In sepsis and trauma, pathogens and injured tissue provoke a systemic inflammatory reaction which can lead to overwhelming inflammation. Concurrent with the innate hyperinflammatory response is adaptive immune suppression that can become chronic. A current key issue today is that patients who undergo intensive medical care after sepsis or trauma have a high mortality rate after being discharged. This high mortality is thought to be associated with persistent immunosuppression. Knowledge about the pathophysiology leading to this state remains fragmented. Immunosuppressive cytokines play an essential role in mediating and upholding immunosuppression in these patients. Specifically, the cytokines Interleukin-10 (IL-10), Transforming Growth Factor-β (TGF-β) and Thymic stromal lymphopoietin (TSLP) are reported to have potent immunosuppressive capacities. Here, we review their ability to suppress inflammation, their dynamics in sepsis and trauma and what drives the pathologic release of these cytokines. They do exert paradoxical effects under certain conditions, which makes it necessary to evaluate their functions in the context of dynamic changes post-sepsis and trauma. Several drugs modulating their functions are currently in clinical trials in the treatment of other pathologies. We provide an overview of the current literature on the effects of IL-10, TGF-β and TSLP in sepsis and trauma and suggest therapeutic approaches for their modulation.

Persistent Inflammation, Immune Suppression, and Catabolism Syndrome (PICS) is a disease state affecting patients who have a prolonged recovery after the acute phase of a large inflammatory insult. Trauma and sepsis are two pathologies after which such an insult evolves. In this review, we will focus on the key clinical determinants of PICS: Immunosuppression and cellular dysfunction. Currently, relevant immunosuppressive functions have been attributed to both innate and adaptive immune cells. However, there are significant gaps in our knowledge, as for trauma and sepsis the immunosuppressive functions of these cells have mostly been described in acute phase of inflammation so far, and their clinical relevance for the development of prolonged immunosuppression is mostly unknown. It is suggested that the initial immune imbalance determines the development of PCIS. Additionally, it remains unclear what distinguishes the onset of immune dysfunction in trauma and sepsis and how this drives immunosuppression in these cells. In this review, we will discuss how regulatory T cells (Tregs), innate lymphoid cells, natural killer T cells (NKT cells), TCR-a CD4 À CD8 À doublenegative Tcells (DN Tcells), and B cells can contribute to the development of post-traumatic and septic immunosuppression. Altogether, we seek to fill a gap in the understanding of the contribution of lymphocyte immunosuppression and dysfunction to the development of chronic immune disbalance. Further, we will provide an overview of promising diagnostic and therapeutic interventions, whose potential to overcome the detrimental immunosuppression after trauma and sepsis is currently being tested.

Objectives We set out to examine the prevalence and persistence of mutations conferring high-level nonnucleoside reverse transcriptase (NNRTI)-resistance in a cohort of HIV-infected children who had failed prophylaxis to prevent mother-to-child-transmission (PMTCT). Design A prospective observational cohort study at the Pediatric HIV Clinic at Kalafong Provincial Tertiary Hospital in Pretoria, South Africa. Methods Children referred for initiation of antiretroviral therapy (ART) were enrolled from July 2010 through February 2013. HIV drug resistance testing was performed using the oligonucleotide ligation assay (OLA) on dried blood spots (DBS) collected at enrolment and monthly follow-up visits for 2 years. Results South African children who failed HIV-prophylaxis had a high prevalence of NNRTI-resistant HIV (46/88; 52%). Among children with NNRTI-resistance, the frequency of the predominant resistant variant in each child’s HIV-quasispecies was high (median 96%) at study entry (median age 7.5 months), and in 26 out of 27 followed a median of 13 months persisted at a high frequency (median 89%). Conclusion Our finding that infants who fail HIV-prophylaxis frequently have long-lived NNRTI-resistant HIV suggests that resistance will likely persist through 36 months of age, when children qualify for NNRTI-based ART. These children may benefit from HIV drug resistance testing to guide selection of their treatment.

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Background: Sepsis is defined as a dysregulated host response to infection, resulting in life-threatening organ dysfunction. It is now understood that this dysregulation not only constitutes excessive inflammation, but also sustained immune suppression. Immune-modulatory therapies thus have great potential for novel sepsis therapies. Here, we provide a review of biomarkers and functional assays designed to immunologically stage patients with sepsis as well as therapies designed to alter the innate and adaptive immune systems of patients with sepsis beneficially. Methods: A search of PubMed/MEDLINE and clinicaltrials.gov was performed between October 1, 2019 and December 22, 2019 using search terms such as ''sepsis immunotherapy,'' ''sepsis biomarkers,'' ''sepsis clinical trials,'' and variations thereof. Results: Despite more than 30 years of research, there is still no Food and Drug Administration (FDA)-cleared biomarker that has proven to be effective in either identifying patients with sepsis who are at an increased risk of adverse outcomes or responsive to specific interventions. Similarly, past clinical trials investigating new treatment strategies have rarely stratified patients with sepsis. Overall, the results of these trials have been disappointing. Novel efforts to properly gauge an individual patient's immune response and choose an appropriate immunomodulatory agent based on the results are underway. Conclusion: Our evolving understanding of the different mechanisms perturbing immune homeostasis during sepsis strongly suggests that future successes will depend on finding the right therapy for the right patient and administering it at the right time. For such a personalized medicine approach, novel biomarkers and functional assays to properly stage the patient with sepsis will be crucial. The growing repertoire of immunomodulatory agents at our disposal, as well as re-appraisal of agents that have already been tested in unstratified cohorts of patients with sepsis, may finally translate into successful treatment strategies for sepsis.

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