Altered transcriptomic immune responses of maintenance hemodialysis patients to the COVID-19 mRNA vaccine.

Background: End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines. Methods: The immune response to the COVID-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and 7 d after the second dose (V2D7) using anti-spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified 6 mo after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response. Results: Transcriptomic analyses demonstrated differing time courses of immune responses, with prolonged myeloid cell activity in HD at 1 wk after the first vaccination dose. HD also demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p<0.05). Anti-spike IgG remained elevated above baseline at 6 mo in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development. Conclusions: Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance HD subjects comparable to healthy controls and identify transcriptomic and clinical predictors of anti-spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of ESRD. Funding: F30HD102093, F30HL151182, T32HL144909, R01HL138628. This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.

Coordinated elimination of bacterial taxa optimally attenuates alloimmunity and prolongs allograft survival.

This study aimed to dissect the relationship between specific gut commensal bacterial subgroups, their functional metabolic pathways, and their impact on skin allograft outcome and alloimmunity. We previously showed that oral broad-spectrum antibiotic (Abx) pretreatment in mice delayed skin, heart, and lung allograft rejection and dampened alloimmune responses. Here, rationally designed Abx combinations targeting major bacterial groups were used to elucidate their individual contribution to modulating alloimmune responses. Abx cocktails targeting intestinal gram-negative, gram-positive, or anaerobic/gram-positive bacteria by oral gavage, all delayed skin allograft rejection, and reduced alloreactive T cell priming to different extents. Notably, the most pronounced extension of skin allograft survival and attenuation of alloimmunity were achieved when all gut bacterial groups were simultaneously targeted. These results suggest a model in which the strength of the alloimmune response is additively tuned up by gut microbial diversity. Shotgun metagenomic sequencing enabled strain-level resolution and identified a shared commensal, Parabacteroides distasonis, as the most enriched following all Abx treatments. Oral administration of P.distasonis to mice harboring a diverse microbiota significantly prolonged skin allograft survival, identifying a probiotic with therapeutic benefit in transplantation.

Microbiota-dependent and -independent effects of obesity on transplant rejection and hyperglycemia.

Obesity is associated with dysbiosis and a state of chronic inflammation that contributes to the pathogenesis of metabolic diseases, including diabetes. We have previously shown that obese mice develop glucose intolerance, increased alloreactivity, and accelerated transplant rejection. In the present study, we investigated the influence of the microbiota on diet-induced obesity (DIO)-associated transplant rejection and hyperglycemia. Antibiotic treatment prolonged graft survival and reduced fasting glycemia in high-fat diet (HFD)-fed specific-pathogen-free (SPF) mice, supporting a role for the microbiota in promoting accelerated graft rejection and hyperglycemia induced by DIO. Further supporting a microbiota-dependent effect, fecal microbiota transfer from DIO SPF mice into germ-free mice also accelerated graft rejection when compared with lean mice-fecal microbiota transfer. Notably, HFD could be also detrimental to the graft independently from microbiota, obesity, and hyperglycemia. Thus, whereas HFD-associated hyperglycemia was exclusively microbiota-dependent, HFD affected transplant outcomes via both microbiota-dependent and -independent mechanisms. Importantly, hyperglycemia in DIO SPF mice could be reduced by the addition of the gut commensal Alistipes onderdonkii, which alleviated both HFD-induced inflammation and glucose intolerance. Thus, microbial dysbiosis can be manipulated via antibiotics or select probiotics to counter some of the pathogenic effects of obesity in transplantation.

Oral administration of the commensal Alistipes onderdonkii prolongs allograft survival.

Intestinal commensals can exert immunomodulatory effects on the host, with beneficial or detrimental consequences depending on underlying diseases. We have previously correlated longer survival of minor mismatched skin grafts in mice with the presence of an intestinal commensal bacterium, Alistipes onderdonkii. In this study, we investigated its sufficiency and mechanism of action. Oral administration of A onderdonkii strain DSM19147 but not DSM108265 was sufficient to prolong minor mismatched skin graft survival through inhibition of tumor necrosis factor production. Through metabolomic and metagenomic comparisons between DSM19147 and DSM108265, we identified candidate gene products associated with the anti-inflammatory effect of DSM19147. A onderdonkii DSM19147 can lower inflammation both at a steady state and after transplantation and may serve as an anti-inflammatory probiotic beneficial for transplant recipients.

Immune response to the mRNA COVID-19 vaccine in hemodialysis patients: cohort study.

Background: End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines. Methods: A transcriptomic analysis of the immune response to the Covid-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells (PBMCs) was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and seven days after the second dose (V2D7) using anti-Spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified six months after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response. Results: Transcriptomic analyses demonstrated differing time courses of immune responses, with predominant T cell activity in controls one week after the first vaccination dose, compared to predominant myeloid cell activity in HD at this time point. HD demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p < 0.05). Anti-spike IgG remained elevated above baseline at six months in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development. Conclusion: Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance hemodialysis subjects (HD) comparable to healthy controls (HC) and identify transcriptomic and clinical predictors of anti-Spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of end stage renal disease (ESRD). Funding: F30HD102093, F30HL151182, T32HL144909, R01HL138628This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.

Predicting Mood Disturbance Severity with Mobile Phone Keystroke Metadata: A BiAffect Digital Phenotyping Study.

BACKGROUND: Mood disorders are common and associated with significant morbidity and mortality. Better tools are needed for their diagnosis and treatment. Deeper phenotypic understanding of these disorders is integral to the development of such tools. This study is the first effort to use passively collected mobile phone keyboard activity to build deep digital phenotypes of depression and mania. OBJECTIVE: The objective of our study was to investigate the relationship between mobile phone keyboard activity and mood disturbance in subjects with bipolar disorders and to demonstrate the feasibility of using passively collected mobile phone keyboard metadata features to predict manic and depressive signs and symptoms as measured via clinician-administered rating scales. METHODS: Using a within-subject design of 8 weeks, subjects were provided a mobile phone loaded with a customized keyboard that passively collected keystroke metadata. Subjects were administered the Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) weekly. Linear mixed-effects models were created to predict HDRS and YMRS scores. The total number of keystrokes was 626,641, with a weekly average of 9791 (7861), and that of accelerometer readings was 6,660,890, with a weekly average 104,076 (68,912). RESULTS: A statistically significant mixed-effects regression model for the prediction of HDRS-17 item scores was created: conditional R2=.63, P=.01. A mixed-effects regression model for YMRS scores showed the variance accounted for by random effect was zero, and so an ordinary least squares linear regression model was created: R2=.34, P=.001. Multiple significant variables were demonstrated for each measure. CONCLUSIONS: Mood states in bipolar disorder appear to correlate with specific changes in mobile phone usage. The creation of these models provides evidence for the feasibility of using passively collected keyboard metadata to detect and monitor mood disturbances.

Opportunity missed: medical consultation, resource use, and quality of care of patients undergoing major surgery.

BACKGROUND: There is growing interest in collaborative management of surgical patients. However, few data describe how medical consultation influences quality of care or resource use. The objective of this study was to determine whether medical consultation improves care in surgical patients. METHODS: Observational cohort of patients undergoing surgery between May 1, 2004, and May 31, 2006, at a university-based hospital. The outcomes included costs, hospital length of stay, use of preventive therapies (such as perioperative beta-blockers) and clinical outcomes. RESULTS: Of 1,282 patients, 117 (9.1%) underwent a perioperative medical consultation. Consulted patients were of a similar age, sex, and race, but more frequently had an American Society of Anesthesiologists score of 4 or higher (34.2% vs 13.0%; P < .001), diabetes mellitus (29.1% vs 16.1%; P < .001), vascular disease (35.0% vs 10.6%; P < .01), or chronic renal failure (23.9% vs 5.6%; P < .001). After adjusting for severity of illness and likelihood of receiving a consultation, patients were just as likely to have a serum glucose level of less than 200 mg/dL (<11.1 mmol/L), receive perioperative beta-blockers, or receive venous thromboembolism prophylaxis. Consulted patients had a longer adjusted length of stay (12.98% longer; 95% confidence interval, 1.61%-25.61%) and higher adjusted costs (24.36% higher; 95% confidence interval, 13.54%-36.34%). Patients who had a consultation from a generalist did not receive different quality of care, but had costs and length of stay similar to nonconsulted patients. Our results may be influenced by unaccounted referral bias or severity of illness. CONCLUSIONS: Perioperative internal medicine consultation produces inconsistent effects on efficiency and quality of care in surgical patients. Modifying the consultative model may represent an opportunity to improve care.