Polymorphisms in ACE, ACE2, AGTR1 genes and severity of COVID-19 disease.

BACKGROUND: Infection by the SARS-Cov-2 virus produces in humans a disease of highly variable and unpredictable severity. The presence of frequent genetic single nucleotide polymorphisms (SNPs) in the population might lead to a greater susceptibility to infection or an exaggerated inflammatory response. SARS-CoV-2 requires the presence of the ACE2 protein to enter in the cell and ACE2 is a regulator of the renin-angiotensin system. Accordingly, we studied the associations between 8 SNPs from AGTR1, ACE2 and ACE genes and the severity of the disease produced by the SARS-Cov-2 virus. METHODS: 318 (aged 59.6±17.3 years, males 62.6%) COVID-19 patients were grouped based on the severity of symptoms: Outpatients (n = 104, 32.7%), hospitalized on the wards (n = 73, 23.0%), Intensive Care Unit (ICU) (n = 84, 26.4%) and deceased (n = 57, 17.9%). Comorbidity data (diabetes, hypertension, obesity, lung disease and cancer) were collected for adjustment. Genotype distribution of 8 selected SNPs among the severity groups was analyzed. RESULTS: Four SNPs in ACE2 were associated with the severity of disease. While rs2074192 andrs1978124showed a protector effectassuming an overdominant model of inheritance (G/A vs. GG-AA, OR = 0.32, 95%CI = 0.12-0.82; p = 0.016 and A/G vs. AA-GG, OR = 0.37, 95%CI: 0.14-0.96; p = 0.038, respectively); the SNPs rs2106809 and rs2285666were associated with an increased risk of being hospitalized and a severity course of the disease with recessive models of inheritance (C/C vs. T/C-T/T, OR = 11.41, 95% CI: 1.12-115.91; p = 0.012) and (A/A vs. GG-G/A, OR = 12.61, 95% CI: 1.26-125.87; p = 0.0081). As expected, an older age (OR = 1.47), male gender (OR = 1.98) and comorbidities (OR = 2.52) increased the risk of being admitted to ICU or death vs more benign outpatient course. Multivariable analysis demonstrated the role of the certain genotypes (ACE2) with the severity of COVID-19 (OR: 0.31, OR 0.37 for rs2074192 and rs1978124, and OR = 2.67, OR = 2.70 for rs2106809 and rs2285666, respectively). Hardy-Weinberg equilibrium in hospitalized group for I/D SNP in ACE was not showed (p<0.05), which might be due to the association with the disease. No association between COVID-19 disease and the different AGTR1 SNPs was evidenced on multivariable, nevertheless the A/A genotype for rs5183 showed an higher hospitalization risk in patients with comorbidities. CONCLUSIONS: Different genetic variants in ACE2 were associated with a severe clinical course and death groups of patients with COVID-19. ACE2 common SNPs in the population might modulate severity of COVID-19 infection independently of other known markers like gender, age and comorbidities.

Predictive Value of Immune Cell Functional Assay for Non-Cytomegalovirus Infection in Lung Transplant Recipients: A Multicenter Prospective Observational Study.

INTRODUCTION: Immune cell functional assay (ImmuKnow®) is a non-invasive method that measures the state of cellular immunity in immunosuppressed patients. We studied the prognostic value of the assay for predicting non-cytomegalovirus (CMV) infections in lung transplant recipients. METHODS: A multicenter prospective observational study of 92 patients followed up from 6 to 12 months after transplantation was performed. Immune cell functional assay was carried out at 6, 8, 10, and 12 months. RESULTS: Twenty-three patients (25%) developed 29 non-CMV infections between 6 and 12 months post-transplant. At 6 months, the immune response was moderate (ATP 225-525ng/mL) in 14 (15.2%) patients and low (ATP<225ng/mL) in 78 (84.8%); no patients had a strong response (ATP≥525ng/mL). Only 1 of 14 (7.1%) patients with a moderate response developed non-CMV infection in the following 6 months compared with 22 of 78 (28.2%) patients with low response, indicating sensitivity of 95.7%, specificity of 18.8%, positive predictive value (PPV) of 28.2%, and negative predictive value (NPV) of 92.9% (AUC 0.64; p=0.043). Similar acute rejection rates were recorded in patients with mean ATP≥225 vs. <225ng/mL during the study period (7.1% vs. 9.1%, p=0.81). CONCLUSION: Although ImmuKnow® does not seem useful to predict non-CMV infection, it could identify patients with a very low risk and help us define a target for an optimal immunosuppression.

Treatment With Systemic Steroids in Severe Chronic Obstructive Pulmonary Disease Exacerbations: Use of Short Regimens in Routine Clinical Practice and Their Impact on Hospital Stay. / Tratamiento con esteroides sistémicos en agudización grave de enfermedad pulmonar obstructiva crónica: empleo de pautas cortas en práctica clínica habitual y relación con la estancia hospitalaria.

INTRODUCTION: It is not known whether clinical practice guidelines for the treatment of COPD exacerbations with short coursesofsystemic corticosteroids(SC-SCS) are followed in clinical practice. METHOD: Prospective, observational cohort study in patients admitted due to severe COPD exacerbation. The primary endpoint was the percentage of patients who received SC-SCS as treatment for severe exacerbation (doses of 200-300mg for 5-6 days). Secondary variables were percentageof patients with duration or reduced dose, dose in the first 24hours, days of intravenous systemic corticosteroids (SCS), and duration of hospital length of stay (LOS). Simple linear regression was performed with LOS as a dependent variable and multivariate analysis with factors associated with LOS. RESULTS: 158 patients were evaluated. 4.4% (7) patients received SC-SCS, 8.7% received a reduced dose and duration was reduced in 15.8%. The median dose and duration of SCS were 602.5mg (200-1625) and 14 (4-36) days, respectively. We observed an association between days of SCSand LOS (P<.001) and doses of intrahospitalSCSand LOS (P<.001). Factors associated with LOS were doses of intrahospitalSCS received (.01 [95% CI:.007-.013]; P<0.001), days of steroid treatment (.14 [95% CI .03-.25], P=.009) and PAFI (pO2/FiO2 ratio) at admission (-.012 [95% CI: -.012 to -.002], P=.015). CONCLUSIONS: The SCS schedules used in routine clinical practice are longer and administered at a higher dose than recommended, leading toa longer hospital stay.

Endothelial adhesion molecules and multiple organ failure in patients with severe sepsis.

OBJECTIVE: To determine if serum levels of endothelial adhesion molecules were associated with the development of multiple organ failure (MOF) and in-hospital mortality in adult patients with severe sepsis. DESIGN: This study was a secondary data analysis of a prospective cohort study. SETTING: Patients were admitted to two tertiary intensive care units in San Antonio, TX, between 2007 and 2012. PATIENTS: Patients with severe sepsis at the time of intensive care unit (ICU) admission were enrolled. Inclusion criteria were consistent with previously published criteria for severe sepsis or septic shock in adults. Exclusion criteria included immunosuppressive medications or conditions. INTERVENTIONS: None. MEASUREMENTS: Baseline serum levels of the following endothelial cell adhesion molecules were measured within the first 72h of ICU admission: Intracellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule-1 (VCAM-1), and Vascular Endothelial Growth Factor (VEGF). The primary and secondary outcomes were development of MOF (⩾2 organ dysfunction) and in-hospital mortality, respectively. MAIN RESULTS: Forty-eight patients were enrolled in this study, of which 29 (60%) developed MOF. Patients that developed MOF had higher levels of VCAM-1 (p=0.01) and ICAM-1 (p=0.01), but not VEGF (p=0.70) compared with patients without MOF (single organ failure only). The area under the curve (AUC) to predict MOF according to VCAM-1, ICAM-1 and VEGF was 0.71, 0.73, and 0.54, respectively. Only increased VCAM-1 levels were associated with in-hospital mortality (p=0.03). These associations were maintained even after adjusting for APACHE and SOFA scores using logistic regression. CONCLUSIONS: High levels of serum ICAM-1 was associated with the development of MOF. High levels of VCAM-1 was associated with both MOF and in-hospital mortality.

Lung Cancer in HIV-Infected Patients.

The widespread use of HAART for persons living with HIV since 1996 has resulted in a dramatic decline in AIDS-related mortality. However, other comorbidities are increasing, such as metabolic disturbances or cancers, including solid organ malignancies. Among the latest, lung cancer, especially the adenocarcinoma subtype, is on the rise. HIV infection, even controlling for smoking, is an independent risk factor for developing lung cancer. HIV could promote lung cancers through immunosuppression, chronic inflammation, and a direct oncogenic effect. Smoking, lung infections, and chronic pulmonary diseases are risk factors for lung cancer. All may contribute to the cumulative incidence of lung cancer in persons living with HIV. It is double that in the general population. The role of HAART in lung cancer development in persons living with HIV is not well established. Although data supporting it could be too preliminary, persons living with HIV should be considered within high-risk groups that could benefit from screening strategies with low-dose computed tomography, especially those with airway obstruction and emphysema. Current evidence suggests that quitting smoking strategies in persons living with HIV achieve abstinence rates comparable to those in healthy HIV-negative smokers.

Risk stratification for COPD diagnosis through an active search strategy in primary care.

BACKGROUND: The aim of this study was to identify the percentage of undiagnosed patients with COPD through the implementation of an active search strategy in a selected subject population. METHODS: An observational, cross-sectional, multicenter study was conducted in a primary care setting in Spain. General practitioners gave their diagnostic impression of COPD (yes/no) on the basis of clinical criteria of subjects with respiratory symptoms and tobacco exposure. Subsequently, post-bronchodilator spirometry and quality-of-life tests were performed. Multivariate logistic regression techniques using receiver operating characteristic (ROC) curves were used to identify the combination of variables that best discriminates COPD. RESULTS: A total of 2,758 patients were screened at 368 primary care centers, of which 1,725 patients were included in the study. Seven hundred and ninety-three patients (46%) were diagnosed with COPD. Clinical judgment resulted in suspected COPD in 1,393 (81%) of the subjects. The best variables to discriminate COPD were a history of lower respiratory tract infections, cough, and dyspnea. This combination identified COPD with a ROCAUC of 0.61 denoting a poor discriminative ability. CONCLUSION: Employing an active search strategy leads to a new COPD diagnosis in almost half of the subjects. Screening of COPD with post-bronchodilator spirometry should be considered mandatory for any high-risk subject visiting the general practitioner clinic for any reason.

Organized Pneumonia Secondary to Increasing Doses of Temozolomide.

Surgery, radiotherapy (RT), and chemotherapy have a role in the control of tumor growth, progression, and recurrence in high-grade gliomas. Temozolomide has been incorporated as the main chemotherapy agent for managing these tumors. Here, we present a case of a patient who developed a severe organizing pneumonia after increasing doses of temozolomide for a high-grade glioma.

Diffuse interstitial lung disease as a first manifestation of Waldenström's macroglobulinemia: case report and review of the literature.

Waldenström's macroglobulinemia (WM) is a lymphoid malignancy characterized by infiltration, mainly of the bone marrow and lymph nodes, by small mature lymphocytes showing plasmacytoid differentiation, associated with an IgM monoclonal band, and, in general, a low degree of aggressiveness. We present the first case reported in the Spanish literature of interstitial lung disease presenting as MW and we review the literature.

[From exclusion to uncertainty: the route to diagnosing idiopathic pulmonary fibrosis]. / De la exclusión a la certidumbre. El recorrido hacia el diagnóstico de la fibrosis pulmonar idiopática.

Idiopathic pulmonary fibrosis (IPF) is a differentiated disease within the idiophatic interstitial pneumonias. IPF is progressive and fibrosing and is limited to the lungs. This entity generally affects persons older than 50 years old and is associated with the radiological and/or histological pattern of usual interstitial pneumonia (UIP). Clinically, IPF causes progressive exertional dyspnea and nonproductive cough. In most patients, physical examination reveals fine bibasilar inspiratory crackles and 50% of patients have digital clubbing. There are no specific laboratory alterations. Bronchoalveolar lavage and transbronchial biopsy will not establish the diagnosis of IPF but are useful to exclude other entities. Definitive diagnosis requires: a) exclusion of other, defined clinical entities or diffuse pulmonary diseases of known cause, and b) the presence of a histological pattern of UIP on analysis of pulmonary tissue from surgical biopsy, radiological evidence of the defined pattern of UIP on high-resolution computed tomography, or both.