Estudio Anatómico y Prevalencia del Canalis sinuosus Evaluado Mediante Cone Beam CT en Pacientes Chilenos / Anatomical Study and Prevalence of Canalis sinuosus Evaluated by Cone Beam CT in Chilean Patients

Canalis sinuosus, canal intraóseo localizado en región maxilar anterior, contiene elementos vasculonerviosos alveolares anterosuperiores. Diversas intervenciones en región maxilar anterior como colocación de implantes, exodoncias, instalación de microtornillos ortodóncicos, procedimientos quirúrgicos, entre otros, pueden comprometer al Canalis sinuosus y/o sus canales accesorios dañando los elementos contenidos en su interior causando complicaciones como hemorragias, parestesia, disestesia, etc. Dado el gran desconocimiento de su existencia, el Canalis sinuosus frecuentemente es confundido con lesiones patológicas y/o endodónticas. Clásicamente la literatura lo describe como una variación anatómica variación anatómica, sin embargo, presenta elevadas prevalencias (51,7 %-100 %), siendo cuestionada esta aseveración. Determinar prevalencia y característica s anatómicas del Canalis sinuosus mediante Cone Beam CT en pacientes chilenos del centro radiológico IMAPROX® entre 2017- 2021. Análisis retrospectivo de 220 CBCT maxilares anonimizados, considerando variables sexo, presencia del Canalis sinuosus, Canalis sinuosus uni/bilateral, diámetro mayor del Canalis sinuosus, presencia/número de accesorios. Análisis estadístico uni y bivariado. 100 % de prevalencia del Canalis sinuosus en ambos sexos, presencia bilateral 100 %. Diámetro mayor promedio del Canalis sinuosus: 2,58 mm. El 76,8 % presentó accesorios, siendo más prevalente la presencia de 2 CA (34,1 %). Una estructura anatómica normal habitual debe presentar sobre 50 % de prevalencia para ser considerada como tal, pero no hay consensos en criterios empleados para definir variación anatómica o estructura anatómica normal habitual. Literatura describe al Canalis sinuosus como variación anatómica, pero estudios actuales muestran elevadas prevalencias: Rusia 67 %, Brasil 88 %, Turquía, Colombia y Chile 100 %. Este estudio encontró 100 % de prevalencia, sugiriendo que Canalis sinuosus es una estructura anatómica normal habitual. Sin embargo, Canalis sinuosus es poco conocido asociándose a numerosas complicaciones por procedimientos odontológicos y/o quirúrgicos en RMA pudiendo generar hemorragias, parestesia/disestesia, dolor agudo, etc. Elevadas prevalencias reportadas sugieren que Canalis sinuosus es una estructura anatómica normal habitual y no una variación anatómica, pero se requieren más estudios y consensos para aseverarlo. Es de relevancia clínica conocer la existencia y localización del Canalis sinuosus para evitar complicaciones.

Canalis sinuosus, an intraosseous canal located in the anterior maxillary region, contains anterosuperior alveolar vascular-nervous elements. Various interventions in anterior maxillary region such as implant placement, extractions, installation of orthodontic microscrews, surgical procedures, among others, can compromise the Canalis sinuosus and/or its accessory canals, damaging the elements contained inside, causing complications such as bleeding, paresthesia, dysesthesia, etc. Given the great ignorance of its existence, Canalis sinuosus is frequently confused with pathological and/or endodontic lesions. Classically, the literature describes it as an anatomical variation, however, it presents high prevalence (51.7 %-100 %), this assertion being questioned. Objective: to determine the prevalence and anatomical characteristics of Canalis sinuosus using Cone Beam CT in Chilean patients from the IMAPROX® radiological center between 2017-2021. Retrospective analysis of 220 anonymous maxillary CBCT, considering variables sex, presence of Canalis sinuosus, uni/bilateral Canalis sinuosus, largest diameter of Canalis sinuosus, presence/number of accessory canals. Univariate and bivariate statistical analysis. The 100 % prevalence of Canalis sinuosus in both sexes, 100 % bilateral presence. Canalis sinuosus average major diameter: 2.58 mm, 76.8 % presented accessory canals, with the presence of 2 accessory canals being more prevalent (34.1 %). A habitual normal anatomical structure must have a prevalence of over 50 % to be considered as such, but there is no consensus on the criteria used to define anatomical variation or normal anatomical structure. Literature describes Canalis sinuosus as anatomical variation, but current studies show high prevalence: Russia 67 %, Brazil 88 %, Turkey, Colombia and Chile 100 %. This study found 100 % prevalence, suggesting that Canalis sinuosus is an normal anatomical structure. However, Canalis sinuosus is little known as it is associated with numerous complications from dental and/or surgical procedures in anterior maxillary region, which can cause bleeding, paresthesia/ dysesthesia, acute pain, etc. High reported prevalences suggest that Canalis sinuosus is an normal anatomical structure and not an anatomical variation, but more studies and consensus are required to confirm this. It is clinically relevant to know the existence and location of Canalis sinuosus to avoid complications.

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.

El cuidado en los comportamientos sociales humanos durante la Prehistoria / Care in human social behaviour during Prehistory

En este trabajo se busca mostrar que los cuidados y los comportamientos sociales humanos estaban presentes ya durante la Prehistoria. A partir de las evidencias arqueológicas se puede observar cómo especies humanas anteriores a la nuestra desarrollaron complejas estructuras sociales en las que la importancia de la unión del grupo era fundamental para la supervivencia. El cuidado hacia niños, ancianos y enfermos, se demuestra gracias al análisis de los restos prehistóricos hallados y de la pervivencia de estos en el contexto arqueológico. Este cuidado prehistórico no solo fue físico, sino que también tuvo un componente psicológico y mental tanto en vida como después de la muerte

This paper seeks to show the reader, that human care and social behaviour were already present in Prehistory. From archaeological evidence it can be seen how ancient human species developed complex social structures in which the importance of unity was paramount to survival. Care for children, seniors and patients is demonstrated thanks to the analysis of the prehistoric remains found and their preservation in the archaeological context. This prehistoric care wasn't only physical, but also a psychological and mental component in life and after death

Intensive care medicine research agenda on invasive fungal infection in critically ill patients.

PURPOSE: To describe concisely the current standards of care, major recent advances, common beliefs that have been contradicted by recent trials, areas of uncertainty, and clinical studies that need to be performed over the next decade and their expected outcomes with regard to Candida and Aspergillus infections in non-neutropenic patients in the ICU setting. METHODS: A systematic review of the medical literature taking account of national and international guidelines and expert opinion. RESULTS: Severe invasive fungal infections (IFIs) are becoming increasingly frequent in critically ill patients. Approximately 80% of IFIs are due to Candida spp. and 0.3-19% to Aspergillus spp. Recent observations emphasize the necessity of building a worldwide sentinel network to monitor the emergence of new fungal species and changes in susceptibility. Robust data on the attributable mortality are essential for the design of clinical studies with mortality endpoints. Although early antifungal therapy for Candida has been recommended in patients with risk factors, sepsis of unknown cause, and positive Candida serum biomarkers [ß-1 â†’ 3-D-glucan (BDG) and Candida albicans germ tube antibody (CAGTA)], its usefulness and influence on outcome need to be confirmed. Future studies may specifically address the optimal diagnostic and therapeutic strategies for patients with abdominal candidiasis. Better knowledge of the pharmacokinetics of antifungal molecules and tissue penetration is a key issue for intensivists. Regarding invasive aspergillosis, further investigation is needed to determine its incidence in the ICU, its relationship with influenza outbreaks, the clinical impact of rapid diagnosis, and the significance of combination treatment. CONCLUSIONS: Fundamental questions regarding IFI have to be addressed over the next decade. The clinical studies described in this research agenda should provide a template and set priorities for the clinical investigations that need to be performed.

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.

A randomized, placebo-controlled trial of preemptive antifungal therapy for the prevention of invasive candidiasis following gastrointestinal surgery for intra-abdominal infections.

BACKGROUND: Patients undergoing emergency gastrointestinal surgery for intra-abdominal infection are at risk of invasive candidiasis (IC) and candidates for preemptive antifungal therapy. METHODS: This exploratory, randomized, double-blind, placebo-controlled trial assessed a preemptive antifungal approach with micafungin (100 mg/d) in intensive care unit patients requiring surgery for intra-abdominal infection. Coprimary efficacy variables were the incidence of IC and the time from baseline to first IC in the full analysis set; an independent data review board confirmed IC. An exploratory biomarker analysis was performed using logistic regression. RESULTS: The full analysis set comprised 124 placebo- and 117 micafungin-treated patients. The incidence of IC was 8.9% for placebo and 11.1% for micafungin (difference, 2.24%; [95% confidence interval, -5.52 to 10.20]). There was no difference between the arms in median time to IC. The estimated odds ratio showed that patients with a positive (1,3)-ß-d-glucan (ßDG) result were 3.66 (95% confidence interval, 1.01-13.29) times more likely to have confirmed IC than those with a negative result. CONCLUSIONS: This study was unable to provide evidence that preemptive administration of an echinocandin was effective in preventing IC in high-risk surgical intensive care unit patients with intra-abdominal infections. This may have been because the drug was administered too late to prevent IC coupled with an overall low number of IC events. It does provide some support for using ßDG to identify patients at high risk of IC. CLINICAL TRIALS REGISTRATION: NCT01122368.

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.

Empirical antifungal therapy with an echinocandin in critically-ill patients: prospective evaluation of a pragmatic Candida score-based strategy in one medical ICU.

BACKGROUND: Invasive candidiasis (IC) is a life-threatening ICU-acquired infection. A strong correlation between time to antifungal therapy (AFT) administration and outcome has been established. Empirical therapy benefit should be balanced with the risk of echinocandin overuse. We assessed therefore a decision rule that aimed at guiding empirical therapy. METHODS: A 45-month prospective cohort study in a teaching medical ICU. All of the patients with suspected IC (uncontrolled sepsis despite broad spectrum antibiotics without any bacterial proven infection in patients with Candida score ≥ 3 points including multifocal Candida sp. colonization) were eligible. The primary endpoint was proven IC diagnosis (i.e., candidemia) following treatment onset. Timing of AFT administration was also investigated in those latter patients. Antifungal therapy step-down and discontinuation was done according to international guidelines in patients with candidemia. Otherwise, echinocandin discontinuation was encouraged in patients without proven IC, excepting when a clinical improvement was achieved without any other explanation that antifungals initiation (i.e., probable IC). In addition, a survival multivariate analysis using a Cox model was conducted. RESULTS: Fifty-one patients were given an echinocandin with respect to our decision rule. Among them, candidemia was diagnosed thereafter in 9 patients. Over the same period, antifungal therapy was triggered by candidemia announcement (i.e., definite therapy) in 12 patients who did not fulfill criteria for empirical therapy before. Time elapsed from candidemia onset to echinocandin therapy initiation was shortened (0.4 [0.5] vs. 2.4 [2.8] hours; p = 0.04) when it was given empirically. In addition, 18 patients clinically improved under empirical antifungal therapy without any obvious other explanation, despite IC remained unproven. Moreover, echinocandin exposure duration was independently related to survival in those patients. Over the same period, our predefined criteria for empirical therapy were overruled in 55 cases. None of them develop IC thereafter. Finally, Our decision rule allowed IC early recognition of proven/probable IC with sensitivity, specificity, positive and negative predictive value of 69.2%, 82.1%, 69.2% and 82.1%, respectively. CONCLUSION: Implementation of pragmatic guidelines for empirical AFT based on CS and fungal colonization assessment could be useful in selecting patients who really benefit from an echinocandin.

What's new in the clinical and diagnostic management of invasive candidiasis in critically ill patients.

Invasive candidiasis (IC) is a severe complication in the ICU setting. A high proportion of ICU patients become colonized with Candida species, but only 5-30 % develop IC. Progressive colonization and major abdominal surgery are well-known risk factors for Candida infection. IC is difficult to predict and early diagnosis remains a major challenge. In addition, microbiological documentation often occurs late in the course of infection. Delays in initiating appropriate treatment have been associated with increased mortality. In an attempt to decrease Candida-related mortality, an increasing number of critically ill patients without documented IC receive empirical systemic antifungal therapy, leading to concern for antifungal overuse. Scores/predictive rules permit the stratification and selection of IC high-risk patients who may benefit from early antifungal therapy. However, they have a far better negative predictive value than positive predictive value. New IC biomarkers [mannan, anti-mannan, (1,3)-ß-D-glucan, and polymerase chain reaction] are being increasingly used to enable earlier diagnosis and, ideally, to provide prognostic information and/or therapeutic monitoring. Although reasonably sensitive and specific, these techniques remain largely investigational, and their clinical usefulness has yet to be established.

Biomarcadores en la sepsis. ¿Simplificando lo complejo? / Biomarkers in sepsis: Simplifying the complexity?

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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.

Assessment of candidemia-attributable mortality in critically ill patients using propensity score matching analysis.

INTRODUCTION: Candidemia in critically ill patients is usually a severe and life-threatening condition with a high crude mortality. Very few studies have focused on the impact of candidemia on ICU patient outcome and attributable mortality still remains controversial. This study was carried out to determine the attributable mortality of ICU-acquired candidemia in critically ill patients using propensity score matching analysis. METHODS: A prospective observational study was conducted of all consecutive non-neutropenic adult patients admitted for at least seven days to 36 ICUs in Spain, France, and Argentina between April 2006 and June 2007. The probability of developing candidemia was estimated using a multivariate logistic regression model. Each patient with ICU-acquired candidemia was matched with two control patients with the nearest available Mahalanobis metric matching within the calipers defined by the propensity score. Standardized differences tests (SDT) for each variable before and after matching were calculated. Attributable mortality was determined by a modified Poisson regression model adjusted by those variables that still presented certain misalignments defined as a SDT > 10%. RESULTS: Thirty-eight candidemias were diagnosed in 1,107 patients (34.3 episodes/1,000 ICU patients). Patients with and without candidemia had an ICU crude mortality of 52.6% versus 20.6% (P < 0.001) and a crude hospital mortality of 55.3% versus 29.6% (P = 0.01), respectively. In the propensity matched analysis, the corresponding figures were 51.4% versus 37.1% (P = 0.222) and 54.3% versus 50% (P = 0.680). After controlling residual confusion by the Poisson regression model, the relative risk (RR) of ICU- and hospital-attributable mortality from candidemia was RR 1.298 (95% confidence interval (CI) 0.88 to 1.98) and RR 1.096 (95% CI 0.68 to 1.69), respectively. CONCLUSIONS: ICU-acquired candidemia in critically ill patients is not associated with an increase in either ICU or hospital mortality.

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.