Host adaptive immunity deficiency in severe pandemic influenza.

INTRODUCTION: Pandemic A/H1N1/2009 influenza causes severe lower respiratory complications in rare cases. The association between host immune responses and clinical outcome in severe cases is unknown. METHODS: We utilized gene expression, cytokine profiles and generation of antibody responses following hospitalization in 19 critically ill patients with primary pandemic A/H1N1/2009 influenza pneumonia for identifying host immune responses associated with clinical outcome. Ingenuity pathway analysis 8.5 (IPA) (Ingenuity Systems, Redwood City, CA) was used to select, annotate and visualize genes by function and pathway (gene ontology). IPA analysis identified those canonical pathways differentially expressed (P < 0.05) between comparison groups. Hierarchical clustering of those genes differentially expressed between groups by IPA analysis was performed using BRB-Array Tools v.3.8.1. RESULTS: The majority of patients were characterized by the presence of comorbidities and the absence of immunosuppressive conditions. pH1N1 specific antibody production was observed around day 9 from disease onset and defined an early period of innate immune response and a late period of adaptive immune response to the virus. The most severe patients (n = 12) showed persistence of viral secretion. Seven of the most severe patients died. During the late phase, the most severe patient group had impaired expression of a number of genes participating in adaptive immune responses when compared to less severe patients. These genes were involved in antigen presentation, B-cell development, T-helper cell differentiation, CD28, granzyme B signaling, apoptosis and protein ubiquitination. Patients with the poorest outcomes were characterized by proinflammatory hypercytokinemia, along with elevated levels of immunosuppressory cytokines (interleukin (IL)-10 and IL-1ra) in serum. CONCLUSIONS: Our findings suggest an impaired development of adaptive immunity in the most severe cases of pandemic influenza, leading to an unremitting cycle of viral replication and innate cytokine-chemokine release. Interruption of this deleterious cycle may improve disease outcome.

Maternal physiological changes at rest induced by exercise during pregnancy: A randomized controlled trial.

OBJECTIVE: to analyse maternal physiological changes in several areas (cardiovascular, metabolic, renal and hepatic) related to the regular practice of a supervised exercise program. METHODS: This is an unplanned secondary analysis from a randomized controlled trial carried out in a single maternity unit in Madrid, Spain (NCT 02,756,143). From November 2014 to June 2015, 92 women were randomly assigned to perform a mild-moderate supervised exercise program during pregnancy (Intervention group, IG) or to continue with their routine pregnancy care (control group, CG). For the purpose of this study we collected clinical and analytical data (heart blood pressure, weight, blood glucose, AST, ALT, blood Creatinine and blood Uric acid) available from all obstetric visits and examined the differences between groups. RESULTS: We did not find any differences in: pregnancy weight (IG: 11.4 ± 4.4 Kg vs. CG: 10.1 ± 5.3 Kg; p = 0.173); fasting glucose at 10+0-12+6 weeks (IG: 78.48±8.34 vs. CG: 76±13.26, p = 0.305) or at 34+0-36+4 weeks (IG: 73.25±10.27 vs CG: 73.45± 8.29,p = 0.920), and 50 gs glucose tolerance at 24+4-26+6weeks (IG: 116.23±35.07 vs CG: 116.36±25.98, p = 0.984); Aspartate-amino-transferase at 10+0-12+6 weeks (IG: 15.38±4.17 vs CG: 17.33±7.05, p = 0.124) and at 34+0-36+4 weeks (IG: 21.65±5.25 vs CG: 19.53±8.32, p = 0.165) or Alanine-amino- transferase at 10+0-12+6 weeks (IG: 27.50±10.63 vs CG: 28.27±11.77, p = 0.746) or at 34+0-36+4 weeks (IG: 22.93±9.23 vs CG: 20.84±13.49, p = 0.407); blood Creatinine concentrations at 34+0-36+4 weeks (IG: 0.595±0.401 vs CG: 0.575±0.100, p = 0.757) and blood uric acid concentrations at 34+0-36+4 weeks (IG: 3.526 ± 0.787 vs CG: 3.262±0.672, p = 0.218). Heart blood pressure was similar between groups except at 27+0-28+6 weeks, where systolic blood pressure was significantly lower in the CG in comparison to the IG (116.31±10.8 mmHg vs. 120.22 ± 10.3 mmHg, p = 0.010). CONCLUSION: Regular supervised exercise during pregnancy does not alter normal maternal physiology.

Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza.

INTRODUCTION: Human host immune response following infection with the new variant of A/H1N1 pandemic influenza virus (nvH1N1) is poorly understood. We utilize here systemic cytokine and antibody levels in evaluating differences in early immune response in both mild and severe patients infected with nvH1N1. METHODS: We profiled 29 cytokines and chemokines and evaluated the haemagglutination inhibition activity as quantitative and qualitative measurements of host immune responses in serum obtained during the first five days after symptoms onset, in two cohorts of nvH1N1 infected patients. Severe patients required hospitalization (n = 20), due to respiratory insufficiency (10 of them were admitted to the intensive care unit), while mild patients had exclusively flu-like symptoms (n = 15). A group of healthy donors was included as control (n = 15). Differences in levels of mediators between groups were assessed by using the non parametric U-Mann Whitney test. Association between variables was determined by calculating the Spearman correlation coefficient. Viral load was performed in serum by using real-time PCR targeting the neuraminidase gene. RESULTS: Increased levels of innate-immunity mediators (IP-10, MCP-1, MIP-1beta), and the absence of anti-nvH1N1 antibodies, characterized the early response to nvH1N1 infection in both hospitalized and mild patients. High systemic levels of type-II interferon (IFN-gamma) and also of a group of mediators involved in the development of T-helper 17 (IL-8, IL-9, IL-17, IL-6) and T-helper 1 (TNF-alpha, IL-15, IL-12p70) responses were exclusively found in hospitalized patients. IL-15, IL-12p70, IL-6 constituted a hallmark of critical illness in our study. A significant inverse association was found between IL-6, IL-8 and PaO2 in critical patients. CONCLUSIONS: While infection with the nvH1N1 induces a typical innate response in both mild and severe patients, severe disease with respiratory involvement is characterized by early secretion of Th17 and Th1 cytokines usually associated with cell mediated immunity but also commonly linked to the pathogenesis of autoimmune/inflammatory diseases. The exact role of Th1 and Th17 mediators in the evolution of nvH1N1 mild and severe disease merits further investigation as to the detrimental or beneficial role these cytokines play in severe illness.

Influence of intrauterine dispositive in human papillomavirus clearance.

INTRODUCTION: An important inverse relation between IUD use and risk of cervical cancer has been proved. Women who used IUD had half the risk of developing cervical cancer. The mechanism how IUD is a protector factor is still unknown. Could be improving the clearance of HPV infection or stopping progression to cancer from preneoplasic lesion. The aim of the study is to check if IUD increases HPV clearance, that is, checking if after 1 year HPV infection disappears in more patients using IUD than those not using it. STUDY DESIGN: This is a cohort case-control prospective study, carried out in Universitary Hospital La Zarzuela in Madrid, Spain, performed between October 2015 and April 2018. No pregnant women between 25-50 years old, with HPV cervical infection were enrolled. We separated the participants into two groups: an IUD group, with women starting using IUD and non IUD group, with women using any other contraceptive method or none. HPV genotyping of cervical cytology samples were performed initially on enrolment day and one year after. RESULTS: 254 participants were enrolled at the beginning of the study, 85 in the IUD group and 169 in the control group (non IUD). 179 participants completed the study, 54 (31%) in IUD group and 120 participants in non IUD group (69%). 38 women from IUD group cleared HPV infection (69.5%) and 65 women from control group cleared it (54.2%) (p = 0.044). An association in logistic regression was observed in HPV clearance with different factors. Firstly, higher percentage of patients with IUD clear the HPV infection than those in control group significantly associated (OR = 0.698, CI 95%; 0.251-0.998, p = 0.046). Clearance was higher in patients with low-risk HPV infection comparing with high risk HPV (OR = 1.078, CI 95%; 1.126-4.6.281, p = 0.026) and in patients with only one HPV type than those with more than one (OR = 0.194, CI 95%; 0.084-0.403, p < 0.001). CONCLUSIONS: In Spanish women with HPV infection, the HPV clearance between IUD and non IUD groups show results with statistical significance, patients with IUD have higher clearance rates. There were differences also between suffering one HPV type or more than one, and having low-risk HPV or high-risk HPV infection.

ALOX5 promoter genotype and response to montelukast in moderate persistent asthma.

BACKGROUND: It was hypothesized that asthmatic patients with mutant alleles in the leukotriene pathway should not respond to leukotriene receptor antagonists and the concept of a tailored treatment is increasingly supported. METHODS: Sixty-one patients (mean age 24.9 years, range 14-52) with moderate persistent asthma were clinical and immunological assess prior and after a 6-month treatment with montelukast. Tandem repeat polymorphisms were genotyped in the promoter (-147 to -176) of 5-lipoxygenase gene (ALOX5). RESULTS: Thirty-two patients (52.5%) were homozygous for the five repeats allele; 17 (27.9%) were heterozygous (4/5 repeats) and 12 (19.7%) were homozygous for 4/4 repeats. After the montelukast treatment decrease number of asthma exacerbations, improvement of FEV(1) and decreased use of beta(2) agonists was observed in patients with 5/5 or 4/5 repeats. Conversely, the patients with 4/4 repeats genotype did not modify these data after treatment. CONCLUSIONS: It was confirmed that ALOX5 promoter polymorphisms have a clear influence in montelukast response in atopic moderate persistent asthma patients. The genetic study could identify those patients most likely to respond to montelukast.

A new method for detection of pandemic influenza virus using High Resolution Melting analysis of the neuraminidase gene.

Diagnostic methods based upon exclusive detection of haemagglutinin do not detect sequence variation in other gene segments of the Influenza A virus. A complementary approach is described based upon high-resolution melting curve analysis of the neuraminidase gene, an approach with the potential ability to detect small changes in the neuraminidase sequence without the need for specific probes.