ABSTRACT
Rationale: While oxygen therapy is standard for patients with pneumonia, a potential for increased oxidant damage exists. Understanding how oxygen therapy impacts inflammatory lung injury with SARS-CoV-2 infection (COVID-19) and related viruses will inform patient management. We investigated the effects of fractional inspired oxygen concentrations (FiO2s) of 30 or 60% in a mouse hepatitis virus-1 (MHV-1) model of acute lung injury we developed in A/J mice. Methods: MHV-1, a ß-coronavirus like SARS-CoV-2, can be studied at Biosafety Level-2. Intratracheal installation of MHV-1 in our model produces inflammatory lung injury, progressive arterial desaturation, and lethality over 14d, similar to COVID-19. Using this model, we compared outcomes in animals exposed in sealed chambers to atmospheric FiO2s of 21, 30 or 60% beginning 2h after of MHV-1 challenge and continuing for up to 14d. In each of three experiments, MHV-1 challenged animals were randomized to receive FiO2s of 21, 30 or 60% (10 animals per FiO2 group per experiment, 90 animals total). In another experiment, 30 animals challenged with noninfected viral culture medium were randomized to the same three FiO2s. Animals were observed for up to 14d. Results: Compared to FiO2 21%, chambers with FiO2 30 and 60% had similar humidities and temperatures but slightly lower carbon dioxide levels (CO2, p≤0.05) but all chamber CO2s were in the range of 400-2000 ppm. Compared to animals surviving with FiO2 21% in each of the three experiments [#survivors/#total animals (%)] [1/10 (10%);5/10 (50%);4/10 (40%)], and their survival times (Figure-1), survival was reduced in respective experiments with FiO2 30% [1/10 (10%);2/10 (20%);0/10 (0%)] and FiO2 60% [0/10 (0%);0/10 (0%);0/10 (0%)]. Patterns of survival were similar comparing the three experiments for each FiO2 and when combined, there was a significant dose-related difference in survival across the three FiO2's (p<0.0001) (Figure-1). Compared to FiO2 21%, survival decreased with FiO2 30% (p=0.06) and more so with FiO2 60% (p<0.0001) (log-rank test with Dunnett-Hsu adjustment). All animals challenged with noninfected viral culture medium and exposed similarly to FiO2s 21, 30 or 60% (n=10 per group) survived except one 30% animal that died at 12d despite appearing well. Conclusions: FiO2s of 30 and 60% that are considered therapeutic and relatively safe clinically, markedly worsened survival in mice with MHV-1 pneumonia, a ß-coronavirus like SARS-CoV-2. These findings emphasize the need to better understand how oxygen therapy impacts the pathogenesis of SARS-CoV-2 in patients.
ABSTRACT
Rationale: While inspired fractional inspired oxygen concentrations (FiO2s) > 0.60 are avoided clinically when possible due in large part to animal study findings, FiO2s ≤ 0.60 have generally been thought relatively safe in hypoxemic patients. However, increasing attention is now being focused on the effects of conservative versus liberal therapeutic oxygen protocols in critically ill patients, especially in light of the prolonged courses of oxygen therapy SARS-CoV-2 patients are receiving. Notably, in the development of a lethal ß-coronavirus pneumonia model in mice that produces lung injury and progressive reductions in oxygen saturations like SARS-CoV-2, we found that atmospheric FiO2s as low as 0.30 reduced survival compared to room air. This finding prompted us to systematically examine the literature for the experience with FiO2s ≤0.60 but >0.21 in animal models of lung infection and non-infectious injury. Preliminary results from this review are presented here. Methods: In collaboration with a Biomedical Librarian, we performed a systematic literature search of Pubmed, EMBASE, and the Web of Science for relevant citations of published studies through September 30, 2021, using individualized search strategies for each database. Published studies that investigated animals challenged with a lung infection or other injury, and that compared outcomes, including survival, measures of organ injury or other changes, in animals administered therapeutic oxygen levels (FiO2 ≤0.60 but >0.21) versus ones administered room air (FiO2=0.21) were selected for further review. Results: After preliminary title and review of 12,446 retrieved reports and then removal of 2,049 duplicates, 51 s were found that described studies specifically examining an FiO2 ≤0.60 but >0.21 in a preclinical animal model with or without an infectious or noninfectious challenge. Based on findings, animals were challenged with bacteria in 14 studies, lipopolysaccharide in 2, acid aspiration in 2, mechanical ventilation in 1, while 12 each examined the effects of oxygen alone or oxygen with another pharmacologic agent. No study examined FiO2s ≤0.60 with viral challenge. By contrast, we found 520 s specifically describing investigations of FiO2s >0.60 and 258 describing the use of “hyperoxic” oxygen administration in similar types of models. Conclusions: A large preclinical literature identified the adverse effects of FiO2s ≥0.60 and hyperoxia and informed clinical practice. While similar preclinical studies examining FiO2s ≤0.60 are limited, they may be just as informative and should be encouraged in light of ongoing questions regarding the benefits and risks of conservative versus liberal therapeutic oxygen protocols.
ABSTRACT
ationale H mmune checkpoint inhibitor CI whether prior ICI treatment worsens or improves outcomes with this virus. To address this issue, we performed a systematic review of studies of cancer patients with COVID-19 that ret
ABSTRACT
Rationale: Immune stimulation with immune checkpoint inhibitors (ICIs) has emerged as a highly effective treatment for several cancer types. Research also suggests these agents may be therapeutic for viral infections. However, by interrupting inhibitory signaling pathways, ICIs can cause immune-related adverse events including pneumonitis. A critical question during the present SARS-CoV-2 pandemic has been whether prior ICI treatment aggravates or improves virus-associated lung injury. Methods: To address this question, we first developed a lethal coronavirus acute lung injury model in A/J mice by infecting them intratracheally (IT) with mouse hepatitis virus-1 (MHV-1), a betacoronavirus that can be studied at Biosafety Level-2 (Study-1). We then investigated the effects of anti-PD-L1 monoclonal antibody (anti-PD-L1mAb;clone 10F.9G2, Bio X Cell) pretreatment on outcomes with MHV-1 lung challenge (Study-2). Results: In Study 1 testing 8 increasing doses of virus [5 to 2000 plaque forming units (PFU)/mouse], IT administration of 12.5 (n=8), 25 (n=8), or 50 (n=16) PFU/mouse produced lethality rates closest to 50% (Figure A). At 14d, surviving mice receiving any of these three doses had decreased circulating lymphocyte and increased lavage lymphocyte percentages and protein concentrations compared to diluent-challenged control animals (p≤0.04 averaged across the three MHV doses). Experiments in noninfected animals showed that compared to isotype-mAb (control) treatment, 4 doses of anti-PD-L1mAb (300μg/mouse) administered intraperitoneally every 3d significantly reduced lung immune cell PD-L1 expression (normalized mean fluorescence intensity, p=0.04;Figure B) and produced anti-PD-L1mAb levels at 14d consistent with those measured in ICI-treated cancer patients ( 283.2 ± 112.4 ug/mL). Therefore, in Study 2, mice were treated with either isotype-mAb or anti-PD-L1mAb (300ug/mouse, every 3 days) starting 12d before and continuing until 3d after IT challenge with 25 or 50PFU/mouse of MHV-1 (Experiments 1 and 2 respectively). Compared to control animals [12 survivors of 12 total animals in Experiment 1 (100%), and 4 of 12 in Experiment-2 (33%)], survival was decreased with PD-L1-mAb in both experiments [11 of 12, (91%) and 2 of 12 (17%), respectively] but these survival differences were not significant (p>0.05) (Figure C). Conclusions: Intratracheal MHV-1 challenge in A/J mice produced lethality and late changes in circulating lymphocytes and lung lavage lymphocytes and protein that appear consistent with changes observed clinically with SARS-CoV2 infection. Prior treatment with anti-PD-L1mAb in this model did not improve and potentially aggravated the lethal effects of MHV-1, but requires further study.