We previously reported that macrophage exposure to attenuated strains of pathogenic mycobacteria at multiplicities of infection (MOI) ≤ 10 triggers TNF-α-mediated apoptosis which reduces the viability of intracellular bacilli. Virulent strains were found to suppress macrophage apoptosis, and it was proposed that apoptosis is an innate defense against intracellular Mycobacterium tuberculosis analogous to apoptosis of virus-infected cells. The potential similarity of host cell responses to intracellular infection with mycobacteria and viruses suggests that M. tuberculosis might lyse infected macrophage when that niche is no longer needed. To investigate this question, we challenged murine macrophages with high intracellular bacillary loads. A sharp increase in cytolysis within 24 h was observed at MOI ≥ 25. The primary death mode was apoptosis, based on nuclear morphology and phosphatidyl serine exposure, although the apoptotic cells progressed rapidly to necrosis. Apoptosis at high MOI differs markedly from low MOI apoptosis: it is potently induced by virulent M. tuberculosis, it is TNF-α-independent, and it does not reduce mycobacterial viability. Caspase inhibitors failed to prevent high MOI apoptosis, and macrophages deficient in caspase-3, MyD88, or TLR4 were equally susceptible as wild type. Apoptosis was reduced in the presence of cathepsin inhibitors, suggesting the involvement of lysosomal proteases in this novel death response. We conclude that the presence of high numbers of intracellular M. tuberculosis bacilli triggers a macrophage cell death pathway that could promote extracellular spread of infection and contribute to the formation of necrotic lesions in tuberculosis.

The course of FVC in SSc was highly variable, with improvement and stability experienced even by those with low baseline FVC. Trajectory modelling was able to identify SSc patients who were most likely to experience FVC decline and thus could be a useful tool for patient management as well as clinical trial design.

Objective: The aim of this observational study was to determine the optimal timing of interleukin-6 receptor inhibitor (IL6ri) administration for coronavirus disease 2019 (COVID-19). Methods: Patients with COVID-19 were given an IL6ri (sarilumab or tocilizumab) based on iteratively reviewed guidelines. IL6ri were initially reserved for critically ill patients, but after review, treatment was liberalized to patients with lower oxygen requirements. Patients were divided into two groups: those requiring ≤45% fraction of inspired oxygen (FiO 2 ) (termed stage IIB) and those requiring >45% FiO 2 (termed stage III) at the time of IL6ri administration. The main outcomes were all-cause mortality, discharge alive from hospital, and extubation. Results: A total of 255 COVID-19 patients were treated with IL6ri (149 stage IIB and 106 stage III). Patients treated in stage IIB had lower mortality than those treated in stage III (adjusted hazard ratio (aHR) 0.24, 95% confidence interval (CI) 0.08–0.74). Overall, 218 (85.5%) patients were discharged alive. Patients treated in stage IIB were more likely to be discharged (aHR 1.43, 95% CI 1.06–1.93) and were less likely to be intubated (aHR 0.43, 95% CI 0.24–0.79). Conclusions: IL6ri administration prior to >45% FiO 2 requirement was associated with improved COVID-19 outcomes. This can guide clinical management pending results from randomized controlled trials

Most patients with PH secondary to SSc manifest favorable hemodynamic responses to epoprostenol in the short term. Long-term epoprostenol was generally well tolerated and provides a potential therapeutic option for patients with PH secondary to SSc.

Human immunodeficiency virus (HIV)-positive persons are predisposed to pulmonary infections, even after receiving effective highly active antiretroviral therapy. The reasons for this are unclear but may involve changes in innate immune function. HIV type 1 infection of macrophages impairs effector functions, including cytokine production. We observed decreased constitutive tumor necrosis factor alpha (TNF-␣) concentrations and increased soluble tumor necrosis factor receptor type II (sTNFRII) in bronchoalveolar lavage fluid samples from HIV-positive subjects compared to healthy controls. Moreover, net proinflammatory TNF-␣ activity, as measured by the TNF-␣/sTNFRII ratio, decreased as HIV-related disease progressed, as manifested by decreasing CD4 cell count and increasing HIV RNA (viral load). Since TNF-␣ is an important component of the innate immune system and is produced upon activation of Toll-like receptor (TLR) pathways, we hypothesized that the mechanism associated with deficient TNF-␣ production in the lung involved altered TLR expression or a deficit in the TLR signaling cascade. We found decreased Toll-like receptor 1 (TLR1) and TLR4 surface expression in HIV-infected U1 monocytic cells compared to the uninfected parental U937 cell line and decreased TLR message in alveolar macrophages (AMs) from HIV-positive subjects. In addition, stimulation with TLR1/2 ligand (Pam 3 Cys) or TLR4 ligand (lipopolysaccharide) resulted in decreased intracellular phosphorylated extracellular signal-regulated kinase and subsequent decreased transcription and expression of TNF-␣ in U1 cells compared to U937 cells. AMs from HIV-positive subjects also showed decreased TNF-␣ production in response to these TLR2 and TLR4 ligands. We postulate that HIV infection alters expression of TLRs with subsequent changes in mitogen-activated protein kinase signaling and cytokine production that ultimately leads to deficiencies of innate immune responses that predispose HIV-positive subjects to infection.

CPET/RHC testing in subjects with SSc and potentially multifactorial dyspnea adds potentially useful diagnostic information unavailable from noninvasive testing.

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Background: The efficacy and safety of prophylactic full-dose anticoagulation and antiplatelet therapy in critically-ill COVID-19 patients remains uncertain. Methods: COVID-PACT was a multicenter, 2x2 factorial, open-label, randomized-controlled trial with blinded endpoint adjudication in ICU-level patients with COVID-19. Patients were randomized to a strategy of full-dose anticoagulation or standard-dose prophylactic anticoagulation. Absent an indication for antiplatelet therapy, patients were additionally randomized to either clopidogrel or no antiplatelet therapy. The primary efficacy outcome was the hierarchical composite of death due to venous or arterial thrombosis, pulmonary embolism, clinically-evident deep venous thrombosis (DVT), type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute limb ischemia, or clinically-silent DVT, through hospital discharge or 28 days. The primary efficacy analyses included an unmatched win-ratio and time-to-first event analysis while patients were on-treatment. The primary safety outcome was fatal or life-threatening bleeding. The secondary safety outcome was GUSTO moderate/severe bleeding. Recruitment was stopped early in 03/2022 (∼50% planned recruitment) due to waning ICU-level COVID-19 rates. Results: At 34 centers in the United States, 390 patients were randomized between anticoagulation strategies and 292 between antiplatelet strategies (382 and 290 in the on-treatment analyses). At randomization, 99% of patients required advanced respiratory therapy, including 15% requiring invasive mechanical ventilation; 40% required invasive ventilation during hospitalization. Comparing anticoagulation strategies, a greater proportion of wins occurred with full-dose anticoagulation (12.3%) versus standard-dose prophylactic anticoagulation (6.4%; win ratio 1.95, 95%CI 1.08-3.55, p=0.028). Results were consistent in time-to-event analysis for the primary efficacy endpoint (full-dose versus standard-dose incidence 19/191 [9.9%] vs 29/191 [15.2%]; HR 0.56, 95%CI 0.32-0.99, p=0.046). The primary safety endpoint occurred in 4 (2.1%) on full-dose and in 1 (0.5%) on standard-dose (p=0.19); the secondary safety endpoint occurred in 15 (7.9%) versus 1 (0.5%; p=0.002). There was no difference in all-cause mortality (HR 0.91, 95%CI 0.56-1.48; p=0.70). There were no differences in the primary efficacy or safety endpoints with clopidogrel versus no antiplatelet therapy. Conclusions: In critically-ill patients with COVID-19, full-dose anticoagulation, but not clopidogrel, reduced thrombotic complications with an increase in bleeding, driven primarily by transfusions in hemodynamically stable patients, and no apparent excess in mortality.