HIV-1 DNA and Immune Activation Levels Differ for Long-Lived T-Cells in Lymph Nodes, Compared with Peripheral Blood, during Antiretroviral Therapy.

Elucidating the mechanisms underlying the persistence and location of the HIV reservoir is critical for developing cure interventions. While it has been shown that levels of T-cell activation and the size of the HIV reservoir are greater in rectal tissue and lymph nodes (LN) than in blood, the relative contributions of T-cell subsets to this anatomic difference are unknown. We measured and compared HIV-1 DNA content, expression of the T-cell activation markers CD38 and HLA-DR, and expression of the exhaustion markers programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) in naive, central memory (CM), transitional memory (TM), and effector memory (EM) CD4+ and CD8+ T-cells in paired blood and LN samples among 14 people with HIV who were receiving antiretroviral therapy. HIV-1 DNA levels, T-cell immune activation, and TIGIT expression were higher in LN than in blood, especially in CM and TM CD4+ T-cell subsets. Immune activation was significantly higher in all CD8+ T-cell subsets, and memory CD8+ T-cell subsets from LN had higher levels of PD-1 expression, compared with blood, while TIGIT expression levels were significantly lower in TM CD8+ T-cells. The differences seen in CM and TM CD4+ T-cell subsets were more pronounced among participants with CD4+ T-cell counts of <500 cells/µL within 2 years after antiretroviral therapy initiation, thus highlighting increased residual dysregulation in LN as a distinguishing feature of and a potential mechanism for individuals with suboptimal CD4+ T-cell recovery during antiretroviral therapy. IMPORTANCE 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.

Increased homeostatic cytokines and stability of HIV-infected memory CD4 T-cells identify individuals with suboptimal CD4 T-cell recovery on-ART.

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.

Whole Genome Sequence of a Treponema pallidum Strain From a Formalin-Fixed, Paraffin-Embedded Fine Needle Aspirate of a Cervical Lymph Node.

ABSTRACT: A patient with unilateral cervical lymphadenopathy suspicious for malignancy underwent a fine needle aspiration. Histology demonstrated mixed inflammatory infiltrates with abundant spirochetes. Sufficient spirochete DNA was extracted from paraffin-embedded tissue sections to obtain the near-complete genome sequence of a macrolide-resistant strain belonging to the SS14 omega strain of Treponema pallidum .

Two cases of multi-inflammatory syndrome in children (MIS-C) in adults in 2020.

BACKGROUND: Late complications and longer-lasting sequelae of COVID-19 infection in adults can occur. Cardiovascular involvement including reduced ejection fraction, coronary artery aneurysms, and pericardial involvement have been reported. Prompt recognition is the first step and secondly, these cardiovascular phenomena require an alternative set of therapeutics from the standard of care for acute COVID-19 infection. CASE PRESENTATION: Here we describe two cases that fulfill the current case definition of the recently defined multisystem inflammatory syndrome in adults (MIS-A). One patient is a 27-year-old white female and the other a 21-year-old French creole male, both without any prior medical history. Both were hospitalized and found to have significant cardiac dysfunction and treated with IVIG, high dose aspirin, and corticosteroids with resolution of their acute illnesses and cardiac sequelae. CONCLUSION: Not only does the immediate impact of this viral infection need to be addressed, but also the long-term complications that could arise if not recognized and treated promptly as seen in our two cases. Patients can develop acute cardiovascular collapse and cardiogenic shock which requires high level of care and treatment within an intensive care unit. Depending on the complications, patients may require treatment for congestive heart failure, pericarditis, or even coronary artery disease acutely with close follow up to ensure improvement or resolution.

Risk factors and epidemiology of Clostridium difficile infection in hematopoietic stem cell transplant recipients during the peritransplant period.

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.

A Case of Disseminated Mycobacterium Haemophilum in a Kidney Transplant Recipient Presenting With Subcutaneous Nodules.

INTRODUCTION: Dermatologic manifestations of diseases in solid organ transplant recipients are common due to long-term immunosuppression. CASE PRESENTATION: We present the case of a 63-year-old man with a kidney transplant who exhibited subcutaneous nodules on lower extremities, cytopenia, and asymptomatic pulmonary infiltrate. Through a skin biopsy and 16S ribosomal RNA (rRNA) sequencing, Mycobacterium haemophilum was identified. His clinical course was complicated by empyema, septic arthritis, and recurrence of his skin manifestations, despite ongoing antimicrobial treatment. DISCUSSION: This case emphasizes the challenges and potential complications associated with M haemophilum infections in solid organ transplant recipients receiving long-term immunosuppressive therapy. It highlights the importance of employing advanced diagnostic techniques when evaluating dermatologic manifestations in these patients. The patient's complex clinical course also underscores the difficulties involved in effectively addressing and managing complications that may arise even after initiating therapy.

COVID-19 Infection Outcomes and Testing Outreach Efforts Among People Living With HIV in Milwaukee, Wisconsin.

INTRODUCTION: 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 who receive care at the Froedtert & Medical College of Wisconsin Adult Infectious Disease Clinic and who had a COVID-19 test performed during May 2020 through 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: Four hundred sixty-two COVID-19 tests completed on 793 PLWH were included, with 40 (8.7%) positive tests and 422 (91.3%) negative tests on a predominantly young, male, and virally suppressed cohort. Most patients had mild to moderate COVID-19 infection (20/27, 74.07%), with 1 patient requiring hospitalization and zero deaths. Three hundred fourteen (39.59%) patients accepted outreach for COVID-19 testing; 171 were tested in our health system, with 72 of those tests occurring within 2 weeks. Outreach efforts demonstrated a statistically significant increase in COVID-19 testing (P < 0.001). CONCLUSIONS: In this largely young, male, virally suppressed cohort of PLWH, most COVID-19 co-infections were associated with mild to moderate disease severity, with 1 hospitalization and zero deaths. Individualized patient outreach efforts were associated with a significant increase in COVID-19 testing, most of which occurred after a single phone call. This outreach process could have utility in other public health arenas, though may be limited by larger patient populations.

CD4 rate of increase is preferred to CD4 threshold for predicting outcomes among virologically suppressed HIV-infected adults on antiretroviral therapy.

OBJECTIVES: Immune 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. METHODS: We 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. RESULTS: We 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 p<0.01, respectively). All four CD4 metrics showed modest predictive capacity. CONCLUSIONS: Using 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 <100 cells/µl/year to identify patients at risk for adverse events.

Characteristics and Antibiotic Use Associated With Short-Term Risk of Clostridium difficile Infection Among Hospitalized Patients.

OBJECTIVES: Polymerase chain reaction (PCR) has been shown to have an excellent sensitivity and specificity for the detection of Clostridium difficile infection (CDI). Little is known about risk factors for CDI within 14 days of an initial negative test. We sought to determine the characteristics among hospitalized patients associated with risk of short-term acquisition of CDI. METHODS: A case-control study was conducted. Cases were patients who converted from PCR negative to positive within 14 days. Each case was matched with three controls. Conditional logistic regression was used to estimate the association between patient characteristics and CDI. RESULTS: Of the 30 patients in our study who had a positive PCR within 14 days of a first negative PCR (cases), 15 (50%) occurred within 7 days of the initial test. Cases had a higher proportion of intravenous vancomycin use in the previous 8 weeks (odds ratio [OR], 3.38; 95% confidence interval [CI], 1.34-8.49) and were less likely to have recent antiviral agent use (OR, 0.30; 95% CI, 0.11-0.83) compared with controls. CONCLUSIONS: In hospitalized patients, treatment with intravenous vancomycin within the prior 8 weeks of a first negative PCR test for C difficile is a risk factor for short-term risk for hospital-acquired CDI. Repeat testing guidelines for C difficile PCR should take into consideration patients who may be at high risk for short-term acquisition of CDI.