A genome-wide association study of adults with community-acquired pneumonia.

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.

Results of phase 2 randomized multi-center study to evaluate the safety and efficacy of infusion of memory T cells as adoptive therapy in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia and/or lymphopenia (RELEASE NCT04578210).

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 × 106/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.

Performance of a Highly Sensitive Mycobacterium tuberculosis Complex Real-Time PCR Assay for Diagnosis of Pulmonary Tuberculosis in a Low-Prevalence Setting: a Prospective Intervention Study.

The potential impact of routine real-time PCR testing of respiratory specimens from patients with presumptive tuberculosis in terms of diagnostic accuracy and time to tuberculosis treatment inception in low-prevalence settings remains largely unexplored. We conducted a prospective intervention cohort study. Respiratory specimens from 1,020 patients were examined by acid-fast bacillus smear microscopy, tested by a real-time Mycobacterium tuberculosis complex PCR assay (Abbott RealTime MTB PCR), and cultured in mycobacterial media. Seventeen patients tested positive by PCR (5 were acid-fast bacillus smear positive and 12 acid-fast bacillus smear negative), and Mycobacterium tuberculosis was recovered from cultures for 12 of them. Patients testing positive by PCR and negative by culture (n = 5) were treated and deemed to have responded to antituberculosis therapy. There were no PCR-negative/culture-positive cases, and none of the patients testing positive for nontuberculous mycobacteria (n = 20) yielded a positive PCR result. The data indicated that routine testing of respiratory specimens from patients with presumptive tuberculosis by the RealTime MTB PCR assay improves the tuberculosis diagnostic yield and may reduce the time to antituberculosis treatment initiation. On the basis of our data, we propose a novel mycobacterial laboratory algorithm for tuberculosis diagnosis.

The potential role of 13-valent pneumococcal conjugate vaccine in preventing respiratory complications in bacteraemic pneumococcal community-acquired pneumonia.

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.

Accuracy of PaO2 /FiO2 calculated from SpO2 for severity assessment in ED patients with pneumonia.

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.

Does prolonged onset of symptoms have a prognostic significance in community-acquired pneumonia?

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.

Is it possible to predict which patients with mild pneumonias will develop hypoxemia?

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.

Assessment of analysis of urinary pneumococcal antigen by immunochromatography for etiologic diagnosis of community-acquired pneumonia in adults.

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.