 26, 27 Apr. 2012, pp. 515-521 Reference #2: 2.M. Fiegl, R. Greil, C. Pechlaner, J. Krugmann, S. Dirnhofer, Intravascular large B-cell lymphoma with a fulminant clinical course: a case report with definite diagnosis post mortem, Annals of Oncology, Volume 13, Issue 9, 2002 September, pp.1503–1506 Reference #3: 3.Ponzoni, Maurilio, et al. “Definition, Diagnosis, and Management of Intravascular Large B-Cell Lymphoma: Proposals and Perspectives From an International Consensus Meeting.” Journal of Clinical Oncology, vol 25, no. 21, 20 July 2007, pp. 3168-3173 DISCLOSURES: No relevant relationships by Lewis Attas, source=Admin input No relevant relationships by Alyssa Foster, source=Web Response No relevant relationships by Manuel Katz, source=Web Response No relevant relationships by Dan Ran-Castillo, source=Web Response No relevant relationships by Jonathan Shammash, source=Web Response No relevant relationships by Matthew Tavares, source=Web Response

Intravascular Large B-cell Lymphoma: A Report of Two Cases

One of the rare variants of extranodal large B-cell lymphoma is intravascular large B-cell lymphoma (IVLBCL). Characteristics of IVLBCL include intraluminal selective proliferation of atypical lymphoid cells in small to medium-sized vessels. The etiologic of IVLBCL is unknown, but due to the growth pattern of this tumor, it is speculated that IVLBCL is caused by a defect in homing receptor of tumor cells. IVLBCL can involve any organ but central nervous system, lungs, and skin are the most involved sites. IVLBCL does not usually involve lymph nodes. IVLBCL mainly occurs in the middle aged to elderly population with a slight male predominance. Generally, IVLBCL is aggressive and rapidly fatal if left untreated. We here reported two cases of IVLBCL who succumbed to the disease at initial phase of treatment to emphasize the difficulty in diagnosis of IVLBCL due to its exclusive intravascular growth pattern and fulminant clinical course.

Comprehensive molecular genetic studies of Epstein-Barr virus-negative aggressive Natural killer-cell leukemia/lymphoma

EBV-negative aggressive NK-cell leukemia/lymphoma (ANKL) is a recently recognized, rare NK-cell neoplasm that preferentially affects non-Asians and has a fulminant clinical course. Little is known about the genetic alterations of this disease. In this study, we performed comprehensive molecular genetic studies, including chromosomal analysis, fluorescence in situ hybridization, single nucleotide polymorphism (SNP) microarray, and next-generation sequencing (NGS), on 4 patients diagnosed in our institution. The results demonstrated that our EBV-negative ANKLs have highly complex genomic profiles characterized by near-triploid/near-tetraploid karyotype (3 of 3) with numerous structural abnormalities, inactivation of TP53 (3 of 3), overexpression of c-Myc (4 of 4), strong expression of PD-L1 in neoplastic cells (2 of 4), and gain of the 11q23-ter region (2 of 2). Our study provides important insights of EBV-negative ANKL, which share many of the genetic features with their EBV-positive counterpart. The strong expression of Programmed death-ligand 1 (PD-L1) suggests that immune checkpoint inhibitors may be further explored as a potential therapeutic option for this highly aggressive, chemotherapy-resistant NK-cell neoplasm.