IT'S ALWAYS COCAINE: A RARE CASE OF LEVAMISOLEINDUCED COCAINE ASSOCIATED VASCULITIS WITH PULMONARY AND RENAL INVOLVEMENT

CASE: 58 year old woman presents with 1 month of dyspnea and productive cough. She also reported loss of smell and hematuria for 1 week. History was notable for hypertension, COPD, substance abuse, specifically crack cocaine, and unstable housing. On admission she was tachypneic and hypoxic, requiring supplemental O2. Exam revealed bilateral crackles, elevated JVP, and mild lower extremity edema, but no skin changes or rashes. Laboratory studies showed an elevated creatine of 7.9. CT chest imaging showed extensive bilateral ground glass opacities with increased septal lines. Infectious work-up, including SARSCoV-2 PCR, was negative. Dialysis was initiated for new renal failure. To determine the etiology of the renal failure, autoimmune studies were obtained and showed a positive ANA and p-ANCA (1:640) and a negative MPO and PR3. Kidney biopsy was consistent with levamisole-induced vasculitis (LIV) from cocaine use. Treatment with steroids was initiated. She was discharged on steroid therapy and outpatient hemodialysis. She had repeated admissions for volume overload due to missed dialysis, and she developed heart failure within the year. She was unable to make appointments to start outpatient rituximab therapy. IMPACT/DISCUSSION: Levamisole-induced vasculitis (LIV) is a complication of use of cocaine adulterated with levamisole. Levamisole is an antihelminthic medication with well known immunomodulatory effects. Increasingly used as a cocaine adulterant, it is believed to be a component of over 80% of cocaine samples in the US. Its use is thought to be driven by levamisole's synergistic effect on the dopaminergic effects of cocaine. Levamisole-induced vasculitis is a p-ANCA associated vasculitis associated with long-term use of cocaine mixed with levamisole. It has been reported with both inhaled cocaine and smoking crack cocaine. Levamisole is thought to induce production of autoantibodies including p-ANCA, ANA, and lupus anticoagulant leading to immune complex deposition and secondary hypercoagulability. The most commonly reported presentation is cutaneous purpuric lesions, most notably the ear, tip of the nose, and malar eminence. LIV can occur without skin involvement and renal and pulmonary involvement including nephritis, renal failure, and hypersensitivity pneumonitis, has been reported. LIV with significant organ involvement is often treated with steroids. Additional immunosuppressive therapies including rituximab, cyclophosphamide, and plasmapheresis have been reported in severe cases. CONCLUSION: This case illustrates a rare presentation of LIV marked by with renal failure and absence of skin lesions. While the health effects of cocaine are well known, the adverse effects of agents used to cut cocaine are less readily considered. LIV should be considered in a patient with substance use disorder presenting with new vasculitis. As this case illustrates, factors like unstable housing and ongoing substance use disorder can complicate management.

Prospective Evaluation of Serial Protein Biomarker Measurements in Sepsis-Induced Acute Respiratory Distress Syndrome

RATIONALE: Protein biomarkers including soluble receptor for advanced glycation end-products (sRAGE), angiopoietin-2 (Ang- 2), and surfactant protein-D (SP-D) have been studied for diagnosis or prognostication in acute respiratory distress syndrome (ARDS). However, prior studies of ARDS biomarkers often included heterogeneous populations, and rarely examined serial measurements. Our aim was to determine the association between serially measured sRAGE, Ang-2, and SP-D levels and ARDS development in patients with sepsis. METHODS: Adult patients admitted to the medical ICU at Grady Memorial Hospital within 72 hours of sepsis diagnosis were enrolled into this prospective observational cohort study within 48 hours of ICU admission. Patients who already had ARDS at the time of screening were excluded. After obtaining informed consent, serial plasma samples were collected on day 1, 2, and 3 of enrollment, and were analyzed for sRAGE, Ang-2, and SP-D levels using ELISA. The patients were followed for up to 28 days for relevant clinical characteristics and outcomes. The primary outcome was ARDS development according to the Berlin Definition. The secondary outcome was mortality. Pulmonary sepsis was defined as the primary infection being pneumonia (including COVID19) or aspiration pneumonia. The biomarker levels and their changes from day 1 to days 2/3 were compared between those who developed ARDS versus those who did not. RESULTS: Among 80 patients with sepsis enrolled between September 1, 2020 and June 22, 2021, 15 patients (18.8%) developed ARDS and 65 patients (81.3%) did not. ARDS patients had higher proportions of pulmonary sepsis (14/15 [93.3%] vs. 30/65 [46.2%], p=0.001) and COVID19 (7/15 [46.7%] vs. 7/65 [10.8%], p=0.003) compared to non-ARDS patients. ARDS patients had higher SP-D levels on days 1 and 2, and had a greater increase in sRAGE levels from day 1 to day 3, compared to non-ARDS patients (Figure 1A- 1B). Within the ARDS group, those who died had higher sRAGE levels on day 1 compared to those who survived (Figure 1C). CONCLUSIONS: In this analysis, ARDS patients had higher SP-D and a greater increase in sRAGE over time compared to non- ARDS patients. Non-survivors of ARDS also had higher sRAGE compared to survivors. Our findings suggest that early serial biomarker measurements may be useful for identifying sepsis patients at risk of developing ARDS and adverse clinical outcomes, and for risk stratifying sepsis patients in ARDS clinical trials focused on early therapeutics and prevention. Larger studies are needed for more detailed analyses and confirmation of these findings.

Severe COVID-19 Is an Acquired Red Cell Disease- Potential Mechanisms Underlying Endothelialitis

Rationale As the SARS-CoV-2 pandemic continues, there is an imperative to understand the pathophysiology underlying the associated critical illness. Evidence exists that COVID-19 is a systemic vasculopathy associated with a hypercoaguable state and recent meta analyses have shown that standard inflammatory biomarkers in critically ill COVID-19 patients are not significantly elevated when compared with similarly ill patients with non-SARS-CoV-2- related sepsis. Leveraging our novel microvasculature-on-a-chip microfluidics platform which permits tight biomechanical control, we investigate how physical interactions between the endothelium and COVID-19 patient red blood cells (RBCs) may directly cause endothelialitis. Methods In a single ICU, we enrolled patients with sepsis (SOFA score ≥3), and categorized as either resultant from COVID-19 (n=14) or alternative infection (n=15), collecting clinical data and whole blood. These samples were perfused through our systems comprising microchannels of 2 distinct diameters (40μm and 60μm) to approximate the size of postcapillary venules at physiologic shear rates (200 s-1 to 1000 s-1). Mean and peak velocity measurements as well as red cell aggregation were recorded using cell tracking with high resolution video microscopy. Plasma was prepared from these collections for measurement of syndecan-1 via ELISA to examine endothelial disturbance. Results Comparing demographic and clinical data, no significant differences were measured in co-morbidities, SOFA score or 30 day mortality between the two patient populations whereas there was a higher incidence of vasopressor use in the non-COVID sepsis group. There was no difference in mean or maximum velocity, however, blood from COVID-19 sepsis patients demonstrated increased red cell aggregation under dynamic conditions at lower shear rates (200 s-1- 400 s-1) when compared with patients with sepsis from non-COVID-19 causes (Figure, right panel). This effect was more pronounced in the smaller channel size. Additionally, syndecan-1 levels in patients with COVID-19 were elevated compared with patients with non-COVID-19 related sepsis, (812±357 ng/mL vs 469 ±193, p=0.15, Figure, left panel). Conclusions Our data support the hypothesis that COVID-19 results in an acquired RBC membrane pathology leading to aggregation. To our knowledge, this is the first study that proposes such a mechanism. We theorize this phenomenon directly disrupts the endothelial glycocalyx as the aggregates "rub" against it. Further work to isolate effects of red cell aggregation, cytokines and proteinases in plasma on endothelium and to demonstrate hypercoagulability in our microvasculature-on-chip system are underway. We believe our work suggests that therapies specifically targeting RBC aggregation may be beneficial for COVID-19 patients.