Summary Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used as antiviral agents for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV2) infection. We performed a systematic review to examine whether prior clinical studies that compared the effects of CQ and HCQ to a control for the treatment of non‐SARS‐CoV2 infection supported the use of these agents in the present SARS‐CoV2 outbreak. PubMed, EMBASE, Scopus and Web of Science (PROSPERO CRD42020183429) were searched from inception through 2 April 2020 without language restrictions. Of 1766 retrieved reports, 18 studies met our inclusion criteria, including 17 prospective controlled studies and one retrospective study. CQ or HCQ were compared to control for the treatment of infectious mononucleosis (EBV, n = 4), warts (human papillomavirus, n = 2), chronic HIV infection ( n = 6), acute chikungunya infection ( n = 1), acute dengue virus infection ( n = 2), chronic HCV ( n = 2), and as preventive measures for influenza infection ( n = 1). Survival was not evaluated in any study. For HIV, the virus that was most investigated, while two early studies suggested HCQ reduced viral levels, four subsequent ones did not, and in two of these CQ or HCQ increased viral levels and reduced CD4 counts. Overall, three studies concluded CQ or HCQ were effective; four concluded further research was needed to assess the treatments' effectiveness; and 11 concluded that treatment was ineffective or potentially harmful. Prior controlled clinical trials with CQ and HCQ for non‐SARS‐CoV2 viral infections do not support these agents' use for the SARS‐CoV2 outbreak.
Rationale:Cell-free hemoglobin (CFH) levels are elevated in septic shock and higher in non-survivors. Whether CFH is only a marker of sepsis severity or is involved in pathogenesis is unknown. Objective:To investigate whether CFH worsens sepsis-associated injuries and to determine potential mechanisms of harm. Methods&Results:Fifty-one, 10-12kg purpose-bred beagles were randomized to receive Staphylococcus aureus intrapulmonary challenges or saline followed by CFH infusions (oxyhemoglobin >80%) or placebo. Animals received antibiotics, and intensive care-support for 96h. CFH significantly increased mean pulmonary arterial pressures and right ventricular afterload in both septic and non-septic animals, effects that were significantly greater in non-survivors. These findings are consistent with CFH-associated nitric oxide (NO) scavenging and were associated with significantly depressed cardiac function, and worsened shock, lactate levels, metabolic acidosis and multi-organ failure. In septic animals only, CFH administration significantly increased mean alveolar-arterial oxygenation gradients, also to a significantly greater degree in non-survivors. CFH associated iron levels were significantly suppressed in infected animals, suggesting that bacterial iron uptake worsened the pneumonia. Notably, cytokine levels were similar in survivors and non-survivors and not predictive of outcome. Conclusions:In the absence and presence of infection, CFH infusions resulted in pulmonary hypertension, cardiogenic shock and multi-organ failure, likely through NO scavenging. In the presence of infection alone, CFH infusions worsened oxygen exchange and lung injury, presumably by supplying iron that promoted bacterial growth. CFH elevation, a known consequence of clinical septic shock, adversely impacts sepsis outcomes through more than one mechanism and is a biologically plausible, non-antibiotic, non-cytokine target for therapeutic intervention.
Anti-toxin agents for severe B. anthracis infection will only be effective if they add to the benefit of the two mainstays of septic shock management, antibiotic therapy and titrated hemodynamic support. Both of these standard therapies could negate benefits related to anti-toxin treatment. At present, three anthrax anti-toxin antibody preparations have received US Food and Drug Administration (FDA) approval: Raxibacumab, Anthrax Immune Globulin Intravenous (AIGIV) and ETI-204. Each agent is directed at the protective antigen component of lethal and edema toxin. All three agents were compared to placebo in antibiotic-treated animal models of live B. anthracis infection, and Raxibacumab and AIGIV were compared to placebo when combined with standard hemodynamic support in a 96 h canine model of anthrax toxin-associated shock. However, only AIG has actually been administered to a group of infected patients, and this experience was not controlled and offers little insight into the efficacy of the agents. To provide a broader view of the potential effectiveness of these agents, this review examines the controlled preclinical experience either in antibiotic-treated B. anthracis models or in titrated hemodynamic-supported toxin-challenged canines. The strength and weaknesses of these preclinical experiences are discussed.
Bacillus anthracis edema toxin (ET) inhibited lethal toxin stimulated pulmonary artery pressure (Ppa) and increased lung cAMP levels in our previous study. We therefore examined whether ET inhibits hypoxic pulmonary vasoconstriction (HPV). Following baseline hypoxic measures in isolated perfused lungs from healthy rats, compared to diluent, ET perfusion reduced maximal Ppa increases [mean(±sem) percent of maximal Ppa increase with baseline hypoxia] during 6min hypoxic periods (FiO2=0%) at 120min (16±6% vs. 51±6%, p=0.004) and 180min (11.4% vs. 55±6%, p=0.001). Protective antigen-mAb (PA-mAb) and adefovir inhibit host cell edema factor uptake and cAMP production respectively. In lungs perfused with ET following baseline measures, compared to placebo, PA-mAb treatment increased Ppa during hypoxia at 120 and 180min (56±6% vs. 10±4% and 72±12% vs. 12±3% respectively, p≤0.01) as did adefovir (84±10% vs 16.8% and 123±21% vs. 26±11%, respectively, p≤0.01). Compared to diluent, lung perfusion with ET for 180min reduced the slope of the relationships between Ppa and increasing concentrations of endothelin-1 (ET-1)(21.12±2.96 vs. 3.00±0.76×108cmH2O/M, p<0.0001) and U46619, a thromboxane A2 analogue (7.15±1.01 vs. 3.74±0.31×107cmH2O/M, p=0.005) added to perfusate. In lungs isolated from rats after 15h of in vivo infusions with either diluent, ET alone or ET with PA-mAb, compared to diluent, the maximal Ppa during hypoxia and the slope of the relationship between change in Ppa and ET-1 concentration added to the perfusate were reduced in lungs from animals challenged with ET alone (p≤0.004) but not with ET and PA-mAb together (p≥0.73). Inhibition of HPV by ET could aggravate hypoxia during anthrax pulmonary infection.
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