Hemophagocytic Lymphohistiocytosis

Hemophagocytic Lymphohistocytosis is a rare, aggressive and life threatening condition characterized by excessive immune activation. In view of a variable clinical presentation, lack of specificity of the clinical and laboratory findings and outcomes limited by delay in identification warrants discussion to help in this challenging diagnosis. A 57 year old female initially presented for a CT of the chest after failed outpatient treatment for pneumonia; imaging denoted diffuse lymphadenopathy, she followed up with Hematology/Oncology, having two fine needle aspirations with inconclusive results. Approximately 2 months later she presented to the ED with progressive shortness of breath, hypoxia and chest pain associated with fatigue and cough. Physical exam was significant for only bilateral crackles at the lung bases. She was diagnosed with a subsegmental PE after imaging, pneumonia and lactic acidosis, and was subsequently admitted to the MICU and started on broad-spectrum antibiotics and heparin. General surgery was consulted for excisional biopsy of the lymph node, resulting in a T Cell Lymphoma with underlying B Cell Lympohma. In post-op she became tachycardiac, tachypneiac and hypoxic. Over the next 5 days, she became anemic, thrombocytopenic, febrile, hypercalcemic, hyperuricemiac and hypofirbinogenemic, and develope d splenomegaly with worsening lactic acidosis. HLH was ultimately identified with a severely elevated Ferritin level and elevated IL-2 (CD25) receptor, at which time she was also exhibiting tumor lysis syndrome and hemodynamic instability; subsequently leading to the patients’ death. Although rare, this case illustrates the necessity for early identification of HLH and initiation of treatment, especially in the setting of an unclear clinical picture delaying diagnosis.https://scholarlycommons.henryford.com/merf2019caserpt/1105/thumbnail.jp

Primary Effusion Lymphoma in an HIV negative male with history of Kaposi Sarcoma

Background: Primary effusion lymphoma, a subtype of Non-Hodgkin’s lymphoma, is linked with HHV-8. This disease is associated with immunocompromised patients such as those who have HIV, solid organ transplant carriers, or chronic hepatitis C. Primary effusion lymphoma frequently commences in the pleura, pericardium, and peritoneum. Case: A 77 year old middle eastern male with history of tobacco usage was admitted for fatigue and hypotension. Chest x-ray revealed bilateral pleural effusions. He had received a diagnostic and therapeutic thoracentesis. Cytology revealed that it was positive for HHV-8, a diagnostic criteria for primary effusion lymphoma. The patient was tested for HIV, HTLV, and hepatitis B/C. The testing was negative. The patient later revealed that he had Kaposi sarcoma a year prior to presentation on his right leg that was removed by his dermatologist. After having multiple thoracenteses, the patient later had a pleurex catheter placed. Given the patient’s other heart comorbidities, he was evaluated by oncology, and they had recommended a more palliative approach. Conclusion: This was a rather unusual diagnosis in an ailment that typically is associated with HIV. The first line treatment for primary effusion lymphoma is cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone along with HAART in those who are HIV positive. The therapy is less clear for those who are HIV negative due to being an extremely rare patient population. There has been less than 30 cases described in this subset population and they have typically been elderly, Mediterranean males. They key diagnostic criteria in diagnosing primary effusion lymphoma is the expression of HHV-8 in the malignant cells. Prognosis remains poor despite the use of chemotherapy; median survival is 6 months.https://scholarlycommons.henryford.com/merf2019caserpt/1099/thumbnail.jp

Metformin Induced Lactic Acidosis

Background: Metformin induced lactic acidosis is estimated to affect less than 10 cases per 100,000 patients. Metformin is the first line treatment for diabetes mellitus II due to its excellent safety profile along with its reasonable efficacy. However, metformin induced lactic acidosis may present, particularly in those with renal or hepatic impairment. Metformin’s mechanism of action is thought to be inhibiting gluconeogenesis in the liver. This impacts lactate metabolism as lactate is primarily metabolized in the liver as a substrate of gluconeogenesis. With normal renal function, lactate will be cleared by the kidneys. However, in the setting of decreased renal clearance, this can allow for the accumulation of metformin and as a result, significant acidosis as lactate accumulates. Case: A 61 year old male with a history of type 2 diabetes mellitus, prior CVA with residual left sided weakness, and CKD was admitted for lethargy with symptoms that may have begun three weeks prior to presentation. On arrival, he was immediately intubated for airway protection. Initial lab work revealed a blood glucose of 15, anion gap of 21, creatinine of 3.63 with unknown baseline renal function, lactate of 9, and a white blood cell count of 31.9. ABG revealed a pH of 6.91, pCO2 of 10.5, and a bicarbonate of 2.0. Imaging of the head, chest, abdomen and pelvis were unremarkable except for evidence of old infarct. The patient was subsequently started on IV ceftriaxone, vancomycin, and ampicillin for suspected meningitis and was started on hemodialysis due to oliguria. Blood cultures had returned positive for enterococcus and antibiotics were later de-escalated to IV ampicillin while lactic acid levels continued to rise. Towards the end of the hospital course, family had elected to withdraw care due to progressive decline. A metformin level that was drawn on admission had returned at 30 mcg/mL (reference limit 0.10 mcg/mL.) Discussion: This patient’s presentation of altered mental status with significant metabolic acidosis in the setting of acute kidney injury created a significant differential diagnosis that was further confounded by various overlapping features in this case. The patient’s presumed case was thought to arise as a bacterial infection with concurrent usage of metformin causing an acute kidney injury superimposed on chronic kidney disease allowing for toxic levels of metformin accumulation. Lactic acid can be generally thought as type A due to tissue hypoperfusion such as from sepsis or type B from metformin, malignancy, or alcohol. This patient’s case is thought to have favored both type A and type B.https://scholarlycommons.henryford.com/merf2020caserpt/1051/thumbnail.jp

Project #91: Optimizing Vascular Access to Reduce CLABSI

Henry Ford Macomb Hospital experienced an increase in Central Line Associated Bloodstream Infections (CLABSI) in 2021. A significant portion were occurring in the MICU and were associated with Candida sp. Bloodstream infections negatively impact patient outcomes, provider workload, and are costly, with a median cost of $48,108 based on a meta-analysis conducted by AHRQ in 2017. By end of 2022, HFM aimed to reduce CLABSI incidence by 50%.https://scholarlycommons.henryford.com/qualityexpo2023/1004/thumbnail.jp

Proteomic exosome evaluation in patients with sepsis and septic shock compared to healthy controls

Learning Objectives: Sepsis is the body\u27s response to infectious agents. The understanding of the pathogenic mechanisms leading to multi-organ dysfunction and death in up to 45% of septic patients is limited. Membrane nano-sized vesicles (exosomes) are important carriers of intracellular information containing mRNA and proteins. This exosomes may contribute to the pathogenesis of organ dysfunction and to-date have not sufficiently evaluated. We hypothesize that plasma exosome proteomic profiles of septic patients differ from healthy controls. Methods: Pilot exploratory evaluation of plasma exosome proteomic profiles for 2 female septic patients, 2 female and one male healthy control. Plasma exosomes were isolated using Invitrogen Total Exosome Isolation Kit. Exosome proteomic profiles were analyzed using standard preparation with reversed phase chromatography, ionization and fusion mass spectroscopy followed by data analysis using Proteome Discoverer. Statistical analysis was performed using correlation, heat map (HMA) and principal component analysis (PCA) along with linear modeling using the limma package from Bioconductor (V3.34.0). Results: Mass spectroscopy quantified 313 proteins. Using results of HMA and PCA we were able to conclude that the exosome proteomic profiles of septic patients were similar to each other and that these profiles were similar in healthy controls. Linear modeling identified 60 differently expressed proteins in septic patients (p-value ≤0.05). After adjusting for multiple comparison using False-Discovery-Rate methods, 7 proteins remained significantly different (q value ≤0.1). These proteins are serum amyloid A-2 (AA2), coagulation factor 8 (FA8), immunoglobulin heavy constant Δ (IGHD), immunoglobulin κ variable 1-8 (KV108), von Willebrand factor (VWF), serum amyloid A-4 (SAA4), and cytoplasmatic Actin1 (ACTB). KV108 and ACTB are more abundant in healthy controls while the other 5 proteins in septic patients. Conclusions: Plasma proteomic exosome profiles from septic patients differ from healthy controls. Future research should address how exosomes contribute to the pathogenesis of multi-organ dysfunction in sepsis

Extracellular vesicle size in early sepsis

Introduction: Sepsis continues to be a disease with high mortality and morbidity. Pathophysiologic understanding continues to be limited. Research has focused in the past on freely circulating inflammatory cells, cytokines, RNAs and DNAs without yielding much insight into the complex processes of these entities in the development of multiorgan dysfunction. Cell to cell communication and organ crosstalk is not only dependent on the free circulating markers, but may be more precisely modulated by extracellular vesicles (EV) such as exosomes and microvesicles, which contain protein markers along with RNA and DNA components in a defined structure. The composition of these vesicles along with variation in their size and amount could be another important puzzle piece to understand the pathophysiology of sepsis. Hypothesis: We aimed to examine variations size distribution of extracellular vesicles in patients with sepsis at time of their presentation and compare these with healthy controls healthy controls. Methods: Blood plasma samples were obtained from 10 patients at the time of presentation to the emergency department and 6 healthy control, after informed consent (HFHS IRB 1578, IRB 11000). Plasma was immediately frozen and stored at -80°C. For EV extraction samples were defrosted once and Invitrogen™ Total Exosome Extraction kit (from plasma) was used, according to manufactures protocol. EV pellets were re-suspended in PBS. Nanoparticle tracking analysis (NTA, NanoSight NS 300) was done at a standard dilution of 1:5.000. Western blots (ALIX, CD63, CD9, HSP70) and electron microscopy was conducted to confirm presence of EVs. Results: The average size of extracellular vesicles on NTA for patients with sepsis was 82.3 ± 106.5 nm and for healthy controls 71.3 ± 30.8 nm, p = 0.03. The average size of extracellular vesicles was 79.6 ± 152.1 nm for sepsis survivors (N = 6), 86.5 ± 28.3 for sepsis nonsurvivors (N = 4) and 71.3 ± 30.8 nm for healthy controls, p = 0.05. There was no statistical difference in the particle size between sepsis survivors and sepsis non-survivors. Conclusion: Size of extracellular vesicles in patients with sepsis at the time of presentation to the emergency department differs from the size of extracellular vesicles in healthy volunteers. Outlook: Differences in extracellular vesicle size at the time of presentation potentially indicate increased cellular processes and may be used in the future to aid diagnosis of sepsis

Extracellular vesicle size in early sepsis

Introduction: Sepsis continues to be a disease with high mortality and morbidity. Pathophysiologic understanding continues to be limited. Research has focused in the past on freely circulating inflammatory cells, cytokines, RNAs and DNAs without yielding much insight into the complex processes of these entities in the development of multiorgan dysfunction. Cell to cell communication and organ crosstalk is not only dependent on the free circulating markers, but may be more precisely modulated by extracellular vesicles (EV) such as exosomes and microvesicles, which contain protein markers along with RNA and DNA components in a defined structure. The composition of these vesicles along with variation in their size and amount could be another important puzzle piece to understand the pathophysiology of sepsis. Hypothesis: We aimed to examine variations size distribution of extracellular vesicles in patients with sepsis at time of their presentation and compare these with healthy controls healthy controls. Methods: Blood plasma samples were obtained from 10 patients at the time of presentation to the emergency department and 6 healthy control, after informed consent (HFHS IRB 1578, IRB 11000). Plasma was immediately frozen and stored at -80°C. For EV extraction samples were defrosted once and Invitrogen™ Total Exosome Extraction kit (from plasma) was used, according to manufactures protocol. EV pellets were re-suspended in PBS. Nanoparticle tracking analysis (NTA, NanoSight NS 300) was done at a standard dilution of 1:5.000. Western blots (ALIX, CD63, CD9, HSP70) and electron microscopy was conducted to confirm presence of EVs. Results: The average size of extracellular vesicles on NTA for patients with sepsis was 82.3 ± 106.5 nm and for healthy controls 71.3 ± 30.8 nm, p = 0.03. The average size of extracellular vesicles was 79.6 ± 152.1 nm for sepsis survivors (N = 6), 86.5 ± 28.3 for sepsis nonsurvivors (N = 4) and 71.3 ± 30.8 nm for healthy controls, p = 0.05. There was no statistical difference in the particle size between sepsis survivors and sepsis non-survivors. Conclusion: Size of extracellular vesicles in patients with sepsis at the time of presentation to the emergency department differs from the size of extracellular vesicles in healthy volunteers. Outlook: Differences in extracellular vesicle size at the time of presentation potentially indicate increased cellular processes and may be used in the future to aid diagnosis of sepsis

Extracellular vesicle size in early sepsis

Introduction: Sepsis continues to be a disease with high mortality and morbidity. Pathophysiologic understanding continues to be limited. Research has focused in the past on freely circulating inflammatory cells, cytokines, RNAs and DNAs without yielding much insight into the complex processes of these entities in the development of multiorgan dysfunction. Cell to cell communication and organ crosstalk is not only dependent on the free circulating markers, but may be more precisely modulated by extracellular vesicles (EV) such as exosomes and microvesicles, which contain protein markers along with RNA and DNA components in a defined structure. The composition of these vesicles along with variation in their size and amount could be another important puzzle piece to understand the pathophysiology of sepsis. Hypothesis: We aimed to examine variations size distribution of extracellular vesicles in patients with sepsis at time of their presentation and compare these with healthy controls healthy controls. Methods: Blood plasma samples were obtained from 10 patients at the time of presentation to the emergency department and 6 healthy control, after informed consent (HFHS IRB 1578, IRB 11000). Plasma was immediately frozen and stored at -80°C. For EV extraction samples were defrosted once and Invitrogen™ Total Exosome Extraction kit (from plasma) was used, according to manufactures protocol. EV pellets were re-suspended in PBS. Nanoparticle tracking analysis (NTA, NanoSight NS 300) was done at a standard dilution of 1:5.000. Western blots (ALIX, CD63, CD9, HSP70) and electron microscopy was conducted to confirm presence of EVs. Results: The average size of extracellular vesicles on NTA for patients with sepsis was 82.3 ± 106.5 nm and for healthy controls 71.3 ± 30.8 nm, p = 0.03. The average size of extracellular vesicles was 79.6 ± 152.1 nm for sepsis survivors (N = 6), 86.5 ± 28.3 for sepsis nonsurvivors (N = 4) and 71.3 ± 30.8 nm for healthy controls, p = 0.05. There was no statistical difference in the particle size between sepsis survivors and sepsis non-survivors. Conclusion: Size of extracellular vesicles in patients with sepsis at the time of presentation to the emergency department differs from the size of extracellular vesicles in healthy volunteers. Outlook: Differences in extracellular vesicle size at the time of presentation potentially indicate increased cellular processes and may be used in the future to aid diagnosis of sepsis