Comparison of systemic inflammatory profiles in COVID-19 and community-acquired pneumonia patients: a prospective cohort study

10 páginasAntecedentes: Las respuestas inflamatorias contribuyen al daño tisular en la COVID-19 y la neumonía adquirida en la comunidad (NAC). Aunque se han descrito valores predictivos de diferentes biomarcadores inflamatorios en ambas enfermedades, las similitudes y diferencias de los perfiles inflamatorios entre estas afecciones siguen siendo inciertas. Por lo tanto, nuestro objetivo fue determinar las similitudes y diferencias de los perfiles inflamatorios entre la COVID-19 y la NAC, y su asociación con los resultados clínicos. Métodos: Se realizó un estudio de cohorte observacional prospectivo en un hospital de referencia en América Latina. Se incluyeron pacientes con neumonía por COVID-19 confirmada y NAC. Se utilizaron ensayos de citocinas Multiplex (Luminex) para medir la concentración plasmática de 14 citocinas al ingreso hospitalario. Después de comparar similitudes y diferencias en el perfil inflamatorio entre pacientes con COVID-19 y NAC, se utilizó un método de clasificación no supervisado (es decir, agrupamiento jerárquico) para identificar subpoblaciones dentro de los pacientes con COVID-19 y NAC. Resultados: Se incluyeron 160 pacientes, 62,5% fueron diagnosticados con COVID-19 (100/160) y 37,5% con NAC (60/160). Utilizando el agrupamiento jerárquico, los pacientes con COVID-19 y NAC se dividieron en función de su perfil inflamatorio: respuesta inmune pauci, moderada e hiperinflamatoria. La subpoblación hiperinflamatoria de COVID-19 tuvo la mortalidad más alta. La subpoblación hiperinflamatoria de COVID-19, en comparación con la pauciinflamatoria, tuvo niveles más altos de IL-10 (mediana [RIC] 61,4 [42,0-109,4] frente a 13,0 [5,0-24,9], P: < 0,001), IL-6 (48,1 [22,3-82,6] frente a 9,1 [0,1-30,4], P: < 0,001), entre otros. Los pacientes con NAC hiperinflamatoria frente a pauciinflamatoria se caracterizaron por una elevación de IFN2 (48,8 [29,7-110,5] frente a 3,0 [1,7-10,3], P: < 0,001), TNFα (36,3 [24,8-53,4] frente a 13,1 [11,3-16,9], P: < 0,001), entre otros. Las subpoblaciones hiperinflamatorias en COVID-19 y NAC en comparación con las subpoblaciones pauciinflamatorias correspondientes tenían niveles más altos de MCP-1. Conclusiones: Nuestros datos destacan tres subpoblaciones distintas en COVID-19 y NAC, con diferencias en los perfiles de marcadores inflamatorios y riesgos de resultados clínicos adversos

Major alteration of lung microbiome and the host responses in critically ill COVID-19 patients with high viral load

Patients with COVID-19 under invasive mechanical ventilation are at higher risk of developing ventilator-associated pneumonia (VAP), associated with increased healthcare costs, and unfavorable prognosis. The underlying mechanisms of this phenomenon have not been thoroughly dissected. Therefore, this study attempted to bridge this gap by performing a lung microbiota analysis and evaluating the host immune responses that could drive the development of VAP. In this prospective cohort study, mechanically ventilated patients with confirmed SARS-CoV-2 infection were enrolled. Nasal swabs (NS), endotracheal aspirates (ETA), and blood samples were collected initially within 12 h of intubation and again at 72 h post-intubation. Plasma samples underwent cytokine and metabolomic analyses, while NS and ETA samples were sequenced for lung microbiome examination. The cohort was categorized based on the development of VAP. Data analysis was conducted using RStudio version 4.3.1. In a study of 36 COVID-19 patients on mechanical ventilation, significant differences were found in the nasal and pulmonary microbiome, notably in Staphylococcus and Enterobacteriaceae, linked to VAP. Patients with VAP showed a higher SARS-CoV-2 viral load in respiratory samples, elevated neutralizing antibodies, and reduced inflammatory cytokines, including IFN-δ, IL-1β, IL-12p70, IL-18, IL-6, TNF-α, and CCL4. Metabolomic analysis revealed changes in 22 metabolites in non-VAP patients and 27 in VAP patients, highlighting D-Maltose-Lactose, Histidinyl-Glycine, and various phosphatidylcholines, indicating a metabolic predisposition to VAP. This study reveals a critical link between respiratory microbiome alterations and ventilator-associated pneumonia in COVID-19 patients with higher SARS-CoV-2 viral loads in respiratory samples, elevated neutralizing antibodies, and reduced inflammatory cytokines, including IFN-δ, IL-1β, IL-12p70, IL-18, IL-6, TNF-α, and CCL4. These findings provide novel insights into the underlying mechanisms of VAP, with potential implications for management and prevention

The relation of nasopharyngeal colonization by Streptococcus pneumoniae in comorbid adults with unfavorable outcomes in a low-middle income country

Purpose: Streptococcus pneumoniae (Spn) is the primary bacterial cause of lower respiratory tract infections (LRTI) globally, particularly impacting older adults and children. While Spn colonization in children is linked to LRTI, its prevalence, and consequences in adults with comorbidities remain uncertain. This study aims to provide novel data in that regard. Methods: This prospective study of outpatient adults with chronic diseases was conducted in Colombia. Data on demographics, vaccination, and clinical history was collected in a RedCap database. Nasopharyngeal aspirate samples were examined for Spn colonization using traditional cultures and quantitative—real time polymerase chain reaction (q-rtPCR). Patients were followed for 18 months, with colonization prevalence calculated and factors influencing colonization and its impact on clinical outcomes analyzed through logistic regressions. Results: 810 patients were enrolled, with 10.1% (82/810) identified as colonized. The mean (SD) age was 62 years (±15), and 48.6% (394/810) were female. Major comorbidities included hypertension (52.2% [423/810]), cardiac conditions (31.1% [252/810]), and chronic kidney disease (17.4% [141/810]). Among all, 31.6% (256/810) received the influenza vaccine in the previous year, and 10.7% (87/810) received anti-Spn vaccines. Chronic kidney disease (OR 95% CI; 2.48 [1.01–6.15], p = 0.04) and chronic cardiac diseases (OR 95% CI; 1.62 [0.99–2.66], p = 0.05) were independently associated with Spn colonization. However, colonization was not associated with the development of LRTI (OR 95%CI; 0.64 [0.14–2.79], p = 0.55) or unfavorable outcomes (OR 95% CI;1.17 [0.14–2.79], p = 0.54) during follow-up. Conclusions: Chronic kidney and cardiac diseases are independently associated with Spn colonization. However, Spn colonization was not associated with LRTI/unfavorable outcomes in adult patients with chronic comorbidities in our cohort

Longitudinal analysis of lung microbiome, immune response, and metabolism in ventilator-associated pneumonia: a cohort study

Rationale: Ventilator-associated pneumonia (VAP) is a common complication in patients under invasive mechanical ventilation (IMV), yet its underlying mechanisms remain poorly understood. This study investigated the lung microbiome, inflammatory response, and metabolism in patients undergoing IMV to identify factors that may predispose them to developing VAP. Objectives: To investigate how changes in lung microbiome composition, inflammatory response, and metabolic profiles may predispose patients undergoing IMV to develop VAP. Methods: Patients requiring IMV for at least 48 h due to non-infectious respiratory failure were enrolled. Bronchoalveolar lavage (BAL) samples were collected at baseline, upon VAP diagnosis, or after 72 h for non-VAP cases. DNA sequencing, cytokine quantification, and metabolomic analyses were performed. Results: Of the 80 patients, 41 (51%) developed VAP. No significant differences in alpha or beta diversity of the lung microbiome were observed between groups. However, both groups showed changes in microbiome composition over time, suggesting an impact of IMV. Tumour necrosis factor-alpha (TNF-α) lung levels were significantly higher in VAP patients, while lung interleukin-1 beta (IL-1β) increased in all patients. Metabolomic analysis revealed shifts in pentose phosphate and citric acid cycle pathways, indicating a transition to anaerobic metabolism in the lungs of VAP patients. Conclusions: Mechanical ventilation was associated with temporal changes in lung microbiome composition independent of VAP development. VAP cases exhibited higher TNF-α levels and metabolic profiles indicative of anaerobic adaptation, while IL-1β elevations were primarily linked to mechanical ventilation rather than infection

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in  ~ 80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

ISARIC-COVID-19 dataset: A Prospective, Standardized, Global Dataset of Patients Hospitalized with COVID-19

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