Validation of sTREM-1 and IL-6 based algorithms for outcome prediction of COVID-19.

BACKGROUND: A prospective observational cohort study of COVID-19 patients in a single Emergency Department (ED) showed that sTREM-1- and IL-6-based algorithms were highly predictive of adverse outcome (Van Singer et al. J Allergy Clin Immunol 2021). We aim to validate the performance of these algorithms at ED presentation. METHODS: This multicentric prospective observational study of PCR-confirmed COVID-19 adult patients was conducted in the ED of three Swiss hospitals. Data of the three centers were retrospectively completed and merged. We determined the predictive accuracy of the sTREM-1-based algorithm for 30-day intubation/mortality. We also determined the performance of the IL-6-based algorithm using data from one center for 30-day oxygen requirement. RESULTS: 373 patients were included in the validation cohort, 139 (37%) in Lausanne, 93 (25%) in St.Gallen and 141 (38%) in EOC. Overall, 18% (93/373) patients died or were intubated by day 30. In Lausanne, 66% (92/139) patients required oxygen by day 30. The predictive accuracy of sTREM-1 and IL-6 were similar compared to the derivation cohort. The sTREM-1-based algorithm confirmed excellent sensitivity (90% versus 100% in the derivation cohort) and negative predictive value (94% versus 100%) for 30-day intubation/mortality. The IL-6-based algorithm performance was acceptable with a sensitivity of 85% versus 98% in the derivation cohort and a negative predictive value of 60% versus 92%. CONCLUSION: The sTREM-1 algorithm demonstrated good reproducibility. A prospective randomized controlled trial, comparing outcomes with and without the algorithm, is necessary to assess its safety and impact on hospital and ICU admission rates. The IL-6 algorithm showed acceptable validity in a single center and need additional validation before widespread implementation.

Pharmacologic Treatments and Supportive Care for Middle East Respiratory Syndrome.

Available animal and cell line models have suggested that specific therapeutics might be effective in treating Middle East respiratory syndrome (MERS). We conducted a systematic review of evidence for treatment with pharmacologic and supportive therapies. We developed a protocol and searched 5 databases for studies describing treatment of MERS and deaths in MERS patients. Risk of bias (RoB) was assessed by using ROBINS-I tool. We retrieved 3,660 unique citations; 20 observational studies met eligibility, and we studied 13 therapies. Most studies were at serious or critical RoB; no studies were at low RoB. One study, at moderate RoB, showed reduced mortality rates in severe MERS patients with extracorporeal membrane oxygenation; no other studies showed a significant lifesaving benefit to any treatment. The existing literature on treatments for MERS is observational and at moderate to critical RoB. Clinical trials are needed to guide treatment decisions.

Preparing intensive care for the next pandemic influenza.

Few viruses have shaped the course of human history more than influenza viruses. A century since the 1918-1919 Spanish influenza pandemic-the largest and deadliest influenza pandemic in recorded history-we have learned much about pandemic influenza and the origins of antigenic drift among influenza A viruses. Despite this knowledge, we remain largely underprepared for when the next major pandemic occurs.While emergency departments are likely to care for the first cases of pandemic influenza, intensive care units (ICUs) will certainly see the sickest and will likely have the most complex issues regarding resource allocation. Intensivists must therefore be prepared for the next pandemic influenza virus. Preparation requires multiple steps, including careful surveillance for new pandemics, a scalable response system to respond to surge capacity, vaccine production mechanisms, coordinated communication strategies, and stream-lined research plans for timely initiation during a pandemic. Conservative models of a large-scale influenza pandemic predict more than 170% utilization of ICU-level resources. When faced with pandemic influenza, ICUs must have a strategy for resource allocation as strain increases on the system.There are several current threats, including avian influenza A(H5N1) and A(H7N9) viruses. As humans continue to live in closer proximity to each other, travel more extensively, and interact with greater numbers of birds and livestock, the risk of emergence of the next pandemic influenza virus mounts. Now is the time to prepare and coordinate local, national, and global efforts.

The "wing-heeled" traveler.

Intoxication syndromes may be travel acquired, and are related to intentional or accidental inhalational or percutaneous exposures or ingestions. Due to their myriad clinical presentations, initial differential diagnosis of such intoxications in returned travelers is broad, and typically requires detailed history and laboratory investigations to disentangle. We herein use a case-based clinical problem solving approach to illumination of a mercury intoxication syndrome, which presented in a 48-year-old VFR traveler to Guyana. Common clinical presentations, differential diagnoses, laboratory investigations, and therapeutic interventions are discussed.

Use of an HIV-risk screening tool to identify optimal candidates for PrEP scale-up among men who have sex with men in Toronto, Canada: disconnect between objective and subjective HIV risk.

INTRODUCTION: Identifying appropriate pre-exposure prophylaxis (PrEP) candidates is a challenge in planning for the safe and effective roll-out of this strategy. We explored the use of a validated HIV risk screening tool, HIV Incidence Risk Index for Men who have Sex with Men (HIRI-MSM), to identify "optimal" candidates among MSM testing at a busy sexual health clinic's community testing sites in Toronto, Canada. METHODS: Between November 2014 and April 2015, we surveyed MSM undergoing anonymous HIV testing at community testing sites in Toronto, Canada, to quantify "optimal" candidates for scaling up PrEP roll-out, defined as being at high objective HIV risk (scoring ≥10 on the HIRI-MSM), perceiving oneself at moderate-to-high HIV risk and being willing to use PrEP. Cascades were constructed to identify barriers to broader PrEP uptake. The association between HIRI-MSM score and both willingness to use PrEP and perceived HIV risk were explored in separate multivariable logistic regression analyses. RESULTS: Of 420 respondents, 64.4% were objectively at high risk, 52.5% were willing to use PrEP and 27.2% perceived themselves at moderate-to-high HIV risk. Only 16.4% were "optimal" candidates. Higher HIRI-MSM scores were positively associated with both willingness to use PrEP (aOR=1.7 per 10 score increase, 95%CI=1.3-2.2) and moderate-to-high perceived HIV risk (aOR=1.7 per 10 score increase, 95%CI=1.2-2.3). The proportion of men who were "optimal" candidates increased to 42.9% when the objective HIV risk cut-off was changed to top quartile of HIRI-MSM scores (≥26). In our full cascade, a very low proportion (5.3%) of MSM surveyed could potentially benefit from PrEP under current conditions. The greatest barrier in the cascade was low perception of HIV risk among high-risk men, but considerable numbers were also lost in downstream cascade steps. Of men at high objective HIV risk, 68.3% did not perceive themselves to be at moderate-to-high HIV risk, 23.6% were unaware of PrEP, 40.1% were not willing to use PrEP, 47.6% lacked a family physician with whom they felt comfortable discussing sexual health, and 31.6% had no means to cover the cost of PrEP. CONCLUSIONS: A higher HIRI-MSM cut-off may be helpful for identifying candidates for PrEP scale-up. Improving engagement in the PrEP cascade will require interventions to simultaneously address multiple barriers.

Impact of CMV therapy with valganciclovir on immune activation and the HIV viral load in semen and blood: an observational clinical study.

BACKGROUND: The HIV RNA viral load (VL) in vaginal secretions and semen is an independent predictor of HIV transmission. Blood VL is associated with semen VL, and local mucosal factors, such as semen cytomegalovirus (CMV) reactivation, may play an important role. METHODS: Twenty-one HIV-CMV-coinfected, antiretroviral-naive men received 900 mg of oral valganciclovir once daily for 2 weeks in an open-label study. Blood and semen were collected at baseline, after 2 weeks of valganciclovir, and 2 months after therapy completion. The primary end point was change in semen HIV levels at 2 weeks, and the secondary end points were change in semen HIV VL at 2 months and change in semen CMV levels. RESULTS: The HIV VLs fell significantly at 2 weeks in semen (median 3.44-3.02 log10 copies/mL, P = 0.02) and blood (median 3.61-3.10 log10 copies/mL, P < 0.01) and returned to baseline after therapy completion (median 3.24 and 3.71 log10 copies/mL in semen and blood, respectively). Semen CMV levels also fell on treatment (median 2.13-1.62 log10 copies/mL, P < 0.01) and continued to fall after therapy completion (median 0.91 log10 copies/mL at week 8, P < 0.001 vs. baseline). The reduced semen CMV VL was associated with decreased semen T-cell activation and enhanced CMV-specific T-cell responses in blood; changes in the semen HIV VL were not associated with immune parameters. CONCLUSIONS: Although valganciclovir therapy was associated with reduced HIV and semen CMV levels, these results suggest that the reduced HIV VL was a direct drug effect rather than a CMV antiviral effect or CMV-associated immune alterations.

Murine Plasmodium chabaudi malaria increases mucosal immune activation and the expression of putative HIV susceptibility markers in the gut and genital mucosae.

OBJECTIVE: To evaluate if systemic murine malarial infection enhances HIV susceptibility through parasite-induced mucosal immune alterations at sites of HIV sexual exposure. BACKGROUND: Malaria and HIV have a high degree of geographical overlap and interact substantially within coinfected individuals. We used a murine model to test the hypothesis that malaria might also enhance HIV susceptibility at mucosal sites of HIV sexual exposure. METHODS: Female C57/BL6 mice were infected with Plasmodium chabaudi malaria using a standardized protocol. Blood, gastrointestinal tissues, upper and lower genital tract tissues, and iliac lymph nodes were sampled 10 days postinfection, and the expression of putative HIV susceptibility and immune activation markers on T cells was assessed by flow cytometry. RESULTS: P. chabaudi malaria increased expression of mucosal homing integrin α4ß7 on blood CD4 and CD8 T cells, and these α4ß7 T cells had significantly increased co-expression of both CCR5 and CD38. In addition, malaria increased expression of the HIV co-receptor CCR5 on CD4 T cells from the genital tract and gut mucosa as well as mucosal T-cell expression of the immune activation markers CD38, Major Histocompatibility Complex -II (MHC-II) and CD69. CONCLUSIONS: Systemic murine malarial infection induced substantial upregulation of the mucosal homing integrin α4ß7 in blood as well as gut and genital mucosal T-cell immune activation and HIV co-receptor expression. Human studies are required to confirm these murine findings and to examine whether malarial infection enhances the sexual acquisition of HIV.

Blunted IL17/IL22 and pro-inflammatory cytokine responses in the genital tract and blood of HIV-exposed, seronegative female sex workers in Kenya.

BACKGROUND: Identifying the immune correlates of reduced susceptibility to HIV remains a key goal for the HIV vaccine field, and individuals who are HIV-exposed, seronegative (HESN) may offer important clues. Reduced systemic immune activation has been described in HESN individuals. Conversely, pro-inflammatory T cell subsets, particularly CD4+ T cells producing the cytokine IL17 (Th17 cells), may represent a highly susceptible target for HIV infection after sexual exposure. Therefore, we characterized the cellular pro-inflammatory and IL17/IL22 cytokine immune milieu in the genital mucosa and blood of HESN female sex workers (FSWs). METHODS AND RESULTS: Blinded lab personnel characterized basal and mitogen-induced gene and cytokine immune responses in the cervix and blood of HESN FSWs (n = 116) and non-FSW controls (n = 17) using qPCR and ELISA. IL17 and IL22 production was significantly reduced in both the cervix and blood of HESNs, both in resting cells and after mitogen stimulation. In addition, HESN participants demonstrated blunted production of both pro-inflammatory cytokines and ß-chemokines. DISCUSSION AND CONCLUSIONS: We conclude that HIV exposure without infection was associated with blunted IL17/IL22 and pro-inflammatory responses, both systemically and at the site of mucosal HIV exposure. It will be important for further studies to examine the causal nature of the association and to define the cell subsets responsible for these differences.

Glucagon-like peptide-1 receptor activation inhibits growth and augments apoptosis in murine CT26 colon cancer cells.

Obesity, accompanying or independent of type 2 diabetes mellitus (T2DM), is associated with higher rates of malignancy. Hence, there is considerable interest in understanding whether therapies used to treat obese patients with T2DM impact cancer cell growth. Glucagon-like peptide-1 (GLP-1) is produced in enteroendocrine cells and secreted after meal ingestion. GLP-1 regulates blood glucose through multiple mechanisms, principally inhibition of glucagon and stimulation of insulin secretion. GLP-1 also exerts independent effects promoting cell growth and survival, and sustained activation of GLP-1 receptor (GLP-1R) signaling in rodent thyroid glands leads to C-cell hyperplasia and medullary thyroid cancer. Hence, whether therapies based on GLP-1R activation modify growth or survival of cancer cells is of ongoing interest. We studied the biological actions of GLP-1 in mouse CT26 colon cancer cells that express a functional GLP-1R. The GLP-1R agonist exendin (Ex)-4 (exenatide) increased intracellular cAMP levels and inhibited the activity of signaling kinases glycogen synthase kinase 3 and ERK1/2 in CT26 cells. The Ex-4-induced inactivation of glycogen synthase kinase 3, but not ERK1/2, was dependent on protein kinase A and blocked by the GLP-1R antagonist Ex(9-39). Furthermore, Ex-4 altered cell morphology, induced apoptosis, and inhibited proliferation of CT26 cells in vitro. Moreover Ex-4 decreased CT26 colony formation in soft agar and augmented apoptosis induced by irinotecan. Twice-daily treatment of CT26 tumor-bearing BALB/c mice with Ex-4 for 2 wk increased tumor apoptosis. Hence, GLP-1R activation reduces growth and survival in CT26 colon cancer cells that express the endogenous classical GLP-1R.

Sigmoid Th17 populations, the HIV latent reservoir, and microbial translocation in men on long-term antiretroviral therapy.

OBJECTIVE: Th17 cells play an important role in mucosal defence and repair and are highly susceptible to infection by HIV. Antiretroviral therapy (ART) suppresses HIV viremia and can restore CD4(+) numbers in the blood and gastrointestinal mucosa, but the resolution of systemic inflammation and gut microbial translocation is often incomplete. We hypothesized that this might relate to persistent dysregulation of gut CD4(+) Th17 subsets. METHODS: Blood and sigmoid biopsies were collected from HIV-uninfected men, chronically HIV-infected, ART-naive men, and men on effective ART for more than 4 years. Sigmoid provirus levels were assayed blind to participant status, as were CD4(+) Th17 subsets, systemic markers of microbial translocation, and cellular immune activation. RESULTS: There was minimal CD4(+) Th17 dysregulation in the blood until later stage HIV infection, but gastrointestinal Th17 depletion was apparent much earlier, along with increased plasma markers of microbial translocation. Plasma lipopolysaccharide (LPS) remained elevated despite overall normalization of sigmoid Th17 populations on long-term ART, although there was considerable interindividual variability in Th17 reconstitution. An inverse correlation was observed between plasma LPS levels and gut Th17 frequencies, and higher plasma LPS levels correlated with an increased gut HIV proviral reservoir. CONCLUSION: Sigmoid Th17 populations were preferentially depleted during HIV infection. Despite overall CD4(+) T-cell reconstitution, sigmoid Th17 frequencies after long-term ART were heterogeneous and higher frequencies were correlated with reduced microbial translocation.