Gadolinium retention effect on macrophages - a potential cause of MRI contrast agent Dotarem toxicity.

Gadolinium is a component of the MRI contrast agent Dotarem. Although Dotarem is the least toxic among MRI contrasts used, gadolinium present in Dotarem accumulates for many years in various organs and tissues exerting toxic effects. We showed previously that gadolinium remains in macrophages for at least 7 days after exposure to Dotarem. However, very little is known about the effect of gadolinium retention on the immune cells such as macrophages. We studied the effect of 1-day and 7-day retention of gadolinium on various functions and molecular pathways of macrophages. Gadolinium retention for 7 days decreased macrophage adhesion and motility and dysregulated the expression of adhesion and fibrotic pathway-related proteins such as Notch1 and its ligand Jagged1, adhesion/migration-related proteins PAK1 and Shp1, immune response-related transcription factors Smad3 and TCF19, and chemokines CXCL10 and CXCL13, and dysregulated the mRNA expression of fibrosis-related genes involved in extracellular matrix (ECM) synthesis, such as Col6a1, Fibronectin, MMP9, and MMP12. It also completely (below a level of detection) shut down the transcription of anti-inflammatory M2 macrophage polarization marker the Arg-1. Such changes, if they occur in MRI patients, can be potentially detrimental to the patient's immune system and immune response-related processes.

Immunosuppression-Free Life after Pediatric Liver Transplant: A Case-Control Study from the Society of Pediatric Liver Transplant (SPLIT) Registry.

OBJECTIVE: To compare long-term outcomes of pediatric liver transplant (LT) recipients off immunosuppression (IS) with matched controls on IS using data from the Society of Pediatric Liver Transplant (SPLIT) registry. STUDY DESIGN: This was a retrospective case-control study. SPLIT participants <18 years of age, ≥4 years after isolated LT, and off IS for ≥1 year (cases) were age- and sex-matched 1:2 to patients with the same primary diagnosis and post-LT follow-up duration (controls). Primary outcomes included retransplantation, allograft rejection, IS comorbidities, and prevalence of SPLIT-derived composite ideal outcome (c-IO) achieved at the end of the follow-up period. Differences were compared using multiple linear regression for continuous outcomes and logistic regression for dichotomous data. RESULTS: The study cohort was composed of 33 cases (42.4% male, 60.6% biliary atresia, median age at LT of 0.7 [P25, P75, 0.5, 1.6] years, median IS withdrawal time of 9 [P25, P75, 6, 12] years after LT) and 66 age- and sex-matched controls. No cases required retransplantation. Cases and controls had similar growth parameters, laboratory values, calculated glomerular filtration rates, rates of post-transplant lymphoproliferative disease, graft rejection, and attainment of c-IO. CONCLUSIONS: No differences in allograft rejection rates, IS complications, or c-IO prevalence were seen between SPLIT patients off IS and age- and sex-matched controls remaining on IS. Discontinuation of IS most commonly occurred in the context of rigorously designed IS withdrawal trials. The available sample size was small, affecting generalizability to the broader pediatric LT population.

Innate immune cell dysfunction and systemic inflammation in children with chronic liver diseases undergoing transplantation.

Advanced liver diseases (ALD) can affect immune function and compromise host defense against infections. In this study, we examined the phenotypic and functional alterations in circulating monocyte and dendritic cells (DCs) in children with ALD undergoing liver transplantation (LT). Children were stratified into 2 clusters, C1 (mild) and C2 (severe), on the basis of laboratory parameters of ALD and compared with healthy pediatric controls. Children in C2 had a significant reduction in frequencies of nonclassical monocytes and myeloid DCs. Children in C2 displayed monocyte and DC dysfunction, characterized by lower human leucocyte antigen DR expression and reduced interleukin 12 production, and had an increased incidence of infections before and after LT. Children in C2 demonstrated immune dysregulation with elevations of pro- and anti-inflammatory cytokines in plasma. Alterations of innate immune cells correlated with multiple laboratory parameters of ALD, including plasma bile acids. In vitro, monocytes cultured with specific bile acids demonstrated a dose-dependent reduction in interleukin 12 production, similar to alterations in children with ALD. In conclusion, a cohort of children with ALD undergoing LT exhibited innate immune dysfunction, which may be related to the chronic elevation of serum bile acids. Identifying at-risk patients may permit personalized management pre- and post-transplant, thereby reducing the incidence of infection-related complications.

Multisystem inflammatory syndrome in children associated with SARS-CoV-2 in a solid organ transplant recipient.

We present the case of a 3-year-old female liver transplant recipient with a history of Caroli disease who presented with positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction (RT-PCR) test and was ultimately diagnosed with multisystem inflammatory syndrome in children (MIS-C) complicated by portal vein thrombosis. To the best of our knowledge, this is the first case report of MIS-C in a pediatric solid organ transplant (SOT) recipient. Based on our patient, MIS-C could be a potential complication of Coronavirus disease 2019 (COVID-19) in SOT recipients and may have a negative outcome on transplant graft function.

COVID-19 associated parotitis.

As the 2019 coronavirus pandemic has unfolded, an increasing number of atypical presentations of COVID-19 have been reported. As patients with COVID-19 often present to emergency departments for initial care, it is important that emergency clinicians are familiar with these atypical presentations in order to prevent disease transmission. We present a case of a 21-year-old woman diagnosed in our ED with COVID-19 associated parotitis and review the epidemiology and management of parotitis. We discuss the importance of considering COVID-19 in the differential of parotitis and other viral-associated syndromes and emphasize the importance of donning personal protective equipment during the initial evaluation.

Prolapsed Nasal Polyp Causing Acute Airway Obstruction: An Exceptional Presentation.

Although nasal polyposis is a common clinical entity, there is limited literature describing the rare presentation of sudden prolapse of a massive nasal polyp resulting in an airway emergency in an adult. We present the first case report to our knowledge of a patient without any preceding sinonasal symptoms or history of anticoagulation who experienced acute upper airway obstruction due to sudden hemorrhage and prolapse of a large nasal polyp. Based on our experience treating this patient, we discuss special considerations in all phases of care to ensure safe and effective management of such an exceptional clinical scenario.

Extended Survival After Surgical Resection for Pituitary Metastases: Clinical Features, Management, and Outcomes of Metastatic Disease to the Sella.

BACKGROUND: Patients with pituitary metastasis (PM) have a relatively poor prognosis. We describe the presentation, management, and outcomes of patients with PM. SUBJECTS, MATERIALS, AND METHODS: We performed a retrospective review of patients diagnosed with PM at a single institution from 1996 to 2015. Eighty-five patients diagnosed with metastasis to the pituitary or sella turcica by pathology or based on a combination of neuroimaging and clinical findings were included. Univariate and multivariable Cox regressions evaluated associations between clinical factors and overall survival. RESULTS: The most frequent sites of primary malignancies resulting in PM were lung (26%) and breast (26%). Median age at diagnosis was 60 years (range, 18-95). The most common complaints at diagnosis included visual deficits (62%), headache (47%), and cranial nerve palsy (31%). Seventy percent of patients had pituitary insufficiency-adrenal insufficiency (59%), hypothyroidism (59%), or diabetes insipidus (28%). Management of PM included radiation therapy (76%), chemotherapy (68%), surgical resection (21%), or combination therapy (71%). Fifty percent and 52% of patients who received surgical treatment and irradiation, respectively, reported symptomatic improvement. Median overall survival (OS) was 16.5 months (95% confidence interval: 10.7-25.4). On multivariable analysis, a primary cancer site other than lung or breast (p = .020), age <60 years (p = .030), and surgical resection (p = .016) were associated with longer OS. CONCLUSION: Patients <60 years of age, those with primary tumor sites other than lung or breast, and those who undergo surgical resection of the pituitary lesion may have prolonged survival. Surgical resection and radiation treatment resulted in symptomatic improvement in ~50% of patients. IMPLICATIONS FOR PRACTICE: This study is the largest original series of patients with metastatic disease to the sella. In patients with pituitary metastasis, younger age, primary site other than lung or breast, and metastatic resection may prolong survival. Resection and radiation led to symptomatic improvement in ∼50% of patients. Seventy percent of patients had hypopituitarism. These hormonal deficiencies can be life threatening and can result in substantial morbidity if left untreated. Patients should be treated using a multimodality approach-including a potential role for surgery, radiation, chemotherapy, and hormone replacement-with the goal of improving survival and quality of life.

Biliary Atresia as a Disease Starting In Utero: Implications for Treatment, Diagnosis, and Pathogenesis.

Biliary atresia (BA) is the most common reason for pediatric liver transplant. BA's varied presentation, natural history, and treatment with the Kasai portoenterostomy have been well described; however, when BA starts relative to birth has not been clearly defined. In this review, we discuss laboratory, imaging, and clinical data which suggest that most if not all forms of BA may start before birth. This early onset has implications in terms of delivering treatments earlier and identifying possible factors underlying BA's etiology.

Longitudinal assessment of T cell inhibitory receptors in liver transplant recipients and their association with posttransplant infections.

Current immunosuppression regimens in organ transplantation primarily inhibit T cells. However, T cells are also critical in protective immunity, especially in immune-compromised patients. In this study, we examined the association of T cell dysfunction, as marked by expression of T cell exhaustion molecules, and posttransplant infections in a cohort of liver transplant patients. We focused on Programmed Death 1 (PD-1) and T cell Ig- and mucin-domain molecule 3 (Tim-3), which are potent co-inhibitory receptors, and their persistent expression often leads to T cell dysfunction and compromised protective immunity. We found that patients with the highest expression of PD-1 +Tim-3+ T cells in the memory compartment before transplantation had increased incidence of infections after liver transplantation, especially within the first 90 days. Longitudinal analysis in the first year showed a strong association between variability of PD-1 and Tim-3 expression by T cells and infectious episodes in transplant patients. Furthermore, T cells that expressed PD-1 and Tim-3 had a significantly reduced capacity in producing interferon (IFN)-γ in vitro, and this reduced IFN-γ production could be partially reversed by blocking PD-1 and Tim-3. Interestingly, the percentage of Foxp3+ regulatory T cells in liver transplant patients was stable in the study period. We concluded that the functional status of T cells before and after liver transplantation, as shown by PD-1 and Tim-3 expression, may be valuable in prognosis and management of posttransplant infections.

ABO-incompatible deceased donor pediatric liver transplantation: Novel titer-based management protocol and outcomes.

ABO-ILT have re-emerged as an alternate option for select patients awaiting transplant. However, treatment protocols for children undergoing deceased donor ABO-ILT are not standardized. We implemented a novel IS protocol for children undergoing deceased donor ABO-ILT based on pretransplant IH titers. Children with high pretransplant IH titers (≥1:32) underwent an enhanced IS protocol including plasmapheresis, rituximab, IVIG, and mycophenolate, while children with IH titers ≤1:16 received steroids and tacrolimus. We retrospectively assessed our outcomes of ABO-ILT with ABO-compatible recipients of similar age and diagnosis over a 2-year period. Ten children with median age of 8.9 months underwent ABO-ILT, 4 of 10 patients underwent enhanced IS due to high IH titers. Rates of complications (rejection, infections, biliary, and vascular) at both 1 year and up to 3 years post-transplant were comparable between the groups. Patients with ABO-ILT had good graft function with 100% survival at a median follow-up of 3.3 years. In conclusion, IS tailored to pretransplant IH titers in pediatric deceased donor ABO-ILT is feasible and can achieve outcomes similar to ABO-CLT at 1 and 3 years post-transplantation.

Prevalence of Olfactory Impairment in Granulomatosis with Polyangiitis.

Granulomatosis with Polyangiitis (GPA) is a rare disease of unknown origin. It may damage all organs and systems, even olfactory and taste sense. The aim of the study was to determine the sense of smell in patients with GPA and to identify factors related to disease course, activity, and duration, which may be associated with olfactory dysfunction. The comparison of olfactory function screening scores with Sniffin' Sticks standardized norms showed that 74% of the investigated patients had olfactory dysfunction. The olfactory performance was diminished in all parts of Sniffin' Sticks test: threshold scores 4.4 vs. 7.1 (p = 0.007); odor discrimination 9.0 vs. 11.9 (p = 0.008); and olfactory identification 9.8 vs. 12.2 (p = 0.011) in the GPA patients vs. control subjects, respectively. Scores acquired during all three parts of the test were combined to assess the TDI-score. The median TDI-score in the GPA group (27.5) was significantly lower than that in the control group (32.0) (p = 0.002). Active nasal and paranasal sinus inflammation in GPA leads to olfactory dysfunction, the patients are often unaware of. The dysfunction is permanent and does not abates along with decreasing intensity of the inflammatory process. GPA therapy should include recommendations on nutrition, personal hygiene, and food poisoning prevention.

Antibiotic Treatment of Hospitalized Patients with Pneumonia Complicated by Clostridium Difficile Infection.

Clostridium difficile infection (CDI) is one of the most common gastrointestinal complication after antimicrobial treatment. It is estimated that CDI after pneumonia treatment is connected with a higher mortality than other causes of hospitalization. The aim of the study was to assess the relationship between the kind of antibiotic used for pneumonia treatment and mortality from post-pneumonia CDI. We addressed the issue by examining retrospectively the records of 217 patients who met the diagnostic criteria of CDI. Ninety four of those patients (43.3 %) came down with CDI infection after pneumonia treatment. Fifty of the 94 patients went through severe or severe and complicated CDI. The distribution of antecedent antibiotic treatment of pneumonia in these 50 patients was as follows: ceftriaxone in 14 (28 %) cases, amoxicillin with clavulanate in 9 (18 %), ciprofloxacin in 8 (16.0 %), clarithromycin in 7 (14 %), and cefuroxime and imipenem in 6 (12 %) each. The findings revealed a borderline enhancement in the proportion of deaths due to CDI in the ceftriaxone group compared with the ciprofloxacin, cefuroxime, and imipenem groups. The corollary is that ceftriaxone should be shunned in pneumonia treatment. The study demonstrates an association between the use of a specific antibiotic for pneumonia treatment and post-pneumonia mortality in patients who developed CDI.

Antibiotic Treatment of Hospitalized Patients with Pneumonia Complicated by Clostridium Difficile Infection.

Clostridium difficile infection (CDI) is one of the most common gastrointestinal complication after antimicrobial treatment. It is estimated that CDI after pneumonia treatment is connected with a higher mortality than other causes of hospitalization. The aim of the study was to assess the relationship between the kind of antibiotic used for pneumonia treatment and mortality from post-pneumonia CDI. We addressed the issue by examining retrospectively the records of 217 patients who met the diagnostic criteria of CDI. Ninety four of those patients (43.3 %) came down with CDI infection after pneumonia treatment. Fifty of the 94 patients went through severe or severe and complicated CDI. The distribution of antecedent antibiotic treatment of pneumonia in these 50 patients was as follows: ceftriaxone in 14 (28 %) cases, amoxicillin with clavulanate in 9 (18 %), ciprofloxacin in 8 (16.0 %), clarithromycin in 7 (14 %), and cefuroxime and imipenem in 6 (12 %) each. The findings revealed a borderline enhancement in the proportion of deaths due to CDI in the ceftriaxone group compared with the ciprofloxacin, cefuroxime, and imipenem groups. The corollary is that ceftriaxone should be shunned in pneumonia treatment. The study demonstrates an association between the use of a specific antibiotic for pneumonia treatment and post-pneumonia mortality in patients who developed CDI.

Lund-Mackay System for Computed Tomography Evaluation of Paranasal Sinuses in Patients with Granulomatosis and Polyangiitis.

Granulomatosis with polyangiitis (GPA), a disease capable of affecting any organ, most often acts upon the upper respiratory tract. Diagnostic imaging is primarily represented by computed tomography (CT) of paranasal sinuses. The aim of this study was to define the characteristic changes in paranasal CT in patients with GPA and to evaluate diagnostic usefulness of the Lund-Mackey scoring system (L-M System). The study encompassed 43 patients with GPA of the mean age of 47.7 ± 12.8 years who were treated topically with mupirocin. We found that inflammation occurred mainly in the maxillary sinuses (72%). The mean L-M score was 5.8 ± 6.1. The right maxillary sinus had the highest percentage (12.6%) of score hits of 1, i.e., partial opacification and the left ostiomeatal complex had the highest percentage (7.6%) of score of 2, i.e., complete opacification or obstruction. The following changes were the most characteristic for GPA: sinus mucosal thickening, widespread bone damage, and osteogenesis. We conclude that the long-term topical mupirocin treatment of GPA may inhibit nasal bone damage, but also may led to permanent rhinological changes of the rhinosinusitis type. The Lund-Mackey staging system is a useful diagnostic imaging option in GPA patients.

Retrospective Assessment of the Utility of Imaging, Fine-Needle Aspiration Biopsy, and Intraoperative Frozen Section in the Management of Parotid Neoplasms: The Weill Cornell Medical College Experience.

BACKGROUND/AIMS: Preoperative identification of malignant parotid lesions remains challenging, and thus, some surgeons use frozen section (FS) to assist them in their decision making. We evaluated the pathologic and cost benefit of FS after fine-needle aspiration (FNA) at our institution. METHODS: We assessed medical data for 260 patients undergoing parotidectomy with FS. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were calculated for radiology, FNA, and FS. RESULTS: The sensitivities, specificities, and accuracies of FNA and FS were 75.0, 96.4, and 93.2%, and 75.0, 100, and 96.8%, respectively. FS detected 0% of FNA false negatives and 80% of false positives. The additional pathology charge for FS alone per correctly identified benign lesion after a positive FNA was USD 1,443. CONCLUSION: FNA and FS are more reliable in the prognostication of the final pathology than radiology. At our center, FS appears to be of limited clinical use after benign FNAs, but may be more useful after positive, indeterminate, and nondiagnostic FNAs.

Management of Tracheobronchial Stenosis in Chondrodysplasia Punctata.

Chondrodysplasia punctata (CDP) is a rare congenital syndrome characterized by aberrant, punctate deposition of calcium during endochondral bone formation, resulting in the characteristic finding of epiphyseal stippling on radiographs. While otolaryngologic manifestations such as nasomaxillary hypoplasia and mixed hearing loss are common, tracheobronchial calcification occurs rarely in neonates with CDP. The management of CDP-related airway stenosis is complex and there is limited literature pertaining to outcomes of airway interventions. Herein, we describe the clinical course and outcome of tracheal dilation for a newborn patient with CDP. Laryngoscope, 134:1464-1468, 2024.

Herbal and dietary supplement induced liver injury leading to hepatitis-associated severe aplastic anemia: A case report.

Herbal and dietary supplements (HDS) are a common etiology of drug induced liver injury and, specifically, Herbalife® supplements have been implicated. Hepatitis associated aplastic anemia (HAAA) is a rare and potentially fatal complication after acute hepatitis characterized by pancytopenia. While there have been rare cases of HDS leading to HAAA, no cases of Herbalife® induced liver injury leading to HAAA have been reported from this specific HDS. We report a unique case of severe aplastic anemia developing after sub-fulminant liver failure associated with chronic HDS use. This case illustrates the importance of warning the public about HDS as their use continues to increase. It is not only important to recognize HDS as etiology, but also for healthcare providers to carefully monitor these patients after resolution of liver injury for the development of HAAA.

Protein biomarkers GDF15 and FGF21 to differentiate mitochondrial hepatopathies from other pediatric liver diseases.

BACKGROUND: Mitochondrial hepatopathies (MHs) are primary mitochondrial genetic disorders that can present as childhood liver disease. No recognized biomarkers discriminate MH from other childhood liver diseases. The protein biomarkers growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) differentiate mitochondrial myopathies from other myopathies. We evaluated these biomarkers to determine if they discriminate MH from other liver diseases in children. METHODS: Serum biomarkers were measured in 36 children with MH (17 had a genetic diagnosis); 38 each with biliary atresia, α1-antitrypsin deficiency, and Alagille syndrome; 20 with NASH; and 186 controls. RESULTS: GDF15 levels compared to controls were mildly elevated in patients with α1-antitrypsin deficiency, Alagille syndrome, and biliary atresia-young subgroup, but markedly elevated in MH (p<0.001). FGF21 levels were mildly elevated in NASH and markedly elevated in MH (p<0.001). Both biomarkers were higher in patients with MH with a known genetic cause but were similar in acute and chronic presentations. Both markers had a strong performance to identify MH with a molecular diagnosis with the AUC for GDF15 0.93±0.04 and for FGF21 0.90±0.06. Simultaneous elevation of both markers >98th percentile of controls identified genetically confirmed MH with a sensitivity of 88% and specificity of 96%. In MH, independent predictors of survival without requiring liver transplantation were international normalized ratio and either GDF15 or FGF21 levels, with levels <2000 ng/L predicting survival without liver transplantation (p<0.01). CONCLUSIONS: GDF15 and FGF21 are significantly higher in children with MH compared to other childhood liver diseases and controls and, when combined, were predictive of MH and had prognostic implications.