Effects of intubation timing in patients with COVID-19 throughout the four waves of the pandemic: a matched analysis.

BACKGROUND: The primary aim of our study was to investigate the association between intubation timing and hospital mortality in critically ill patients with coronavirus disease 2019 (COVID-19)-associated respiratory failure. We also analysed both the impact of such timing throughout the first four pandemic waves and the influence of prior noninvasive respiratory support on outcomes. METHODS: This is a secondary analysis of a multicentre, observational and prospective cohort study that included all consecutive patients undergoing invasive mechanical ventilation due to COVID-19 from across 58 Spanish intensive care units (ICUs) participating in the CIBERESUCICOVID project. The study period was between 29 February 2020 and 31 August 2021. Early intubation was defined as that occurring within the first 24 h of ICU admission. Propensity score matching was used to achieve a balance across baseline variables between the early intubation cohort and those patients who were intubated after the first 24 h of ICU admission. Differences in outcomes between early and delayed intubation were also assessed. We performed sensitivity analyses to consider a different time-point (48 h from ICU admission) for early and delayed intubation. RESULTS: Of the 2725 patients who received invasive mechanical ventilation, a total of 614 matched patients were included in the analysis (307 for each group). In the unmatched population, there were no differences in mortality between the early and delayed groups. After propensity score matching, patients with delayed intubation presented higher hospital mortality (27.3% versus 37.1%; p=0.01), ICU mortality (25.7% versus 36.1%; p=0.007) and 90-day mortality (30.9% versus 40.2%; p=0.02) compared with the early intubation group. Very similar findings were observed when we used a 48-h time-point for early or delayed intubation. The use of early intubation decreased after the first wave of the pandemic (72%, 49%, 46% and 45% in the first, second, third and fourth waves, respectively; first versus second, third and fourth waves p<0.001). In both the main and sensitivity analyses, hospital mortality was lower in patients receiving high-flow nasal cannula (HFNC) (n=294) who were intubated earlier. The subgroup of patients undergoing noninvasive ventilation (n=214) before intubation showed higher mortality when delayed intubation was set as that occurring after 48 h from ICU admission, but not when after 24 h. CONCLUSIONS: In patients with COVID-19 requiring invasive mechanical ventilation, delayed intubation was associated with a higher risk of hospital mortality. The use of early intubation significantly decreased throughout the course of the pandemic. Benefits of such an approach occurred more notably in patients who had received HFNC.

Contribution of Candida biomarkers and DNA detection for the diagnosis of invasive candidiasis in ICU patients with severe abdominal conditions.

BACKGROUND: To assess the performance of Candida albicans germ tube antibody (CAGTA), (1 → 3)-ß-D-glucan (BDG), mannan antigen (mannan-Ag), anti-mannan antibodies (mannan-Ab), and Candida DNA for diagnosing invasive candidiasis (IC) in ICU patients with severe abdominal conditions (SAC). METHODS: A prospective study of 233 non-neutropenic patients with SAC on ICU admission and expected stay ≥ 7 days. CAGTA (cutoff positivity ≥ 1/160), BDG (≥80, 100 and 200 pg/mL), mannan-Ag (≥60 pg/mL), mannan-Ab (≥10 UA/mL) were measured twice a week, and Candida DNA only in patients treated with systemic antifungals. IC diagnosis required positivities of two biomarkers in a single sample or positivities of any biomarker in two consecutive samples. Patients were classified as neither colonized nor infected (n = 48), Candida spp. colonization (n = 154) (low-grade, n = 130; high-grade, n = 24), and IC (n = 31) (intra-abdominal candidiasis, n = 20; candidemia, n = 11). RESULTS: The combination of CAGTA and BDG positivities in a single sample or at least one of the two biomarkers positive in two consecutive samples showed 90.3 % (95 % CI 74.2-98.0) sensitivity, 42.1 % (95 % CI 35.2-98.8) specificity, and 96.6 % (95 % CI 90.5-98.8) negative predictive value. BDG positivities in two consecutive samples had 76.7 % (95 % CI 57.7-90.1) sensitivity and 57.2 % (95 % CI 49.9-64.3) specificity. Mannan-Ag, mannan-Ab, and Candida DNA individually or combined showed a low discriminating capacity. CONCLUSIONS: Positive Candida albicans germ tube antibody and (1 → 3)-ß-D-glucan in a single blood sample or (1 → 3)-ß-D-glucan positivity in two consecutive blood samples allowed discriminating invasive candidiasis from Candida spp. colonization in critically ill patients with severe abdominal conditions. These findings may be helpful to tailor empirical antifungal therapy in this patient population.

Husbandry Protocols for Juvenile Loggerhead Sea Turtles (Caretta caretta) Based on Stress Response to Stocking Density and Dry-Dock Time.

When necessary, sea turtles are held captive for veterinarian care and research purposes. Protocols and basic guidelines have been described for husbandry of sea turtles with veterinarian needs but not considering physiological indicators of animal welfare. Because all sea turtle are imperiled species, monitoring their welfare is important. The aim of this study was to standardize husbandry protocols for loggerhead (Caretta caretta) juveniles held under seminatural conditions, based on circulating concentration of plasma corticosterone (Cort) and behavior. Two experiments were performed to analyze physiological and behavioral responses of the animals facing changes in stocking density and different dry-docking times. Cort analyses suggested that the number of animals per tank can be modified occasionally, without affecting their health and welfare. However, dry-docking time should be < 30 min, as indicated by the significant elevation of circulating Cort at ≥ 30 min, rising from 1.51- ng/ml to 5.28-ng/ml. Protocols tested did not affect behavioral responses, except for the breaths per move, which increased while Cort increased, despite differences exhibited by experimental animals in behavioral responses according to daily times (morning vs afternoon) and the sex of the animals.

Negative predictive value of procalcitonin to rule out bacterial respiratory co-infection in critical covid-19 patients.

BACKGROUND: Procalcitonin (PCT) and C-Reactive Protein (CRP) are useful biomarkers to differentiate bacterial from viral or fungal infections, although the association between them and co-infection or mortality in COVID-19 remains unclear. METHODS: The study represents a retrospective cohort study of patients admitted for COVID-19 pneumonia to 84 ICUs from ten countries between (March 2020-January 2021). Primary outcome was to determine whether PCT or CRP at admission could predict community-acquired bacterial respiratory co-infection (BC) and its added clinical value by determining the best discriminating cut-off values. Secondary outcome was to investigate its association with mortality. To evaluate the main outcome, a binary logistic regression was performed. The area under the curve evaluated diagnostic performance for BC prediction. RESULTS: 4635 patients were included, 7.6% fulfilled BC diagnosis. PCT (0.25[IQR 0.1-0.7] versus 0.20[IQR 0.1-0.5]ng/mL, p<0.001) and CRP (14.8[IQR 8.2-23.8] versus 13.3 [7-21.7]mg/dL, p=0.01) were higher in BC group. Neither PCT nor CRP were independently associated with BC and both had a poor ability to predict BC (AUC for PCT 0.56, for CRP 0.54). Baseline values of PCT<0.3ng/mL, could be helpful to rule out BC (negative predictive value 91.1%) and PCT≥0.50ng/mL was associated with ICU mortality (OR 1.5,p<0.001). CONCLUSIONS: These biomarkers at ICU admission led to a poor ability to predict BC among patients with COVID-19 pneumonia. Baseline values of PCT<0.3ng/mL may be useful to rule out BC, providing clinicians a valuable tool to guide antibiotic stewardship and allowing the unjustified overuse of antibiotics observed during the pandemic, additionally PCT≥0.50ng/mL might predict worsening outcomes.

Drivers of litter ingestion by sea turtles: Three decades of empirical data collected in Atlantic Europe and the Mediterranean.

Sea turtles are considered as bio-indicators for monitoring the efficiency of restoration measures to reduce marine litter impacts on health. However, the lack of extended and standardised empirical data has prevented the accurate analysis of the factors influencing litter ingestion and the relationships with individual health. Historic data collected from 1988 and standard data collected from 2016 were harmonised to enable such analyses on necropsied loggerhead turtles (Caretta caretta) in eight Mediterranean and North-East Atlantic countries. Litter was found in 69.24 % of the 1121 individuals, mostly single-use and fishing-related plastics. Spatial location, sex and life history stage explained a minor part of litter ingestion. While no relationships with health could be detected, indicating that all individuals can be integrated as bio-indicators, the mechanistic models published in literature suggest that the high proportion of plastics in the digestive contents (38.77 % per individual) could have long-term repercussions on population dynamics.

Direct association between pharyngeal viral secretion and host cytokine response in severe pandemic influenza.

BACKGROUND: Severe disease caused by 2009 pandemic influenza A/H1N1virus is characterized by the presence of hypercytokinemia. The origin of the exacerbated cytokine response is unclear. As observed previously, uncontrolled influenza virus replication could strongly influence cytokine production. The objective of the present study was to evaluate the relationship between host cytokine responses and viral levels in pandemic influenza critically ill patients. METHODS: Twenty three patients admitted to the ICU with primary viral pneumonia were included in this study. A quantitative PCR based method targeting the M1 influenza gene was developed to quantify pharyngeal viral load. In addition, by using a multiplex based assay, we systematically evaluated host cytokine responses to the viral infection at admission to the ICU. Correlation studies between cytokine levels and viral load were done by calculating the Spearman correlation coefficient. RESULTS: Fifteen patients needed of intubation and ventilation, while eight did not need of mechanical ventilation during ICU hospitalization. Viral load in pharyngeal swabs was 300 fold higher in the group of patients with the worst respiratory condition at admission to the ICU. Pharyngeal viral load directly correlated with plasma levels of the pro-inflammatory cytokines IL-6, IL-12p70, IFN-γ, the chemotactic factors MIP-1ß, GM-CSF, the angiogenic mediator VEGF and also of the immuno-modulatory cytokine IL-1ra (p < 0.05). Correlation studies demonstrated also the existence of a significant positive association between the levels of these mediators, evidencing that they are simultaneously regulated in response to the virus. CONCLUSIONS: Severe respiratory disease caused by the 2009 pandemic influenza virus is characterized by the existence of a direct association between viral replication and host cytokine response, revealing a potential pathogenic link with the severe disease caused by other influenza subtypes such as H5N1.

Five-year outcome of peripherally inserted central catheters in adults: a separated infectious and thrombotic complications analysis.

OBJECTIVE: To assess infectious and thrombotic complications of peripherally inserted central catheters (PICCs) in adults. DESIGN: A 5-year prospective cohort study. SETTING: Tertiary-care teaching hospital in Seville, Spain. PATIENTS: Adult patients undergoing PICC insertion. METHODS: Catheter-associated bloodstream infection (CABSI) including catheter-related bloodstream infection (CRBSI), primary bacteremia (PB), and upper extremity deep vein thrombosis (UEDVT) were recorded. Independent predictors of complications were assessed by multivariate analysis. RESULTS: In total, 1,142 PICCs were inserted, with 153,191 catheter days (median, 79). Complications included 66 cases of CABSI (5.78%; 0.43‰ catheter days), 38 cases of CRBSI (3.33%; 0.25‰ catheter days), 28 cases of PB (2.45%; 0.18‰ catheter days), and 23 cases of UEDVT (2.01%; 0.15‰ catheter days). The median times to infection were 24, 41, and 60 days for CRBSI, PB, and UEDVT, respectively. Parenteral nutrition (odds ratio [OR], 3.40; 95% confidence interval [CI], 1.77-6.52) and admission to the hematology ward (OR, 4.90; 95% CI, 2.25-10.71) were independently associated with CRBSI and PB, respectively. Admission to the hematology ward (OR, 12.46; 95% CI, 2.49-62.50) or to the oncology ward (OR, 7.89; 95% CI, 1.77-35.16) was independently associated with UEDVT. The crude mortality rate was 24.8%. Only 2 patients died of complications. CONCLUSIONS: PICCs showed a low rate of thrombotic and infectious complications. Compared to PB, CRBSI showed significantly different risk factors, a higher incidence density per catheter days, and a shorter median time to infection. Separate analyses of CRBSI and PB are more specific and clinically useful when analyzing infectious complications.

Assessment of captive rearing conditions on loggerhead hatchlings: Effect of handling frequency and stocking density.

Frequently, stranded sea turtles require rehabilitation under controlled conditions. Currently, few publications have described the conditions under which rehabilitation is to take place, particularly with respect to the hatchling life stage. To address this paucity of data, we conducted some experiments to assist rehabilitating facilities assess their handling of hatchlings. While in captivity, hatchlings are routinely handled, for example, for data collection and cleaning. Standardization of handling and housing protocols is necessary to define the most adequate rearing conditions to maintain hatchling welfare. Accordingly, the aim of this study was to assess plasma circulating corticosterone (Cort) concentration and growth, as a biomarker for the stress of hatchling loggerhead sea turtles (Caretta caretta) under controlled conditions. We performed two experiments to analyze handling frequency and stocking density. In both, Cort was measured and correlated with variations in animal weight and length. In handling experiments, Cort exhibited no significant increase when hatchlings were handled once a week, whereas Cort was significantly elevated when hatchlings were handled once every 2 weeks, suggesting that hatchlings have the ability to acclimate to frequent handling. However, hatchlings exhibited similar growth and mortality, regardless of handling regime. In stocking density experiments, hatchling isolation induced a significant elevation of Cort, in comparison with hatchlings placed with conspecifics at increasing densities. Growth increased in singly housed hatchlings, while mortality increased in tanks with three or more hatchlings. The results obtained suggest that Cort, growth, and mortality should be measured to assess hatchling welfare when kept under controlled conditions.

Mortality comparison between the first and second/third waves among 3,795 critical COVID-19 patients with pneumonia admitted to the ICU: A multicentre retrospective cohort study.

BACKGROUND: It is unclear whether the changes in critical care throughout the pandemic have improved the outcomes in coronavirus disease 2019 (COVID-19) patients admitted to the intensive care units (ICUs). METHODS: We conducted a retrospective cohort study in adults with COVID-19 pneumonia admitted to 73 ICUs from Spain, Andorra and Ireland between February 2020 and March 2021. The first wave corresponded with the period from February 2020 to June 2020, whereas the second/third waves occurred from July 2020 to March 2021. The primary outcome was ICU mortality between study periods. Mortality predictors and differences in mortality between COVID-19 waves were identified using logistic regression. FINDINGS: As of March 2021, the participating ICUs had included 3795 COVID-19 pneumonia patients, 2479 (65·3%) and 1316 (34·7%) belonging to the first and second/third waves, respectively. Illness severity scores predicting mortality were lower in the second/third waves compared with the first wave according with the Acute Physiology and Chronic Health Evaluation system (median APACHE II score 12 [IQR 9-16] vs 14 [IQR 10-19]) and the organ failure assessment score (median SOFA 4 [3-6] vs 5 [3-7], p<0·001). The need of invasive mechanical ventilation was high (76·1%) during the whole study period. However, a significant increase in the use of high flow nasal cannula (48·7% vs 18·2%, p<0·001) was found in the second/third waves compared with the first surge. Significant changes on treatments prescribed were also observed, highlighting the remarkable increase on the use of corticosteroids to up to 95.9% in the second/third waves. A significant reduction on the use of tocilizumab was found during the study (first wave 28·9% vs second/third waves 6·2%, p<0·001), and a negligible administration of lopinavir/ritonavir, hydroxychloroquine, and interferon during the second/third waves compared with the first wave. Overall ICU mortality was 30·7% (n = 1166), without significant differences between study periods (first wave 31·7% vs second/third waves 28·8%, p = 0·06). No significant differences were found in ICU mortality between waves according to age subsets except for the subgroup of 61-75 years of age, in whom a reduced unadjusted ICU mortality was observed in the second/third waves (first 38·7% vs second/third 34·0%, p = 0·048). Non-survivors were older, with higher severity of the disease, had more comorbidities, and developed more complications. After adjusting for confounding factors through a multivariable analysis, no significant association was found between the COVID-19 waves and mortality (OR 0·81, 95% CI 0·64-1·03; p = 0·09). Ventilator-associated pneumonia rate increased significantly during the second/third waves and it was independently associated with ICU mortality (OR 1·48, 95% CI 1·19-1·85, p<0·001). Nevertheless, a significant reduction both in the ICU and hospital length of stay in survivors was observed during the second/third waves. INTERPRETATION: Despite substantial changes on supportive care and management, we did not find significant improvement on case-fatality rates among critical COVID-19 pneumonia patients. FUNDING: Ricardo Barri Casanovas Foundation (RBCF2020) and SEMICYUC.

Host adaptive immunity deficiency in severe pandemic influenza.

INTRODUCTION: Pandemic A/H1N1/2009 influenza causes severe lower respiratory complications in rare cases. The association between host immune responses and clinical outcome in severe cases is unknown. METHODS: We utilized gene expression, cytokine profiles and generation of antibody responses following hospitalization in 19 critically ill patients with primary pandemic A/H1N1/2009 influenza pneumonia for identifying host immune responses associated with clinical outcome. Ingenuity pathway analysis 8.5 (IPA) (Ingenuity Systems, Redwood City, CA) was used to select, annotate and visualize genes by function and pathway (gene ontology). IPA analysis identified those canonical pathways differentially expressed (P < 0.05) between comparison groups. Hierarchical clustering of those genes differentially expressed between groups by IPA analysis was performed using BRB-Array Tools v.3.8.1. RESULTS: The majority of patients were characterized by the presence of comorbidities and the absence of immunosuppressive conditions. pH1N1 specific antibody production was observed around day 9 from disease onset and defined an early period of innate immune response and a late period of adaptive immune response to the virus. The most severe patients (n = 12) showed persistence of viral secretion. Seven of the most severe patients died. During the late phase, the most severe patient group had impaired expression of a number of genes participating in adaptive immune responses when compared to less severe patients. These genes were involved in antigen presentation, B-cell development, T-helper cell differentiation, CD28, granzyme B signaling, apoptosis and protein ubiquitination. Patients with the poorest outcomes were characterized by proinflammatory hypercytokinemia, along with elevated levels of immunosuppressory cytokines (interleukin (IL)-10 and IL-1ra) in serum. CONCLUSIONS: Our findings suggest an impaired development of adaptive immunity in the most severe cases of pandemic influenza, leading to an unremitting cycle of viral replication and innate cytokine-chemokine release. Interruption of this deleterious cycle may improve disease outcome.

Data Collection on Marine Litter Ingestion in Sea Turtles and Thresholds for Good Environmental Status.

The following protocol is intended to respond to the requirements set by the European Union's Marine Strategy Framework Directives (MSFD) for the D10C3 Criteria reported in the Commission Decision (EU), related to the amount of litter ingested by marine animals. Standardized methodologies for extracting litter items ingested from dead sea turtles along with guidelines on data analysis are provided. The protocol starts with the collection of dead sea turtles and classification of samples according to the decomposition status. Turtle necropsy must be performed in authorized centers and the protocol described here explains the best procedure for gastrointestinal (GI) tract isolation. The three parts of the GI (esophagus, stomach, intestine) should be separated, opened lengthways and contents filtered using a 1 mm mesh sieve. The article describes the classification and quantification of ingested litter, classifying GI contents into seven different categories of marine litter and two categories of natural remains. The quantity of ingested litter should be reported as total dry mass (weight in grams, with two decimal places) and abundance (number of items). The protocol proposes two possible scenarios to achieve the Good Environmental Status (GES). First: "There should be less than X% of sea turtles having Y g or more plastic in the GI in samples of 50-100 dead turtles from each sub-region", where Y is the average weight of plastic ingested and X% is the percentage of sea turtles with more weight (in grams) of plastic than Y. The second one, which considers the food remain versus plastic as a proxy of individual health, is: "There should be less than X% of sea turtles having more weight of plastic (in grams) than food remains in the GI in samples of 50-100 dead turtles from each sub-region".

Clindamycin but not Intravenous Immunoglobulins reduces mortality in a retrospective cohort of critically ill patients with bacteremic Group A Streptococcal infections / Tratamiento con clindamicina, y no con inmunoglobulinas intravenosas, disminuye la mortalidad en una cohorte retrospectiva de pacientes críticos con bacteriemia por Streptococcus del Grupo A

Objectives. Mortality of patients requiring Intensive Care Unit (ICU) admission for an invasive group A streptococcal (GAS) infection continues being high. In critically ill patients with bacteremic GAS infection we aimed at determining risk factors for mortality. Patients and methods. Retrospective multicentre study carried out in nine ICU in Southern Spain. All adult patients admitted to the participant ICUs from January 2014 to June 2019 with one positive blood culture for S. pyogenes were included in this study. Patient characteristics, infection-related variables, therapeutic interventions, failure of organs, and outcomes were registered. Risk factors independently associated with ICU and in-hospital mortalities were determined by multivariate regression analyses. Results. Fifty-seven patients were included: median age was 63 (45-73) years, median SOFA score at admission was 11 (7-13). The most frequent source was skin and soft tissue infection (n=32) followed by unknown origin of bacteremia (n=12). In the multivariate analysis, age (OR 1.079; 95% CI 1.016-1.145), SOFA score (OR 2.129; 95% CI 1.339-3.383) were the risk factors for ICU mortality and the use of clindamycin was identified as a protective factor (OR 0.049; 95% CI 0.003-0.737). Age and SOFA were the independent factors associated with hospital mortality however the use of clindamycin showed a strong trend but without reaching statistical significance (OR 0.085; 95% CI 0.007-1.095). (AU)

Objetivo. La mortalidad de los pacientes que requieren ingreso en la Unidad de Cuidados Intensivos (UCI) por una infección invasiva por estreptococos del grupo A (GAS) continúa siendo inaceptablemente alta. El objetivo del estudio fue determinar los factores de riesgo de mortalidad en pacientes críticos con infección estreptocócica bacterémica del grupo A. Pacientes y métodos. Estudio retrospectivo multicéntrico realizado en nueve UCI del sur de España. Se incluyeron pacientes consecutivos ingresados en las UCI participantes desde enero de 2014 hasta junio de 2019 con un hemocultivo positivo para S. pyogenes. Se registraron las características de los pacientes, las variables relacionadas con la infección, las intervenciones terapéuticas, el fracaso de los órganos y el pronóstico. Se determinaron mediante análisis de regresión multivariante los factores de riesgo asociados de forma independiente con la mortalidad en UCI y hospitalaria. Resultados. Se incluyeron cincuenta y siete pacientes: la mediana de edad fue de 63 (45-73) años, la mediana de la puntuación SOFA al ingreso fue de 11 (7-13). El foco más frecuente fue la infección de la piel y los tejidos blandos (n=32) seguida de la bacteriemia de origen desconocido (n=12). En el análisis multivariante, la edad (OR 1,079; IC del 95%: 1,016-1,145), y la puntuación SOFA (OR 2,129; IC del 95%: 1,339-3,383) se identificaron como factores de riesgo para la mortalidad en UCI. El uso de clindamicina se identificó como un factor protector (OR 0,049; IC del 95%: 0,003-0,737). La edad y la SOFA se asociaron de forma independiente con la mortalidad hospitalaria, mientras que el tratamiento con clindamicina mostró una tendencia fuerte pero sin alcanzar significación estadística (OR 0,085; IC del 95%: 0,007-1,095). (AU)

Is routine ophthalmoscopy really necessary in candidemic patients?

The purpose of this study was to determine among patients with candidemia the real rate of ophthalmoscopy and the impact of performing ocular assessment on the outcome of the disease. We performed a post hoc analysis of a prospective, multicenter, population-based candidemia surveillance program implemented in Spain during 2010-2011 (CANDIPOP). Ophthalmoscopy was performed in only 168 of the 365 patients with candidemia (46%). Ocular lesions related to candidemia were found in only 13/168 patients (7.7%), of whom 1 reported ocular symptoms (incidence of symptomatic disease in the whole population, 0.27% [1/365]). Ophthalmological findings led to a change in antifungal therapy in only 5.9% of cases (10/168), and performance of the test was not related to a better outcome. Ocular candidiasis was not associated with a worse outcome and progressed favorably in all but 1 evaluable patient, who did not experience vision loss. The low frequency of ophthalmoscopy and ocular involvement and the asymptomatic nature of ocular candidiasis, with a favorable outcome in almost all cases, lead us to reconsider the need for systematic ophthalmoscopy in all candidemic patients.

The protective association of endogenous immunoglobulins against sepsis mortality is restricted to patients with moderate organ failure.

BACKGROUND: Pre-evaluation of endogenous immunoglobulin levels is a potential strategy to improve the results of intravenous immunoglobulins in sepsis, but more work has to be done to identify those patients who could benefit the most from this treatment. The objective of this study was to evaluate the impact of endogenous immunoglobulins on the mortality risk in sepsis depending on disease severity. METHODS: This was a retrospective observational study including 278 patients admitted to the ICU with sepsis fulfilling the SEPSIS-3 criteria, coming from the Spanish GRECIA and ABISS-EDUSEPSIS cohorts. Patients were distributed into two groups depending on their Sequential Organ Failure Assessment score at ICU admission (SOFA < 8, n = 122 and SOFA ≥ 8, n = 156), and the association between immunoglobulin levels at ICU admission with mortality was studied in each group by Kaplan-Meier and multivariate logistic regression analysis. RESULTS: ICU/hospital mortality in the SOFA < 8 group was 14.8/23.0%, compared to 30.1/35.3% in the SOFA ≥ 8 group. In the group with SOFA < 8, the simultaneous presence of total IgG < 407 mg/dl, IgM < 43 mg/dl and IgA < 219 mg/dl was associated with a reduction in the survival mean time of 6.6 days in the first 28 days and was a robust predictor of mortality risk either during the acute or during the post-acute phase of the disease (OR for ICU mortality: 13.79; OR for hospital mortality: 7.98). This predictive ability remained in the absence of prior immunosuppression (OR for ICU mortality: 17.53; OR for hospital mortality: 5.63). Total IgG < 407 mg/dl or IgG1 < 332 mg/dl was also an independent predictor of ICU mortality in this group. In contrast, in the SOFA ≥ 8 group, we found no immunoglobulin thresholds associated with neither ICU nor hospital mortality. CONCLUSIONS: Endogenous immunoglobulin levels may have a different impact on the mortality risk of sepsis patients based on their severity. In patients with moderate organ failure, the simultaneous presence of low levels of IgG, IgA and IgM was a consistent predictor of both acute and post-acute mortalities.

ß-D-Glucan and Candida albicans germ tube antibody in ICU patients with invasive candidiasis.

PURPOSE: To assess the performance of (1→3)-ß-D-glucan (BDG) and Candida albicans germ tube antibody (CAGTA) for the diagnosis of invasive candidiasis (IC) in a prospective cohort of 107 unselected, non-neutropenic ICU patients. METHODS: BDG (cutoff positivity ≥80 pg/mL) and CAGTA (cutoff positivity ≥1/160) assays were performed twice a week. Confounding factors included amoxicillin-clavulanate and piperacillin-tazobactam treatments, recent surgery, Gram-positive bloodstream infection, renal replacement therapy, and enteral nutrition. Patients were classified as neither colonized nor infected (n = 29), Candida spp. colonization (n = 63) (low grade, n = 32; high grade, n = 31), and invasive candidiasis (IC) (n = 15). RESULTS: BDG levels were higher in patients with IC and high-grade colonization than in the remaining groups (p = 0.012), and two consecutive measurements ≥80 pg/mL discriminated IC from the remaining groups (sensitivity 80%, specificity 75.7%). For the discrimination between IC and Candida spp. colonization, the AUC for the maximum value of BDG was 0.667 (95% CI 0.544-0.790) and for the maximum value of CAGTA 0.545 (95% CI 0.395-0.694). Significant changes of BDG and CAGTA kinetics in IC patients treated with antifungals were not observed. In patients neither colonized nor infected or with low-grade Candida spp. colonization, none of the confounding factors was associated with a significant increase in BDG positivity. CONCLUSIONS: Two consecutive BDG levels ≥80 pg/mL allowed discrimination among IC and high-grade colonization. Systemic antifungal therapy could not be monitored with biomarker kinetics, and BDG levels were not subject to interference by confounding factors in either colonized or infected patients or with low-grade colonization.

IgM levels in plasma predict outcome in severe pandemic influenza.

BACKGROUND: Little is known on the participation of immunoglobulin isotypes and subclasses in the pathogenesis of the severe disease caused by the pandemic influenza virus (influenza A(H1N1)pdm09). OBJECTIVES: (1) To evaluate the association between plasma levels of IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE and outcome in patients with severe pandemic influenza. (2) To evaluate the association between immunoglobulin and cytokine levels in these patients. STUDY DESIGN: 40 critically ill patients with community acquired pneumonia and influenza A(H1N1)pdm09 infection were recruited from November 2010 to February 2011. Plasma samples were collected during the first 24h following admission to the ICU. Immunoglobulins and 17 major cytokines were profiled in plasma. RESULTS: 15 patients died (37.5%). When the association between clinical variables and prognosis was assessed, prior immunosuppression, APACHE II score, levels of IgG2 and levels of IgM were associated with outcome in a univariate Cox regression analysis. Kaplan Meier analysis showed that patients with levels of IgG2 and IgM < 59 and<58 mg/dl respectively died earlier. Multivariate Cox regression analysis showed that APACHE II score and levels of IgM were the best predictors of outcome, being levels of IgM a protective factor against mortality. IgM was the immunoglobulin showing the largest number of negative correlations with cytokine levels. CONCLUSIONS: Our results support a central role of IgM in preventing uncontrolled inflammatory response and mortality in severe pandemic influenza. Early assessment of IgM could contribute to guide clinical decisions in these patients.

Value of ß-D-glucan and Candida albicans germ tube antibody for discriminating between Candida colonization and invasive candidiasis in patients with severe abdominal conditions.

PURPOSE: To assess the value of (1→3)-ß-D: -glucan (BDG), Candida albicans germ tube antibody (CAGTA), C-reactive protein (CRP), and procalcitonin (PCT) levels for the diagnosis of invasive candidiasis (IC) and for differentiating Candida spp. colonization from infection in ICU patients with severe abdominal conditions (SAC). METHODS: Prospective study of 176 non-neutropenic patients, with SAC at ICU admission, and expected to stay at least 7 days. Surveillance cultures and BDG, CAGTA, CRP, and PCT levels were performed on the third day of ICU stay and twice a week for four consecutive weeks. Patients were grouped into invasive candidiasis (IC), Candida colonization, and neither colonized/nor infected. The classification and regression tree (CART) analysis was used to predict IC in colonized patients. The discriminatory ability of the obtained prediction rule was assessed by the area under the ROC curve (AUC). RESULTS: The probabilities of IC were 59.3 % for the terminal node of BDG greater than 259 pg/mL and 30.8 % for BDG less than 259 pg/mL and CAGTA positivity, whereas there was a 93.9 % probability in predicting the absence of IC for BDG less than 259 pg/mL and negative CAGTA. Using a cutoff of 30 % for IC probability, the prediction rule showed 90.3 % sensitivity, 54.8 % specificity, 42.4 % positive predictive value, and 93.9 % negative predictive value with an AUC of 0.78 (95 % confidence interval 0.76-0.81). Significant differences in CRP (p = 0.411) and PCT (p = 0.179) among the studied groups were not found. CONCLUSIONS: BDG with a positive test for CAGTA accurately differentiated Candida colonization from IC in patients with SAC, whereas CRP and PCT did not.