Citations

Abstract Hemophagocytic lymphohistiocytosis (HLH) is a rare but critical hyperinflammatory condition that affects around 1.5% of liver transplant patients, with mortality rates reaching up to 33%. This syndrome is characterized by intense, dysregulated activation of macrophages and T-cells, sparking a cytokine surge that leads to severe systemic inflammation and rapid organ failure. Prompt identification and early management are crucial to improve outcomes. Case Presentation: A 61-year-old man with Hepatitis C-induced end-stage liver disease (MELD score 20) underwent a deceased-donor liver transplant. Postoperative complications included atrial fibrillation, stress cardiomyopathy, and a right-sided pleural effusion treated with thoracentesis and extended course of antibiotics. Two weeks later, he presented with fever, hypotension, and nausea, prompting the initiation of IV Zosyn, Vancomycin and Posaconazole. Despite fluid resuscitation, he became hemodynamically unstable, necessitating ICU transfer for vasopressor support. While in the ICU, his condition worsened, with increased fever, tachycardia, anuria and hypoxic respiratory failure that required intubation and continuous renal replacement therapy. Marked hyperferritinemia (ferritin 62,000 µg/L) and hypofibrinogenemia (91 mg/dL) raised suspicion for HLH, with an H score of 244. Comprehensive infectious workup ruled out CMV, EBV, HSV, and other pathogens. Bone marrow biopsy confirmed hemophagocytosis (Figure 1), and flow cytometry ruled out malignant infiltration. Given the strong suspicion for HLH and no identifiable infectious trigger, he was initiated on Dexamethasone, Etoposide, and Ruxolitinib, which lowered ferritin levels and improved vasopressor requirements. However, mentation declined, and imaging revealed a right frontal subarachnoid hemorrhage, likely from disseminated intravascular coagulation, precluding surgical intervention. Despite transient improvement, he developed ventilator associated pneumonia secondary to Stenotrophomonas infections and vancomycin-sensitive Enterococcus bacteremia, leading to refractory hypoxemia. After family and multi-disciplinary team discussions, care was withdrawn. Discussion: HLH remains an exceedingly rare, rapidly fatal syndrome in liver transplant recipients, with only 11 cases documented. Early recognition of HLH can be challenging, as its features, such as fever, cytopenias, and organ dysfunction, overlap with common post-transplant complications, which can delay diagnosis. HLH can be differentiated into primary (genetic) and secondary (acquired) forms, with the latter more common among adults, often triggered by infection, malignancies and autoimmune disorders. Immunosuppressants may inadvertently modulate HLH risk by tempering macrophage and T-cell activation, yet, paradoxically, also predisposing patients to secondary triggers. Clinicians should maintain vigilance for HLH in post-transplant patients with unexplained systemic inflammation, as early intervention is critical, often with Etoposide based regimens to modulate hypercytokinemia, though prognosis remains guarded due to multiorgan failure.

Abstract IntroductionPatients with interstitial lung disease (ILD) who are admitted to the intensive care unit (ICU) face significant challenges, with high rates of morbidity and mortality. Despite the severity of outcomes in this population, the potential impact of gender disparities on ICU outcomes in ILD has not been well studied.MethodsWe analyzed data from the NIS spanning 2016 to 2018, focusing on adults (≥18 years) hospitalized with ILD (J84), and defined ICU stays using ICD codes for central line placement and mechanical ventilation. The NIS, part of the Healthcare Cost and Utilization Project, provides a weighted, nationally representative sample of U.S. hospitalizations. Demographic, clinical, and hospital characteristics were collected, with race/ethnicity categorized per NIS classifications. Multivariable logistic and linear regression models adjusted for potential confounders to evaluate gender differences in outcomes.ResultsOur study identified 810,295 adult hospitalizations with ILD, of which 42,080 required ICU-level care. Of these, 46.7% were female. Female ICU patients were younger (mean age 66.9 ± 13.8 vs. 69.1 ± 12.7, p<0.001), more likely to be African American (17.0% vs. 10.9%, p<0.001), and less likely to be Caucasian (63.7% vs. 69.2%, p<0.001). Females were more often from lower-income ZIP codes (33.2% vs. 38.3%, p<0.001) and had lower rates of tobacco use disorder (35.0% vs. 43.9%, p<0.001). Mortality was significantly lower in females (40.5% vs. 48.1%, p<0.001). After adjusting for confounders, female gender was independently associated with reduced mortality risk (adjusted odds ratio 0.77, 95% CI 0.70-0.84, p<0.001) and a shorter length of hospital stay (adjusted difference 1.15 days, 95% CI 0.54-1.77).ConclusionOur study highlights notable gender differences in outcomes for patients with ILD admitted to the ICU. Female patients had a significantly lower risk of mortality and shorter hospital stays than male patients, even after adjusting for key clinical and socioeconomic confounders. These findings are consistent with emerging evidence that biological sex and gender-related factors play a critical role in disease expression and outcomes in ILD.Several mechanisms may explain these gender disparities. Sex hormones, such as estrogen, have been shown to exert protective effects in pulmonary fibrosis models, potentially influencing the disease course in women. Incorporating these considerations into clinical practice and future research will be vital for advancing individualized, patient-centered medicine in ILD.

Abstract Introduction:Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by excessive immune activation and cytokine release, leading to multi-organ failure and mortality. Despite guideline management to include chemotherapy and transplantation, the characteristics and predictors of critical outcomes in post-transplant-associated hemophagocytic lymphohistiocytosis (PT-HLH) remain poorly understood. Methods:This study is a retrospective cohort analysis of patients admitted to acute care hospitals in the U.S. with HLH between 2016 and 2018. We utilized the National Inpatient Sample, identifying HLH patients using International Classification of Diseases, Tenth Revision-Clinical Modification (ICD-10-CM) codes D76.1, D76.2, and D76.3. Patient demographics, such as age, gender, race, ethnicity, zip code, and insurance status, were obtained from the NIS, while hospital-level characteristics, location and teaching vs. non-teaching status, were considered in the study amongst others. We examined the baseline epidemiology of transplant status, including ICU-related outcomes and resource utilization in patients with and without transplants. Data were analyzed using STATA weighted function, with logistic regression for categorical outcomes. Results:Out of 8,330 adult HLH hospitalizations, 520 (6.2%) were transplant recipients. Among these, 350 (67%) had bone marrow transplants, 90 (17%) had kidney transplants, and 30 (5.8%) had liver transplants. The mean age of HLH patients was 50 ± 19 years; transplant patients were younger (mean age 46 ± 17 years) compared to non-transplant patients (50 ± 18 years), p<0.05. Transplant patients were more likely to be male (72.1% vs. 50.1%, p<0.05), have CMV infection (14.4% vs. 4.1%, p<0.05), be Hispanic (20.8% vs. 14.7%, p<0.05), come from higher median household income areas (38.8% vs. 24.5%, p<0.05), and be treated in teaching hospitals (96.1% vs. 85.8%, p<0.05). Among HLH patients who died in the hospital, 130 (25%) were transplant recipients, compared to 1,180 (15.1%) non-transplant recipients, p<0.05. After adjusting for potential confounders, transplant status was associated with a higher risk of mortality (adjusted odds ratio 1.77, 95% CI 1.11-2.83) and sepsis (adjusted odds ratio o1.78, 95% CI 1.08-2.92). Discussion:In examining a national cohort of PT-HLH cases, our findings review potential risk factors for critical care-related outcomes in post-transplant associated HLH care. PT-HLH patients in our cohort presented with distinct characteristics compared to non-transplant HLH cases. ICU-related outcomes showed statistically significant differences between transplant and non-transplant HLH patients. Specifically, transplant status remained independently associated with a higher risk of mortality and sepsis. Our findings underscore the importance of tailoring treatment plans to each patient's specific risk profile.

Takayasu arteritis is a chronic, large vessel vasculitis that typically affects the aorta and its main branches. We present a case of a 33-year-old male patient who was diagnosed with Takayasu arteritis after being admitted for acute cardiogenic shock requiring inotropes. Initial transthoracic echocardiography demonstrated severe biventricular dysfunction. Computed tomography imaging of his chest showed pulmonary infarcts. Patient subsequently developed sudden lower extremity weakness and bowel incontinence, and urgent magnetic resonance imaging of his spine demonstrated thoracolumbar vascular myelopathy. Transesophageal echocardiography revealed diffuse symmetrical thickening of the walls of the aorta; findings suggestive of aortitis. Patient was initiated on intravenous corticosteroid and systemic anticoagulation. Subsequent computed tomography angiography demonstrated irregular luminal contour of the aortic arch, and complete occlusion of the left subclavian artery, abdominal aorta, superior mesenteric artery, and left renal artery. He underwent an emergent aortoiliac thrombectomy. He was transitioned to oral prednisone, tocilizumab, and azathioprine with excellent recovery.

Abstract Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking; activating mutations in LRRK2 are linked to Parkinson’s disease. Rab phosphorylation is a transient event that can be reversed by phosphatases, including PPM1H, that acts on phosphoRab8A and phosphoRab10. Here we report a phosphatome-wide siRNA screen that identified PPM1M as a phosphoRab12-preferring phosphatase that also acts on phosphoRab8A and phosphoRab10. Upon knockout from cells or mice, PPM1M displays selectivity for phosphoRab12. As shown previously for mice harboring LRRK2 pathway mutations, knockout of Ppm1m leads to primary cilia loss in striatal cholinergic interneurons. We have also identified a rare PPM1M mutation in patients with Parkinson’s disease that is catalytically inactive when tested in vitro and in cells. These findings identify PPM1M as a key player in the LRRK2 signaling pathway and provide a new therapeutic target for the possible benefit of patients with Parkinson’s disease. Teaser Parkinson’s linked Rab phosphorylation is reversed by PPM1M; the inactive D440N variant is implicated in rare patient cases.

Background: Owing to reduced bleeding risks, radial is favored over femoral for access site selection in patients referred for coronary angiography, with specific benefits in patients presenting with acute coronary syndrome. However, studies were often limited to patients without coronary artery bypass grafts (CABG), given the technical challenges of the radial approach in these patients. Methods: We evaluated patients with prior CABG undergoing coronary angiography with or without percutaneous coronary intervention (PCI) from 2015-2020 at our institution. We reviewed access site and bleeding outcomes as defined in the NCDR CathPCI registry. Additional outcomes included procedural duration, fluoroscopy time, contrast volume, and clinical events. Results: Of the 1,546 patients studied, 280 (18%) patients had radial access while 1,266 (82%) patients had femoral access. Over the study time period, frequency of radial access for post CABG catheterization procedures increased from 0% in 2015 to 45% in 2020. There were no statistically significant differences in comorbidities, bleeding events, complications, or mortality between radial vs femoral (Table). Fluoroscopy time was higher for radial vs femoral (14.9 mins vs 13.3 mins, p=0.04). Conclusion: Over time, radial access choice in post CABG patients increased, without significant differences with respect to bleeding events or complications as compared to femoral, though at increased fluoroscopy times.

Objective We describe the demographics, clinical features, disease course, and survival of polyarteritis nodosa (PAN) through an international collaboration (GLOBAL‐PAN). Methods Patients with PAN were recruited between 1990 and 2020 from observational cohorts of nine countries across Europe, Japan, and North America. Eligibility was retrospectively defined using the European Medicines Agency classification algorithm. Patients with PAN related to hepatitis B virus (n = 12) and two monogenic diseases mimicking PAN, deficiency of adenosine deaminase 2 enzyme (n = 16) or familial Mediterranean fever (n = 11), were excluded. Data regarding organ involvement, relapse, disease‐related damage, and survival were analyzed. Results Three hundred fifty‐eight patients (female:male ratio 174:184), including those with systemic PAN (sPAN, n = 282) and cutaneous PAN (n = 76), were included. Twenty‐five were pediatric onset. Mean ± SD age at diagnosis was 44.3 ± 18.1 years. Constitutional symptoms (71.5%), cutaneous involvement (70.5%), musculoskeletal findings (69.1%), and neurologic features (48.0%) were common manifestations. Among patients with sPAN, gastrointestinal involvement and proteinuria over 400 mg/day were reported in 52.2% and 11.2%, respectively. During a median (interquartile range) 59.6 (99.5) months of follow‐up, relapse occurred in 48.5% of patients. One, 5‐ and 10‐year survival rates for sPAN were 97.1%, 94.0%, and 89.0%, respectively. Predictors of death for sPAN included age ≥65 years at diagnosis, serum creatinine at diagnosis >140 μmol/L, gastrointestinal manifestations, and central nervous system (CNS) involvement. Conclusion The spectrum of PAN remains a complex, multifaceted disease. Relapse is common. Age ≥65 years and serum creatinine >140 μmol/L at diagnosis, as well as gastrointestinal and CNS involvement, are independent predictors of death in sPAN. image