Lymphocyte HVEM/BTLA co-expression after critical illness demonstrates severity indiscriminate upregulation, impacting critical illness-induced immunosuppression.

Introduction: The co-regulatory molecule, HVEM, can stimulate or inhibit immune function, but when co-expressed with BTLA, forms an inert complex preventing signaling. Altered HVEM or BTLA expression, separately have been associated with increased nosocomial infections in critical illness. Given that severe injury induces immunosuppression, we hypothesized that varying severity of shock and sepsis in murine models and critically ill patients would induce variable increases in HVEM/BTLA leukocyte co-expression. Methods: In this study, varying severities of murine models of critical illness were utilized to explore HVEM+BTLA+ co-expression in the thymic and splenic immune compartments, while circulating blood lymphocytes from critically ill patients were also assessed for HVEM+BTLA+ co-expression. Results: Higher severity murine models resulted in minimal change in HVEM+BTLA+ co-expression, while the lower severity model demonstrated increased HVEM+BTLA+ co-expression on thymic and splenic CD4+ lymphocytes and splenic B220+ lymphocytes at the 48-hour time point. Patients demonstrated increased co-expression of HVEM+BTLA+ on CD3+ lymphocytes compared to controls, as well as CD3+Ki67- lymphocytes. Both L-CLP 48hr mice and critically ill patients demonstrated significant increases in TNF-α. Discussion: While HVEM increased on leukocytes after critical illness in mice and patients, changes in co-expression did not relate to degree of injury severity of murine model. Rather, co-expression increases were seen at later time points in lower severity models, suggesting this mechanism evolves temporally. Increased co-expression on CD3+ lymphocytes in patients on non-proliferating cells, and associated TNF-α level increases, suggest post-critical illness co-expression does associate with developing immune suppression.

How many tests does it take? Minimizing preoperative testing prior to surgical placement of gastrostomy tubes in children.

BACKGROUND: Gastrostomy tubes (GTs) provide life-saving enteral access for children. Although upper gastrointestinal (UGI) series and impedance studies (ISs) detect gastroesophageal reflux disease (GERD) or malrotation, their benefit for preoperative evaluation of asymptomatic patients requiring GT placement is controversial. This study investigated the value of routine preoperative testing and whether specific patient characteristics could guide the selective use of these studies. METHODS: The charts of children who underwent GT placement from 2003 to 2019 were reviewed retrospectively. Demographics, preoperative evaluation, and postoperative course were evaluated. RESULTS: Three hundred forty-three patients underwent GT placement, 61% with preoperative testing. Seven of 190 UGI (4%) series demonstrated malrotation, and 39 of 141 (28%) ISs revealed severe GERD. Although all malrotations were surgically addressed, only 59% (23/39) of IS-proven GERD cases prompted simultaneous fundoplication. Age <1 year was associated with a positive UGI series (6.7% positive vs 1.0%; P < 0.05), but no other patient characteristics were associated with either positive UGI series or IS. Elimination of the 96% of UGI series that did not alter care represented a cost savings of $89,487-$229,665 and avoided the radiation exposure from testing; elimination of the 84% of ISs that did not alter eventual treatment would have saved $127,776-$266,563. CONCLUSION: Routine preoperative evaluation with UGI series and IS can increase healthcare costs without substantially altering care. The only patients potentially benefiting from routine UGI series were <1 year old. Instead, a targeted, symptom-based preoperative evaluation may streamline the process by decreasing preoperative testing and minimizing cost and radiation exposure.

Adding Infectious Insult to Traumatic Injury: The Impact of Infectious Complications in End-of-Life Decision Making.

Background: Trauma increases the risk for infection, but it is unknown how infection affects goals-of-care (GOC) decision making. We sought to determine how infections impact transition to comfort measures only (CMO), hypothesizing that infectious complications would expedite withdrawal of life-sustaining treatment (WOLST). Patients and Methods: We performed a retrospective review at a level-one trauma center over two years for adult patients without pre-existing advance directives who were made CMO with length of stay longer than one day. Demographics, injuries, and hospital course including infections and the GOC timeline were collected. Patients were divided on the basis of infection development, defined as an infectious complication requiring antibiotics or more invasive intervention, with subgroup analysis comparing those with single versus multiple infections. The primary end point was time to death or discharge. Results: Two hundred thirty-two patients met inclusion criteria and 72 developed an infection. Pneumonia was the most common infection (53.8%). Although those in the infection group had no substantial difference in demographics or comorbidities, they had higher emergency department Glasgow Coma Scale (GCS; 14 vs. 13), lower rate of head injury (28.6 vs. 49%), and higher time to death or discharge (12 vs. 2 days). Goals-of-care discussions were initiated later based on time to first family meeting (7 vs. 1 days), most occurring after the first infection. Subsequent analysis showed that versus those with a single infection (n = 38), those with multiple infections (n = 34) had a higher time to death or discharge (16.5 vs. 10.5 days) despite no difference in demographics, comorbidities, or trauma severity. Time to first family meeting was longer (8.5 vs. 4.5 days) with most occurring after the first infection. Conclusions: We did not find that development of an infection shortens time to WOLST. The increased time to death or discharge in the setting of multiple infections and similar patient populations may be a marker of provider approach to GOC plus family beliefs. Infectious complications play an uncertain role in end-of-life discussions after trauma.

Emerging therapeutic targets for sepsis.

Introduction: Sepsis is characterized by a dysregulated host response to infection. Sepsis-associated morbidity/mortality demands concerted research efforts toward therapeutic interventions which are reliable, broadly effective, and etiologically based. More intensive and extensive investigations on alterations in cellular signaling pathways, gene targeting as a means of modifying the characteristic hyper and/or hypo-immune responses, prevention through optimization of the microbiome, and the molecular pathways underlying the septic immune response could improve outcomes.] Areas covered: The authors discuss key experimental mammalian models and clinical trials. They provide an evaluation of evolving therapeutics in sepsis and how they have built upon past and current treatments. Relevant literature was derived from a PubMed search spanning 1987-2020.Expert opinion: Given the complex nature of sepsis and the elicited immune response, it is not surprising that a single cure-all therapeutic intervention, which is capable of effectively and reliably improving patient outcomes has failed to emerge. Innovative approaches seek to address not only the disease process but modify underlying patient factors. A true improvement in sepsis-associated morbidity/mortality will require a combination of unique therapeutic modalities.

SHP2 inhibitor PHPS1 ameliorates acute kidney injury by Erk1/2-STAT3 signaling in a combined murine hemorrhage followed by septic challenge model.

BACKGROUND: Hypovolemic shock and septic challenge are two major causes of acute kidney injury (AKI) in the clinic setting. Src homology 2 domain-containing phosphatase 2 (SHP2) is one of the major protein phosphatase tyrosine phosphatase (PTPs), which play a significant role in maintaining immunological homeostasis by regulating many facets of immune cell signaling. In this study, we explored whether SHP2 signaling contributed to development of AKI sequential hemorrhage (Hem) and cecal ligation and puncture (CLP) and whether inactivation of SHP2 through administration of its selective inhibitor, phenylhydrazonopyrazolone sulfonate 1 (PHPS1), attenuated this injury. METHODS: Male C57BL/6 mice were subjected to Hem (a "priming" insult) followed by CLP or sham-Hem plus sham-CLP (S/S) as controls. Samples of blood and kidney were harvested at 24 h post CLP. The expression of neutrophil gelatinase-associated lipocalin (NGAL), high mobility group box 1 (HMGB1), caspase3 as well as SHP2:phospho-SHP2, extracellular-regulated kinase (Erk1/2): phospho-Erk1/2, and signal transducer and activator of transcription 3 (STAT3):phospho-STAT3 protein in kidney tissues were detected by Western blotting. The levels of creatinine (Cre) and blood urea nitrogen (BUN) in serum were measured according to the manufacturer's instructions. Blood inflammatory cytokine/chemokine levels were detected by ELISA. RESULTS: We found that indices of kidney injury, including levels of BUN, Cre and NGAL as well as histopathologic changes, were significantly increased after Hem/CLP in comparison with that in the S/S group. Furthermore, Hem/CLP resulted in elevated serum levels of inflammatory cytokines/chemokines, and induced increased levels of HMGB1, SHP2:phospho-SHP2, Erk1/2:phospho-Erk1/2, and STAT3:phospho-STAT3 protein expression in the kidney. Treatment with PHPS1 markedly attenuated these Hem/CLP-induced changes. CONCLUSIONS: In conclusion, our data indicate that SHP2 inhibition attenuates AKI induced by our double-hit/sequential insult model of Hem/CLP and that this protective action may be attributable to its ability to mitigate activation of the Erk1/2 and STAT3 signaling pathway. We believe this is a potentially important finding with clinical implications warranting further investigation.