Steven M Opal

Lifespan · Infectious diseases

Despite the dramatic increase in antimicrobial resistance, there is a dearth of antibiotics in development and few pharmaceutical companies working in the field. Further, any new antibiotics are likely to have a short shelf life. Ab-based interventions offer alternatives that are not likely to be circumvented by the widely prevalent antibiotic resi...

Endotoxin removal therapy with polymyxin B immobilized fiber column (PMX) has been clinically applied for sepsis and septic shock patients since 1994. The effectiveness and usefulness of this therapy have been demonstrated for more than a quarter of a century. However, a documented survival benefit has not yet been demonstrable in a large, multicen...

Soft-tissue bacterial infection can progress to severe sepsis and septic shock as a result of a disproportionate inflammatory response, characterized by an excessive release of cytokines and influx of immune cells. Reltecimod (previously known as AB103 or p2TA), a peptide derived from the T-cell receptor CD28, modulates the host immune response by...

Patients with COVID-19 infection are at risk of acute respiratory disease syndrome (ARDS) and death. The tissue receptor for COVID-19 is ACE2, and higher levels of ACE2 can protect against ARDS. Angiotensin receptor blockers and statins upregulate ACE2. Clinical trials are needed to determine whether this drug combination might be used to treat pat...

Importance Norepinephrine, the first-line vasopressor for septic shock, is not always effective and has important catecholaminergic adverse effects. Selepressin, a selective vasopressin V1a receptor agonist, is a noncatecholaminergic vasopressor that may mitigate sepsis-induced vasodilatation, vascular leakage, and edema, with fewer adverse effects...

The role of biomarkers for detection of sepsis has come a long way. Molecular biomarkers are taking front stage at present, but machine learning and other computational measures using bigdata sets are promising. Clinical research in sepsis is hampered by lack of specificity of the diagnosis; sepsis is a syndrome with no uniformly agreed definition....

Importance Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy. Objective To determine the effect of human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy. Design, Setting, and Partic...

Importance Sepsis is a heterogeneous syndrome. Identification of distinct clinical phenotypes may allow more precise therapy and improve care. Objective To derive sepsis phenotypes from clinical data, determine their reproducibility and correlation with host-response biomarkers and clinical outcomes, and assess the potential causal relationship wi...

Background. Severe gram-negative bacterial infections and sepsis are major causes of morbidity and mortality. Dysregulated, excessive proinflammatory cytokine expression contributes to the pathogenesis of sepsis. A CD28 mi-metic peptide (AB103; previously known as p2TA) that attenuates CD28 signaling and T-helper type 1 cytokine responses was teste...

Ninety years ago, Gregory Shwartzman first reported an unusual discovery following the intradermal injection of sterile culture filtrates from principally Gram-negative strains from bacteria into normal rabbits. If this priming dose was followed in 24 h by a second intravenous challenge (the provocative dose) from same culture filtrate, dermal necr...

The nature of the pathogen responsible for initiating the septic process has a major impact on the host: pathogen interaction and the ultimate outcome for the patient. Potential pathogens must first evade an impressive array of innate and adaptive host defense mechanisms to invade and disseminate within a previously healthy human. Such a pathogen-d...

Purpose: The CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing ~ 23% immunoglobulin (Ig) M, ~ 21% IgA, and ~ 56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP). Methods: In this double-blind, phase II study (NCT01420744), 160 patients with sCAP requiring invasive me...

Septic shock carries substantial morbidity and mortality. The failure of many promising therapies during late-phase clinical trials prompted calls for alternative trial designs. We describe an innovative trial evaluating selepressin, a novel selective vasopressin V1a receptor agonist, for adults with septic shock. SEPSIS-ACT (Selepressin Evaluation...

The immune responses of humans and animals to insults (i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged pro-inflammatory stimuli bringing about chronic inflammation can lead to life-threat...

Because of its high incidence and clinical complexity, sepsis is a major challenge to clinicians and researchers and a global burden to healthcare systems and society. Despite recent progress, short- and long-term morbidity, mortality and costs remain high in both developed and developing countries. Thus, further improvements in supportive interven...

The emergence of multi-drug resistant (MDR) microbial pathogens threatens the very foundation upon which standard antibacterial chemotherapy is based. We must consider non-antibiotic solutions to manage invasive bacterial infections. Transition from antibiotics to non-traditional treatments poses real clinical challenges that will not be easy to so...

For more than two decades, sepsis was defined as a microbial infection that produces fever (or hypothermia), tachycardia, tachypnoea and blood leukocyte changes. Sepsis is now increasingly being considered a dysregulated systemic inflammatory and immune response to microbial invasion that produces organ injury for which mortality rates are declinin...

Objectives: To describe the quality of life among sepsis survivors. Design: Secondary analyses of two international, randomized clinical trials (A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis [derivation cohort] and PROWESS-SHOCK [validation cohort]). Setting: ICUs in North and South America, Europe, Africa, Asi...

Despite considerable efforts to promote early identification and treatment of sepsis, each year several million individuals worldwide develop sepsis-induced multiple organ dysfunction, requiring admission to intensive care and institution of life support, and frequently progressing to death or protracted illness and incomplete recovery. Sepsis is n...

Innate Defense Regulators (IDRs) are short synthetic peptides that target the host innate immune system via an intracellular adaptor protein which functions at key signaling nodes. In this work, further details of the mechanism of action of IDRs have been discovered. The studies reported here show that the lead clinical IDR, SGX94, has broad-spectr...

Importance Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.Objective To evaluate and, as...

The effective and robust separation of biomolecules of interest from patient samples is an essential step in diagnostic applications. We present a platform for the fast extraction of nucleic acids from clinical specimens utilizing paramagnetic PMPs, an oil-water interface, a small permanent magnet and a microfluidic channel to separate and purify c...

RT-PCR standard curve. a) The standard curve was formed from serial dilutions ranging from 109 to 105 copies/mL. Amplification efficiency was calculated to be 99.8%. b) RT-qPCR amplification plot for samples 177, 78 and 193. (TIF)

Peak shift in extracted RNA. RNA Electropherogram for patient sample 193 processed both by kit and oil chip method. The peak shift towards the right for the oil chip sample was observed. (TIF)

Total RNA yield from both methods for 28 separate clinical nasal swab samples, given by optical density measurements. Etot for Column 4 is calculated as the ratio of OD260 measurements of chip-extracted RNA to kit-extracted RNA. (DOC)

RT-PCR of patient samples. Electropherogram of Bioanalyzer DNA 1000 gel assaying RT-PCR products of processed patient samples 590, 177 and 474, the last of which tested negative for influenza A. cDNA concentrations (ng/μL) are given next to respective peaks. (TIF)

Quantitative RT-PCR was performed on kit- and chip-extracted samples. (DOC)

Coagulation abnormalities are commonly found in critically ill patients. A myriad of altered coagulation parameters are often detectable, such as thrombocytopenia, prolonged global coagulation times, reduced levels of coagulation inhibitors, or high levels of fibrin split products. Each of these derangements in clotting may derive from a variety of...

Organ dysfunction induced by sepsis has been consistently associated with worse outcome and death. Regardless of the organ compromised, epithelial dysfunction is present throughout the body, affecting those organs that contain epithelia like the skin, lungs, liver, gut and kidneys. Despite their obvious differences, sepsis seems to alter common fea...

The sirtuin family consists of seven NAD+-dependent enzymes affecting a broad array of regulatory protein networks by primarily catalyzing the deacetylation of key lysine residues in regulatory proteins. The enzymatic activity of SIRT1 can be enhanced by small molecule activators known as SIRT1 activator compounds (STACs). We tested the therapeutic...

Objective: To determine the efficacy of anakinra (recombinant interleukin-1 receptor antagonist) in improving 28-day survival in sepsis patients with features of macrophage activation syndrome. Despite equivocal results in sepsis trials, anakinra is effective in treating macrophage activation syndrome, a similar entity with fever, disseminated int...

Microbial cell walls contain pathogenic lipids including lipopolysaccharide (LPS) in gram-negative bacteria, lipoteichoic acid in gram-positive bacteria, and phospholipomannan in fungi. These pathogen lipids are major ligands for innate immune receptors and figure prominently in triggering the septic inflammatory response. Alternatively, pathogen l...

Treatments targeting the Ebola virus may eventually be shown to work, but they will not have an impact on overall Ebola mortality in West Africa. Endothelial dysfunction is responsible for the fluid and electrolyte imbalances seen in Ebola patients. Because inexpensive generic statins and angiotensin receptor blockers restore endothelial barrier in...

The prevention and treatment of sepsis in the immunocompromised host present a challenging array of diagnostic and management issues. The neutropenic patient has a primary defect in innate immune responses and is susceptible to conventional and opportunistic pathogens. The solid organ transplant patient has a primary defect in adaptive immunity and...

Background. Natural killer (NK) and natural killer T (NKT) cells contribute to the innate host defense but their role in bacterial sepsis remains controversial. Methods. C57BL/6 mice were infected intratracheally with 5 × 105 cfu of Streptococcus pneumoniae. Animals were divided into sham group (Sham); pretreated with isotype control antibody (CON)...

Sepsis is a common and lethal syndrome: although outcomes have improved, mortality remains high. No specific anti-sepsis treatments exist; as such, management of patients relies mainly on early recognition allowing correct therapeutic measures to be started rapidly, including administration of appropriate antibiotics, source control measures when n...

Severe community-acquired pneumonia is defined as community-acquired pneumonia that requires intensive medical care. Mortality in these patients is still high depending on time and admission. Since bad outcomes may occur despite antibiotic therapy to treat severe community-acquired pneumonia, the focus has shifted to targeting the host response. Th...

IMT504 is a novel immunomodulatory oligonucleotide that has immunotherapeutic properties in early preclinical and clinical studies. IMT504 was tested in a neutropenic rat model of Pseudomonas aeruginosa bacteremia and sepsis. This animal system recapitulates many of the pathologic processes found in neutropenic patients with gram-negative, bacteria...

The endothelium provides an essential and selective membrane barrier that regulates the movement of water, solutes, gases, macromolecules and the cellular elements of the blood from the tissue compartment in health and disease. Its structure and continuous function is essential for life for all vertebrate organisms. Recent evidence indicates that t...

Background: Severe gram-negative bacterial infections and sepsis are major causes of morbidity and mortality. Dysregulated, excessive proinflammatory cytokine expression contributes to the pathogenesis of sepsis. A CD28 mimetic peptide (AB103; previously known as p2TA) that attenuates CD28 signaling and T-helper type 1 cytokine responses was teste...

Background: Translocation of gut-derived Gram-negative bacterial (GNB) lipopolysaccharide (LPS, or endotoxin) is a source of systemic inflammation that exacerbates HIV, cardiovascular and gastrointestinal diseases and malnutrition. The oral administration of bovine colostrum (BC) reduces endotoxemia in patients with impaired gut barrier function....

Interferon gamma (IFN-γ) autoantibodies are a relatively recently discovered clinical entity, which have been shown to be associated with disseminated non-tuberculous mycobacterial (NTM) infections and other opportunistic infections. Interestingly, isolated NTM infections (without disseminated NTM infection) have not been shown to be a good predict...

Coronaviruses have traditionally been associated with mild upper respiratory tract infections throughout the world. In the fall of 2002, a new coronavirus emerged in in Asia causing severe viral pneumonia, i.e., severe acute respiratory syndrome (SARS). Nearly a decade following the SARS epidemic, a new coronavirus causing severe viral pneumonia ha...

The newly emerging human pathogen influenza A H7N9 represents a potentially major threat to human health. The virus was first shown to be pathogenic in humans in 2013, and outbreaks continue to occur in China to the present time. The current incident mortality rate is disturbingly high despite the frequent use of antiviral therapy and intensive car...

IMPORTANCE Necrotizing soft-tissue infections (NSTI) have high morbidity and mortality rates despite aggressive surgical debridement and antibiotic therapy. AB103 is a peptide mimetic of the T-lymphocyte receptor, CD28. We hypothesized that AB103 will limit inflammatory responses to bacterial toxins and decrease the incidence of organ failure. OBJE...

The developmental pipeline for novel therapeutics to treat sepsis has diminished to a trickle compared to previous years of sepsis research. While enormous strides have been made in understanding the basic molecular mechanisms that underlie the pathophysiology of sepsis, a long list of novel agents have now been tested in clinical trials without a...

It has been previously shown that mice subjected to an aerosol exposure of Yersinia pestis and treated with β-lactam antibiotics after a delay of 42h died at an accelerated rate compared to controls. It was hypothesized that endotoxin release in antibiotic treated mice accounted for the accelerated death rate in the plague aerosolized mice. Imipene...

Introduction: Adult hemophagocytic syndrome (HPS) is a fulminant, fatal form of MODS, sharing features and markers of severe sepsis [fever, coagulopathy, hepatobiliary dysfunction (HBD), cytopenias, hyperferritinemia, central nervous system dysfunction and increased expression of CD163]. Despite the equivocal results of IL-1 receptor blockade in se...

As demonstrated by the recent 2012/2013 flu epidemic, the continual emergence of new viral strains highlights the need for accurate medical diagnostics in multiple community settings. If rapid, robust, and sensitive diagnostics for influenza subtyping were available, it would help identify epidemics, facilitate appropriate antiviral usage, decrease...

The therapeutic approach to sepsis is following an evolutionary process of scientific discovery as articulated in the landmark work by Kuhn, The Structure of Scientific Revolutions, first published 50 years ago. Incremental advances, beginning with the introduction of antimicrobials and most recently highlighted by revised, evidence-based guideline...

Multi-antibiotic drug-resistant (MDR) gram-negative bacilli are becoming a major threat to the standard care of septic patients. Empiric antimicrobial drug regimens to cover likely bacterial pathogens have to be altered in keeping with the spread of MDR pathogens in the health care setting and in the community. Reliable antibiotics for broad spectr...

The seemingly inexorable spread of antibiotic resistance genes among microbial pathogens now threatens the long-term viability of our current antimicrobial therapy to treat severe bacterial infections such as sepsis. Antibiotic resistance is reaching a crisis situation in some bacterial pathogens where few therapeutic alternatives remain and pan-re...

This work presents the clinical application of a robust and unique approach for RNA amplification, called a Simple Method for Amplifying RNA Targets (SMART), for the detection and subtype identification of H1N1 pandemic, H1N1 seasonal, and H3N2 seasonal influenza virus. While all the existing amplification techniques rely on the diffusion of two mo...

Setzer and colleagues demonstrate that older animals are more susceptible to ventilator-induced lung injury than young animals and develop a more pronounced local and systemic cytokine response to high tidal volumes. These data have significant implications for older patients receiving mechanical ventilation if these findings can be translated to h...

The word, sepsis, dates back more than 2 millennia but has, over the past 2 centuries, come to be applied first to the clinical state evoked by invasive infection and, more recently, to describe the syndrome resulting from the host response to infection. Further refinements embodied in the recently published Sepsis-3 definition underline the concep...

Staphylococcus aureus and group A Streptococcus pyogenes (GAS) express superantigen (SAg) exotoxin proteins capable of inducing lethal shock. To induce toxicity, SAgs must bind not only to the major histocompatibility complex II molecule of antigen-presenting cells and the variable β chain of the T-cell receptor but also to the dimer interface of t...

The prognostic impact of endotoxemia detection in sepsis is unclear. Endotoxemia is detectable in <70% of patients with Gram-negative (GN) bacteremias. Mortality proportion data were available from 27 published studies of patients with GN bacteremia in various settings. Among ten studies restricted to specific types of GN bacteremia, endotoxemia wa...

Eritoran is a synthetic lipid A antagonist that blocks lipopolysaccharide (LPS) from binding at the cell surface MD2-TLR4 receptor. LPS is a major component of the outer membrane of gram-negative bacteria and is a potent activator of the acute inflammatory response. To determine if eritoran, a TLR4 antagonist, would significantly reduce sepsis-indu...