Elevated Creatinine Kinase Research Articles

Neurological manifestations temporally associated with SARS-CoV-2 infection in pediatric patients in Mexico.

PurposeTo describe the temporal association of specific acute neurological symptoms in pediatric patients with confirmed SARS-CoV-2 infection between May and August 2020.MethodsWe performed a recollection of all the clinical and laboratory data of patients having acute neurological symptoms temporally associated with SARS-CoV-2 infection at a third-level referral hospital in Mexico City (Instituto Nacional de Pediatría). Patients in an age group of 0–17 years with acute neurological signs (including ascending weakness with areflexia, diminished visual acuity, encephalopathy, ataxia, stroke, or weakness with plasma creatinine kinase (CK) elevation) were evaluated.ResultsOut of 23 patients with neurological manifestations, 10 (43%) had a confirmed SARS-CoV-2 infection. Among the infected patients, 5 (50%) were males aged 2–16 years old (median age 11.8 years old). Four (40%) patients confirmed a close contact with a relative positive for SARS-CoV-2, while 6 (60%) cases had a history of SARS-CoV-2–related symptoms over the previous 2 weeks. The following diagnoses were established: 3 cases of GBS, 2 of ON, 2 of AIS, one of myositis with rhabdomyolysis, one ACA, and one of anti-NMDA-R encephalitis.ConclusionsNeurological manifestations temporally associated with SARS-CoV-2 infection were noticed in the pediatric population even without respiratory symptoms. In this study, 2 of 6 symptomatic patients had mild respiratory symptoms and 4 had unspecific symptoms. During this pandemic, SARS-CoV-2 infection should be considered as etiology in patients with acute neurological symptoms, with or without previous respiratory manifestations, particularly in teenagers.

Dysphagia in Dermatomyositis Due to Esophageal Adenocarcinoma

A 71-year-old man with a 20-pack-year smoking history presented with 4 weeks of progressive dysphagia to solids and liquids, symmetric upper and lower extremity proximal muscle weakness, and violaceous erythematous rash over the dorsum of hands and eyelids (Figure A). Laboratory work-up showed elevated creatinine kinase 15,985 U/L (normal, 22-198), aldolase 35.6 U/L (1–7.5), and erythrocyte sedimentation rate 73 mm/h (0–22). Muscle biopsy revealed perimysial lymphocytic inflammation consistent with dermatomyositis (DM).

Elevated Creatinine Kinase in Peripheral Neuropathy Is Associated With Muscle Cramping.

Introduction: Serum Creatinine Kinase (CK) is a non-specific marker of muscle damage. There has been limited investigation of the association between peripheral neuropathy and CK elevation (hyperCKemia).Methods: We performed a chart review to investigate the CK level in peripheral neuropathies. Demographics, clinical history, physical exam, electrodiagnostic data, CK level, statin use, etiology of neuropathy, and concomitant neuromuscular disorders were recorded. HyperCKemia was defined using our laboratory cutoff values of >180 U/L (women) and >220 U/L (men).Results: We identified 450 patients with peripheral neuropathy who had CK testing, 92 (20.4%) of whom had hyperCKemia. Sixty-one of those patients (13.5% of the total figure) had a concomitant etiology that could explain the CK elevation. Thirty-one patients (6.9%) had no other identifiable etiology for their hyperCKemia beyond the neuropathy. The average CK level in the latter cohort with hyperCKemia was 376 U/L (women: 312 U/L; men: 444 U/L). The frequency of cramping was greater in patients with elevated vs. normal CK (p < 0.0001).Discussion: HyperCKemia can occur in patients with peripheral neuropathy and appears to associate with cramping.

Severe acute kidney injury in COVID-19 patients is associated with in-hospital mortality

Although the lungs are major targets for COVID-19 invasion, other organs—such as the kidneys—are also affected. However, the renal complications of COVID-19 are not yet well explored. This study aimed to identify the incidence of acute kidney injury (AKI) in patients with COVID-19 and to evaluate its impact on patient outcomes. This retrospective study included 704 patients with COVID-19 who were hospitalized at two hospitals in Daegu, Korea from February 19 to March 31, 2020. AKI was defined according to the serum creatinine criteria in the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. The final date of follow-up was May 1, 2020. Of the 704 patients, 28 (4.0%) developed AKI. Of the 28 patients with AKI, 15 (53.6%) were found to have AKI stage 1, 3 (10.7%) had AKI stage 2, and 10 (35.7%) had AKI stage 3. Among these patients, 12 (42.9%) recovered from AKI. In the patients with AKI, the rates of admission to intensive care unit (ICU), administration of mechanical ventilator (MV), and in-hospital mortality were significantly higher than in patients without AKI. Multivariable analysis revealed that old age (Hazard ratio [HR] = 4.668, 95% confidence interval [CI] = 1.250–17.430, p = 0.022), high neutrophil-to-lymphocyte ratio (HR = 1.167, 95% CI = 1.078–1.264, p < 0.001), elevated creatinine kinase (HR = 1.002, 95% CI = 1.001–1.004, p = 0.007), and severe AKI (HR = 12.199, 95% CI = 4.235–35.141, p < 0.001) were independent risk factors for in-hospital mortality. The Kaplan-Meier curves showed that the cumulative survival rate was lowest in the AKI stage 3 group (p < 0.001). In conclusion, the incidence of AKI in patients with COVID-19 was 4.0%. Severe AKI was associated with in-hospital death.

Acute Papillary Muscle Rupture Immediately After ST-Segment Elevation Acute Myocardial Infarction: A Case Report and Review

Papillary Muscle Rupture (PMR) is a rare complication (0.5-5%) with high mortality that usually occurs two to seven days after Acute Myocardial Infarction (AMI). However, rapid diagnosis and concomitant treatment can improve early and long-term outcomes. We describe a rare PMR occurring immediately after AMI. The patient complained of exertional chest pain and dyspnea in cardiogenic shock, and was diagnosed with acute PMR by echocardiography. Electrocardiogram showed STsegment elevation in inferior leads, and the time course of creatinine kinase elevation indicated early onset of AMI. Herein, we describe an unusual PMR immediately after AMI and further review PMR.

Pregabalin-Induced Myopathy in a Double Lung Transplant Recipient

Pregabalin is a gamma-aminobutyric acid (GABA) derivative that was commercially approved by the Food and Drug Administration (FDA) in 2004. It is commonly used in the treatment of diabetic neuropathy, peripheral neuropathy, and spinal cord injury. We present the case of a 36-year-old Caucasian male double lung transplant recipient who presented with an 18-month history of fatigue and muscle weakness. He had elevated creatinine kinase level and his muscle biopsy showed evidence of drug-induced myopathy that improved after the cessation of pregabalin. We present a case of drug-induced myopathy as a rare complication of pregabalin therapy in a double lung transplant recipient.

Thoracic Pain and Pericardial Effusion in a Patient With Chronic Pancreatitis

Question: A 48-year-old male patient with chronic pancreatitis presented with progressive epigastric and thoracic pain and dysphagia over the previous 2 weeks. Physical examination revealed cachexia and mild peripheral edema. Laboratory tests showed no elevation of cardiac troponin or creatinine kinase, and the electrocardiography was unremarkable. The medical history of the patient included previous drainage of a large (9 × 8 cm) pancreatic pseudocyst, which was located between the stomach and the diaphragm and had been drained with a lumen-apposing metal stent (LAMS) 4 months earlier (Figure A).

BETWEEN A WET STONE AND A HARD PLACE: SEVERE HYPOXIA, RHABDOMYOLYSIS, AND ACUTE RENAL FAILURE IN A CASE OF LEGIONELLA PNEUMOPHILIA PNEUMONIA

SESSION TITLE: Fellows Chest Infections Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Legionella pneumophilia (LP) is a formidable pathologic organism of the respiratory tract. Fewer than 10% of cases of community-acquired pneumonia (CAP) are caused by LP. Common clinical manifestations include fever, vomiting, diarrhea, shortness of breath, and lab abnormalities including hyponatremia and transaminitis. Chest imaging typically reveals a unilateral or bilateral patchy consolidation. Extrapulmonary manifestations of LP are rare but include meningitis, pyelonephritis, and skin and soft tissue infections. CASE PRESENTATION: A 60-year-old female presented to the emergency department by ambulance after collapsing while leaving work as a home health nurse assistant. Her history was notable for alcohol and tobacco abuse. Symptoms included generalized weakness, intermittent non-productive cough, nausea, and decreased oral intake for the past two days. In the emergency department, she was found to be febrile to 39.6 degrees C, tachypneic, tachycardic, and hypoxic on room air which improved initially on three liters by nasal cannula. Physical exam was notable for bibasilar crackles, wheezing, and decreased breath sounds in the left lung field. Laboratory data were significant for acute renal failure with a creatinine of 3.0mg/dL, leukocytosis to 29,000, and positive legionella urinary antigen. Chest x-ray revealed a large, dense, left-sided consolidation. She was treated with Azithromycin and Ceftriaxone, but later required intubation and mechanical ventilation due to severe hypoxia. Her oxygenation continued to worsen, prompting neuromuscular blockade and prone positioning. Further evaluation of her acute renal failure revealed markedly elevated creatinine kinase, consistent with rhabdomyolysis. Judicious use of maintenance fluids with intermittent dosing of diuretics was initiated in the setting of severe hypoxia with subsequent improvement in her renal function. DISCUSSION: LP can cause severe CAP requiring mechanical ventilation and, in this case, neuromuscular blockade and prone positioning. Rhabdomyolysis causing acute renal failure is a rare extrapulmonary complication of LP that has been described in the literature in fewer than twenty cases. It is unclear if the mechanism of injury is due to endotoxin or exotoxin-mediated release from septicemia or direct pathological invasion of LP into muscular tissue. Over half of the cases who developed rhabdomyolysis due to LP infection required hemodialysis with most patients experiencing complete renal recovery. This case illustrates a classic, severe, unilateral, dense consolidative pneumonia caused by LP with the rare complications of rhabdomyolysis and renal failure and recovery without hemodialysis. CONCLUSIONS: LP can cause myriad extrapulmonary manifestations. This case demonstrates the difficult balance of treating rhabdomyolysis and acute renal failure with concomitant severe hypoxemia, both occurring due to the same etiology. Reference #1: Buzzard JW, Zuzek Z, Alencherry BP, Packer CD. Evaluation and Treatment of Severe Rhabdomyolysis in a Patient with Legionnaires' Disease. Cureus. 2019;11(9):e5773. Published 2019 Sep 26. doi:10.7759/cureus.5773 Reference #2: Laivier C, Bleuze MO, Hantson P, Devos J. Extreme Rhabdomyolysis, Acute Renal Failure, and Protracted Ileus in a Case of Legionella Pneumonia. Case Rep Crit Care. 2019;2019:3472627. Published 2019 Jan 29. doi:10.1155/2019/3472627 Reference #3: McConkey J, Obeius M, Valentini J, Beeson MS. Legionella pneumonia presenting with rhabdomyolysis and acute renal failure: a case report. J Emerg Med. 2006;30(4):389-392. doi:10.1016/j.jemermed.2005.07.016 DISCLOSURES: No relevant relationships by Mohamed Abdalla, source=Web Response No relevant relationships by Angela Birdwell, source=Web Response No relevant relationships by Omar Enriquez, source=Web Response No relevant relationships by Vincent Gould, source=Web Response no disclosure on file for Audrey Haywood

SLE / Polymyositis Overlap Syndrome

Inflammatory myopathies (IM) is a rare inflammatory muscle disorder, which can be broadly divided into 5 subgroups. The accurate diagnosis of subtype of IM can be challenging due to a diverse presentation of the disease. On the other hand, skeletal muscle complication is common in patients with systemic lupus erythematosus (SLE) in the form of myalgia or myopathy. Inflammatory myopathy is a rare association of SLE and the diagnosis and treatment can be quite challenging. A 43-year-old lady with underlying systemic lupus erythematosus (SLE), presented with subacute onset progressively worsening muscle weakness involving upper limbs and lower limbs. Neurological examination showed findings consistent with proximal myopathy, with proximal power of 3/5 and distal power of 4/5. She has elevated creatinine kinase, ALT and AST level. Her myositis-specific autoantibodies were positive for anti-Ku antibodies. Her electromyography showed evidence of active myopathy of the upper and lower limb. Here, we would like to report a case of polymyositis in a patient with SLE.

Prediction of Long-Term Outcomes in ST-Elevation Myocardial Infarction and Non-ST Elevation Myocardial Infarction with and without Creatinine Kinase Elevation-Post-Hoc Analysis of the J-MINUET Study.

Background: A Japanese prospective, nation-wide, multicenter registry (J-MINUET) showed that long-term outcomes were worse in non-ST elevation acute myocardial infarction (NSTEMI), diagnosed by increased cardiac troponin levels, compared to STEMI. This was observed in both non-STEMI with elevated creatine kinase (CK) (NSTEMI+CK) and non-STEMI without elevated CK (NSTEMI-CK). However, predictive factors for long-term outcomes in STEMI, NSTEMI+CK, and NSTEMI-CK have not been elucidated. Methods: Using the Cox proportional hazards model, we determined significant independent predictors of long-term outcomes from a total of 111 parameters evaluated in the J-MINUET study in each of our groups, including STEMI, NSTEMI+CK, and NSTEMI-CK. Then, we calculated the risk score using the regression coefficients for the determined independent predictors for the strict prediction of long-term outcomes. Results: Prognostic factors, as well as composite cardiovascular events and all-cause death, were different between STEMI, NSTEMI+CK, and NSTEMI-CK. Risk scores could effectively and powerfully predict both composite cardiovascular events and all-cause death in each group. Conclusions: The prediction of long-term outcomes using cored parameters of baseline demographics and clinical characteristics is feasible and could prove useful in establishing therapeutic strategies in patients with STEMI, NSTEMI+CK, and NSTEMI-CK.

Patterns of liver injury in COVID-19 - a German case series.

Reports of liver injury in patients with novel coronavirus disease 2019 (COVID-19) are emerging from China and the USA. A wide variety of liver function test abnormalities and few cases of severe liver failure have been reported. No data on the hepatic phenotype from Europe are available at current. We report a case series of 44 consecutive patients hospitalized for COVID-19 in Germany. At the time of admission, aspartate aminotransferase greater than the upper limit of normal was present in 70%, while alanine aminotransferase was elevated in 15.8%. Markers of cholestatic liver injury were altered only in a minority of patients. During hospitalization, 31% and 22% experienced increasing aspartate aminotransferase and alanine aminotransferase, respectively, when transaminases were normal at admission. Severe liver injury defined by 3×> upper limit of normal was observed in 9.1% over a mean time of 10.5 days. Importantly, patients exhibited cytotoxicity including lactate dehydrogenase and creatinine kinase elevations, but no signs of relevant liver function impairment. In summary, in a case series of hospitalized patients in Germany, cytotoxicity in the absence of severe liver dysfunction at admission and only few cases suggestive of severe liver injury during hospital were observed.

Utility of Immunohistochemistry and Western Blot in Profiling Clinically Suspected Cases of Congenital Muscular Dystrophy.

Objective:Immunocharacterization of congenital muscular dystrophy (CMD) to determine the frequency of various subtypes in a large Indian Cohort.Materials and Methods:This retrospective (2014-2017) study was carried on muscle biopsies of clinically suspected cases of CMD with histological evidence of dystrophy/myopathic features. Immunohistochemistry (IHC) to antibodies against laminin (α2, α5,β1,γ1), Collagen-VI (A1,2,3), and Western blot (WB) for α-dystroglycan and POMT1 was performed.Results:The study included 57 cases, of which 15 cases (26.3%) had mean age at presentation of 3.5 years, M: F = 1.5:1, elevated creatinine kinase (CK) (mean 1657 U/L), global developmental delay, multiple contractures, abnormal facies, white matter hyperintensities and showed laminin-α2 deficiency (Merosin deficient CMD). In addition, secondary reduction in laminin-β1, over-expression of laminin-α5, and preserved laminin-γ1 was noted. Ullrich CMD constituted 11/57 cases (19.2%) with mean age at presentation of 5.3 years, M: F = 1.2:1 and normal CK. They presented with proximal muscle weakness, soft velvety palms and soles, contractures, and joint hyperextensibility. Collagen-VI (A1,2,3) showed either complete (n = 3) or sarcolemmal specific (n = 8) loss of staining. Out of the remaining 31 cases, WB for α-dystroglycan was performed in 17 cases which showed deficiency in seven (12.3%). Three of these in addition revealed secondary partial loss of laminin-α2. WB for POMT1 showed deficiency in a single case clinically diagnosed Walker–Warburg syndrome, who presented with seizures and classical features of pachygyria, lissencephaly, and cerebellar cyst on MRI. Twenty-four cases (42.2%) remained uncharacterized and need genetic evaluation.Conclusion:The study helped in characterizing 57.8% of the proband. Immunotyping helps to direct mutational analysis for targeted genes and offers a potential route for prenatal diagnosis.

Immune mediated necrotizing myopathy: A rare complication of statin therapy.

Immune mediated necrotizing myopathy (IMNM) is part of the inflammatory myopathies group of diseases and presents with muscle weakness, myalgias and elevated serum creatine phosphokinase (CPK). Statin-induced IMNM is a rare complication. We present a patient with IMNM secondary to simvastatin use. The patient presented with proximal myopathy, dysphagia, and elevated creatinine kinase levels, and was subsequently found to have anti-3- hydroxy-3-methylglutaryl-CoA reductase (HMGCR) autoantibodies with a necrotizing process on muscle biopsy. This patient’s case was further complicated by sequelae of multiple disease processes, ultimately leading to deterioration of his health.

Early Clinical and Sociodemographic Experience with Patients Hospitalized with COVID-19 at a Large American Healthcare System

Background: Despite over one million cases of novel coronavirus disease 2019 (COVID-19) in the United States, limited data, including socioeconomic information and treatment strategies, exist regarding patients hospitalized with the viral infection. Methods: In this case series, we identified patients with COVID-19 admitted to 3 Partners Healthcare hospitals in Boston, Massachusetts between March 7th, 2020, and March 30th, 2020. Patient characteristics; treatment strategies; clinical outcomes including mortality, intensive care utilization, and cardiovascular events were determined. Findings: A total of 247 patients hospitalized with COVID-19 over the study period were identified; the median age was 61 (interquartile range [IQR]: 50-76 years), 58% were men, 30% of Hispanic ethnicity, 21% enrolled in Medicaid, and 12% dual-enrolled Medicare/Medicaid. The median estimated household income was $66,701 [IQR: $50,336- $86,601]. Among patients with employment data (204): 89 (36%) were retired, 23 (9.3%) worked in hospitality, 10 (4%) were healthcare workers, 5 (2%) worked in public transportation, and 21 (8.5%) were unemployed. The majority of patients were treated with hydroxychloroquine (72%), and statins (76%; newly initiated in 34%). Among those treated with hydroxychloroquine with available electrocardiogram data (172), 38% developed QTc prolongation. Discontinuation of statin therapy due to elevated creatinine kinase or elevated liver biochemical tests was also common (29%). New atrial fibrillation/flutter occurred in 8.9% of patients and ventricular tachycardia (non-sustained/sustained) in 7.3% of patients. Other cardiovascular events including myocardial infarction (4.9%) and venous thromboembolism (2.8%) were less common. Within the follow-up period, 103 (42%) required intensive care. At the end of the data collection period (April 19, 2020), 170 patients (68.8%) were discharged alive, 51 patients (20.7%) remain admitted, and 26 patients (10.5%) have died. Interpretation: Patients hospitalized with COVID-19 are frequently of vulnerable socioeconomic status and often require intensive care. Early in the pandemic, off-label drug prescriptions were common. Funding Statement: American Heart AssociationDeclaration of Interests: Dr. Wasfy reports a grant from the American Heart Association (18 CDA 34110215). Dr. Natarajan is supported by a Hassenfeld Scholar Award from the Massachusetts General Hospital, a grant from Fondation Leducq (TNE-18CVD04), and National Heart, Lung, and Blood Institute grants (R01HL148565, R01HL148050, R01HL142711); has received grant support from Amgen, Apple, and Boston Scientific; and has served as a scientific advisor to Apple and Blackstone Life Sciences. Dr. Januzzi is supported by the Hutter Family Professorship, is a Trustee of the American College of Cardiology, has received grant support from Novartis Pharmaceuticals and Abbott Diagnostics, consulting income from Abbott, Janssen, Jana Care, Novartis, Prevencio, and Roche Diagnostics, and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, and Takeda. Dr. Hibbert receives grant support from the National Heart, Lung and Blood Institute (RO1-AI138999-01, UO1-HL123022-06). The remaining authors have no relevant conflicts of interest to disclose. Ethics Approval Statement: The study was approved by the Partners Healthcare Institutional Review Board and informed consent was waived based on secondary use of data from medical record review.

Clinical profile and outcome of patients with Crimean Congo haemorrhagic fever: a hospital based observational study from Rajasthan, India.

Crimean Congo haemorrhagic fever (CCHF) is an emerging zoonotic infection with high mortality. Nosocomial spread is described secondary to body fluid contact. Patients meeting the case definition for viral haemorrhagic fever (VHF) from August to November 2019 were tested for CCHF after ruling out dengue, malaria, scrub typhus and leptospirosis in a tertiary teaching hospital in western Rajasthan, India. Diagnosis was confirmed using both quantitative reverse transcription polymerase chain reaction and immunoglobulin M/immunoglobulin G enzyme-linked immunosorbent assay for all patients. All hospital contacts were line listed and tested and symptomatic high-risk contacts received ribavirin post-exposure prophylaxis. Cohorting, personal protective equipment use and hand washing were employed to prevent nosocomial spread. Four patients tested positive for CCHF. We encountered uncommon initial presentations involving motor weakness and supraventricular tachycardia. Elevated serum lactate dehydrogenase and creatinine kinase were useful in clinical diagnosis. Only one patient survived despite ribavirin therapy. There was zero nosocomial transmission. A partial segment of nucleocapsid of amplified CCHF virus was 99.62% identical to the Afghanistan and Oman strains. The distribution of CCHF appears to be expanding, with CCHF emerging as endemic in Rajasthan, India. In this setting of high mortality, hand washing and PPE use prevented nosocomial transmission.

Cervicofacial and mediastinal emphysema following minor dental procedure: a case report and review of the literature

BackgroundSubcutaneous cervical emphysema is a clinical sign associated with many conditions, including laryngotracheal trauma, pneumothorax and necrotizing deep tissue infections.Case presentationWe discuss a case of a 76-year-old man presenting with extensive cervical emphysema a few hours after a minor dental filling procedure. The CT-scan revealed a significant amount of air within the cervical and mediastinal spaces, reaching lobar bronchi. Vitals were within normal values Bloodwork demonstrated an elevation of creatinine kinase (3718; normal < 150) and mild leukocytosis (WBC = 11.6). We decided to proceed to an urgent cervical exploration to exclude necrotizing fasciitis. This revealed air but no tissue necrosis nor abnormal fluid. The patient improved clinically and was discharged two days later with oral antibiotics. Although cervicofacial subcutaneous emphysema following dental procedures has been reported, it is usually less extensive and involving more invasive procedures using air-driven handpieces.ConclusionAs an otolaryngologist confronted with extensive subcutaneous emphysema following a potential entry route for an aggressive infection, given the seriousness of this diagnosis, the decision of whether or not to perform a diagnostic surgical exploration should remain.

1098 Atrial thickening: a surprisingly "gouty" heart

Abstract Case Presentation A 49 year-old male presented to the emergency department with fever and lower limb myalgia for 5 days. His past history was notable for acute episodes of microcrystalline pyrophosphate oligoarthritis for which he was receiving allopurinol 100mg, colchicine 1mg and prednisolone 5mg. Physical examination was unrevealing. Laboratory workup showed normocytic normochromic anemia (Hb 12.8g/dL), leukocytosis (22 490 /mm3), neutrophilia (86.8%), increased C-reactive protein (CRP 26mg/dL), low procalcitonin (0.82ng/mL) and mildly elevated creatinine-kinase (83 UI/L). The patient was admitted with fever of unknown origin and started on ceftriaxone after blood and urine cultures. He remained febrile with persistently heightened inflammation. Cultures, infectious and auto-immune tests, bone marrow biopsy, myelogram and abdominopelvic CT scan were negative. Three weeks later, syncope due to complete atrioventricular (AV) block led to temporary pacemaker implantation. Transoesophageal echocardiography (TOE) revealed a left atrial (LA) wall thickening, evident on MRI as an 8-10mm T2-hyperintensity sign, with right atrial (RA) and ventricular sparing. PET/CT scan showed an 18F FDG uptake exclusively in the LA. As a neoplasia was highly suspected, a transspeptal biopsy was attempted, yet the sample was scarce for analysis. Thus, a biopsy via sternotomy was performed, now sampling both the LA and RA. Indeed, repeated TOE showed de novo RA involvement with a prominent nodular finding (19x24mm) in the lateral wall. Myocyte inflammation and necrosis accompanied with granulocyte infiltration (mostly neutrophils but also eosinophils) was observed in all samples. There were no findings suggestive of neoplasia. The patient was still on allopurinol, which has been reported to involve the myocardium in a late (type IV) hypersensitivity reaction (the so-called DRESS syndrome), even in the absence of systemic inflammation. Thus, allopurinol was stopped and 1mg/Kg prednisolone was started. The patient significantly improved and was discharged home with negative CRP the following two weeks. After 1 month, MRI was repeated and no atrial inflammation was found. After 4 months follow-up, he is doing well on 2.5mg of prednisolone and febuxostat 80mg.

A novel noncoding FKRP mutation in early onset limb-girdle muscular dystrophy.

Limb-girdle muscular dystrophy 2I (LGMD2I, LGMD R9) (OMIM: muscular dystrophy—dystroglycanopathy [limb-girdle], type C, 5) is an autosomal recessive disorder caused by mutations in the fukutin-related protein ( FKRP ) gene.1 The phenotypic spectrum associated with FKRP is heterogeneous; the most severe phenotype, Walker-Warburg-like syndrome, is characterized by congenital hypotonia, progressive muscle weakness and atrophy, ocular and brain malformations, severe motor developmental delay, and profound intellectual disability. Milder phenotypes include the onset of disease from infancy to adulthood and variable clinical course including asymptomatic elevated serum creatinine kinase (CK), early onset rapidly progressive course with loss of ambulation in teenage years, late onset with slow progression, and primary cardiomyopathy with minimal skeletal muscle weakness.1,2 LGMD2I is typically characterized by proximal muscle weakness, calf hypertrophy, hypotonia, elevated CK level, normal cognition, and no structural brain abnormalities. Dilated cardiomyopathy and respiratory muscle weakness can be seen.1 Mutations in the FKRP gene reduce specific O-mannose-linked glycosylation of alpha-dystroglycan, leading to the instability of the linkage between the dystrophin–glycoprotein complex and laminin alpha 2 in the basement membrane of skeletal muscle.3 The most common FKRP mutation seen in LGMD2I is c.826C>A (p.Leu276Ile). Patients who are homozygous for this mutation typically have a milder phenotype, whereas compound heterozygotes have a relatively severe clinical course. In patients heterozygous for c.826C>A, clinical severity may correspond best to the mutation in the second allele.1,4 We describe a 9-year-old boy with LGMD2I who has the c.826C>A mutation in FKRP on 1 allele and a novel variant on the second allele. The authors acknowledge Ms. Terese Nelson who performed the histology and immunostaining and Mr. Joel Carl for assembling the figure

Neurologic complications of acute hepatitis E virus infection.

ObjectiveTo assess the prevalence and clinical features of neurologic involvement in patients with acute hepatitis E virus (HEV) infection in Southern Switzerland.MethodsAmong 1,940 consecutive patients investigated for acute hepatitis E, we identified 141 cases of acute of HEV infection (anti-HEV immunoglobulin M and immunoglobulin G both reactive and/or HEV RNA positive) between June 2014 and September 2017. Neurologic cases were followed up for 6 months. We compared patients with and without neurologic symptoms.ResultsNeurologic symptoms occurred in 43 acute HEV cases (30.4%) and consisted of neuralgic amyotrophy (NA, n = 15, 10.6%) and myalgia (n = 28, 19.8%). All NA cases were immunocompetent. Men had higher odds (OR = 5.2, CI 1.12–24.0, p = 0.03) of developing NA after infection with HEV, and in 3 couples simultaneously infected with HEV, only men developed NA. Bilateral involvement of NA was predominant (2:1) and occurred only in men. Seven NA cases were viremic (all genotype 3), but HEV was undetectable in their CSF. In the acute phase of NA, 9 patients were treated with intravenous immunoglobulin and 4 with prednisone, reporting no side effects and improvement in pain and strength. Myalgia occurred both without (n = 16) or with (n = 12) concomitant elevated serum creatinine kinase. Seven cases with myalgia in the shoulder girdle did not have muscle weakness (“forme fruste” of NA).ConclusionsNeurologic symptoms occurred in one-third of acute HEV infections and consisted of NA and myalgia. NA seems to occur more frequently in men infected by HEV and has a predominant (but not exclusive) bilateral involvement.

T Cells Expressing an Anti-B-Cell Maturation Antigen (BCMA) Chimeric Antigen Receptor with a Fully-Human Heavy-Chain-Only Antigen Recognition Domain Induce Remissions in Patients with Relapsed Multiple Myeloma

Chimeric antigen receptor (CAR) T cells expressing B-cell maturation antigen (BCMA) can target and kill multiple myeloma (MM). BCMA was chosen as a target for MM because it is expressed by almost all cases of MM but has a restricted expression pattern on normal cells. CAR antigen-recognition domains made up of monoclonal antibody-derived, single-chain-variable fragments (scFv) are potentially immunogenic. To reduce the risk of recipient immune responses against CAR T cells, we used the sequence of a novel anti-BCMA, fully-human, heavy-chain-only binding domain designated FHVH33. The FHVH33 binding domain sequence was from TeneoBio, Inc. FHVH33 is smaller than a scFv. FHVH33 lacks the light chain, artificial linker sequence, and 2 associated junctions of a scFv, so it is predicted to be less immunogenic than a scFv, especially murine-derived scFvs. We constructed a CAR incorporating FHVH33, CD8α hinge and transmembrane domains, a 4-1BB costimulatory domain, and a CD3ζ T-cell activation domain. The CAR, FHVH33-CD8BBZ, is encoded by a γ-retroviral vector. FHVH33-CD8BBZ-expressing T cells (FHVH-BCMA-T) exhibited a full range of T-cell functions in vitro and eliminated tumors and disseminated malignancy in mice (Lam et al, Blood (ASH abstract) 2017 vol 130: 504). We are conducting the first clinical trial of FHVH-BCMA-T. Patients receive conditioning chemotherapy on days -5 to -3 with 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine followed by infusion of FHVH-BCMA-T on day 0. This dose-escalation trial has 5 planned dose levels (DL). Twelve patients have received FHVH-BCMA-T on 3 DLs, 0.75x106, 1.5x106 and 3x106 CAR+ T cells/kg of bodyweight. Three patients were enrolled on the trial but not treated. The median age of patients enrolled was 63 (range 52-70); patients received a median of 6 lines of anti-myeloma therapy (range 3-10) prior to treatment with FHVH-BCMA-T. Ten patients out of 12 patients have achieved objective responses (OR). Five patients have obtained CRs or VGPRs to date. One patient achieved a partial remission (PR) 26 weeks after FHVH-BCMA-T infusion through a continued decrease in a measurable plasmacytoma. Five out of 7 patients who had myeloma with high-risk cytogenetics had an OR (Table). ORs occurred in patients with large soft-tissue plasmacytomas. Loss of BCMA expression on myeloma cells after treatment was documented in 2 patients. Two patients who developed progressive MM after CAR T-cell infusion had evidence of minimal residual disease in bone marrow 1-2 months post infusion of CAR T cells (patients 7,8). Eleven out of 12 patients had cytokine release syndrome (CRS); CRS grades ranged from 1-3 (Lee et al. Biol Blood Marrow Transplant 25 (2019) 625-638). The median peak C reactive protein (CRP) of the patients with CRS was 156.3 mg/L. Of 12 patients, 1 received the interleukin-6-receptor antagonist tocilizumab on day +6 to treat grade 3 CRS with hypotension requiring low-dose pressor therapy, grade 2 ejection fraction (EF) decrease and elevation of creatinine kinase (CK). All parameters returned to baseline by day +10. Patient 12 had a grade 3 decrease in EF which resolved by day +29. Two patients had grade 2 neurotoxicity that resolved without intervention: patient 3 had headaches, dysarthria and word-finding difficulties that resolved after 6 days while patient 6 had headaches on day +4. Patient 12 had grade 3 neurotoxicity with confusion on day +2; she was given dexamethasone with improvement in mental status the same day. After attaining a response, patient 6 died from influenza complications 6 weeks after FHVH-BCMA-T infusion. A median of 10.6% (range 1.1-46) of bone marrow T cells were CAR+ when assessed 14 days after FHVH-BCMA-T infusion. We assessed blood CAR+ cells by quantitative PCR. The median peak level of CAR+ cells was 76.5 cells/µl (range 3-347 cells/µl) and the median day post-infusion of peak blood CAR+ cell levels was 13 (range 9-14). The results from this phase 1 trial demonstrate that FHVH-BCMA-T cells can induce responses at low dose levels. Patients who had no CRS or low-grade CRS achieved objective responses. Toxicity was limited and reversible. Accrual to this trial continues. A maximum tolerated dose has not been determined yet. These results encourage further development of FHVH CAR-T. Table Disclosures Manasanch: Janssen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Merck: Research Funding; Skyline Diagnostics: Research Funding; Sanofi: Research Funding; Quest Diagnostics: Research Funding; Celgene: Honoraria. Trinklein:Teneobio, Inc.: Employment, Equity Ownership. Buelow:Teneobio, Inc.: Employment, Equity Ownership. Kochenderfer:Kite and Celgene: Research Funding; Bluebird and CRISPR Therapeutics: Other: received royalties on licensing of his inventions. OffLabel Disclosure: Cyclophosphamide and fludarabine are used in combination for conditioning chemotherapy prior to CAR T-cell infusion