Background Acute tubulointerstitial nephritis (AIN) is one of the few causes of acute kidney injury with diagnosis-specific treatment options. However, due to the need to obtain a kidney biopsy for histological confirmation, AIN diagnosis can be delayed, missed, or incorrectly assumed. Here, we identify and validate urinary CXCL9, an IFN-γ-induced chemokine involved in lymphocyte chemotaxis, as a diagnostic biomarker for AIN.Methods In a prospectively enrolled cohort with pathologist-adjudicated histological diagnoses, termed the discovery cohort, we tested the association of 180 immune proteins measured by an aptamer-based assay with AIN and validated the top protein, CXCL9, using sandwich immunoassay. We externally validated these findings in 2 cohorts with biopsy-confirmed diagnoses, termed the validation cohorts, and examined mRNA expression differences in kidney tissue from patients with AIN and individuals in the control group.Results In aptamer-based assay, urinary CXCL9 was 7.6-fold higher in patients with AIN than in individuals in the control group (P = 1.23 × 10–5). Urinary CXCL9 measured by sandwich immunoassay was associated with AIN in the discovery cohort (n = 204; 15% AIN) independently of currently available clinical tests for AIN (adjusted odds ratio for highest versus lowest quartile: 6.0 [1.8–20]). Similar findings were noted in external validation cohorts, where CXCL9 had an AUC of 0.94 (0.86–1.00) for AIN diagnosis. CXCL9 mRNA expression was 3.9-fold higher in kidney tissue from patients with AIN (n = 19) compared with individuals in the control group (n = 52; P = 5.8 × 10–6).Conclusion We identified CXCL9 as a diagnostic biomarker for AIN using aptamer-based urine proteomics, confirmed this association using sandwich immunoassays in discovery and external validation cohorts, and observed higher expression of this protein in kidney biopsies from patients with AIN.Funding This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) awards K23DK117065 (DGM), K08DK113281 (KM), R01DK128087 (DGM), R01DK126815 (DGM and LGC), R01DK126477 (KNC), UH3DK114866 (CRP, DGM, and FPW), R01DK130839 (MES), and P30DK079310 (the Yale O’Brien Center). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Dennis G. Moledina, Wassim Obeid, Rex N. Smith, Ivy Rosales, Meghan E. Sise, Gilbert Moeckel, Michael Kashgarian, Michael Kuperman, Kirk N. Campbell, Sean Lefferts, Kristin Meliambro, Markus Bitzer, Mark A. Perazella, Randy L. Luciano, Jordan S. Pober, Lloyd G. Cantley, Robert B. Colvin, F. Perry Wilson, Chirag R. Parikh
BACKGROUND. IgE-mediated anaphylaxis is a potentially fatal systemic allergic reaction for which there are no currently FDA-approved preventative therapies. Bruton’s tyrosine kinase (BTK) is an essential enzyme for IgE-mediated signaling pathways, and is an ideal pharmacologic target to prevent allergic reactions. In this open-label trial, we evaluated the safety and efficacy of acalabrutinib, a BTK inhibitor that is FDA-approved to treat some B cell malignancies, in preventing clinical reactivity to peanut in adults with peanut allergy. METHODS. After undergoing graded oral peanut challenge to establish their baseline level of clinical reactivity, 10 patients had a 6-week rest period, then received four standard doses of 100 mg acalabrutinib twice daily and underwent repeat food challenge. The primary endpoint was the change in patients’ threshold dose of peanut protein to elicit an objective clinical reaction. RESULTS. At baseline, patients tolerated a median of 29 mg of peanut protein before objective clinical reaction. During subsequent food challenge on acalabrutinib, patients’ median tolerated dose significantly increased to 4,044 mg (range, 444 – 4,044 mg). Seven patients tolerated the maximum protocol amount (4,044 mg) of peanut protein with no clinical reaction, and the other 3 patients’ peanut tolerance increased between 32- and 217-fold. Three patients experienced a total of 4 adverse events that were considered to be possibly related to acalabrutinib; all events were transient and nonserious. CONCLUSION. Acalabrutinib pretreatment achieved clinically-relevant increases in patients’ tolerance to their food allergen, thereby supporting the need for larger, placebo-controlled trials. TRIAL REGISTRATION. ClinicalTrials.gov NCT05038904 FUNDING. AstraZeneca Pharmaceuticals, the Johns Hopkins Institute for Clinical and Translational Research, the Ludwig Family Foundation, and NIH grants AI143965 and AI106043.
Ragha V. Suresh, Collin Dunnam, Dhananjay Vaidya, Robert A. Wood, Bruce S. Bochner, Donald W. MacGlashan, Jr., Melanie C. Dispenza
BACKGROUND. SARS-CoV-2 infection in Africa has been characterized by less severe disease than elsewhere but the profile of SARS-CoV-2 specific adaptive immunity in this largely asymptomatic spread has not been studied. METHODS. We collected blood and nasopharyngeal samples from rural Kenyans (n=80) without respiratory symptoms since 2019, had no contact with COVID-19 cases or received COVID-19 vaccines and were negative for current SARS-CoV-2 infection. We analyzed spike-specific antibodies and T cells specific for SARS-CoV-2 structural (membrane, nucleocapsid and spike) and accessory (ORF3a, ORF7, ORF8) proteins. Pre-pandemic samples collected in urban Nairobi, Kenya (n=13) between 2015-2016 and samples of mild-moderately symptomatic COVID-19 convalescents (n=36) living in the urban environment of Singapore were also studied. RESULTS. Among asymptomatic Kenyans, we detected anti-spike antibodies in 41.0% and T cell responses against ≥2 SARS-CoV-2 proteins in 82.5%. The pre-pandemic samples from Nairobi had low-level, monospecific responses. Furthermore, distinct from cellular immunity in European and Asian COVID-19 convalescents, strong T cell immunogenicity was observed against viral accessory proteins (ORF3a, ORF8) and not structural proteins, as well as a higher IL-10/IFN-γ ratio cytokine profile. CONCLUSIONS. The high incidence of T cell responses against different SARS-CoV-2 proteins in largely seronegative participants suggests that serosurveys underestimate SARS-CoV-2 prevalence in settings where asymptomatic infections prevail. Similar observations have been made with other coronavirus infections such as MERS and SARS-CoV-1. The functional and antigen-specific profile of SARS-CoV-2 specific T cells in these African individuals suggests that genetic or environmental factors play a role in the development of protective antiviral immunity. FUNDINGS. U.S. Centers for Disease Control and Prevention, Division of Global Health Protection; the Singapore Ministry of Health’s National Medical Research Council.
Taraz Samandari, Joshua Ongalo, Kimberly McCarthy, Richard K. Biegon, Philister Madiega, Anne Mithika, Joseph Orinda, Grace M. Mboya, Patrick Mwaura, Omu Anzala, Clayton Onyango, Fredrick O. Oluoch, Eric M. Osoro, Charles-Antoine Dutertre, Nicole Tan, Shou Kit Hang, Smrithi Hariharaputran, David C. Lye, Amy Herman-Roloff, Nina Le Bert, Antonio Bertoletti
BACKGROUND We previously demonstrated the safety of stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) in patients with advanced solid tumors. This phase I clinical trial was expanded to study the safety of partial tumor irradiation (partial-Rx). We assessed irradiated local failure (LF) and clinical outcomes with correlations to biomarkers including CD8+ T cell radiomics score (RS) and circulating cytokines.METHODS Patients received SBRT to 2–4 metastases and pembrolizumab for up to 7 days after SBRT. Tumors measuring up to 65 cc received the full radiation dose (complete-Rx), whereas tumors measuring more than 65 cc received partial-Rx. Landmark analysis was used to assess the relationship between tumor response and overall survival (OS). Multivariable analysis was performed for RS and circulating cytokines.RESULTS In the combined (expansion plus original) cohort, 97 patients (219 metastases) were analyzed and received SBRT+P. Forty-six (47%) patients received at least 1 partial-Rx treatment. There were 7 (7.2%)dose-limiting toxicities (DLTs). 1-year LF was 7.6% overall, and 13.3% and 5.4% for partial-Rx and complete-Rx tumors, respectively (HR 2.32, 95% CI 0.90–5.97, P = 0.08). The overall, unirradiated, and irradiated objective response rates were 22%, 12%, and 34%, respectively. Irradiated tumor response to SBRT+P was associated with prolonged OS; 1-year OS was 71% (responders), 42% (mixed-responders), and 0% (nonresponders) (P < 0.01). High-RS was significantly associated with improved LF, progression-free survival (PFS), and OS. Elevated circulating IL-8 was independently associated with inferior PFS and OS.CONCLUSION SBRT+P is safe in patients with large, advanced solid tumors. Additional studies are warranted to assess noninferiority of complete versus partial irradiation of tumors in the setting of immunotherapy.TRIAL REGISTRATION Clinicaltrials.gov NCT02608385FUNDING Merck Investigator Studies Program; Hillman Fellows for Innovative Cancer Research Program; NIH grants UM1CA186690-06, P50CA254865-01A1, P30CA047904-32, and R01DE031729-01A1.
Mark C. Korpics, Benjamin E. Onderdonk, Rebekah E. Dadey, Jared H. Hara, Lilit Karapetyan, Yuanyuan Zha, Theodore G. Karrison, Adam C. Olson, Gini F. Fleming, Ralph R. Weichselbaum, Riyue Bao, Steven J. Chmura, Jason J. Luke
BACKGROUND. Adoptive transfer of EBV-specific T cells can restore specific immunity in immunocompromised patients with EBV-associated complications. METHODS. We provide results of a personalized T-cell manufacturing program evaluating donor, patient, T-cell product and outcome data. Patient-tailored clinical-grade EBV-specific cytotoxic T-lymphocyte (EBV-CTL) products from stem cell donors (SCD), related third party donors (TPD) or unrelated TPD from the allogeneic T-cell donor registry (alloCELL) established at Hannover Medical School were manufactured by immunomagnetic selection using CliniMACS Plus or Prodigy device and EBV PepTivators EBNA-1 and Select. Consecutive manufacturing processes were evaluated and patient outcome and side effects were retrieved by retrospective chart analysis. RESULTS. Forty clinical-grade EBV-CTL products from SCDs, related or unrelated TPDs were generated for 37 patients with and without transplantation (Tx) history within 5 days (median) after donor identification. 34 patients received 1-14 EBV-CTL products (fresh and cryopreserved). EBV-CTL transfer led to complete response in 20 of 29 patients who were evaluated for clinical response. No infusion-related toxicity was reported. EBV-specific T cells in patients’ blood were detectable in 16/18 monitored patients (89 %) after transfer and correlated with clinical response. CONCLUSION. In conclusion, personalized clinical-grade manufacturing of EBV-CTL products via immunomagnetic selection from SCD, related or unrelated TPD is feasible in a timely manner. Overall, EBV-CTL were clinically effective and well-tolerated. Our data suggest EBV-CTL as promising therapeutic approach for immunocompromised patients with refractory EBV-associated diseases beyond HSCT as well as patients with pre-existing organ dysfunction. TRIAL REGISTRATION. Not applicable. FUNDING. This study was in part funded by the German Research Foundation (DFG, 158989968/SFB 900), the Deutsche Kinderkrebsstiftung (DKS 2013.09), the Wilhelm-Sander-Stiftung (http://www.wilhelm-sander-stiftung.de, 2015.097.1), the Ellen-Schmidt-Program of the Hannover Medical School, and the German Federal Ministry of Education and Research (reference number: 01EO0802).
Agnes Bonifacius, Britta Lamottke, Sabine Tischer-Zimmermann, Rebecca Schultze-Florey, Lilia Goudeva, Hans-Gert Heuft, Lubomir Arseniev, Rita Beier, Gernot Beutel, Gunnar Cario, Birgit Fröhlich, Johann Greil, Leo Hansmann, Justin Hasenkamp, Michaela Höfs, Patrick Hundsdoerfer, Edgar Jost, Kinan Kafa, Oliver Kriege, Nicolaus Kröger, Stephan Mathas, Roland Meisel, Michaela Nathrath, Mervi Putkonen, Sarina Ravens, Hans Christian Reinhardt, Elisa Sala, Martin G. Sauer, Clemens Schmitt, Roland Schroers, Nina Kristin Steckel, Ralf Ulrich Trappe, Mareike Verbeek, Daniel Wolff, Rainer Blasczyk, Britta Eiz-Vesper, Britta Maecker-Kolhoff
BACKGROUND. Despite guidelines promoting the prevention and aggressive treatment of ventilator-associated pneumonia (VAP), the importance of VAP as a driver of outcomes in mechanically ventilated patients, including patients with severe COVID-19, remains unclear. We aimed to determine the contribution of unsuccessful treatment of VAP to mortality in patients with severe pneumonia. METHODS. We performed a single-center prospective cohort study of 585 mechanically ventilated patients with severe pneumonia and respiratory failure, 190 of whom had COVID-19, who underwent at least one bronchoalveolar lavage. A panel of ICU physicians adjudicated pneumonia episodes and endpoints based on clinical and microbiologic data. Given the relatively long ICU length of stay among patients with COVID-19, we developed a machine learning approach called CarpeDiem, which groups similar ICU patient-days into clinical states based on electronic health record data. RESULTS.CarpeDiem revealed that the long ICU length of stay among patients with COVID-19 is attributable to long stays in clinical states characterized primarily by respiratory failure. While VAP was not associated with mortality overall, mortality was higher in patients with one episode of unsuccessfully treated VAP compared with successfully treated VAP (76.4% versus 17.6%, P < 0.001). In all patients, including those with COVID-19, CarpeDiem demonstrated that unresolving VAP was associated with transitions to clinical states associated with higher mortality. CONCLUSIONS. Unsuccessful treatment of VAP is associated with greater mortality. The relatively long length of stay among patients with COVID-19 is primarily due to prolonged respiratory failure, placing them at higher risk of VAP. FUNDING. U19AI135964
Catherine A. Gao, Nikolay S. Markov, Thomas Stoeger, Anna E. Pawlowski, Mengjia Kang, Prasanth Nannapaneni, Rogan A. Grant, Chiagozie Pickens, James M. Walter, Jacqueline M. Kruser, Luke V. Rasmussen, Daniel Schneider, Justin Starren, Helen K. Donnelly, Alvaro Donayre, Yuan Luo, G.R. Scott Budinger, Richard G. Wunderink, Alexander V. Misharin, Benjamin D. Singer
BACKGOUND. Basic immune processes exhibit circadian rhythms, but it is unclear if rhythms exist in clinical endpoints like vaccine protection. Here, we examined associations between Coronavirus Infectious Disease 2019 (COVID-19) vaccination timing and effectiveness. METHODS. We retrospectively analyzed a large Israeli cohort with timestamped COVID-19 vaccinations (n=1,515,754 patients over 12 years-old, 99.2% receiving BNT162b2). Endpoints included COVID-19 breakthrough infection, COVID-19 associated emergency department (ED) visits, and hospitalizations. Our main comparison was between patients vaccinated during morning (8:00-11:59), afternoon (12:00-15:59), or evening hours (16:00-19:59). We employed Cox regression to adjust for differences in age, sex, and co-morbidities. RESULTS. Breakthrough infections differed based on vaccination time, with lowest rates associated with late morning to early afternoon, and highest rates with evening vaccination. Vaccination timing remained significant after adjustment for patient age, sex, and co-morbidities. Results were consistent in patients who received the basic two-dose series and who received booster doses. The relationship between COVID-19 immunization time and breakthrough infections was sinusoidal, consistent with a biological rhythm that modifies vaccine effectiveness by 8.6-25%. The benefits of daytime vaccination were concentrated in younger (<20 years old) and older patients (>50 years old). COVID-19 related hospitalizations varied significantly with the timing of the second booster dose, an intervention reserved for older and immunosuppressed patients (HR=0.64 morning vs. evening, 0.43-0.97 95% CI, p=0.038). CONCLUSION. We report a significant association between the time of COVID-19 vaccination and its effectiveness. This has implications for mass vaccination programs. FUNDING. National Institutes of Health.
Guy Hazan, Or A. Duek, Hillel Alapi, Huram Mok, Alexander T. Ganninger, Elaine M. Ostendorf, Carrie Gierasch, Gabriel Chodick, David Greenberg, Jeffrey A. Haspel
BACKGROUND. There is increasing evidence, in transgenic mice and in vitro, that inhibitory killer cell immunoglobulin-like receptors (iKIRs) can modulate T cell responses. Furthermore, we have previously shown that iKIRs are an important determinant of T cell-mediated control of chronic virus infection and that these results are consistent with an increase in CD8+ T cell lifespan due to iKIR-ligand interactions. Here we test this prediction and investigate whether iKIRs affect T cell lifespan in humans in vivo. METHODS. We used stable isotope labelling with deuterated water to quantify memory CD8+ T cell survival in healthy individuals and patients with chronic viral infections. RESULTS. We showed that an individual’s iKIR-ligand genotype is a significant determinant of CD8+ T cell lifespan: in individuals with two iKIR-ligand gene pairs, memory CD8+ T cells survived on average for 125 days, in individuals with four iKIR-ligand gene pairs then memory CD8+ T cell lifespan was doubled to 250 days. Additionally, we showed that this survival advantage is independent of iKIR expression by the T cell of interest and further that iKIR-ligand genotype altered CD8+ and CD4+ T cell immune aging phenotype. CONCLUSIONS. Together these data reveal an unexpectedly large impact of iKIR genotype on T cell survival. FUNDING. Wellcome Trust, Medical Research Council, EU Horizon 2020, EU FP7, Leukemia and Lymphoma Research, National Institute of Health Research Imperial Biomedical Research Centre, Imperial College Research Fellowship, National Institute of Health, Jefferiss Trust.
Yan Zhang, Ada W.C. Yan, Lies Boelen, Linda Hadcocks, Arafa Salam, Daniel Padrosa Gispert, Loiza Spanos, Laura Mora Bitria, Neda Nemat-Gorgani, James A. Traherne, Chrissy H. Roberts, Danai A. Koftori, Graham P. Taylor, Daniel Forton, Paul J. Norman, Steven G.E. Marsh, Robert Busch, Derek Macallan, Becca Asquith
BACKGROUND. The stomach-derived hormone ghrelin stimulates appetite, but the ghrelin receptor is also expressed in brain circuits involved in motivation and reward. We examined ghrelin effects on decision making beyond food or drug rewards, using monetary outcomes. METHODS. Thirty participants (50% females) underwent two fMRI scans, in randomized counterbalanced order, while receiving intravenous ghrelin or saline. RESULTS. Striatal representations of reward anticipation were unaffected by ghrelin, while activity during anticipation of losses was attenuated. Temporal discounting rates of monetary rewards were lower overall in the ghrelin condition, an effect driven by women. Discounting rates were inversely correlated with neural activity in a large cluster within the left parietal lobule that included the angular gyrus. Activity in an overlapping cluster was related to behavioral choices, and was suppressed by ghrelin. CONCLUSION. This is to our knowledge the first human study to extend the understanding of ghrelin’s significance beyond the canonical feeding domain or in relation to addictive substances. Contrary to our hypothesis, we find that ghrelin does not affect sensitivity to monetary reward anticipation, but rather results in attenuated loss aversion and lower discounting rates for these rewards. Ghrelin may cause a motivational shift toward caloric rewards rather than globally promoting the value of rewards. TRIAL REGISTRATION. EudraCT 2018-004829-82 FUNDING. Swedish Research Council (MH: 2013-07434) and Marcus and Marianne Wallenberg foundation (GT: 2014.0187). Author LL is supported by NIDA/NIAAA IRP
Michal Pietrzak, Adam Yngve, J. Paul Hamilton, Robin Kämpe, Rebecca Boehme, Anna Asratian, Emelie Gauffin, Andreas Löfberg, Sarah Gustavson, Emil Persson, Andrea J. Capusan, Lorenzo Leggio, Irene Perini, Gustav Tinghög, Markus Heilig
BACKGROUND Lower respiratory tract infection (LRTI) is a leading cause of death in children worldwide. LRTI diagnosis is challenging because noninfectious respiratory illnesses appear clinically similar and because existing microbiologic tests are often falsely negative or detect incidentally carried microbes, resulting in antimicrobial overuse and adverse outcomes. Lower airway metagenomics has the potential to detect host and microbial signatures of LRTI. Whether it can be applied at scale and in a pediatric population to enable improved diagnosis and treatment remains unclear.METHODS We used tracheal aspirate RNA-Seq to profile host gene expression and respiratory microbiota in 261 children with acute respiratory failure. We developed a gene expression classifier for LRTI by training on patients with an established diagnosis of LRTI (n = 117) or of noninfectious respiratory failure (n = 50). We then developed a classifier that integrates the host LRTI probability, abundance of respiratory viruses, and dominance in the lung microbiome of bacteria/fungi considered pathogenic by a rules-based algorithm.RESULTS The host classifier achieved a median AUC of 0.967 by cross-validation, driven by activation markers of T cells, alveolar macrophages, and the interferon response. The integrated classifier achieved a median AUC of 0.986 and increased the confidence of patient classifications. When applied to patients with an uncertain diagnosis (n = 94), the integrated classifier indicated LRTI in 52% of cases and nominated likely causal pathogens in 98% of those.CONCLUSION Lower airway metagenomics enables accurate LRTI diagnosis and pathogen identification in a heterogeneous cohort of critically ill children through integration of host, pathogen, and microbiome features.FUNDING Support for this study was provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute (UG1HD083171, 1R01HL124103, UG1HD049983, UG01HD049934, UG1HD083170, UG1HD050096, UG1HD63108, UG1HD083116, UG1HD083166, UG1HD049981, K23HL138461, and 5R01HL155418) as well as by the Chan Zuckerberg Biohub.
Eran Mick, Alexandra Tsitsiklis, Jack Kamm, Katrina L. Kalantar, Saharai Caldera, Amy Lyden, Michelle Tan, Angela M. Detweiler, Norma Neff, Christina M. Osborne, Kayla M. Williamson, Victoria Soesanto, Matthew Leroue, Aline B. Maddux, Eric A.F. Simões, Todd C. Carpenter, Brandie D. Wagner, Joseph L. DeRisi, Lilliam Ambroggio, Peter M. Mourani, Charles R. Langelier
No posts were found with this tag.