Publications by authors named "Lorenzo Socias"

26 Publications

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Cardiac arrest following unsuspected self-poisoning with doxylamine.

Ther Drug Monit 2022 Jan 11. Epub 2022 Jan 11.

Clinical Toxicology Unit, Clinical Analysis Department. Hospital Universitari Son Llàtzer. Research Institute of Health Sciences (IdISBa). Palma de Mallorca, Spain. Intensive Care Department. Hospital Universitari Son Llàtzer. Research Institute of Health Sciences (IdISBa). Palma de Mallorca, Spain. Intensive Care Department. Hospital Universitari Son Llàtzer. Research Institute of Health Sciences (IdISBa). Palma de Mallorca, Spain. Intensive Care Department. Hospital Universitari Son Llàtzer. Research Institute of Health Sciences (IdISBa). Palma de Mallorca, Spain. Cardiology Department. Hospital Universitari Son Llàtzer. Department of Medicine, Faculty of Medicine, University of the Balearic Islands. Research Institute of Health Sciences (IdISBa). Palma de Mallorca, Spain. Institute of Legal Medicine of the Balearic Islands. Ministry of Justice. Department of Medicine, Faculty of Medicine, University of the Balearic Islands. Palma de Mallorca, Spain. Institute of Legal Medicine of the Balearic Islands. Ministry of Justice. Department of Medicine, Faculty of Medicine, University of the Balearic Islands. Palma de Mallorca, Spain.

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http://dx.doi.org/10.1097/FTD.0000000000000960DOI Listing
January 2022

ICU-Acquired Pneumonia Is Associated with Poor Health Post-COVID-19 Syndrome.

J Clin Med 2021 Dec 31;11(1). Epub 2021 Dec 31.

Hospital de Mataró de Barcelona, 08301 Mataró, Spain.

Background: Some patients previously presenting with COVID-19 have been reported to develop persistent COVID-19 symptoms. While this information has been adequately recognised and extensively published with respect to non-critically ill patients, less is known about the incidence and factors associated with the characteristics of persistent COVID-19. On the other hand, these patients very often have intensive care unit-acquired pneumonia (ICUAP). A second infectious hit after COVID increases the length of ICU stay and mechanical ventilation and could have an influence on poor health post-COVID 19 syndrome in ICU-discharged patients.

Methods: This prospective, multicentre, and observational study was carrid out across 40 selected ICUs in Spain. Consecutive patients with COVID-19 requiring ICU admission were recruited and evaluated three months after hospital discharge.

Results: A total of 1255 ICU patients were scheduled to be followed up at 3 months; however, the final cohort comprised 991 (78.9%) patients. A total of 315 patients developed ICUAP (97% of them had ventilated ICUAP). Patients requiring invasive mechanical ventilation had more persistent post-COVID-19 symptoms than those who did not require mechanical ventilation. Female sex, duration of ICU stay, development of ICUAP, and ARDS were independent factors for persistent poor health post-COVID-19.

Conclusions: Persistent post-COVID-19 symptoms occurred in more than two-thirds of patients. Female sex, duration of ICU stay, development of ICUAP, and ARDS all comprised independent factors for persistent poor health post-COVID-19. Prevention of ICUAP could have beneficial effects in poor health post-COVID-19.
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http://dx.doi.org/10.3390/jcm11010224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8746263PMC
December 2021

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.

Lancet Reg Health Eur 2021 Dec 4;11:100243. Epub 2021 Nov 4.

Critical Care Department, Hospital Universitari Joan XXIII, Tarragona, Spain.

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], <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%, <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%, <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% ( = 1166), without significant differences between study periods (first wave 31·7% vs second/third waves 28·8%,  = 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%,  = 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;  = 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, <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.
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http://dx.doi.org/10.1016/j.lanepe.2021.100243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566166PMC
December 2021

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients.

Crit Care 2021 09 13;25(1):331. Epub 2021 Sep 13.

Department of Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission.

Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes.

Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO/FiO increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO/FiO variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47).

Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO/FiO variation.
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http://dx.doi.org/10.1186/s13054-021-03727-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436582PMC
September 2021

Early oseltamivir treatment improves survival in critically ill patients with influenza pneumonia.

ERJ Open Res 2021 Jan 8;7(1). Epub 2021 Mar 8.

Servei de Pneumologia i Al·lèrgia Respiratòria, Institut Clínic del Tórax, Hospital Clínic de Barcelona, CIBERES, Barcelona, Spain.

Background: The relationship between early oseltamivir treatment (within 48 h of symptom onset) and mortality in patients admitted to intensive care units (ICUs) with severe influenza is disputed. This study aimed to investigate the association between early oseltamivir treatment and ICU mortality in critically ill patients with influenza pneumonia.

Methods: This was an observational study of patients with influenza pneumonia admitted to 184 ICUs in Spain during 2009-2018. The primary outcome was to evaluate the association between early oseltamivir treatment and ICU mortality compared with later treatment. Secondary outcomes were to compare the duration of mechanical ventilation and ICU length of stay between the early and later oseltamivir treatment groups. To reduce biases related to observational studies, propensity score matching and a competing risk analysis were performed.

Results: During the study period, 2124 patients met the inclusion criteria. All patients had influenza pneumonia and received oseltamivir before ICU admission. Of these, 529 (24.9%) received early oseltamivir treatment. In the multivariate analysis, early treatment was associated with reduced ICU mortality (OR 0.69, 95% CI 0.51-0.95). After propensity score matching, early oseltamivir treatment was associated with improved survival rates in the Cox regression (hazard ratio 0.77, 95% CI 0.61-0.99) and competing risk (subdistribution hazard ratio 0.67, 95% CI 0.53-0.85) analyses. The ICU length of stay and duration of mechanical ventilation were shorter in patients receiving early treatment.

Conclusions: Early oseltamivir treatment is associated with improved survival rates in critically ill patients with influenza pneumonia, and may decrease ICU length of stay and mechanical ventilation duration.
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http://dx.doi.org/10.1183/23120541.00888-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938052PMC
January 2021

Low Albumin Levels Are Associated with Poorer Outcomes in a Case Series of COVID-19 Patients in Spain: A Retrospective Cohort Study.

Microorganisms 2020 Jul 24;8(8). Epub 2020 Jul 24.

Vascular and Metabolic Pathologies Group, Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain.

There is limited information available describing the clinical and epidemiological features of Spanish patients requiring hospitalization for coronavirus disease 2019 (COVID-19). In this observational study, we aimed to describe the clinical characteristics and epidemiological features of severe (non-ICU) and critically patients (ICU) with COVID-19 at triage, prior to hospitalization. Forty-eight patients (27 non-ICU and 21 ICU) with positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were analyzed (mean age, 66 years, [range, 33-88 years]; 67% males). There were no differences in age or sex among groups. Initial symptoms included fever (100%), coughing (85%), dyspnea (76%), diarrhea (42%) and asthenia (21%). ICU patients had a higher prevalence of dyspnea compared to non-ICU patients (95% vs. 61%, = 0.022). ICU-patients had lymphopenia as well as hypoalbuminemia. Lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin were significantly higher in ICU patients compared to non-ICU ( < 0.001). Lower albumin levels were associated with poor prognosis measured as longer hospital length (r = -0.472, < 0.001) and mortality (r = -0.424, = 0.003). As of 28 April 2020, 10 patients (8 ICU and 2 non-ICU) have died (21% mortality), and while 100% of the non-ICU patients have been discharged, 33% of the ICU patients still remained hospitalized (5 in ICU and 2 had been transferred to ward). Critically ill patients with COVID-19 present lymphopenia, hypoalbuminemia and high levels of inflammation.
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http://dx.doi.org/10.3390/microorganisms8081106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463882PMC
July 2020

Transcriptomic depression of immunological synapse as a signature of ventilator-associated pneumonia.

Ann Transl Med 2018 Nov;6(21):415

Intensive Care Medicine, Trinity Centre for Health Sciences, St James's University Hospital, Dublin, Ireland.

Background: Ventilator-associated pneumonia (VAP) is one of the most commonly encountered intensive care unit (ICU) acquired infections worldwide. The objective of the study was to identify the immune alteration occurring in patients suffering from VAP at the transcriptomic level and explore its potential use for clinical diagnoses of this disease.

Methods: We performed a prospective observational study in five medical ICUs. Immunological gene expression profiles in the blood of VAP patients were compared with those of controls by using whole transcriptome microarrays and droplet digital polymerase chain reaction (ddPCR) in the first 24 hours following diagnosis.

Results: VAP patients showed significantly lower expression levels of HLA-DOA, HLA-DMA, HLA-DMB, ICOS, ICOSLG, IL2RA, CD1, CD3, CD28 and CD40LG. The molecules coded by these genes participate of the immunological synapse. CD1C, CD40LG and ICOS showed the highest values of area under the receiver operating characteristic curve (AUROC) with a good balance between sensibility and specificity.

Conclusions: Patients with VAP show a transcriptomic depression of genes participating of the immunological synapse. It takes a commonplace event, namely VAP, and highlights a quite significant underlying immune suppressive state. In effect this small study will change how we regard VAP, and proposes that we regard it as an infection in an immune compromised host, and that immunity has a central role for ICU acquired infections. This may in time change clinical practice, as it has profound implications for the role of protocolised care, or bundles, in the prevention of VAP. Quantifying the expression in blood of this genes using ddPCR could be a useful approach for the diagnosis of VAP.
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http://dx.doi.org/10.21037/atm.2018.05.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275407PMC
November 2018

Corticosteroid treatment in critically ill patients with severe influenza pneumonia: a propensity score matching study.

Intensive Care Med 2018 Sep 3;44(9):1470-1482. Epub 2018 Aug 3.

Department of Anaesthesia and Critical Care, St James ́s University Hospital, Trinity Centre for Health Sciences, Multidisciplinary Intensive Care Research Organization (MICRO), Dublin, Ireland.

Purpose: To determine clinical predictors associated with corticosteroid administration and its association with ICU mortality in critically ill patients with severe influenza pneumonia.

Methods: Secondary analysis of a prospective cohort study of critically ill patients with confirmed influenza pneumonia admitted to 148 ICUs in Spain between June 2009 and April 2014. Patients who received corticosteroid treatment for causes other than viral pneumonia (e.g., refractory septic shock and asthma or chronic obstructive pulmonary disease [COPD] exacerbation) were excluded. Patients with corticosteroid therapy were compared with those without corticosteroid therapy. We use a propensity score (PS) matching analysis to reduce confounding factors. The primary outcome was ICU mortality. Cox proportional hazards and competing risks analysis was performed to assess the impact of corticosteroids on ICU mortality.

Results: A total of 1846 patients with primary influenza pneumonia were enrolled. Corticosteroids were administered in 604 (32.7%) patients, with methylprednisolone the most frequently used corticosteroid (578/604 [95.7%]). The median daily dose was equivalent to 80 mg of methylprednisolone (IQR 60-120) for a median duration of 7 days (IQR 5-10). Asthma, COPD, hematological disease, and the need for mechanical ventilation were independently associated with corticosteroid use. Crude ICU mortality was higher in patients who received corticosteroids (27.5%) than in patients who did not receive corticosteroids (18.8%, p < 0.001). After PS matching, corticosteroid use was associated with ICU mortality in the Cox (HR = 1.32 [95% CI 1.08-1.60], p < 0.006) and competing risks analysis (SHR = 1.37 [95% CI 1.12-1.68], p = 0.001).

Conclusion: Administration of corticosteroids in patients with severe influenza pneumonia is associated with increased ICU mortality, and these agents should not be used as co-adjuvant therapy.
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http://dx.doi.org/10.1007/s00134-018-5332-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095489PMC
September 2018

Lower Respiratory Tract Infection and Short-Term Outcome in Patients With Acute Respiratory Distress Syndrome.

J Intensive Care Med 2020 Jun 26;35(6):588-594. Epub 2018 Apr 26.

Multidisciplinary Intensive Care, St James's University Hospital, Dublin, Ireland.

Objective: To assess whether ventilator-associated lower respiratory tract infections (VA-LRTIs) are associated with mortality in critically ill patients with acute respiratory distress syndrome (ARDS).

Materials And Methods: Post hoc analysis of prospective cohort study including mechanically ventilated patients from a multicenter prospective observational study (TAVeM study); VA-LRTI was defined as either ventilator-associated tracheobronchitis (VAT) or ventilator-associated pneumonia (VAP) based on clinical criteria and microbiological confirmation. Association between intensive care unit (ICU) mortality in patients having ARDS with and without VA-LRTI was assessed through logistic regression controlling for relevant confounders. Association between VA-LRTI and duration of mechanical ventilation and ICU stay was assessed through competing risk analysis. Contribution of VA-LRTI to a mortality model over time was assessed through sequential random forest models.

Results: The cohort included 2960 patients of which 524 fulfilled criteria for ARDS; 21% had VA-LRTI (VAT = 10.3% and VAP = 10.7%). After controlling for illness severity and baseline health status, we could not find an association between VA-LRTI and ICU mortality (odds ratio: 1.07; 95% confidence interval: 0.62-1.83; P = .796); VA-LRTI was also not associated with prolonged ICU length of stay or duration of mechanical ventilation. The relative contribution of VA-LRTI to the random forest mortality model remained constant during time. The attributable VA-LRTI mortality for ARDS was higher than the attributable mortality for VA-LRTI alone.

Conclusion: After controlling for relevant confounders, we could not find an association between occurrence of VA-LRTI and ICU mortality in patients with ARDS.
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http://dx.doi.org/10.1177/0885066618772498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272129PMC
June 2020

Procalcitonin (PCT) levels for ruling-out bacterial coinfection in ICU patients with influenza: A CHAID decision-tree analysis.

J Infect 2016 Feb 15;72(2):143-51. Epub 2015 Dec 15.

Multidisciplinary Intensive Care Research Organization (MICRO), Department of Anaesthesia and Critical Care, St James's University Hospital, Trinity Centre for Health Sciences, Dublin, Ireland. Electronic address:

Objectives: To define which variables upon ICU admission could be related to the presence of coinfection using CHAID (Chi-squared Automatic Interaction Detection) analysis.

Methods: A secondary analysis from a prospective, multicentre, observational study (2009-2014) in ICU patients with confirmed A(H1N1)pdm09 infection. We assessed the potential of biomarkers and clinical variables upon admission to the ICU for coinfection diagnosis using CHAID analysis. Performance of cut-off points obtained was determined on the basis of the binominal distributions of the true (+) and true (-) results.

Results: Of the 972 patients included, 196 (20.3%) had coinfection. Procalcitonin (PCT; ng/mL 2.4 vs. 0.5, p < 0.001), but not C-reactive protein (CRP; mg/dL 25 vs. 38.5; p = 0.62) was higher in patients with coinfection. In CHAID analyses, PCT was the most important variable for coinfection. PCT <0.29 ng/mL showed high sensitivity (Se = 88.2%), low Sp (33.2%) and high negative predictive value (NPV = 91.9%). The absence of shock improved classification capacity. Thus, for PCT <0.29 ng/mL, the Se was 84%, the Sp 43% and an NPV of 94% with a post-test probability of coinfection of only 6%.

Conclusion: PCT has a high negative predictive value (94%) and lower PCT levels seems to be a good tool for excluding coinfection, particularly for patients without shock.
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http://dx.doi.org/10.1016/j.jinf.2015.11.007DOI Listing
February 2016

Clinical and Prognostic Profiles of Cardiomyopathies Caused by Mutations in the Troponin T Gene.

Rev Esp Cardiol (Engl Ed) 2016 Feb 24;69(2):149-58. Epub 2015 Oct 24.

Sección de Genética, Hospital Son Espases, Palma de Mallorca, Balearic Islands, Spain.

Introduction And Aims: Mutations in the troponin T gene (TTNT2) have been associated in small studies with the development of hypertrophic cardiomyopathy characterized by a high risk of sudden death and mild hypertrophy. We describe the clinical course of patients carrying mutations in this gene.

Methods: We analyzed the clinical characteristics and prognosis of patients with mutations in the TNNT2 gene who were seen in an inherited cardiac disease unit.

Results: Of 180 families with genetically studied cardiomyopathies, 21 families (11.7%) were identified as having mutations in TNNT2: 10 families had Arg92Gln, 5 had Arg286His, 3 had Arg278Cys, 1 had Arg92Trp, 1 had Arg94His, and 1 had Ile221Thr. Thirty-three additional genetic carriers were identified through family assessment. The study included 54 genetic carriers: 56% were male, and the mean average age was 41 ± 17 years. There were 33 cases of hypertrophic cardiomyopathy, 9 of dilated cardiomyopathy, and 1 of noncompaction cardiomyopathy, and maximal myocardial thickness was 18.5 ± 6mm. Ventricular dysfunction was present in 30% of individuals and a history of sudden death in 62%. During follow-up, 4 patients died and 14 (33%) received a defibrillator (8 probands, 6 relatives). Mean survival was 54 years. Carriers of Arg92Gln had early disease development, high penetrance, a high risk of sudden death, a high rate of defibrillator implantation, and a high frequency of mixed phenotype.

Conclusions: Mutations in the TNNT2 gene were more common in this series than in previous studies. The clinical and prognostic profiles depended on the mutation present. Carriers of the Arg92Gln mutation developed hypertrophic or dilated cardiomyopathy and had a significantly worse prognosis than those with other mutations in TNNT2 or other sarcomeric genes.
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http://dx.doi.org/10.1016/j.rec.2015.06.025DOI Listing
February 2016

IgA level in plasma as a differential factor for influenza infection in severe viral pneumonia.

J Clin Virol 2014 Feb 12;59(2):135-6. Epub 2013 Dec 12.

Unidad de Investigación Biomédica, Hospital Clínico Universitario de Valladolid (ibC), SACYL/IECSCYL, Avda Ramón y Cajal 3, 47005 Valladolid, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.jcv.2013.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7128445PMC
February 2014

IgM levels in plasma predict outcome in severe pandemic influenza.

J Clin Virol 2013 Nov 18;58(3):564-7. Epub 2013 Sep 18.

Servicio de Microbiología, Hospital Clínico Universitario de Valladolid, SACYL, Avda Ramón y Cajal 3, 47005 Valladolid, Spain(2).

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.
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http://dx.doi.org/10.1016/j.jcv.2013.09.006DOI Listing
November 2013

Critical COPD respiratory illness is linked to increased transcriptomic activity of neutrophil proteases genes.

BMC Res Notes 2012 Aug 2;5:401. Epub 2012 Aug 2.

Investigación Biomédica del Clínico (ibC), Hospital Clínico Universitario de Valladolid, Avda Ramón y Cajal 3, 47005 Valladolid, Spain.

Background: Gene expression profiling (GEP) in cells obtained from peripheral blood has shown that this is a very useful approach for biomarker discovery and for studying molecular pathogenesis of prevalent diseases. While there is limited literature available on gene expression markers associated with Chronic Obstructive Pulmonary Disease (COPD), the transcriptomic picture associated with critical respiratory illness in this disease is not known at the present moment.

Findings: By using Agilent microarray chips, we have profiled gene expression signatures in the whole blood of 28 COPD patients hospitalized with different degrees of respiratory compromise.12 of them needed of admission to the ICU, whilst 16 were admitted to the Respiratory Medicine Service. GeneSpring GX 11.0 software was used for performing statistical comparisons of transcript levels between ICU and non-ICU patients. Ingenuity pathway analysis 8.5 (IPA) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to select, annotate and visualize genes by function and pathway (gene ontology). T-test showed evidence of 1501 genes differentially expressed between ICU and non-ICU patients. IPA and KEGG analysis of the most representative biological functions revealed that ICU patients had increased levels of neutrophil gene transcripts, being [cathepsin G (CTSG)], [elastase, neutrophil expressed (ELANE)], [proteinase 3 (PRTN3)], [myeloperoxidase (MPO)], [cathepsin D (CTSD)], [defensin, alpha 3, neutrophil-specific (DEFA3)], azurocidin 1 (AZU1)], and [bactericidal/permeability-increasing protein (BPI)] the most representative ones. Proteins codified by these genes form part of the azurophilic granules of neutrophils and are involved in both antimicrobial defence and tissue damage. This "neutrophil signature" was paralleled by the necessity of advanced respiratory and vital support, and the presence of bacterial infection.

Conclusion: Study of transcriptomic signatures in blood suggests an essential role of neutrophil proteases in COPD patients with critical respiratory illness. Measurement and modulation of the expression of these genes could present an option for clinical monitoring and treatment of severe COPD exacerbations.
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http://dx.doi.org/10.1186/1756-0500-5-401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475085PMC
August 2012

Viral infection is associated with an increased proinflammatory response in chronic obstructive pulmonary disease.

Viral Immunol 2012 Aug 2;25(4):249-53. Epub 2012 Jul 2.

Infection and Immunity Medical Investigation Unit, Hospital Clínico Universitario de Valladolid-IECSCYL, Valladolid, Spain.

The development of new diagnostic methods based on molecular biology has led to evidence of the important role of respiratory viruses in chronic obstructive pulmonary disease (COPD) exacerbations. Cytokines and chemokines are recognized as key actors in the pathogenesis of COPD. The objective of this study was to evaluate the association between viral infection and host cytokine responses in 57 COPD patients hospitalized with an acute exacerbation. Seventeen cytokines were profiled using a Luminex-Biorad multiplex assay in plasma samples collected in the first 24 h following hospital admission. Stepwise linear regression analysis was performed, taking into account the influence of seven potential confounding factors in the results. Twenty-four out of 57 showed radiological signs of community-acquired pneumonia (CAP) at hospital admission, 25 patients required admission to the intensive care unit (ICU), 20 had a bacterial infection, and 20 showed a detectable respiratory virus in pharyngeal swabs. Regression analysis showed that viral infection correlated with higher levels of interleukin-6 (IL-6) (log value of the coefficient of regression B, p=0.47, 0.044), and monocyte chemoattractant protein-1 (MCP-1) (p=0.43, 0.019), and increased admission to the ICU. Viral infection also correlated with higher levels of interferon-γ (IFN-γ) (p=0.70, 0.026), which, in turn, was inversely associated with the severity of illness. Finally, viral infection was independently associated with higher levels of tumor necrosis factor-α (TNF-α) (p=0.40, 0.002). Thus our study demonstrates that in patients with COPD exacerbations, viral infection is directly associated with higher systemic levels of cytokines central to the development of the antiviral response, which are also known to contribute to inflammation-mediated tissue damage. These results reveal a potential specific role of viral infection in the pathogenesis of COPD exacerbations.
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http://dx.doi.org/10.1089/vim.2011.0095DOI Listing
August 2012

Interleukin-6 is a potential biomarker for severe pandemic H1N1 influenza A infection.

PLoS One 2012 5;7(6):e38214. Epub 2012 Jun 5.

Division of Experimental Therapeutics, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.

Pandemic H1N1 influenza A (H1N1pdm) is currently a dominant circulating influenza strain worldwide. Severe cases of H1N1pdm infection are characterized by prolonged activation of the immune response, yet the specific role of inflammatory mediators in disease is poorly understood. The inflammatory cytokine IL-6 has been implicated in both seasonal and severe pandemic H1N1 influenza A (H1N1pdm) infection. Here, we investigated the role of IL-6 in severe H1N1pdm infection. We found IL-6 to be an important feature of the host response in both humans and mice infected with H1N1pdm. Elevated levels of IL-6 were associated with severe disease in patients hospitalized with H1N1pdm infection. Notably, serum IL-6 levels associated strongly with the requirement of critical care admission and were predictive of fatal outcome. In C57BL/6J, BALB/cJ, and B6129SF2/J mice, infection with A/Mexico/4108/2009 (H1N1pdm) consistently triggered severe disease and increased IL-6 levels in both lung and serum. Furthermore, in our lethal C57BL/6J mouse model of H1N1pdm infection, global gene expression analysis indicated a pronounced IL-6 associated inflammatory response. Subsequently, we examined disease and outcome in IL-6 deficient mice infected with H1N1pdm. No significant differences in survival, weight loss, viral load, or pathology were observed between IL-6 deficient and wild-type mice following infection. Taken together, our findings suggest IL-6 may be a potential disease severity biomarker, but may not be a suitable therapeutic target in cases of severe H1N1pdm infection due to our mouse data.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038214PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367995PMC
October 2012

Elevation of creatine kinase is associated with worse outcomes in 2009 pH1N1 influenza A infection.

Intensive Care Med 2012 Jul 18;38(7):1152-61. Epub 2012 Apr 18.

Critical Care Department, Vall D'Hebron University Hospital, Universitat Autònoma de Barcelona (UAB), 08035, Barcelona, Spain.

Background: Current medical knowledge lacks specific information regarding creatine kinase (CK) elevation in influenza A pH1N1 (2009) infection.

Objectives: Primary endpoints were correlation between CK at intensive care unit (ICU) admission and ICU mortality. Secondary endpoints were ICU length of stay (LOS), mechanical ventilation (MV), and requirement of renal replacement techniques (RRT).

Materials And Methods: A prospective multicenter register included all adults admitted for severe acute respiratory insufficiency (SARI) with confirmed pH1N1 in 148 ICUs. Clinical data including demographics, comorbidities, laboratory information, organ involvement, and prognostic data were registered. Post hoc classification of subjects was determined according to CK level. Data are expressed as median (interquartile range).

Results: Five hundred and five (505) patients were evaluable. Global ICU mortality was 17.8 % without documented differences between breakpoints. CK ≥500 UI/L was documented in 23.8 % of ICU admissions, being associated with greater renal dysfunction: acute kidney injury (AKI) was more frequent (26.1 versus 17.1 %, p < 0.05) and twofold requirement of RRT [11 versus 5.6 %, p < 0.05; odds ratio (OR) = 2.09 (95 % confidence interval [CI] 1.01-4.32)]. Increase of CK ≥1,000 UI/L was associated with two or more quadrant involvement on chest X-ray (63.2 versus 40.2 %, p < 0.01) and increased intubation risk (73.9 versus 56.7 %, p = 0.07) and duration of mechanical ventilation (median 15 days versus 11 days, p < 0.01). As a result, CK ≥1,000 UI/L was associated with 5 extra days of ICU and hospital LOS.

Conclusions: CK is a biomarker of severity in pH1N1 infection. Elevation of CK was associated with more complications and increased ICU LOS and healthcare resources.
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http://dx.doi.org/10.1007/s00134-012-2565-5DOI Listing
July 2012

Corticosteroid therapy in patients with primary viral pneumonia due to pandemic (H1N1) 2009 influenza.

J Infect 2012 Mar 2;64(3):311-8. Epub 2012 Jan 2.

Critical Care Department, Hospital Sant Joan Despí Moisès Broggi, Jacint Verdaguer, 90, 08970 Sant Joan Despí, Barcelona, CIBERES, IISPV, Spain.

Objective: During the first pandemic, some patients with pandemic (H1N1) 2009 influenza were treated with corticosteroids. The objective of this study was to assess the effect on survival of corticosteroid therapy in patients with pandemic (H1N1) 2009 influenza.

Methods: Prospective, observational, multicenter study performed in 148 ICU. Data were recorded in the GTEI/SEMICYUC registry. Adult patients with pandemic (H1N1) 2009 influenza confirmed by rt-PCR were included in the analysis. Database records specified corticosteroid type and reason for corticosteroid treatment.

Results: 372 patients with the diagnosis of primary viral pneumonia and completed outcomes treated in an ICU were included in the database. Mechanical ventilation was used in 70.2% of the patients. 136 (36.6%) patients received corticosteroids after a diagnosis of primary viral pneumonia. Obesity (35.6% vs 47.8% p = 0.021) and asthma (7.6% vs 15.4% p = 0.018), were more frequent in the group treated with corticosteroids. A Cox regression analysis adjusted for severity and potential confounding factors found that the use of corticosteroid therapy was not significantly associated with mortality (HR = 1.06, 95% CI 0.626-1.801; p = 0.825).

Conclusions: Corticosteroid therapy in a selected group of patients with primary viral pneumonia due to pandemic (H1N1) 2009 influenza does not improve survival.
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http://dx.doi.org/10.1016/j.jinf.2011.12.010DOI Listing
March 2012

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

BMC Infect Dis 2011 Aug 31;11:232. Epub 2011 Aug 31.

Infection & Immunity Medical Investigation Unit (IMI), Hospital Clínico Universitario-IECSCYL, Avda Ramón, y Cajal 3, 47005 Valladolid, Spain.

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-1β, 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.
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http://dx.doi.org/10.1186/1471-2334-11-232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175217PMC
August 2011

Acute kidney injury in critical ill patients affected by influenza A (H1N1) virus infection.

Crit Care 2011 Feb 22;15(1):R66. Epub 2011 Feb 22.

Critical Care Department, Joan XXIII University Hospital-CIBER Enfermedades Respiratorias, URV, and IISPV, Mallafre i Guasch, ES-43007 Tarragona, Spain.

Introduction: Little information exists about the impact of acute kidney injury (AKI) in critically ill patients with the pandemic 2009 influenza A (H1N1) virus infection.

Methods: We conducted a prospective, observational, multicenter study in 148 Spanish intensive care units (ICUs). Patients with chronic renal failure were excluded. AKI was defined according to Acute Kidney Injury Network (AKIN) criteria.

Results: A total of 661 patients were analyzed. One hundred eighteen (17.7%) patients developed AKI; of these, 37 (31.4%) of the patients with AKI were classified as AKI I, 15 (12.7%) were classified as AKI II and 66 (55.9%) were classified as AKI III, among the latter of whom 50 (75.7%) required continuous renal replacement therapy. Patients with AKI had a higher Acute Physiology and Chronic Health Evaluation II score (19.2 ± 8.3 versus 12.6 ± 5.9; P < 0.001), a higher Sequential Organ Failure Assessment score (8.7 ± 4.2 versus 4.8 ± 2.9; P < 0.001), more need for mechanical ventilation (MV) (87.3% versus 56.2%; P < 0.01, odds ratio (OR) 5.3, 95% confidence interval (CI) 3.0 to 9.4), a greater incidence of shock (75.4% versus 38.3%; P < 0.01, OR 4.9, 95% CI, 3.1 to 7.7), a greater incidence of multiorgan dysfunction syndrome (92.4% versus 54.7%; P < 0.01, OR 10.0, 95% CI, 4.9 to 20.21) and a greater incidence of coinfection (23.7% versus 14.4%; P < 0.01, OR 1.8, 95% CI, 1.1 to 3.0). In survivors, patients with AKI remained on MV longer and ICU and hospital length of stay were longer than in patients without AKI. The overall mortality was 18.8% and was significantly higher for AKI patients (44.1% versus 13.3%; P < 0.01, OR 5.1, 95% CI, 3.3 to 7.9). Logistic regression analysis was performed with AKIN criteria, and it demonstrated that among patients with AKI, only AKI III was independently associated with higher ICU mortality (P < 0.001, OR 4.81, 95% CI 2.17 to 10.62).

Conclusions: In our cohort of patients with H1N1 virus infection, only those cases in the AKI III category were independently associated with mortality.
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http://dx.doi.org/10.1186/cc10046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221999PMC
February 2011

Host adaptive immunity deficiency in severe pandemic influenza.

Crit Care 2010 14;14(5):R167. Epub 2010 Sep 14.

Infection & Immunity Unit, Hospital Clínico Universitario-IECSCYL, Avda, Ramón y Cajal 3, 47005 Valladolid, Spain.

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.
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http://dx.doi.org/10.1186/cc9259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219262PMC
September 2011

Intensive care adult patients with severe respiratory failure caused by Influenza A (H1N1)v in Spain.

Crit Care 2009 11;13(5):R148. Epub 2009 Sep 11.

Critical Care Department, Joan XXIII University Hospital, CIBERes Enfermedades Respiratorias, IISPV, Mallafre Guasch 4, 43007 Tarragona, Spain.

Introduction: Patients with influenza A (H1N1)v infection have developed rapidly progressive lower respiratory tract disease resulting in respiratory failure. We describe the clinical and epidemiologic characteristics of the first 32 persons reported to be admitted to the intensive care unit (ICU) due to influenza A (H1N1)v infection in Spain.

Methods: We used medical chart reviews to collect data on ICU adult patients reported in a standardized form. Influenza A (H1N1)v infection was confirmed in specimens using real-time reverse transcriptase-polymerase-chain-reaction (RT PCR) assay.

Results: Illness onset of the 32 patients occurred between 23 June and 31 July, 2009. The median age was 36 years (IQR = 31 - 52). Ten (31.2%) were obese, 2 (6.3%) pregnant and 16 (50%) had pre-existing medical complications. Twenty-nine (90.6%) had primary viral pneumonitis, 2 (6.3%) exacerbation of structural respiratory disease and 1 (3.1%) secondary bacterial pneumonia. Twenty-four patients (75.0%) developed multiorgan dysfunction, 7 (21.9%) received renal replacement techniques and 24 (75.0%) required mechanical ventilation. Six patients died within 28 days, with two additional late deaths. Oseltamivir administration delay ranged from 2 to 8 days after illness onset, 31.2% received high-dose (300 mg/day), and treatment duration ranged from 5 to 10 days (mean 8.0 +/- 3.3).

Conclusions: Over a 5-week period, influenza A (H1N1)v infection led to ICU admission in 32 adult patients, with frequently observed severe hypoxemia and a relatively high case-fatality rate. Clinicians should be aware of pulmonary complications of influenza A (H1N1)v infection, particularly in pregnant and young obese but previously healthy persons.
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http://dx.doi.org/10.1186/cc8044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784367PMC
March 2010
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