Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that is currently causing a pandemic and has been termed coronavirus disease (COVID-19). The elderly or those with ...preexisting conditions like diabetes, hypertension, coronary heart disease, chronic obstructive pulmonary disease, cerebrovascular disease, or kidney dysfunction are more likely to develop severe cases when infected. Patients with COVID-19 admitted to the ICU have higher mortality than non-ICU patients. Critical illness has consistently posed a challenge not only in terms of mortality but also in regard to long-term outcomes of survivors. Patients who survive acute critical illness including, but not limited to, pulmonary and systemic insults associated with acute respiratory distress syndrome, pneumonia, systemic inflammation, and mechanical ventilation, will likely suffer from post-ICU syndrome, a phenomenon of cognitive, psychiatric, and/or physical disability after treatment in the ICU. Post-ICU morbidity and mortality continue to be a cause for concern when considering large-scale studies showing 12-month mortality risks of 11.8-21%. Previous studies have demonstrated that multiple mechanisms, including cytokine release, mitochondrial dysfunction, and even amyloids, may lead to end-organ dysfunction in patients. We hypothesize that COVID-19 infection will lead to post-ICU syndrome via potentially similar mechanisms as other chronic critical illnesses and cause long-term morbidity and mortality in patients. We consider a variety of mechanisms and questions that not only consider the short-term impact of the COVID-19 pandemic but its long-term effects that may not yet be imagined.
Trauma is the leading cause of death and disability in patients aged 1-46 y. Severely injured patients experience considerable blood loss and hemorrhagic shock requiring treatment with massive ...transfusion of red blood cells (RBCs). Preclinical and retrospective human studies in trauma patients have suggested that poorer therapeutic efficacy, increased severity of organ injury, and increased bacterial infection are associated with transfusion of large volumes of stored RBCs, although the mechanisms are not fully understood.
We developed a murine model of trauma hemorrhage (TH) followed by resuscitation with plasma and leukoreduced RBCs (in a 1:1 ratio) that were banked for 0 (fresh) or 14 (stored) days. Two days later, lungs were infected with Pseudomonas aeruginosa K-strain (PAK). Resuscitation with stored RBCs significantly increased the severity of lung injury caused by P. aeruginosa, as demonstrated by higher mortality (median survival 35 h for fresh RBC group and 8 h for stored RBC group; p < 0.001), increased pulmonary edema (mean 95% CI 106.4 μl 88.5-124.3 for fresh RBCs and 192.5 μl 140.9-244.0 for stored RBCs; p = 0.003), and higher bacterial numbers in the lung (mean 95% CI 1.2 × 10(7) -1.0 × 10(7) to 2.5 × 10(7) for fresh RBCs and 3.6 × 10(7) 2.5 × 10(7) to 4.7 × 10(7) for stored RBCs; p = 0.014). The mechanism underlying this increased infection susceptibility and severity was free-heme-dependent, as recombinant hemopexin or pharmacological inhibition or genetic deletion of toll-like receptor 4 (TLR4) during TH and resuscitation completely prevented P. aeruginosa-induced mortality after stored RBC transfusion (p < 0.001 for all groups relative to stored RBC group). Evidence from studies transfusing fresh and stored RBCs mixed with stored and fresh RBC supernatants, respectively, indicated that heme arising both during storage and from RBC hemolysis post-resuscitation plays a role in increased mortality after PAK (p < 0.001). Heme also increased endothelial permeability and inhibited macrophage-dependent phagocytosis in cultured cells. Stored RBCs also increased circulating high mobility group box 1 (HMGB1; mean 95% CI 15.4 ng/ml 6.7-24.0 for fresh RBCs and 50.3 ng/ml 12.3-88.2 for stored RBCs), and anti-HMGB1 blocking antibody protected against PAK-induced mortality in vivo (p = 0.001) and restored macrophage-dependent phagocytosis of P. aeruginosa in vitro. Finally, we showed that TH patients, admitted to the University of Alabama at Birmingham ER between 1 January 2015 and 30 April 2016 (n = 50), received high micromolar-millimolar levels of heme proportional to the number of units transfused, sufficient to overwhelm endogenous hemopexin levels early after TH and resuscitation. Limitations of the study include lack of assessment of temporal changes in different products of hemolysis after resuscitation and the small sample size precluding testing of associations between heme levels and adverse outcomes in resuscitated TH patients.
We provide evidence that large volume resuscitation with stored blood, compared to fresh blood, in mice increases mortality from subsequent pneumonia, which occurs via mechanisms sensitive to hemopexin and TLR4 and HMGB1 inhibition.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Bacterial pneumonia and sepsis are both common causes of end-organ dysfunction, especially in immunocompromised and critically ill patients. Pre-clinical data demonstrate that bacterial pneumonia and ...sepsis elicit the production of cytotoxic tau and amyloids from pulmonary endothelial cells, which cause lung and brain injury in naïve animal subjects, independent of the primary infection. The contribution of infection-elicited cytotoxic tau and amyloids to end-organ dysfunction has not been examined in the clinical setting. We hypothesized that cytotoxic tau and amyloids are present in the bronchoalveolar lavage fluid of critically ill patients with bacterial pneumonia and that these tau/amyloids are associated with end-organ dysfunction.
Bacterial culture-positive and culture-negative mechanically ventilated patients were recruited into a prospective, exploratory observational study. Levels of tau and Aβ42 in, and cytotoxicity of, the bronchoalveolar lavage fluid were measured. Cytotoxic tau and amyloid concentrations were examined in comparison with patient clinical characteristics, including measures of end-organ dysfunction.
Tau and Aβ42 were increased in culture-positive patients (n = 49) compared to culture-negative patients (n = 50), independent of the causative bacterial organism. The mean age of patients was 52.1 ± 16.72 years old in the culture-positive group and 52.78 ± 18.18 years old in the culture-negative group. Males comprised 65.3% of the culture-positive group and 56% of the culture-negative group. Caucasian culture-positive patients had increased tau, boiled tau, and Aβ42 compared to both Caucasian and minority culture-negative patients. The increase in cytotoxins was most evident in males of all ages, and their presence was associated with end-organ dysfunction.
Bacterial infection promotes the generation of cytotoxic tau and Aβ42 within the lung, and these cytotoxins contribute to end-organ dysfunction among critically ill patients. This work illuminates an unappreciated mechanism of injury in critical illness.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The protein C system plays an active role in modulating severe systemic inflammatory processes such as sepsis, trauma, and acute respiratory distress syndrome (ARDS) via its anticoagulant and ...anti-inflammatory properties. Plasma levels of activated protein C (aPC) are lower than normal in acute inflammation in humans, except early after severe trauma when high plasma levels of aPC may play a mechanistic role in the development of posttraumatic coagulopathy. Thus, following positive results of preclinical studies, a clinical trial (PROWESS) with high continuous doses of recombinant human aPC given for 4 days demonstrated a survival benefit in patients with severe sepsis. This result was not confirmed by subsequent clinical trials, including the recently published PROWESS-SHOCK trial in patients with septic shock and a phase II trial with patients with nonseptic ARDS. A possible explanation for the major difference in outcome between PROWESS and PROWESS-SHOCK trials is that lung-protective ventilation was used for the patients included in the recent PROWESS-SHOCK, but not in the original PROWESS trial. Since up to 75% of sepsis originates from the lung, aPC treatment may not have added enough to the beneficial effect of lung-protective ventilation to show lower mortality. Thus whether aPC will continue to be used to modulate the acute inflammatory response in humans remains uncertain. Because recombinant human aPC has been withdrawn from the market, a better understanding of the complex interactions between coagulation and inflammation is needed before considering the development of new drugs that modulate both coagulation and acute inflammation in humans.
Retrospective analysis of 256 patients with aSAH identified that 34.7% had systolic dysfunction based on transthoracic echocardiography within 72 h of admission. Statistical analysis found a ...correlation between total leukocytes, neutrophils, monocytes, and reduced systolic function, whereas only increased monocytes were predictive of hyperdynamic function. Source of Support Funding was provided by GM127584 and GM127584-S1 to B.M.W. Conflicts of interest The authors declare that they have no conflict of interest.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Lung endothelia in the arteries, capillaries, and veins are heterogeneous in structure and function. Lung capillaries in particular represent a unique vascular niche, with a thin yet highly ...restrictive alveolar-capillary barrier that optimizes gas exchange. Capillary endothelium surveys the blood while simultaneously interpreting cues initiated within the alveolus and communicated via immediately adjacent type I and type II epithelial cells, fibroblasts, and pericytes. This cell-cell communication is necessary to coordinate the immune response to lower respiratory tract infection. Recent discoveries identify an important role for the microtubule-associated protein tau that is expressed in lung capillary endothelia in the host-pathogen interaction. This endothelial tau stabilizes microtubules necessary for barrier integrity, yet infection drives production of cytotoxic tau variants that are released into the airways and circulation, where they contribute to end-organ dysfunction. Similarly, beta-amyloid is produced during infection. Beta-amyloid has antimicrobial activity, but during infection it can acquire cytotoxic activity that is deleterious to the host. The production and function of these cytotoxic tau and amyloid variants are the subject of this review. Lung-derived cytotoxic tau and amyloid variants are a recently discovered mechanism of end-organ dysfunction, including neurocognitive dysfunction, during and in the aftermath of infection.
is an opportunistic pathogen that causes serious infections and hospital-acquired pneumonia in immunocompromised patients.
accounts for up to 20% of all cases of hospital-acquired pneumonia, with an ...attributable mortality rate of ~30-40%. The poor clinical outcome of
-induced pneumonia is ascribed to its ability to disrupt lung barrier integrity, leading to the development of lung edema and bacteremia. Airway epithelial and endothelial cells are important architecture blocks that protect the lung from invading pathogens.
produces a number of virulence factors that can modulate barrier function, directly or indirectly, through exploiting cytoskeleton networks and intercellular junctional complexes in eukaryotic cells. This review summarizes the current knowledge on
virulence factors, their effects on the regulation of the cytoskeletal network and associated components, and molecular mechanisms regulating barrier function in airway epithelial and endothelial cells. A better understanding of these processes will help to lay the foundation for new therapeutic approaches against
-induced pneumonia.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Decrease of plasma activity of ADAMTS13, a metalloenzyme that cleaves von Willebrand factor (VWF) and prevents adhesion and aggregation of platelets, has been reported early after onset of ...systemic inflammation resulting from infections and after severe trauma. Here, we determined whether trauma-induced systemic (sterile) inflammation would be associated with a reduction of plasma ADAMTS13 activity in paediatric patients and its association with disease severity and outcome. Paediatric patients (
n
= 106) with severe trauma at a level 1 paediatric trauma centre between 2014 and 2016 were prospectively enrolled. Blood samples were collected upon arrival and at 24 hours and analysed for plasma levels of ADAMTS13 activity, VWF antigen, collagen binding activity, human neutrophil peptides (HNP) 1–3, coagulation abnormalities, endothelial glycocalyx damage and clinical outcome. Plasma samples were also collected for similar measurements from 52 healthy paediatric controls who underwent elective minor surgery. The median age of patients was 9 years with 81% sustaining blunt trauma. The median injury severity score was 22 and the mortality rate was 11%. Plasma levels of ADAMTS13 activity were significantly lower and plasma levels of VWF antigen and HNP 1–3 proteins were significantly higher for paediatric trauma patients on admission and at 24 hours when compared with controls. Finally, the lowest plasma ADAMTS13 activity was found in patients who died from their injuries. We conclude that relative plasma deficiency of ADAMTS13 activity may be associated with more severe traumatic injury, significant endothelial glycocalyx damage, coagulation abnormalities and mortality after severe trauma in paediatric patients.
ABSTRACTPatients with nosocomial pneumonia exhibit elevated levels of neurotoxic amyloid and tau proteins in the cerebrospinal fluid (CSF). In vitro studies indicate that pulmonary endothelium ...infected with clinical isolates of either Pseudomonas aeruginosa, Klebsiella pneumoniae, or Staphylococcus aureus produces and releases cytotoxic amyloid and tau proteins. However, the effects of the pulmonary endothelium‐derived amyloid and tau proteins on brain function have not been elucidated. Here, we show that P. aeruginosa infection elicits accumulation of detergent insoluble tau protein in the mouse brain and inhibits synaptic plasticity. Mice receiving endothelium‐derived amyloid and tau proteins via intracerebroventricular injection exhibit a learning and memory deficit in object recognition, fear conditioning, and Morris water maze studies. We compared endothelial supernatants obtained after the endothelia were infected with P. aeruginosa possessing an intact P. aeruginosa isolated from patient 103 (PA103) supernatant or defective mutant strain of P. aeruginosa lacking a functional type 3 secretion system needle tip complex (ΔPcrV) supernatant type 3 secretion system. Whereas the PA103 supernatant impaired working memory, the ΔPcrV supernatant had no effect. Immunodepleting amyloid or tau proteins from the PA103 supernatant with the A11 or T22 antibodies, respectively, overtly rescued working memory. Recordings from hippocampal slices treated with endothelial supernatants or CSF from patients with or without nosocomial pneumonia indicated that endothelium‐derived neurotoxins disrupted the postsynaptic synaptic response. Taken together, these results establish a plausible mechanism for the neurologic sequelae consequent to nosocomial bacterial pneumonia.—Balczon, R., Pittet, J.‐F., Wagener, B. M., Moser, S. A., Voth, S., Vorhees, C. V., Williams, M. T., Bridges, J. P., Alvarez, D. F., Koloteva, A., Xu, Y., Zha, X.‐M., Audia, J. P., Stevens, T., Lin, M. T. Infection‐induced endothelial amyloids impair memory. FASEB J. 33, 10300–10314 (2019). www.fasebj.org
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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