Background Understanding the factors associated with disease severity and mortality in Coronavirus disease (COVID-19) is imperative to effectively triage patients. We performed a systematic review to determine the demographic, clinical, laboratory and radiological factors associated with severity and mortality in COVID-19. Methods We searched PubMed, Embase and WHO database for English language articles from inception until May 8, 2020. We included Observational studies with direct comparison of clinical characteristics between a) patients who died and those who survived or b) patients with severe disease and those without severe disease. Data extraction and quality assessment were performed by two authors independently. Results Among 15680 articles from the literature search, 109 articles were included in the analysis. The risk of mortality was higher in patients with increasing age, male gender (RR 1.45, 95%CI 1.23–1.71), dyspnea (RR 2.55, 95%CI 1.88–2.46), diabetes (RR 1.59, 95%CI 1.41–1.78), hypertension (RR 1.90, 95%CI 1.69–2.15). Congestive heart failure (OR 4.76, 95%CI 1.34–16.97), hilar lymphadenopathy (OR 8.34, 95%CI 2.57–27.08), bilateral lung involvement (OR 4.86, 95%CI 3.19–7.39) and reticular pattern (OR 5.54, 95%CI 1.24–24.67) were associated with severe disease. Clinically relevant cut-offs for leukocytosis(>10.0 x109/L), lymphopenia(< 1.1 x109/L), elevated C-reactive protein(>100mg/L), LDH(>250U/L) and D-dimer(>1mg/L) had higher odds of severe disease and greater risk of mortality. Conclusion Knowledge of the factors associated of disease severity and mortality identified in our study may assist in clinical decision-making and critical-care resource allocation for patients with COVID-19.

Background Although the incidence of tuberculosis (TB) is higher in males compared to females, the relationship of sex with TB treatment outcomes has not been adequately studied. Methods We performed a retrospective cohort study and a systematic review and meta-analysis of observational studies during the last 10 years to assess sex differences in clinical and microbiological outcomes in tuberculosis. Results In our cohort of 2,894 patients with drug-susceptible pulmonary TB (1,975 males and 919 females), males had higher adjusted hazards of 9-month mortality due to all causes (HR 1·43,95%CI 1.03-1.98) and infections (HR 1.70, 95%CI 1.09-2.64) and higher adjusted odds ratio for 2-month sputum culture positivity (OR 1.56,95%CI 1.05-2.33) compared to females. Smear positivity at 2 months was not significantly different (OR 1.27, 0.71-2.27) between the sexes. Among 7,896 articles retrieved, 398 articles were included in our systematic review describing a total of 3,957,216 patients. The odds of all-cause mortality were higher in males compared to females in the pooled unadjusted (OR 1.26, 95%CI 1.19-1.34) and adjusted (OR 1.31, 95%CI 1.18-1.45) analyses. Males had higher pooled odds of sputum culture (OR 1.44,95% CI 1.14-1.81) and sputum smear (OR 1.58,95%CI 1.41-1.77) positivity, both at the end of the intensive phase and upon treatment completion. Conclusions Our retrospective cohort showed that male TB patients have higher 9-month all-cause and infection-related mortality, with higher 2-month sputum culture positivity after adjusting for confounding factors. In our meta-analysis, males showed higher all-cause and TB-related mortality and higher sputum culture and smear positivity rates during and after TB treatment.

Lengthy tuberculosis (TB) treatment is required to overcome the ability of a subpopulation of persistent Mycobacterium tuberculosis (Mtb) to remain in a non-replicating, antibiotic-tolerant state characterized by metabolic remodeling, including induction of the Rel Mtb -mediated stringent response. We developed a novel therapeutic DNA vaccine containing a fusion of the rel Mtb gene with the gene encoding the immature dendritic cell-targeting chemokine, MIP-3a/CCL20. To augment mucosal immune responses, intranasal delivery was also evaluated. We found that intramuscular delivery of the MIP-3a/rel Mtb (fusion) vaccine or intranasal delivery of the rel Mtb (nonfusion) vaccine potentiate isoniazid activity more than intramuscular delivery of the DNA vaccine expressing rel Mtb alone in a chronic TB mouse model (absolute reduction of Mtb burden: 0.63 log 10 and 0.5 log 10 colony-forming units, respectively; P=0.0002 and P=0.0052), inducing pronounced Mtbprotective immune signatures. The combined approach involving intranasal delivery of the DNA MIP-3a/rel Mtb fusion vaccine demonstrated the greatest mycobactericidal activity together with isoniazid when compared to each approach alone (absolute reduction of Mtb burden: 1.13 log 10 , when compared to the intramuscular vaccine targeting rel Mtb alone; P<0.0001), as well as robust systemic and local Th1 and Th17 responses. This DNA vaccination strategy may be a promising adjunctive approach combined with standard Frontiers in Immunology frontiersin.org 01

Although lethal toxin (LT) and edema toxin (ET) contribute to lethality during Bacillus anthracis infection, whether they increase vascular permeability and the extravascular fluid accumulation characterizing this infection is unclear. We employed an isolated perfused Sprague-Dawley rat lung model to investigate LT and ET effects on pulmonary vascular permeability. Lungs ( n ≥ 6 per experimental group) were isolated, ventilated, suspended from a force transducer, and perfused. Lung weight and pulmonary artery (Ppa) and left atrial pressures were measured over 4 h, after which pulmonary capillary filtration coefficients (Kf.c) and lung wet-to-dry weight ratios (W/D) were determined. When compared with controls, LT increased Ppa over 4 h and Kf.c and W/D at 4 h ( P < 0.0001). ET decreased Ppa in a significant trend ( P = 0.09) but did not significantly alter Kf.c or W/D ( P ≥ 0.29). Edema toxin actually blocked LT increases in Ppa but not LT increases in Kf.c and W/D. When Ppa was maintained at control levels, LT still increased Kf.c and W/D ( P ≤ 0.004). Increasing the dose of each toxin five times significantly increased and a toxin-directed monoclonal antibody decreased the effects of each toxin ( P ≤ 0.05). Two rho-kinase inhibitors (GSK269962 and Y27632) decreased LT increases in Ppa ( P ≤ 0.02) but actually increased Kf.c and W/D in LT and control lungs ( P ≤ 0.05). A vascular endothelial growth factor receptor inhibitor (ZM323881) had no significant effect ( P ≥ 0.63) with LT. Thus, LT but not ET can increase pulmonary vascular permeability independent of increased Ppa and could contribute to pulmonary fluid accumulation during anthrax infection. However, pulmonary vascular dilation with ET could disrupt protective hypoxic vasoconstriction. NEW & NOTEWORTHY The most important findings from the present study are that Bacillus anthracis lethal toxin increases pulmonary artery pressure and pulmonary permeability independently in the isolated rat lung, whereas edema toxin decreases the former and does not increase permeability. Each effect could be a basis for organ dysfunction in patients with this lethal infection. These findings further support the need for adjunctive therapies that limit the effects of both toxins during infection.

Multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) poses significant challenges to global tuberculosis (TB) control. Host-directed therapies (HDT) offer a novel approach for TB treatment by enhancing immune-mediated clearance of Mtb. Prior preclinical studies found that inhibition of heme oxygenase-1 (HO-1), an enzyme involved in heme metabolism, with tin-protoporphyrin IX (SnPP) significantly reduced mouse lung bacillary burden alone and when co-administered with the first-line antitubercular regimen. Here we evaluated the adjunctive HDT activity of a novel HO-1 inhibitor, stannsoporfin (SnMP), in combination with a novel MDR-TB regimen containing human-equivalent doses comprising a next-generation diarylquinoline, TBAJ-876 (S), pretomanid (Pa), and a new oxazolidinone, TBI-223 (O) (collectively, SPaO) in Mtb-infected BALB/c mice. After 4 weeks of treatment, SPaO + SnMP 5 mg/kg reduced mean lung bacillary burden by an additional 0.69 log10 (P=0.0145) relative to SPaO alone. As early as two weeks post-treatment initiation, SnMP adjunctive therapy differentially altered the expression of pro-inflammatory cytokine genes, and CD38, a marker of M1 macrophages. Next, we evaluated the sterilizing potential of SnMP adjunctive therapy in a BALB/c relapse model. After six weeks of treatment, SPaO + SnMP 10 mg/kg reduced lung bacterial burdens to 0.71 ± 0.23 log10 CFU, a 0.78 log-fold greater decrease in lung CFU compared to SpaO alone. Although adjunctive SnMP did not reduce microbiological relapse rates after 6 weeks of treatment, mice receiving this regimen exhibited the lowest lung CFU upon relapse. SnMP is a promising HDT candidate requiring further study in combination with regimens for drug-resistant TB.

Background: Understanding the factors associated with disease severity and mortality in Coronavirus disease (COVID19) is imperative to effectively triage patients. We performed a systematic review to determine the demographic, clinical, laboratory and radiological factors associated with severity and mortality in COVID-19. Methods: We searched PubMed, Embase and WHO database for English language articles from inception until May 8, 2020. We included Observational studies with direct comparison of clinical characteristics between a) patients who died and those who survived or b) patients with severe disease and those without severe disease. Data extraction and quality assessment were performed by two authors independently. Results: Among 15680 articles from the literature search, 109 articles were included in the analysis. The risk of mortality was higher in patients with increasing age, male gender (RR 1.45; 95%CI 1.23,1.71), dyspnea (RR 2.55; 95%CI 1.88,2.46), diabetes (RR 1.59; 95%CI 1.41,1.78), hypertension (RR 1.90; 95%CI 1.69,2.15). Congestive heart failure (OR 4.76; 95%CI 1.34,16.97), hilar lymphadenopathy (OR 8.34; 95%CI 2.57,27.08), bilateral lung involvement (OR 4.86; 95%CI 3.19,7.39) and reticular pattern (OR 5.54; 95%CI 1.24,24.67) were associated with severe disease. Clinically relevant cut-offs for leukocytosis(>10.0 x109/L), lymphopenia(< 1.1 x109/L), elevated C-reactive protein(>100mg/L), LDH(>250U/L) and D-dimer(>1mg/L) had higher odds of severe disease and greater risk of mortality. Conclusion: Knowledge of the factors associated of disease severity and mortality identified in our study may assist in clinical decision-making and critical-care resource allocation for patients with COVID-19.

Background Tuberculosis (TB) is one of the leading causes of death from a single infectious agent worldwide. The lengthy treatment regimen reflects the unique ability of a subpopulation of “persister” bacteria to remain in a nonreplicating state in the infected host through various adaptive strategies, including induction of the stringent response. The key stringent response enzyme, RelMtb, is essential for long-term Mycobacterium tuberculosis (Mtb) survival under physiologically relevant stresses in vitro and in animal lungs. Recently, our group has generated a therapeutic, parenteral, relMtb DNA vaccine, which induces RelMtb-specific cellular immunity and augments the activity of the first-line drug isoniazid against active TB in mice and guinea pigs. Our group also has applied a novel vaccination strategy involving the fusion of an antigen of interest with the immature dendritic cell (iDC)-targeting chemokine MIP-3α/CCL20, which significantly enhances antigen-specific T-cell responses. We sought to determine if this iDC-targeting strategy improves the immunogenicity of the therapeutic relMtb DNA vaccine. Methods We cloned the relMtb and chemokine MIP-3α genes into the eukaryotic expression plasmid pSectag2b. We conducted an immunogenicity study using C57BL/6J mice, comparing the T-cell responses between the relMtbvs. MIP-3α/relMtb DNA intramuscular vaccination groups. Results Intramuscular administration of the DNA vaccine expressing the MIP-3α/relMtb gene fusion induced increased production of various Mtb-protective cytokines (IL-17α, IL-2, TNF-α, IFN-γ) in various mouse tissues, including the spleen, draining lymph nodes and peripheral blood mononuclear cells, relative to the vaccine expressing relMtb alone. Conclusion Intramuscular immunization with a DNA vaccine expressing relMtb/MIP-3α induces robust in vivo Mtb-protective immune signatures, suggesting this may be a promising adjunctive approach in combination with standard anti-TB therapy. Disclosures All Authors: No reported disclosures

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