Characterization Of Cutaneous Immune-Related Adverse Events Due To Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICI) have been associated with a multitude of immune-related adverse events (irAE), which affect multiple organ systems in the setting of increased immune activation. Cutaneous immune-related adverse events (cirAE) are among the most common irAE, occurring in up to 50% of patients treated with an ICI. The most common cirAE are maculopapular eruption, pruritus (with or without primary cutaneous eruption), lichenoid dermatitis, eczematous dermatitis, psoriasiform eruption, and vitiligo. cirAE are of concern to oncologists and dermatologists alike, as cirAE can necessitate interruption or discontinuation of life-prolonging therapy. There is a paucity of data regarding cirAE in specific patient populations, including patients with skin of color (SOC) and patients with a prior dermatologic diagnosis. Our primary aim was to characterize the spectrum of ICI-induced cirAE diagnosed and treated by the Yale Oncodermatology Clinic. Our second aim was to characterize cirAE among patients with SOC who were diagnosed and treated by the Yale Oncodermatology Clinic. Our third aim was to characterize cirAE among patients with a history of psoriasis or eczema who were diagnosed and treated by the Yale Oncodermatology Clinic. This retrospective case series included all patients treated with an ICI who were referred to the Yale Oncodermatology Clinic for cirAE. Patients seen for any concern other than cirAE were not included within this cohort. Data collection was performed manually due to lack of appropriate International Classification of Diseases 10th Revision (ICD-10) codes for cirAE. All data was entered into a secure REDCap database. Descriptive analyses and chi-square tests were performed using SPSS Statistics. Aim 1: 287 patients were treated by the Yale Oncodermatology Clinic for cirAE. Within this cohort, mean age was 66 (SD 11), 53% of patients were male, and the most common oncologic diagnoses were non-small cell lung cancer (33%), melanoma (22%), and renal cell carcinoma (8.7%). 338 cirAE were reported, of which the most frequently observed were lichenoid dermatitis (18%) and eczematous dermatitis (15%). Aim 2: Of patients treated by the Yale Oncodermatology Clinic, 31 were included in the SOC cohort based on demographic data. The most common cirAE observed in this cohort were lichenoid dermatitis (22%) and eczematous dermatitis (22%). Aim 3: Of patients treated by the Yale Oncodermatology Clinic, 11 had a history of eczema and 18 had a history of psoriasis. Those with a history of eczema were significantly more likely to develop eczematous dermatitis than controls (43%, versus 12%) and those with a history of psoriasis were significantly more likely to develop psoriasiform dermatitis than controls (56%, versus 6.1%). As ICI become a cornerstone of oncologic therapy, it is critical that the presentation and treatment of cirAE in various patient populations are integrated into dermatologic training

Plasma sTNFR1 and IL8 for prognostic enrichment in sepsis trials: a prospective cohort study.

BackgroundEnrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors.MethodsIn a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies.Measurements and main resultsAn admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor.ConclusionsThresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials

Stenotrophomonas maltophilia, a Pathogen of Increasing Relevance to Dermatologists: A Case Report and Review of the Literature

Stenotrophomonas maltophilia is a Gram-negative bacillus that causes skin and soft tissue infections (SSTI), as well as bacteremia, pneumonia, and urinary tract infections. S. maltophilia infections are typically nosocomial and are often transmitted through water sources. Although historically described in immunocompromised hosts, S. maltophilia prevalence is increasing in both immunocompromised and immunocompetent populations. In light of high morbidity and mortality, it is critical that dermatologists are aware of this organism because of the limited options for therapy. Here, we describe a case of a S. maltophilia abscess with bacteremia in a patient with chronic lymphocytic leukemia and aplastic anemia that was successfully treated with trimethoprim–sulfamethoxazole. We also review the current standard of care and propose an algorithm for the treatment of S. maltophilia infection

Higher plasma cystatin C is associated with mortality after acute respiratory distress syndrome: findings from a Fluid and Catheter Treatment Trial (FACTT) substudy.

BackgroundCystatin C is a well-validated marker of glomerular filtration rate in chronic kidney disease. Higher plasma concentrations of cystatin C are associated with worse clinical outcomes in heterogenous populations of critically ill patients and may be superior to creatinine in identifying kidney injury in critically ill patients. We hypothesized that elevated levels of plasma cystatin C in patients with acute respiratory distress syndrome (ARDS) would be associated with mortality risk.MethodsIn a retrospective study, cystatin C was measured by nephelometry on plasma obtained at enrollment from 919 patients in the Fluid and Catheter Treatment Trial. Multivariable logistic regression was performed testing the association between quartiles of cystatin C and 60-day mortality. Analyses were stratified by acute kidney injury (AKI) status identified in the first 7 days after enrollment by Kidney Disease: Improving Global Outcomes (KDIGO) criteria.ResultsCystatin C was significantly higher among those patients who died compared to those who survived to 60 days [1.2 (0.9-1.9) mg/L vs. 0.8 (0.6-1.2) mg/L, p < 0.001]. Compared to the lower three quartiles, subjects in the highest quartile of cystatin C had a significantly higher odds of death at 60 days [OR 1.8 (1.2-2.6), p = 0.003 in adjusted analyses]; the odds of death incrementally rose in higher cystatin C quartiles compared to the lowest quartile (OR 1.1, 1.8, and 2.5). In adjusted analyses stratified by AKI status, compared to subjects in the lower three quartiles, subjects in the highest quartile of cystatin C with AKI had a significantly higher odds of death at 60 days both in participants with AKI [OR 1.6 (1.0-2.4), p = 0.048] and those without AKI [OR 2.4 (1.2-5.0), p = 0.017]. In adjusted analyses, there was no significant association between sex-stratified baseline creatinine quartiles and mortality.ConclusionsHigher plasma levels of cystatin C on enrollment were strongly associated with mortality at 60 days in patients with ARDS with and without AKI identified by creatinine-based definitions. Compared to creatinine, cystatin C may be a better biomarker of kidney function in patients with ARDS and therefore identify patients with multiple organ failure at higher risk of death

Clinician Recognition of the Acute Respiratory Distress Syndrome: Risk Factors for Under-Recognition and Trends Over Time.

ObjectivesThe acute respiratory distress syndrome is common in critically ill patients. Recognition is crucial because acute respiratory distress syndrome is associated with a high mortality rate, and low tidal volume ventilation improves mortality. However, acute respiratory distress syndrome often goes unrecognized. Risk factors for under-recognition and trends over time have not been fully described.DesignRetrospective chart review of patients with acute respiratory distress syndrome from a prospective cohort study of critically ill patients. For each patient's ICU stay, we searched the chart for terms that indicated that acute respiratory distress syndrome was diagnosed, in the differential diagnosis, or treated with low tidal volume ventilation.SettingICUs at a tertiary hospital at the University of California, San Francisco between 2008 and 2016.PatientsCritically ill patients with acute respiratory distress syndrome.InterventionsNone.Measurements and main resultsAcute respiratory distress syndrome was recognized in 70% of patients, and recognition increased from 60% in 2008-2009 to 92% in 2016 (p = 0.004). Use of tidal volumes less than 6.5 mL/kg also increased (p < 0.001) from 20% to 92%. Increased acute respiratory distress syndrome severity (p = 0.01) and vasopressor use (p = 0.04) were associated with greater recognition. Clinician diagnosis of acute respiratory distress syndrome and inclusion of acute respiratory distress syndrome in the differential diagnosis were associated with tidal volumes less than 6.5 mL/kg (51% use of tidal volume ≤ 6.5 mL/kg if acute respiratory distress syndrome recognized vs 15% if not recognized; p = 0.002). Diagnosing acute respiratory distress syndrome was associated with lower tidal volume in multivariate analysis.ConclusionsAlthough acute respiratory distress syndrome recognition and low tidal volume ventilation use have increased over time, they remain less than universal. Clinician recognition of acute respiratory distress syndrome is associated with both systemic and respiratory severity of illness and is also associated with use of low tidal volume ventilation

Alternative Tobacco Product Use in Critically Ill Patients.

Background: Alternative tobacco product (ATP) use has bee linked to critical illness, however, few studies have examined the use of these substances in critically ill populations. We sought to examine ATP use within critically ill patients and to define barriers in accurately assessing use within this population. Methods: We prospectively studied 533 consecutive patients from the Early Assessment of Renal and Lung Injury study, enrolled between 2013 and 2016 at a tertiary referral center and a safety-net hospital. ATP use information (electronic cigarettes, cigars, pipes, hookahs/waterpipes, and snus/chewing tobacco) was obtained from the patient or surrogate using a detailed survey. Reasons for non-completion of the survey were recorded, and differences between survey responders vs. non-responders, self- vs. surrogate responders, and ATP users vs. non-users were explored. Results: Overall, 80% (n = 425) of subjects (56% male) completed a tobacco product use survey. Of these, 12.2% (n = 52) reported current ATP use, while 5.6% reported using multiple ATP products. When restricted to subjects who were self-responders, 17% reported ATP use, while 10% reported current cigarette smoking alone. The mean age of ATP users was 57 ± 17 years. Those who did not complete a survey were sicker and more likely to have died during admission. Subjects who completed the survey as self-responders reported higher levels of ATP use than ones with surrogate responders (p < 0.0001). Conclusion: ATP use is common among critically ill patients despite them being generally older than traditional users. Survey self-responders were more likely than surrogate responders to report use. These findings highlight the importance of improving our current methods of surveillance of ATP use in older adults in the outpatient setting