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This study provides new insights into the contributions of different CD4 + and CD8 + T-cell subsets to the anatomic differences between LN and blood in individuals with HIV who have optimal versus suboptimal CD4 + T-cell recovery. To our knowledge, this is the first study comparing paired LN and blood CD4 + and CD8 + T-cell differentiation subsets, as well as those subsets in immunological responders versus immunological suboptimal responders.

Background - Since the beginning of the Covid-19 pandemic, the incidence and severity of Covid-19 co-infection in people living with HIV (PLWH) has been an area of investigative research. Clinic databases of PLWH provide opportunities to investigate outcomes of Covid-19 co-infection and efficacy of outreach efforts, which are integral to patient care during health crises. Methods - All PLWH over 18 years of age in the Froedtert and Medical College of Wisconsin (F&MCW) with a Covid-19 test performed between May 2020 and March 2021 were included for analysis. All patients received an individualized phone call with Covid-19 testing education and information. Automated data collection and manual chart review were used to acquire information on demographics, outreach efforts, Covid-19 testing results, and Covid-19 clinical course. Results − 462 Covid-19 tests completed on 793 PLWH at F&MCW were included, with 40 (8.7%) positive tests and 422 (91.3%) negative tests, on a predominantly male and virally suppressed cohort. Most patients had mild-moderate Covid-19 infection with one patient requiring hospitalization and zero deaths. Outreach efforts from the F&MCW infectious disease clinic were associated with a significant increase in Covid-19 testing, most of which occurred after one phone call. Conclusions - Outcomes of Covid-19 infection in this cohort support most existing data suggesting co-infection in PLWH is not associated with significantly worse outcomes than patients without HIV. An individualized approach to outreach efforts may have utility in other public health arenas, though could be limited by larger patient populations.

Clinical outcomes are inferior for individuals with HIV having suboptimal CD4 T-cell recovery during antiretroviral therapy (ART). We investigated if the levels of infection and the response to homeostatic cytokines of CD4 T-cell subsets contributed to divergent CD4 T-cell recovery and HIV reservoir during ART by studying virologically-suppressed immunologic responders (IR, achieving a CD4 cell count >500 cells/μL on or before two years after ART initiation), and virologically-suppressed suboptimal responders (ISR, did not achieve a CD4 cell count >500 cells/μL in the first two years after ART initiation). Compared to IR, ISR demonstrated higher levels of HIV-DNA in naïve, central (CM), transitional (TM), and effector (EM) memory CD4 T-cells in blood, both pre- and on-ART, and specifically in CM CD4 T-cells in LN on-ART. Furthermore, ISR had higher pre-ART plasma levels of IL-7 and IL-15, cytokines regulating T-cell homeostasis. Notably, pre-ART PD-1 and TIGIT expression levels were higher in blood CM and TM CD4 T-cells for ISR; this was associated with a significantly lower fold-changes in HIV-DNA levels between pre- and on-ART time points exclusively on CM and TM T-cell subsets, but not naïve or EM T-cells. Finally, the frequency of CM CD4 T-cells expressing PD-1 or TIGIT pre-ART as well as plasma levels of IL-7 and IL-15 predicted HIV-DNA content on-ART. Our results establish the association between infection, T-cell homeostasis, and expression of PD-1 and TIGIT in long-lived CD4 T-cell subsets prior to ART with CD4 T-cell recovery and HIV persistence on-ART., Author summary A major obstacle to curing HIV infection is our incomplete understanding of the mechanisms regulating the immunologic reconstitution of CD4 T-cells and the establishment and persistence of the latent HIV reservoir. In particular, we still do not know whether and to what extent the relative distribution of HIV infection within the various CD4 T-cell subsets influences: (i) the magnitude of the CD4 T-cell reconstitution, and (ii) the size of the persistent HIV reservoir after ART. In this study, we found that immunological suboptimal responders (ISR), people with HIV having a suboptimal CD4 T-cell recovery during ART, compared with immunological responders (IR) presented: i) higher levels of HIV-DNA in multiple CD4 T-cell subsets, and ii) higher expression of PD-1 and TIGIT exclusively on CM and TM CD4 T-cells pre-ART, indicating higher HIV reservoir maintenance. Paradoxically, we found increased plasma levels of IL-7 and IL-15 (T-cell homeostatic cytokines) be associated with suboptimal CD4 T-cell recovery during ART, which could be explained by the lack of response to these cytokines in CD4 T-cells from ISR. Altogether, these data identify a greater abundance of immune checkpoint molecules, an increased maintenance of HIV infection in long-lived CD4 T-cell subsets, and a different responsiveness to IL-7 and IL-15 as key features of and a mechanism for suboptimal CD4 T-cell recovery in ART-treated, people with HIV.

ObjectivesImmune non-responders (INR) have poor CD4 recovery and are associated with increased risk of serious events despite antiretroviral therapy (ART). A clinically relevant definition for INR is lacking.MethodsWe conducted a retrospective analysis of three large cohorts: Infectious Disease Clinic at the Atlanta Veterans Affairs Medical Center, the US Military HIV Natural History Study and Infectious Disease Program of the Grady Health System in Atlanta, Georgia. Two-stage modeling and joint model (JM) approaches were used to evaluate the association between CD4 (or CD4/CD8 ratio) slope within two years since ART initiation and a composite endpoint (AIDS, serious non-AIDS events and death) after two years of ART. We compared the predictive capacity of four CD4 count metrics (estimated CD4 slope, estimated CD4/CD8 ratio slope during two years following ART initiation and CD4 at 1 and 2 years following ART initiation) using Cox regression models.ResultsWe included 2,422 patients. Mean CD4 slope (±standard error) during two years of ART was 102 ± 2 cells/μl/year (95% confidence interval: 98-106 cells/μl/year), this increase was uniform among the three cohorts (p = 0.80). There were 267 composite events after two years on ART. Using the JM approach, a CD4 slope ≥100 cells/μL/year or CD4/CD8 ratio slope >0.1 higher rate per year were associated with lower composite endpoint rates (adjusted hazard ratio [HR] = 0.80, p = 0.04 and HR = 0.75 pConclusionsUsing a complex JM approach, CD4 slope and CD4/CD8 ratio slope the first two years after ART initiation were associated with lower rates of the composite outcome. Moreover, the uniformity observed in the mean CD4 slope regardless of the cohort suggests a common CD4 response pattern independent of age or CD4 nadir. Given the consistency observed with CD4 slope, availability and ease of interpretation, this study provides strong rationale for using CD4 gains

Background Amid growing antimicrobial resistance, there is an increasing focus on antibiotic stewardship efforts to reduce inappropriate antibiotic prescribing. In this context, novel approaches for treating infections without antibiotics are being explored. One such strategy is the use of non-steroidal anti-inflammatory drugs (NSAIDs) for uncomplicated urinary tract infections (UTIs). Therefore, we conducted a systematic review of randomized controlled trials to evaluate the rates of symptom resolution and infectious complications in adult women with uncomplicated UTIs treated with antibiotics versus NSAIDs. Methods We systematically searched PubMed, CINHAL, Scopus, Web of Science Core Collection, EMBASE, and ClinicalTrials.gov from inception until January 13, 2020, for randomized controlled trials comparing NSAIDs with antibiotics for treatment of uncomplicated UTIs in adult women. Studies comparing symptom resolution between groups were eligible. Two authors screened all studies independently and in duplicate; data were abstracted using a standardized template. Risk of bias was assessed using the Cochrane Collaboration tool. Results Five randomized trials that included 1309 women with uncomplicated UTI met inclusion criteria. Three studies (1130 patients) favored antibiotic therapy in terms of symptom resolution. Two studies (179 patients) found no difference between NSAIDs and antibiotics in terms of symptom resolution. Three studies reported rates of pyelonephritis, two of which found higher rates in patients treated with NSAIDs versus antibiotics. Between two studies that reported this outcome (747 patients), patients randomized to NSAIDs received fewer antibiotic prescriptions compared with those in the antibiotics group. Three studies were at low risk of bias, one had an unclear risk of bias, and one was at high risk of bias. Discussion For the outcomes of symptom resolution and complications in adult women with UTI, evidence favors antibiotics over NSAIDs. Prospero CRD42018114133 Electronic supplementary material The online version of this article (10.1007/s11606-020-05745-x) contains supplementary material, which is available to authorized users.

Clostridium difficile was not identified as the causative bacterial agent for antibiotic-related diarrhea until the late 1970s1-3 and is now recognized as the leading cause of infectious nosocomial (hospital-acquired) diarrhea.3,4 The median onset of symptomatic infection after colonization with toxigenic C difficile spores is typically 2 to 3 days.5 Recently, molecular testing has been recognized as an important tool for C difficile infection (CDI) diagnosis, with a sensitivity and specificity of 73% to 100% and 91% to 100%, respectively.6 Due to the high specificity of the test, most institutions using polymerase chain reaction (PCR) to diagnose CDI advocate against repeat testing within 7 days of an initial negative test.7 Short-term acquisition of CDI, meaning a positive PCR test on repeat testing after an initial negative test within 14 days, is rare, but it does occur in 1% to 4% of patients who undergo repeat testing, and the specific risk factors are unknown.7-12 Patients with short-term acquisition of CDI are exclusively inpatients since they are most likely to undergo expedited repeated testing.7,8 Since repeat PCR testing for C difficile is costly, determining which patients would likely benefit from repeat testing could be used to guide laboratory policies.13 The overall goal of this study was to determine if identifiable patient characteristics would improve the efficiency of a short-term repeat testing protocol for detecting C difficile. The objectives of this study were to determine the rate of short-term acquisition (within 14 days) of CDI after an initial negative PCR in our institution and to determine patient characteristics and antibiotic regimens associated with acquisition.

Background Hematopoietic stem cell transplant (HSCT) recipients represent a high-risk group for developing Clostridium difficile (CD) infection (CDI). We aimed to identify specific risk factors for CDI in an HSCT patient population during the peritransplant period. Methods We performed a case–control study within a cohort of HSCT patients who received a transplant from November 2010 to March 2013. Cases had a clinical presentation compatible with CDI and a positive stool sample Xpert® C. difficile test. Controls were CDI negative and matched on age, gender, and transplant type. Peritransplant period was defined as −30 days or time of stem cell mobilization maneuver to 30 days post transplant in autologous SCT or 90 days post transplant in allogeneic SCT. Results Of 781 HSCTs performed during the study period, 650 (83.2%) had a stool sample submitted for CD testing. Eight-six (13.2%) cases with CDI were identified. Most of the cases were diagnosed within a week after transplantation (median of 5 days). In adjusted analysis, prior hospitalization (odds ratio [OR]: 2.01, 95% confidence interval [CI] 1.2-3.36), prior cephalosporin administration (OR 2.72, 95% CI: 1.54-4.83), and prior chemotherapy (OR: 3.26, 95% CI: 1.92-5.5) were significantly associated with CDI. Conclusions Hospitalization, and prior antibiotic and chemotherapy use are risk factors that are not easily modifiable, which emphasizes the need to start investigating preventive or prophylactic strategies in this high-risk population.