Nanotools for Sepsis Diagnosis and Treatment.

Sepsis is one of the leading causes of death worldwide with high mortality rates and a pathological complexity hindering early and accurate diagnosis. Today, laboratory culture tests are the epitome of pathogen recognition in sepsis. However, their consistency remains an issue of controversy with false negative results often observed. Clinically used blood markers, C reactive protein (CRP) and procalcitonin (PCT) are indicators of an acute-phase response and thus lack specificity, offering limited diagnostic efficacy. In addition to poor diagnosis, inefficient drug delivery and the increasing prevalence of antibiotic-resistant microorganisms constitute significant barriers in antibiotic stewardship and impede effective therapy. These challenges have prompted the exploration for alternative strategies that pursue accurate diagnosis and effective treatment. Nanomaterials are examined for both diagnostic and therapeutic purposes in sepsis. The nanoparticle (NP)-enabled capture of sepsis causative agents and/or sepsis biomarkers in biofluids can revolutionize sepsis diagnosis. From the therapeutic point of view, currently existing nanoscale drug delivery systems have proven to be excellent allies in targeted therapy, while many other nanotherapeutic applications are envisioned. Herein, the most relevant applications of nanomedicine for the diagnosis, prognosis, and treatment of sepsis is reviewed, providing a critical assessment of their potentiality for clinical translation.

The challenge of recognising sepsis: Future nanotechnology solutions.

The urgent need to start anti-infective therapeutic interventions in suspected sepsis, and the lack of specific time-critical diagnostic information often lead to the widespread administration of broad-spectrum antimicrobial therapies, increasing the risk of unwanted patient harms and contributing to rising pathogen antimicrobial resistance. Nanotechnology, which involves engineering at the nanoscale, allows for the bespoke development of diagnostic solutions with multi-functionality and high sensitivity that has the potential to help provide time-critical information to make more accurate diagnoses and treatment decisions for sepsis. Nanotechnologies also have the potential to improve upon the current strategies used for novel biomarker discovery. Here we describe some of the current limitations to identifying sepsis and explore the potential role for nanotechnology solutions.

Protein corona fingerprinting to differentiate sepsis from non-infectious systemic inflammation.

Rapid and accurate diagnosis of sepsis remains clinically challenging. The lack of specific biomarkers that can differentiate sepsis from non-infectious systemic inflammatory diseases often leads to excessive antibiotic treatment. Novel diagnostic tests are urgently needed to rapidly and accurately diagnose sepsis and enable effective treatment. Despite investment in cutting-edge technologies available today, the discovery of disease-specific biomarkers in blood remains extremely difficult. The highly dynamic environment of plasma restricts access to vital diagnostic information that can be obtained by proteomic analysis. Here, we employed clinically used lipid-based nanoparticles (AmBisome®) as an enrichment platform to analyze the human plasma proteome in the setting of sepsis. We exploited the spontaneous interaction of plasma proteins with nanoparticles (NPs) once in contact, called the 'protein corona', to discover previously unknown disease-specific biomarkers for sepsis diagnosis. Plasma samples obtained from non-infectious acute systemic inflammation controls and sepsis patients were incubated ex vivo with AmBisome® liposomes, and the resultant protein coronas were thoroughly characterised and compared by mass spectrometry (MS)-based proteomics. Our results demonstrate that the proposed nanoparticle enrichment technology enabled the discovery of 67 potential biomarker proteins that could reproducibly differentiate non-infectious acute systemic inflammation from sepsis. This study provides proof-of-concept evidence that nanoscale-based 'omics' enrichment technologies have the potential to substantially improve plasma proteomics analysis and to uncover novel biomarkers in a challenging clinical setting.

Biomarker-guided antibiotic cessation in sepsis: evidence and future challenges.

Sepsis is a medical emergency, which requires the initiation of broad-spectrum antimicrobial agents as early as possible. In the absence of positive microbiological cultures providing targeted antimicrobial advice, broad-spectrum antibiotics are commonly continued until there is clinical evidence of infection resolution. With an absence of robust evidence to inform when it is safe to stop antimicrobial agents in sepsis, the duration of antimicrobial courses may be longer than is required. Prolonged courses of potent broad-spectrum antimicrobials increase the risk of adverse drug events and contribute to the growing emergence of multidrug resistant pathogens, which is a global public health emergency. The protocolised use of protein biomarkers to guide clinical decision making can be used to help combat excessive durations of antimicrobials in patients with sepsis. This article reviews the current evidence for biomarker-guided antimicrobial discontinuation protocols in sepsis, identifies related evidence gaps and examines future innovation challenges in this field.

Disseminated intravascular coagulation in an under-recognised zoonotic infection.

A 51 year old man presented with severe sepsis, disseminated intravascular coagulation (DIC) and multiorgan dysfunction after a 24 hour history of diarrhoea and malaise. Despite fluid resuscitation and receiving a platelet transfusion, freshfrozen plasma and intravenous broad-spectrum antibiotics, he remained anuric with a worsening metabolic acidosis. He was transferred to critical care for organ support including renal replacement therapy. He subsequently developed purpura fulminans. Blood cultures were positive for Captocytophaga carnimorsis, a gram-negative canine zoonosis that is an underdiagnosed cause of severe sepsis, for which DIC at presentation is characteristic. Treatment is with penicillins and fluoroquinolones. Identification of risk factors for unusual organisms and recognition of DIC allowing prompt treatment is critical for the acute physician.

Endoparasite Community Differences in Sunfish (Lepomis spp.) Above and Below Coal Mine Effluent in Southern Illinois.

Parasite assemblages acquired through trophic interactions in fish hosts are increasingly cited as a means to determine pollution effects on water quality and food web structure. We examined gastrointestinal parasite community changes above and below coal mine input from 597 individuals representing 3 species of sunfish: green sunfish ( Lepomis cyanellus ), bluegill ( L. macrochirus ), and longear sunfish ( L. megalotis ). Hosts were collected from 6 sites in or near the south fork of the Saline River Basin in southern Illinois in the spring and fall of 2006. Three sites received no known effluent from coal mines. An additional 3 sites received effluent termed acid mine drainage (AMD). We recovered 1,064 parasites from 12 genera. The parasite community in sunfish collected downstream nearest to the source of AMD was significantly different from 3 upstream sites. In addition, 2 sites farther downstream receiving AMD were different from 2 of 3 reference sites. However, there was also considerable variability in parasite assemblages between sites grouped as above or below coal mine effluent. Several parasite species responded to changes in water quality. Spinitectus sp. (Nematoda), which uses sensitive mayfly hosts to complete its life cycle, was less abundant at sites downstream of coal mine effluent in both green sunfish and bluegill. In contrast, 2 acanthocephalans ( Neoechinorhynchus sp. and Eocollis arcanus) and a nematode ( Spiroxys sp.) were found in green sunfish more frequently in areas downstream of AMD. This study further suggests metazoan parasites may be useful as indicators of water quality; however, variability among similar sites may limit their application. In addition, strong assemblage differences were found among the 3 sunfish species, suggesting variable habitat usage and potential resource partitioning among congeneric fish hosts in streams.