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    • An association between reconstitution of

    2018-10-23

    An association between reconstitution of CD4 T-cells and impaired lung function, measured as oxygen saturation, has been shown in a murine model for IRIS using Mycobacterium avium (). However, our study investigated the association between paradoxical TB-IRIS, change in MMPs on ART, and pulmonary function post-TB cure among HIV/TB co-infected patients. Our evaluation of lung function demonstrated not only lower FEV1 in TB-IRIS patients compared to non-IRIS controls, but also that the magnitude of the early CD4 cell increase and circulating MMP-8 concentrations following ART p2x receptors were associated with impaired FEV1 post-TB cure. While the number of patients assessed using PFTs was small and this subset may not be entirely representative of the larger cohort with respect to certain MMPs (i.e., MMP-1 and -3) and TB-specific immune responses, the strength of the associations (r=−0.7 and r=−0.6) suggests that further research on this association is needed. Impairment of FEV1, which primarily measures airflow through large airways, fits with the endobronchial involvement characteristic of TB and with at least one anecdotal report of severe bronchiolitis obliterans after ART initiation in HIV/TB (Lawn et al. 2009). While our findings were among advanced HIV/TB patients initiating ART, they urge future studies to investigate end-organ damage in TB-IRIS and more generally among HIV/TB co-infected patients initiating ART. Central nervous system (CNS) impairment following TB-meningitis associated IRIS is also a concern, as significant localized increases in cellular immune function and MMPs have been previously noted (Marais et al. 2014). Mechanistically, reduced lung involvement in advanced HIV-infected patients has been linked to low CD4 counts and reduced concentrations of MMPs, both of which are important to granuloma formation and cavitation (Kwan and Ernst 2011; Post et al. 1995; Walker et al. 2012; Zhang et al. 1994; Law et al. 1996). While we did not determine the source of MMPs, neutrophils may also be involved, as discussed above. Neutrophils, which are noted to be the predominant phagocytic cell type in the airway of TB patients (Eum et al. 2010), were found to express MMP-8 and -9 in the lining of TB cavities (Ong et al. 2015), supporting a possible role in the pathogenesis of the lung impairment we observed. It is plausible that reconstituted CD4 T-cell and neutrophil activity following ART initiation in the setting of incompletely treated TB contribute, in part, to the rise in MMP-8 concentrations on ART, as seen here (Appelberg 1992; Zhang et al. 1992). Neutrophil infiltration to the disease site soon after ART initiation has been suggested in a study of TB meningitis IRIS among HIV-infected patients (Marais et al. 2013). Furthermore, MMP-8 expression differs from other MMPs in that neutrophils contain granules with pre-synthesized MMP-8 and have the potential to secrete MMP-8 rapidly upon activation (Elkington and Friedland 2006; Hasty et al. 1986; Weiss et al. 1985). Thus, the ensuing increase in immune function and MMPs on ART, perhaps driven by neutrophils, could potentially underlie incident lung tissue damage and worsening the airflow obstruction that frequently accompanies TB (Pasipanodya et al. 2010; Hnizdo et al. 2000; Ralph et al. 2013). Our data collection did not include neutrophil numbers, but these findings need confirmation in larger studies where longitudinal assessments of immune and pulmonary function are assessed in more detail. Furthermore, future studies should aim to identify the primary site of lung injury and the predominant form of ventilator defects in HIV/TB co-infected patients following pTB treatment completion. Our study was limited by the relatively small number of patients with PFTs, which restricted our assessment of potential confounding. Another important limitation of our study is that we did not have baseline lung function assessments to determine if patients with pulmonary impairment post-TB treatment completion, as measured here, also started off with worse lung function before ART initiation. However, patients in the study who had abnormal lung function post-cure tended to have lower pre-ART CD4 counts and MMP-8 concentration, both of which are associated with less lung involvement in HIV/TB (Kwan and Ernst 2011; Walker et al. 2012; Law et al. 1996). Additionally, chest radiographs, which we did not have at baseline or during follow-up, would have further enabled evaluation of lung involvement during treatment. Another limitation of our study was that we excluded patients who did not survive to 6months post-ART initiation from our analyses. These patients may have had poor lung function. However, as the aim of our study was to investigate the determinants of lung impairment after TB treatment completion, we excluded deaths as they did not survive to this time point.