Type I and Type II Interferon Coordinately Regulate Suppressive Dendritic Cell Fate and Function during Viral Persistence.

Persistent viral infections are simultaneously associated with chronic inflammation and highly potent immunosuppressive programs mediated by IL-10 and PDL1 that attenuate antiviral T cell responses. Inhibiting these suppressive signals enhances T cell function to control persistent infection; yet, the underlying signals and mechanisms that program immunosuppressive cell fates and functions are not well understood. Herein, we use lymphocytic choriomeningitis virus infection (LCMV) to demonstrate that the induction and functional programming of immunosuppressive dendritic cells (DCs) during viral persistence are separable mechanisms programmed by factors primarily considered pro-inflammatory. IFNγ first induces the de novo development of naive monocytes into DCs with immunosuppressive potential. Type I interferon (IFN-I) then directly targets these newly generated DCs to program their potent T cell immunosuppressive functions while simultaneously inhibiting conventional DCs with T cell stimulating capacity. These mechanisms of monocyte conversion are constant throughout persistent infection, establishing a system to continuously interpret and shape the immunologic environment. MyD88 signaling was required for the differentiation of suppressive DCs, whereas inhibition of stimulatory DCs was dependent on MAVS signaling, demonstrating a bifurcation in the pathogen recognition pathways that promote distinct elements of IFN-I mediated immunosuppression. Further, a similar suppressive DC origin and differentiation was also observed in Mycobacterium tuberculosis infection, HIV infection and cancer. Ultimately, targeting the underlying mechanisms that induce immunosuppression could simultaneously prevent multiple suppressive signals to further restore T cell function and control persistent infections.

The overlap of chronic obstructive pulmonary disease and obstructive sleep apnea in hospitalizations for acute exacerbation of chronic obstructive pulmonary disease.

STUDY OBJECTIVES: This study examined in-hospital outcomes for patients with both chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), also known as COPD-OSA overlap syndrome, during hospitalizations for acute exacerbation of COPD. METHODS: The National Inpatient Sample was used to examine in-hospital mortality, length of stay, costs, and utilization of supportive ventilation in patients with COPD-OSA overlap during acute exacerbation of COPD hospitalizations. A 1-to-1 matched case-control design was utilized to match patients with and without OSA. Multivariate logistic regression modeling was used to examine mortality and ventilatory support, while controlling for potentially confounding diagnoses. RESULTS: COPD-OSA overlap was associated with longer median length of stay (4 days OSA, 3 days non-OSA; P < .001), higher mean costs ($32,197 OSA, $29,011 non-OSA; P < .001), increased utilization of noninvasive positive-pressure ventilation (13.92% OSA, 6.78% non-OSA; P < .001), and when required for greater than 96 hours, earlier initiation of mechanical ventilation (2.53 days OSA, 3.35 days non-OSA; P = .001). However, COPD-OSA overlap was associated with reduced mortality (0.81% OSA, 1.05% non-OSA; P < .001). These differences in mortality (adjusted odds ratio: 0.650; 95% confidence interval: 0.624-0.678) and noninvasive positive-pressure ventilation usage (adjusted odds ratio: 1.998; 95% confidence interval: 1.970-2.026) remained when adjusted for confounders. CONCLUSIONS: Patients with COPD-OSA overlap have higher utilization of supportive ventilation and longer length of stay during acute exacerbation of COPD hospitalizations, contributing to higher costs. The diagnosis of OSA is associated with reduced mortality in these hospitalizations, which may be related to greater utilization of supportive ventilation when OSA is recognized. CITATION: De la Fuente JRO, Greenberg P, Sunderram J. The overlap of chronic obstructive pulmonary disease and obstructive sleep apnea in hospitalizations for acute exacerbation of chronic obstructive pulmonary disease. J Clin Sleep Med. 2024;20(6):863-870.

Necrotizing Soft Tissue Infection and Perforated Viscus After Suction-Assisted Lipectomy.

Suction-assisted lipectomy (SAL) is a commonly performed cosmetic surgery in the United States and has been steadily increasing in popularity over the past few years. As more of these surgeries are performed, several rare but life-threatening complications are being recognized, including necrotizing soft tissue infections (NSTIs). NSTIs require rapid surgical intervention but can be challenging to diagnose, as skin manifestations may be difficult to differentiate from normal post-SAL changes. We present a case of a 44-year-old female who presented with signs of septic shock after SAL of her abdomen and back. She was ultimately found to have an NSTI of her abdominal wall, likely due to perforated viscus that occurred as a complication of her procedure. This case demonstrates the significance of recognizing NSTIs as a potential complication of SAL in ill-appearing patients with non-specific symptoms and septic shock.

Overcoming CD4 Th1 Cell Fate Restrictions to Sustain Antiviral CD8 T Cells and Control Persistent Virus Infection.

Viral persistence specifically inhibits CD4 Th1 responses and promotes Tfh immunity, but the mechanisms that suppress Th1 cells and the disease consequences of their loss are unclear. Here, we demonstrate that the loss of CD4 Th1 cells specifically leads to progressive CD8 T cell decline and dysfunction during viral persistence. Therapeutically reconstituting CD4 Th1 cells restored CD4 T cell polyfunctionality, enhanced antiviral CD8 T cell numbers and function, and enabled viral control. Mechanistically, combined interaction of PD-L1 and IL-10 by suppressive dendritic cell subsets inhibited new CD4 Th1 cells in both acute and persistent virus infection, demonstrating an unrecognized suppressive function for PD-L1 in virus infection. Thus, the loss of CD4 Th1 cells is a key event leading to progressive CD8 T cell demise during viral persistence with important implications for restoring antiviral CD8 T cell immunity to control persistent viral infection.