There is an ongoing need to identify biomarkers that aid this stratification, as they might reveal important subgroups of patients needing targeted therapeutics and treatment [4]. low IgM levels were associated with sepsis, but not SIRS. IgM levels did not differ significantly for culture-positive (CP) compared with culture-negative (CN, no organism found) sepsis samples. KaplanCMeier analysis was used to compare survival curves according to IgM levels, with no significant difference. We observed significantly higher survival in the CP samples when comparing with CN. Cut-off value for IgM (266 g/mL) for diagnosis of sepsis patients was decided using receiver operator characteristic (ROC) curves with 70% sensitivity, 69% specificity and 92% unfavorable predictive values (NPV), respectively. The corresponding area under the curve (AUC) for the discrimination of sepsis patients was AUC = 0.73, and in a subgroup analysis of CP was AUC = 0.77 and for CN was AUC = 0.79. We confirm IgM as a good diagnostic marker of sepsis. These findings show a difference in the pathology between culture-positive versus unfavorable sepsis, SIRS and survival. This indicates that IgM is Rabbit Polyclonal to GSPT1 likely relevant to pathology, because of its role in the early immune response against pathogens, the potentially protective role of natural BIO-5192 IgM antibodies, and supports its application in immunoglobulin therapy. Keywords: immunoglobulins, sepsis, SIRS, culture-negative 1. Introduction Sepsis is usually defined as the dysregulated host response to contamination causing organ dysfunction [1]. This recent definition closely mirrors the previous category of severe sepsis, which is a major cause of morbidity and mortality in both developed and developing countries [2]. Mortality rates remain at around 30%, and higher in septic shock, despite improvements in critical care [3]. The invasion of sterile tissues by infective brokers will trigger a primarily innate immune response, which could lead to the clinical manifestation of sepsis and severe sepsis pathology [4]. In the beginning, it was assumed that this was primarily due to Gram-negative bacteria, but it is now obvious that Gram-positive bacteria, as well as viral, fungal and parasitic organisms, also play an important role in the development of sepsis [5,6,7,8]. A retrospective, longitudinal study over a 20-12 months period reported that in over 50% of sepsis patients, microbiologically confirmed culture-positive (CP) samples were recorded [9] The invading organism distribution showed Gram-positive bacteria (52.1% of cases), Gram-negative bacteria (37.6%), polymicrobial infections (4.7%), anaerobes (1.0%), and fungi (4.6%) [9]. The organism class responsible for the primary infection, has been shown to play BIO-5192 a role in determining the mortality of patients with sepsis. We have previously exhibited that primarily Gram-negative infections are associated with an elevated mortality [8]. However, often no specific organism can be recognized, and 28C49% of severe sepsis incidents have been described as being culture-negative (CN) [10,11]. This is generally explained by a lack of test sensitivity for infecting organisms due to insensitive methodologies applied in the clinical practice or administration of antibiotics [12], but could also be a result of pathophysiological differences between culture-positive and unfavorable sepsis or SIRS [13]. Low immunoglobulin levels have been found in sepsis [14,15,16,17,18]. The IgM isotype is usually produced by B cells in responses to acute contamination, thus endogenous IgM is the first line of the humoral host defense to aid opsonization and clearance of invading organisms [19,20,21]. IgM has been shown to be crucial for controlling both viral and bacterial infections [22,23,24], as its absence prospects to inefficient induction of protective IgG antibody responses [25,26]. Low IgM levels have been shown to be associated with sepsis [27,28,29], possibly caused by a defective B cell response or a selective depletion of IgM generating memory cells [30,31], which may impact early pathogen clearance. Some evidence indicates that IgM-enriched therapy may be beneficial in Gram-negative sepsis, however the data is usually conflicting [32,33,34]. Unknown mechanisms of action of both endogenous immunoglobulins and immunoglobulin preparations in sepsis could explain the controversial results found in clinical trials [35]. There is a clear need to stratify cohorts of patients with clinical manifestation of sepsis into populations according to presence of an invading organism (culture-positive, CP) and its Gram status (Gram-positive versus Gram-negative), compared to absence of an invading organism (culture-negative, CN, i.e., no organism recognized) and compare them to patients where organ dysfunction is a result of a noninfective process known as systemic inflammatory response syndrome (SIRS) [13]. There is an ongoing need to identify biomarkers that aid this stratification, as BIO-5192 they might reveal important subgroups of patients needing targeted.