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    • Although our results suggest an association between NFKBIE

    2018-10-23

    Although our results suggest an association between NFKBIE, and possibly NFKBIA, and susceptibility to IPD, we cannot exclude that the SNPs are in LD with disease-associated polymorphisms in nearby causative protease inhibitor (Gabriel et al., 2002). This makes replication in independent populations important. The Bonferroni method was applied in order to adjust for multiple comparisons. However, this correction is known to be conservative, when a number of SNPs are evaluated for association with traits (Gao et al., 2008). This may increase the risk of making type II errors in our study. To our best knowledge we conducted the largest study of its kind on selected SNPs previously associated with pneumococcal disease. We found that a polymorphism in NFKBIE gene, which is essential for NF-κB in the innate immune response/TLR pathways, predisposed Danish children under the age of five to pneumococcal meningitis.
    Author Contributions
    Funding This work was supported by the Lundbeck Foundation; the Novo Nordisk Foundation; King Christian the 10th Foundation (J. no. 21/2008); Jacob Madsen\'s Foundation (grant number 4360); TrygVesta, Ebba Celinder\'s Foundation (70001278 CCA/ASM); the Danish Medical Association Foundation; the Foundation for Advancement of Medical Science; the Augustinus Foundation (08-0118); Peder Laurits Pedersen\'s Foundation; A.P. Møller Foundation for the Advancement of Medical Science; the Danish Medical Research Council, Preben and Anna Simonsen\'s Foundation; Ferdinand and Ellen Hindsgaul\'s Foundation; Hartmann\'s Foundation and the Dagmar Marshalls Foundation. L.F.L. was supported by a PhD scholarship from the University of Copenhagen.
    Conflict of Interests
    Acknowledgments
    Introduction For many patients with TB, the morbidity of the disease extends long beyond TB treatment completion (Pasipanodya et al. 2010). Indeed, approximately half of patients surviving pulmonary TB (pTB), the most common form of the disease, suffer substantial long-term pulmonary impairment despite microbiologic cure (Pasipanodya et al. 2010; Hnizdo et al. 2000; Ralph et al. 2013). Furthermore, pTB, including cured disease, is a major cause of chronic lung disease worldwide (van Zyl Smit et al. 2010). Nearly 15% of all TB cases and 25% of global TB deaths are HIV-associated (WHO 2014). The underlying mechanisms leading to long-term pulmonary morbidity after TB treatment completion, especially among HIV-infected patients, are unclear (Pasipanodya et al. 2010; Hnizdo et al. 2000; Ralph et al. 2013). Clinically, impaired lung function after TB treatment completion is associated with greater radiographic lung involvement at initial presentation (Plit et al. 1998). Greater initial radiographic lung involvement is also associated with higher CD4 counts in individuals with HIV/TB (Kwan and Ernst 2011; Post et al. 1995). These findings are consistent with a central role of cellular immune responses in cavity formation and structural lung damage in TB (Flynn et al. 1993; Schluger et al. 2002). Mechanistically, matrix metalloproteinases (MMPs), which can degrade lung collagen, have also been implicated in TB-associated lung tissue destruction (Greenlee et al. 2007; Ong et al. 2014; Elkington et al. 2011). However, lower MMP concentrations and reduced TB-associated lung damage assessed radiographically have been associated with HIV infection (Walker et al. 2012). Taken together, these data suggest that patients with HIV may have less lung involvement than those without HIV, but data evaluating this association are conflicting (Hnizdo et al. 2000; Ralph et al. 2013). Antiretroviral therapy (ART) is a critical component of HIV/TB care, conferring a survival advantage to those who initiate ART during treatment of TB (Abdool Karim et al. 2011; Abdool Karim et al. 2010). While ART use in a study of HIV-infected patients was independently associated with airway obstruction (George et al. 2009), a limitation of studies relating HIV to lung damage in TB is that the effects of cellular immune restoration during TB treatment have not been assessed in detail. Rapid cellular immune restoration in the presence of a high TB antigen burden could plausibly drive incident cavity formation and worsening lung damage. Consistent with this hypothesis, case reports have described patients with advanced HIV/pTB and minimal initial radiographic lung involvement who develop massive pulmonary infiltrates, lung cavitation, and bronchiolitis obliterans soon after ART initiation (Meintjes et al. 2008; Lawn et al. 2009). Incident lung damage during immune restoration in HIV/TB may also complicate TB-immune reconstitution inflammatory syndrome (TB-IRIS), but this hypothesis has been relatively unexplored. In one study, HIV/TB co-infected adults who experienced TB-IRIS on ART were found to have higher absolute concentrations of MMPs at the time of the IRIS event compared to controls, but lung function was not assessed (Tadokera et al. 2014).