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Background: Community-acquired pneumonia (CAP) is associated with high morbidity and hospitalization rate. In infectious diseases, host genetics plays a critical role in susceptibility and immune response, and the immune pathways involved are highly dependent on the microorganism and its route of infection. Here we aimed to identify genetic risk loci for CAP using a case-control genome-wide association study (GWAS)., Methods: We performed a GWAS on 3,765 Spanish individuals, including 257 adult patients hospitalized with CAP and 3,508 population controls. Pneumococcal CAP was documented in 30% of patients; the remaining 70% were selected among patients with unidentified microbiological etiology. We tested 7,6 million imputed genotypes using logistic regressions. UK Biobank GWAS of bacterial pneumonia were used for results validation. Subsequently, we prioritized genes and likely causal variants based on Bayesian fine mapping and functional evidence. Imputation and association of classical HLA alleles and amino acids were also conducted., Results: Six independent sentinel variants reached the genome-wide significance (p < 5 × 10 -8 ), three on chromosome 6p21.32, and one for each of the chromosomes 4q28.2, 11p12, and 20q11.22. Only one variant at 6p21.32 was validated in independent GWAS of bacterial and pneumococcal pneumonia. Our analyses prioritized C4orf33 on 4q28.2, TAPBP on 6p21.32, and ZNF341 on 20q11.22. Interestingly, genetic defects of TAPBP and ZNF341 are previously known inborn errors of immunity predisposing to bacterial pneumonia, including pneumococcus and Haemophilus influenzae. Associations were all non-significant for the classical HLA alleles., Conclusions: We completed a GWAS of CAP and identified four novel risk loci involved in CAP susceptibility., (© 2024. The Author(s).)

Background Aims: There are currently no effective anti-viral treatments for coronavirus disease 2019 (COVID-19)-hospitalized patients with hypoxemia. Lymphopenia is a biomarker of disease severity usually present in patients who are hospitalized. Approaches to increasing lymphocytes exerting an anti-viral effect must be considered to treat these patients. Following our phase 1 study, we performed a phase 2 randomized multicenter clinical trial in which we evaluated the efficacy of the infusion of allogeneic off-the-shelf CD45RA - memory T cells containing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells from convalescent donors plus the standard of care (SoC) versus just the SoC treatment., Methods: Eighty-four patients were enrolled in three Spanish centers. The patients were randomized into the infusion of 1 × 10 6 /kg CD45RA - memory T cells or the SoC. We selected four unvaccinated donors based on the expression of interferon gamma SARS-CoV-2-specific response within the CD45RA - memory T cells and the most frequent human leukocyte antigen typing in the Spanish population., Results: We analyzed data from 81 patients. The primary outcome for recovery, defined as the proportion of participants in each group with normalization of fever, oxygen saturation sustained for at least 24 hours and lymphopenia recovery through day 14 or at discharge, was met for the experimental arm. We also observed faster lymphocyte recovery in the experimental group. We did not observe any treatment-related adverse events., Conclusions: Adoptive cell therapy with off-the-shelf CD45RA - memory T cells containing SAR-CoV-2-specific T cells is safe, effective and accelerates lymphocyte recovery of patients with COVID-19 pneumonia and/or lymphopenia., Trial Registration: NCT04578210., Competing Interests: Declaration of Competing Interest CF, AP-M and BS filed patent PCT/EP2021/076516 on Memory T cells as adoptive cell therapy for viral diseases. All other authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

This study found no association of the top two associated FER variants with severity of community-acquired pneumonia. Precise characterisation of phenotypes may be required in order to unravel the genetic mechanisms predisposing to poor outcome in sepsis. https://bit.ly/3jc9SmR., Competing Interests: Conflict of interest: J. Solé-Violán has nothing to disclose. Conflict of interest: E. Hernández-Brito has nothing to disclose. Conflict of interest: J.M. Valencia-Gallardo has nothing to disclose. Conflict of interest: E. Herrera-Ramos has nothing to disclose. Conflict of interest: L. Borderías reports personal fees, nonfinancial support and other from GSK, personal fees from Allergy Therapeutics, nonfinancial support from Novartis, Boehringer and Esteve Teijin, personal fees from AstraZeneca, and nonfinancial support from Menarini, outside the submitted work. Conflict of interest: M.L. Briones has nothing to disclose. Conflict of interest: O. Rajas has nothing to disclose. Conflict of interest: J. Freixinet has nothing to disclose. Conflict of interest: L. Lorente has nothing to disclose. Conflict of interest: A. Payeras has nothing to disclose. Conflict of interest: J. Ferreres has nothing to disclose. Conflict of interest: N. Carbonell has nothing to disclose. Conflict of interest: N. González-Quevedo has nothing to disclose. Conflict of interest: J.M. González-Martin has nothing to disclose. Conflict of interest: F. Rodríguez de Castro has nothing to disclose. Conflict of interest: C. Rodríguez-Gallego has nothing to disclose., (Copyright ©ERS 2021.)

Introduction: Pneumococcal 13-valent vaccine (PCV-13) has a potential role in preventing bacteraemic pneumococcal pneumonia and its complications, but little is known about its ability to specifically prevent respiratory complications. Our aim were to analyse the pneumococcal serotypes associated with the development of respiratory complications and the potential role of PCV-13 in preventing respiratory complications in bacteraemic pneumococcal pneumonia., Material and Methods: We analysed demographic characteristics, comorbidities, antibiotic resistances and the outcomes of a cohort of 65 vaccine-naïve bacteraemic pneumococcal pneumonias, stratified by the pneumococcal serotypes included in PCV13 vs. those not included. Complications were clustered as follows: respiratory complications (hypoxemic respiratory failure; mechanical ventilation), systemic complications (septic shock; multiorgan failure), suppurative complications (empyema; pleural effusion; lung abscess)., Results: From a population of 65 CAP-SP, 47.7% of the isolates belonged to PCV-13 serotypes group. No differences in comorbidities or clinical manifestations were found between groups. With regard to biochemical parameters, we found more profound hypoxemia levels in PCV-13 serotypes group comparing to non-vaccine group [PaO2/FiO2 209 (63) vs. 268 (57); p=0.007]. Global complications were identified in 69.2% (45 patients), and the most frequent were respiratory complications, found in 47.7%. Respiratory complications were detected more frequently in PCV-13 groups compared to non-vaccine groups (61.3% vs. 35.3%; p=0.036). Overall 30-day mortality was 30.8%. Mortality was similar between both groups (25.8% vs. 35.3%; p=0.408)., Conclusions: Pneumococcal 13-valent conjugate vaccine includes the serotypes which cause more respiratory complications in our series; these serotypes were not associated with higher mortality in our series. PCV-13 may have a potential role in preventing respiratory complications due to bacteraemic pneumonoccal pneumonia., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Bite mark evidence has been repeatedly found in criminal cases. Physical comparison of a bite mark to the teeth of available suspects may not always be possible. Experimental studies have shown that the analysis of DNA present in the saliva recovered from bite marks might help in the identification of individuals. However, the application of this approach to an actual criminal case has been reported only once before in forensic literature. Therefore, there is very limited scientific and technical information available on this subject. The current study focuses on a woman found dead in her home; the autopsy ruled the death to be a result of manual strangulation. A bite mark was found on each breast. The single swab technique was used to collect evidence from these bite marks, and an organic extraction method was employed for DNA isolation. Short tandem repeat (STR) sequence typing was performed using a commercially available kit, and the result was compared to the STR profile of a suspect. A full single-source STR profile was obtained from both bite marks, which matched the STR profile of the suspect. To the best of our knowledge, this is the second report on the analysis of DNA isolated from bite marks on the victim used to identify the crime perpetrator. Our results indicated that, contrary to most theoretical indications, a single swab technique for evidence collection and an organic method for DNA isolation could be very useful in solving this class of criminal cases.

Background and Objective: Assessment of oxygenation in patients with community-acquired pneumonia is critical for treatment. The accuracy of percutaneous oxygen saturation (SpO2 ) determined by pulse oximetry is uncertain, and it has limited value in patients receiving supplemental oxygen. We hypothesized that calculation of partial arterial oxygen concentration/inspired oxygen faction (PaO2 /FiO2 ) from SpO2 by the Ellis or Rice equations might adequately correlate with PaO2 /FiO2 measured by arterial blood gases., Methods: We studied 1004 patients with pneumonia in the emergency department with simultaneous measurement of SpO2 and PaO2 from two cohorts from Valencia, Spain and Utah, USA. We compared SpO2 with measured SaO2 , compared the equations' accuracy in calculating PaO2 /FiO2 and determined how often patients would be misclassified at clinically important thresholds. We compared estimated PaO2 /FiO2 to measured PaO2 /FiO2 using the Spearman correlation., Results: Pairwise correlation of SpO2 with SaO2 was moderate (rho = 0.66; P < 0.01). Both equations performed similarly among patients with lower PaO2 /FiO2 ratios. The Ellis equation estimated PaO2 /FiO2 from SpO2 more accurately than the Rice equation in patients with PaO2 /FiO2 ≥200. Simple agreement between calculated and measured P/F was 91% and 92%, respectively., Conclusions: The Ellis equation was more accurate than the Rice equation for estimating PaO2 /FiO2 , especially at higher levels of P/F ratio. Estimation of PaO2 /FiO2 from SpO2 is accurate enough for initial oxygenation assessment. Ellis and Rice equations could misclassify 20% and 30% of patients, respectively, at higher levels of PaO2 /FiO2 . For patients with abnormal oxygenation falling near thresholds for clinical decision making, arterial blood gas measurement preferably on room air is more accurate., (© 2015 Asian Pacific Society of Respirology.)

Background and Objective: Severity assessment is made at the time of the initial clinical presentation in patients with community-acquired pneumonia (CAP). It is unclear how the gap between time of presentation and duration of symptoms onset may impact clinical outcomes. Here we evaluate the association of prolonged onset of symptoms (POS) and the impact on clinical outcomes among hospitalized patients with CAP., Methods: This was a prospective, multicentre study of CAP in Spain. The primary outcomes were the clinical factors associated with POS defined as days from symptoms onset to pneumonia diagnosis >7 days. The secondary outcomes were intensive care unit (ICU) admission, the presence of suppurative complications, septic shock and 30-day mortality., Results: We enrolled 1038 patients diagnosed of CAP: 152 (14.6%) patients had a POS. In multivariate analysis, the presence of prior corticosteroid therapy, alcohol abuse, prior antibiotic therapy, and confusion, urea, respiratory rate, blood pressure and age 65 years or older score 0-1 was independently associated with POS. Patients with POS had a higher incidence of suppurative complications, but not of 30-day mortality when compared with a shorter onset of symptoms., Conclusions: Approximately 15% of patients diagnosed with CAP had POS. Risk factors associated with POS were previous corticosteroids and antibiotic therapy, alcoholism and less severe pneumonia. POS was associated with a higher rate of suppurative complications and less need for ICU admission., (© 2014 Asian Pacific Society of Respirology.)

The role of mannose-binding lectin (MBL) deficiency (MBL2; XA/O and O/O genotypes) in host defences remains controversial. The surfactant proteins (SP)-A1, -A2 and -D, other collectins whose genes are located near MBL2, are part of the first-line lung defence against infection. We analysed the role of MBL on susceptibility to pneumococcal infection and the existence of linkage disequilibrium (LD) among the four genes. We studied 348 patients with pneumococcal community-acquired pneumonia (P-CAP) and 2,110 controls. A meta-analysis of MBL2 genotypes in susceptibility to P-CAP and to invasive pneumococcal disease (IPD) was also performed. The extent of LD of MBL2 with SFTPA1, SFTPA2 and SFTPD was analysed. MBL2 genotypes did not associate with either P-CAP or bacteraemic P-CAP in the case-control study. The MBL-deficient O/O genotype was significantly associated with higher risk of IPD in a meta-analysis, whereas the other MBL-deficient genotype (XA/O) showed a trend towards a protective role. We showed the existence of LD between MBL2 and SP genes. The data do not support a role of MBL deficiency on susceptibility to P-CAP or to IPD. LD among MBL2 and SP genes must be considered in studies on the role of MBL in infectious diseases.

Purpose: Conflicting results about the role of genetic variability at IL6, particularly the -174 G/C single nucleotide polymorphism (SNP), in sepsis have been reported. We studied the genetic variability at IL6 in patients with community-acquired pneumonia (CAP) and pneumococcal CAP (P-CAP)., Methods: This was a multicenter, prospective observational study. IL6 -174 was analyzed in 1,227 white Spanish patients with CAP (306 with P-CAP). IL6 1753 C/G (N = 750), 2954 G/C (N = 845), and haplotypes defined by these SNPs were also studied., Results: In CAP patients the genotype -174 GG were associated with protection against acute respiratory distress syndrome (ARDS) (p = 0.008, OR = 0.4, 95% CI 0.2-0.8). No other significant associations were observed. However, in patients with P-CAP multivariate analysis adjusted for age, gender, co-morbidity, hospital of origin, and severity (pneumonia severity index, PSI) showed that the IL6 -174 GG genotype was protective against the development of ARDS (p = 0.002, OR = 0.25, 95% CI 0.07-0.79), septic shock (p = 0.006, OR = 0.46, 95% CI 0.18-0.79), and multiple organ dysfunction syndrome (p = 0.02, OR = 0.53, 95% CI 0.27-0.89). P-CAP patients homozygous for IL6 -174 G also showed a higher survival in a logistic regression analysis adjusted for age, gender, co-morbidity, hospital of origin, and PSI (p = 0.048, OR = 0.27, 95% CI 0.07-0.98)., Conclusions: Our results indicate that the IL-6 -174 GG genotype is associated with lower severity and mortality in patients with P-CAP. This effect was higher than that observed in patients with CAP irrespective of the causal pathogen involved. Our results highlight the importance of the causal pathogen in genetic epidemiological studies in sepsis.

Introduction: Genetic variability of the pulmonary surfactant proteins A and D may affect clearance of microorganisms and the extent of the inflammatory response. The genes of these collectins (SFTPA1, SFTPA2 and SFTPD) are located in a cluster at 10q21-24. The objective of this study was to evaluate the existence of linkage disequilibrium (LD) among these genes, and the association of variability at these genes with susceptibility and outcome of community-acquired pneumonia (CAP). We also studied the effect of genetic variability on SP-D serum levels., Methods: Seven non-synonymous polymorphisms of SFTPA1, SFTPA2 and SFTPD were analyzed. For susceptibility, 682 CAP patients and 769 controls were studied in a case-control study. Severity and outcome were evaluated in a prospective study. Haplotypes were inferred and LD was characterized. SP-D serum levels were measured in healthy controls., Results: The SFTPD aa11-C allele was significantly associated with lower SP-D serum levels, in a dose-dependent manner. We observed the existence of LD among the studied genes. Haplotypes SFTPA1 6A(2) (P = 0.0009, odds ration (OR) = 0.78), SFTPA(2) 1A(0) (P = 0.002, OR = 0.79), SFTPA1-SFTPA2 6A2-1A(0) (P = 0.0005, OR = 0.77), and SFTPD-SFTPA1-SFTPA(2)C-6A2-1A(0) (P = 0.00001, OR = 0.62) were underrepresented in patients, whereas haplotypes SFTPA2 1A(10) (P = 0.00007, OR = 6.58) and SFTPA1-SFTPA2 6A(3)-1A (P = 0.0007, OR = 3.92) were overrepresented. Similar results were observed in CAP due to pneumococcus, though no significant differences were now observed after Bonferroni corrections. 1A(10) and 6A-1A were associated with higher 28-day and 90-day mortality, and with multi-organ dysfunction syndrome (MODS) and acute respiratory distress syndrome (ARDS) respectively. SFTPD aa11-C allele was associated with development of MODS and ARDS., Conclusions: Our study indicates that missense single nucleotide polymorphisms and haplotypes of SFTPA1, SFTPA2 and SFTPD are associated with susceptibility to CAP, and that several haplotypes also influence severity and outcome of CAP.

Background: Several studies have investigated single nucleotide polymorphisms (SNP) in candidate genes associated with susceptibility, severity or outcome in patients with community-acquired pneumonia (CAP) with conflicting results., Methods: Multi-centre, prospective observational study. We studied 1162 white Spanish patients with CAP and 1413 controls. Severe forms of sepsis were recorded in 325 patients. Subjects were genotyped for the following polymorphisms: TNF -238 and -308, LTA +252, IL6 -174, IL1RN 86bp variable number of tandem repeats and TNFRSF1B+676 (TNFR2 M196R)., Results: No significant differences in genotype or allele frequencies were seen among patients and controls. We did not find any association between TNF, LTA, IL6 and IL1RN polymorphisms with disease severity or outcome. Analysis of 28-day mortality showed a significant difference in the distribution of TNFRSF1B+676 G/T genotypes (p=0.0129). Sequential Kaplan-Meier survival analysis of TNFRSF1B+676 G/T polymorphism showed a protective role of the GT genotype. Cox regression analysis adjusted for age, gender, hospital of origin and comorbidities showed that patients with GT genotypes had lower mortality rates compared to patients with GG or TT genotypes (p=0.02; HR 0.53; 95% CI 0.31-0.90 for 90-day survival; p=0.01; HR 0.41; 95% CI 0.21-0.81 for 28-day survival and p=0.049; HR 0.48; 95% CI 0.23-0.997 for 15-day survival)., Conclusions: Our study does not support a role for the controversial studied polymorphisms of the TNF, LTA, IL6 and IL1RN genes in the susceptibility or outcome of CAP. A protective role of heterozygosity for the functionally relevant TNFRSF1B+676 polymorphism in the outcome of CAP was observed., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Usually, mortality due to mild community-acquired pneumonias (CAP) (Pneumonia severity index (PSI) classes I-III) is low (<3%), but the appearance of hypoxemia significantly increases mortality. Our aim was to determine the clinical parameters associated with risk factors of developing hypoxemia in subjects with mild CAP (PSI I-III) and the clinical outcomes of the hypoxemic group. We analyzed clinical characteristics and the outcomes of patients with mild CAP and hypoxemia (PaO2/FiO2<300), in a prospective, multicenter cohort study of 1195 patients. Mild pneumonias (PSI I-III) were found in 645 cases (53.9%), of which 217 (33.6%) presented hypoxemia according to a PaO2/FiO2<300. Patients with PaO2/FiO2<300 required more ICU admissions, mechanical ventilation, and developed septic shock than other PSI I-III patients. The clinical parameters associated with hypoxemia were: COPD, bilateral chest X-ray involvement, and hypoalbuminemia. We conclude that patients with COPD, those with bilateral chest X-ray involvement, or hypoalbuminemia were significantly more likely to have hypoxemia in mild CAP. Hypoxemic patients with low-risk pneumonia have worse clinical outcomes, including more ICU admission, need for mechanical ventilation and presence of septic shock than non-hypoxemic low-risk patients.

Background: Community-acquired pneumonia (CAP) is the leading cause of death from infection in developed countries. Mannose-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) deficiencies are common primary immunodeficiencies the clinical penetrance of which remains controversial. MBL is a serum lectin that mediates phagocytosis and activates the lectin pathway of complement involving MASP-2., Objective: We sought to evaluate the significance of MBL deficiency (O/O genotypes) and insufficiency (O/O plus XA/O genotypes), as well as MASP-2 deficiency (D105G mutation), in the susceptibility to and severity and outcome of CAP in adults., Methods: MBL and MASP-2 serum levels, as well as lectin pathway activity with regard to MBL2 and MASP2 genotypes, were measured in healthy control subjects. For susceptibility, 848 patients with CAP, 1447 healthy control subjects, and a control group of 519 patients without relevant infectious diseases were studied in a case-control study. Severity and outcome were evaluated in a prospective study of the 848 patients., Results: We found similar frequencies of MBL2 and MASP2 alleles and genotypes among patients and control subjects. However, in a multivariate analysis MBL insufficiency was associated with the development of the most severe forms of sepsis (P = .007), acute respiratory failure (P = .009), multiorgan dysfunction syndrome (P = .036), intensive care unit admission (P = .020), and death (P = .003)., Conclusion: Our large study suggests that MBL plays a redundant role in human defenses against primary infection, at least in adults with CAP, and provides, for the first time, evidence that MBL insufficiency predisposes to higher severity and fatal outcome in patients with CAP, irrespective of the causal microorganisms.

The limitations of conventional microbiologic methods (CMM) for etiologic diagnosis of community pneumococcal pneumonia have made faster diagnostic techniques necessary. Our aim was to evaluate the usefulness of the immunochromatography (ICT) technique for detecting urinary Streptococcus pneumoniae antigen in the etiologic diagnosis of community-acquired pneumonias (CAP). This was a prospective study on in-patients with CAP in a tertiary hospital conducted from October 2000 to March 2004. Apart from using CMM to reach an etiologic diagnosis, we determined pneumococcal antigen in concentrated urine by ICT. We also determined the urinary pneumococcal antigen (UPA) content in patients from two control groups to calculate the specificity of the technique. One group was comprised of in-patients diagnosed with chronic obstructive pulmonary disease (COPD) or asthma, with respiratory infection, and without pneumonia; the other group included fractures. We studied 959 pneumonia patients and determined UPA content in 911 (95%) of them. We diagnosed the etiology of 253 cases (28%) using CMM; S. pneumoniae was the most common etiologic agent (57 cases). ICT analysis was positive for 279 patients (31%). Using this technique, the percentage of diagnoses of pneumococcal pneumonias increased by 26%, while the overall etiologic diagnosis increased from 28 to 49%. The technique sensitivity was 81%; the specificity oscillated between 80% in CAP with nonpneumococcal etiology and 99% for patients with fractures without infections. Determination of UPA is a rapid, simple analysis with good sensitivity and specificity, which increased the percentage of etiologic diagnoses. Positive UPA may persist in COPD patients with probable pneumococcal colonization or recent pneumococcal infections.

We describe a man diagnosed with non-bulbar amyotrophic lateral sclerosis (ALS) who uses 24-h non-invasive ventilator at home, and assisted cough through the use of the mechanical insufflation-exsufflation (MAC) device (CoughAssist, J.H. Emerson). This was essential for the removal of bronchial secretions in order to provide successful non-invasive management (and indeed less suffering for the patient) during an acute respiratory tract infection with hypoxemia and failure of manually assisted cough.