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.

Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway.

Mannose-binding lectin (MBL)-associated serine protease-2 (MASP-2) is an indispensable enzyme for the activation of the lectin pathway of complement. Its deficiency is classified as a primary immunodeficiency associated to pyogenic bacterial infections, inflammatory lung disease, and autoimmunity. In Europeans, MASP-2 deficiency, due to homozygosity for c.359A > G (p.D120G), occurs in 7 to 14/10,000 individuals. We analyzed the presence of the p.D120G mutation in adults (increasing the sample size of our previous studies) and children. Different groups of patients (1495 adults hospitalized with community-acquired pneumonia, 186 adults with systemic lupus erythematosus, 103 pediatric patients with invasive pneumococcal disease) and control individuals (1119 healthy adult volunteers, 520 adult patients without history of relevant infectious diseases, and a pediatric control group of 311 individuals) were studied. Besides our previously reported MASP-2-deficient healthy adults, we found a new p.D120G homozygous individual from the pediatric control group. We also reviewed p.D120G homozygous individuals reported so far: a total of eleven patients with a highly heterogeneous range of disorders and nine healthy controls (including our four MASP-2-deficient individuals) have been identified by chance in association studies. Individuals with complete deficiencies of several pattern recognition molecules of the lectin pathway (MBL, collectin-10 and collectin-11, and ficolin-3) as well as of MASP-1 and MASP-3 have also been reviewed. Cumulative evidence suggests that MASP-2, and even other components of the LP, are largely redundant in human defenses and that individuals with MASP-2 deficiency do not seem to be particularly prone to infectious or autoimmune diseases.

Lethal Influenza in Two Related Adults with Inherited GATA2 Deficiency.

The pathogenesis of life-threatening influenza A virus (IAV) disease remains elusive, as infection is benign in most individuals. We studied two relatives who died from influenza. We Sanger sequenced GATA2 and evaluated the mutation by gene transfer, measured serum cytokine levels, and analyzed circulating T- and B-cells. Both patients (father and son, P1 and P2) died in 2011 of H1N1pdm IAV infection at the ages of 54 and 31 years, respectively. They had not suffered from severe or moderately severe infections in the last 17 (P1) and 15 years (P2). A daughter of P1 had died at 20 years from infectious complications. Low B-cell, NK- cell, and monocyte numbers and myelodysplastic syndrome led to sequence GATA2. Patients were heterozygous for a novel, hypomorphic, R396L mutation leading to haplo-insufficiency. B- and T-cell rearrangement in peripheral blood from P1 during the influenza episode showed expansion of one major clone. No T-cell receptor excision circles were detected in P1 and P3 since they were 35 and 18 years, respectively. Both patients presented an exuberant, interferon (IFN)-γ-mediated hypercytokinemia during H1N1pdm infection. No data about patients with viremia was available. Two previously reported adult GATA2-deficient patients died from severe H1N1 IAV infection; GATA2 deficiency may predispose to life-threatening influenza in adulthood. However, a role of other genetic variants involved in immune responses cannot be ruled out. Patients with GATA2 deficiency can reach young adulthood without severe infections, including influenza, despite long-lasting complete B-cell and natural killer (NK) cell deficiency, as well as profoundly diminished T-cell thymic output.

Saharan dust and the impact on adult and elderly allergic patients: the effect of threshold values in the northern sector of Gran Canaria, Spain.

Gran Canaria Island is frequently impacted by Saharan dust, a health hazard of particular concern to the island population and health agencies. Airborne mineral dust has the severest impact on the higher age groups of the population, and those with respiratory conditions; despite that, on average, the ambient particulate matter (PM) concentrations fall within international PM guidelines. During 2010 and 2011, an epidemiological survey, in parallel with an air quality study, was conducted at the Dr Negrín hospital in Gran Canaria. This included the quarterly monitoring of outpatients and recording of emergency patients with respiratory diseases, together with the measurement of aerosol, meteorological, and PM-related air quality levels. The finer more toxic particles were collected with PM2.5 (particulate matter with aerodynamic diameter less than 2.5 µm) aerosol samplers. The filter samples were gravimetrically and chemically analyzed for their elemental, water-soluble ions, carbon, and mineralogical contents. Individual particle morphology was measured by Scanning Electron Microscopy. Statistical analysis of the chemical and clinical data included the analysis of variance and calculation of Spearman correlation coefficients. No statistically significant relations were found between the allergic control group, the emergency room admissions, pulmonary conditions, medication, and elevated Saharan dust levels. However, changing environmental conditions, such as an increase in humidity or a reduction in ambient air temperature made a significant difference to the outcomes recorded on the health statements of the allergic and respiratory illness groups of the Gran Canary population.

Prevalence of Oropharyngeal Dysphagia and Its Value as a Prognostic Factor in Community-Acquired Pneumonia: A Prospective Case-Control Study.

BACKGROUND: Although oropharyngeal dysphagia (OD) is a common finding in patients with community-acquired pneumonia (CAP), specific recommendations are not provided in the current clinical guidelines. OBJECTIVES: To estimate the prevalence of OD and its associated factors among patients hospitalized for CAP and to assess one-year outcomes according to the presence or absence of OD. METHODS: We studied 226 patients hospitalized for CAP and 226 patients hospitalized for respiratory conditions other than CAP. We screened the risk of OD using the Eating Assessment Tool-10 (EAT-10), followed by the volume-viscosity swallow test (V-VST). RESULTS: A total of 122 (53.9%) patients with CAP had confirmed OD compared with 44 (19.4%) patients without CAP. Patients with CAP and OD were older (p < 0.001; 1.02-1.07) and had less familial/institutional support (p = 0.036; 0.12-0.91) compared to patients with CAP and no OD. OD was more prevalent as the CURB-65 score increased (p < 0.001). Patients with OD spent more time in the hospital (14.5 vs. 11.0 days; p = 0.038) and required more visits to the emergency room (ER). Twenty (16.4%) patients with CAP and OD died after discharge vs. one (0.8%) patient with CAP and no OD (p < 0.001; CI = 2.24-42.60). CONCLUSIONS: The prevalence of OD in hospitalized patients with CAP is higher than in patients hospitalized for other respiratory diagnoses. Advanced age, lower familial/institutional support, and increased CAP severity are associated with OD. Patients with CAP and OD are more frequent ER visitors after discharge and have a higher mortality. In patients with CAP and OD, aspiration pneumonia is likely underestimated.

[Human resources in the National Health System. Medical education. SESPAS Report 2024]. / Recursos humanos del Sistema Nacional de Salud. Formación. Informe SESPAS 2024.

The problems posed by medical education in Spain are diverse. This paper analyzes the system currently used to select candidates who will be admitted to a public faculty of medicine in Spain and some issues arising from the unprecedented increase in both public and private medical schools in our country. The importance of generic competencies in today's medicine and the need to return to a core design in specialist training are other aspects that are discussed. The degree of development of advanced accreditation diplomas and areas of specific competence is also subject to analysis. Finally, the authors emphasize the importance of continuous professional development and the idea of professional recertification as a system that guarantees patients the quality of the care they receive.

Survival and Lung Function Changes in Hypersensitivity Pneumonitis According to Radiological Phenotypes Compared With Idiopathic Pulmonary Fibrosis.

INTRODUCTION: The main objective of this study was to estimate survival and changes in lung function in patients with chronic hypersensitivity pneumonitis (HP), both fibrotic (f-HP) and nonfibrotic (nf-HP), and to compare them with those in patients with idiopathic pulmonary fibrosis (IPF). METHODS: HP was diagnosed based on antigen exposure, HRCT (high-resolution CT scan), BAL (bronchoalveolar lavage), and histology. According to HRCT, HP was classified into fibrotic and non-fibrotic phenotypes. In most cases, IPF was diagnosed based on HRCT findings. RESULTS: We identified 84 patients: 46 with IPF, 18 with f-HP, and 20 with nf-HP. Five-year survival was 23.9% in IPF, 72% in f-HP, and 100% in nf-HP (p <0.0001). Honeycombing was associated with decreased survival in IPF (p <0.001) and in f-HP (p <0.0001). The mean loss of FVC (forced vital capacity) % pred. (percent predicted) was -18.3% in IPF (p =0.001), -4.8% in f-HP, and -6.0% in nf-HP. The mean change in DLCO (diffusion capacity for carbon monoxide) % pred. was -10.2% in IPF (p <0.002), -0.5% in f-HP, and +1.9% in nf-HP. The agreement between radiological phenotypes and histology in HP was 89.6%. CONCLUSIONS: We found shorter survival in IPF, followed by f-HP, and nf-HP. Over time, we did not find significant changes in FVC% pred. or DLCO% pred. in HP, while a significant decline in IPF was noted. In HP, we found strong agreement between radiological phenotypes and histology. Radiological signs suggestive of lung fibrosis in HP were reliable for the diagnosis of f-HP and seem to have intrinsic prognostic value.

The role of mannose-binding lectin in pneumococcal infection.

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.

Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia.

X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4-dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8-207.8, P < 0.001). The patients' susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia.

Autoantibodies against type I IFNs in patients with critical influenza pneumonia.

Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-α2 alone (five patients) or with IFN-ω (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-α2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-ω. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients <70 yr of age (5.7 vs. 1.1%, P = 2.2 × 10-5), but not >70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-α2 and IFN-ω (OR = 11.7, P = 1.3 × 10-5), especially those <70 yr old (OR = 139.9, P = 3.1 × 10-10). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for ∼5% of cases of life-threatening influenza pneumonia in patients <70 yr old.

Influence of genetic variability at the surfactant proteins A and D in community-acquired pneumonia: a prospective, observational, genetic study.

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.

Multi-drug resistant tuberculosis, ten years later. / Tuberculosis multirresistentediez años después.

Drug-resistant tuberculosis, especially those with resistance to rifampicin (RR-TB), has become one of the main obstacles to achieving the dream of eradicating tuberculosis. Furthermore, it is necessary to combine three or four different drugs in the attempt to cure TB, however, unfortunately, there are few available that can be considered genuinely effective. Fortunately, the notable worldwide increase in RR-TB in recent years has led to the investment of resources in the development of new drugs for TB, and other drugs investigated for other diseases have been successfully tested on TB. This has resulted in a clear change in the clinical management of these patients over the last 3-4 years, and it is now easier to design therapeutic regimens and achieve higher success rates. All these changes are updated in this review.

Challenges in understanding host genetics and severity of community-acquired pneumonia.

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.

New antimicrobial molecules and new antibiotic strategies.

Drug options for treatment of infections are increasingly limited. The pharmaceutical industry has found it difficult to discover new antimicrobial agents, and only two novel classes of antibiotics, the oxazolidinones and the cyclic lipopeptides, have entered the market since the late 1960s. Few new agents have reached the market in the last decade with potential interest for community-acquired pneumonia (CAP) treatment, including linezolid (the first oxazolidinone in clinical use), new fluoroquinolones, cefditoren, ertapenem, and telithromycin. Agents currently in clinical development include other novel quinolones and ketolides, broad-spectrum cephalosporin derivatives, faropenem, several glycopeptides, and iclaprim. Other molecules are considered to be promising candidates for the future. In addition to the foregoing agents, alternative treatment approaches have also been introduced into clinical practice, which include the administration of the appropriate antimicrobials in a timely manner and the consideration of the pharmacokinetic-pharmacodynamic properties of the agent(s).

Mannose-binding lectin and mannose-binding lectin-associated serine protease 2 in susceptibility, severity, and outcome of pneumonia in adults.

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.

Tuberculosis multirresistentediez años después / Multi-drug resistant tuberculosis, ten years later

La tuberculosis con resistencia a fármacos, sobre todo la que conlleva resistencia a rifampicina (TB-RR), se ha convertido en uno de los principales obstáculos para alcanzar el sueño de erradicar esta enfermedad. Y es que, para intentar curar la TB es necesario asociar tres o cuatro fármacos diferentes y, lamentablemente, son pocos los disponibles que se puedan considerar auténticamente eficaces. Pero, afortunadamente, el notable incremento que ha habido en los últimos años de la TB-RR en el mundo, ha motivado que se hayan invertido recursos en el desarrollo de nuevos fármacos para la TB, o que otros antimicrobianos investigados para otras enfermedades se hayan probado con éxito en la TB. Esto ha hecho que el manejo clínico de estos pacientes haya cambiado notablemente en los últimos tres a cuatro años, y resulte ahora más sencillo diseñar esquemas terapéuticos y conseguir mayores tasas de éxito. Todos estos cambios se actualizan en esta revisión. (AU)

Drug-resistant tuberculosis, especially those with resistance to rifampicin (RR-TB), has become one of the main obstacles to achieving the dream of eradicating tuberculosis. Furthermore, it is necessary to combine three or four different drugs in the attempt to cure TB, however, unfortunately, there are few available that can be considered genuinely effective. Fortunately, the notable worldwide increase in RR-TB in recent years has led to the investment of resources in the development of new drugs for TB, and other drugs investigated for other diseases have been successfully tested on TB. This has resulted in a clear change in the clinical management of these patients over the last 3-4 years, and it is now easier to design therapeutic regimens and achieve higher success rates. All these changes are updated in this review. (AU)