COVID-19 Respiratory Failure: Targeting Inflammation on VV-ECMO Support.

The outbreak of novel coronavirus (SARS-CoV-2) that causes the respiratory illness COVID-19 has led to unprecedented efforts at containment due to its rapid community spread, associated mortality, and lack of immunization and treatment. We herein detail a case of a young patient who suffered life-threatening disease and multiorgan failure. His clinical course involved rapid and profound respiratory decompensation such that he required support with venovenous extracorporeal membrane oxygenation (VV-ECMO). He also demonstrated hyperinflammation (C-reactive protein peak 444.6 mg/L) with severe cytokine elevation (Interleukin-6 peak > 3000 pg/ml). Through treatment targeting hyperinflammation, he recovered from critical COVID-19 respiratory failure and required only 160 hours of VV-ECMO support. He was extubated 4 days after decannulation, had progressive renal recovery, and was discharged to home on hospital day 24. Of note, repeat SARS-CoV-2 test was negative 21 days after his first positive test. We present one of the first successful cases of VV-ECMO support to recovery of COVID-19 respiratory failure in North America.

Death receptors mediate the adverse effects of febrile-range hyperthermia on the outcome of lipopolysaccharide-induced lung injury.

We have shown that febrile-range hyperthermia enhances lung injury and mortality in mice exposed to inhaled LPS and is associated with increased TNF-α receptor activity, suppression of NF-κB activity in vitro, and increased apoptosis of alveolar epithelial cells in vivo. We hypothesized that hyperthermia enhances lung injury and mortality in vivo by a mechanism dependent on TNF receptor signaling. To test this, we exposed mice lacking the TNF-receptor family members TNFR1/R2 or Fas (TNFR1/R2(-/-) and lpr) to inhaled LPS with or without febrile-range hyperthermia. For comparison, we studied mice lacking IL-1 receptor activity (IL-1R(-/-)) to determine the role of inflammation on the effect of hyperthermia in vivo. TNFR1/R2(-/-) and lpr mice were protected from augmented alveolar permeability and mortality associated with hyperthermia, whereas IL-1R(-/-) mice were susceptible to augmented alveolar permeability but protected from mortality associated with hyperthermia. Hyperthermia decreased pulmonary concentrations of TNF-α and keratinocyte-derived chemokine after LPS in C57BL/6 mice and did not affect pulmonary inflammation but enhanced circulating markers of oxidative injury and nitric oxide metabolites. The data suggest that hyperthermia enhances lung injury by a mechanism that requires death receptor activity and is not directly associated with changes in inflammation mediated by hyperthermia. In addition, hyperthermia appears to enhance mortality by generating a systemic inflammatory response and not by a mechanism directly associated with respiratory failure. Finally, we observed that exposure to febrile-range hyperthermia converts a modest, survivable model of lung injury into a fatal syndrome associated with oxidative and nitrosative stress, similar to the systemic inflammatory response syndrome.

Febrile-range hyperthermia augments lipopolysaccharide-induced lung injury by a mechanism of enhanced alveolar epithelial apoptosis.

Fever is common in critically ill patients and is associated with worse clinical outcomes, including increased intensive care unit mortality. In animal models, febrile-range hyperthermia (FRH) worsens acute lung injury, but the mechanisms by which this occurs remain uncertain. We hypothesized that FRH augments the response of the alveolar epithelium to TNF-alpha receptor family signaling. We found that FRH augmented LPS-induced lung injury and increased LPS-induced mortality in mice. At 24 h, animals exposed to hyperthermia and LPS had significant increases in alveolar permeability without changes in inflammatory cells in bronchoalveolar lavage fluid or lung tissue as compared with animals exposed to LPS alone. The increase in alveolar permeability was associated with an increase in alveolar epithelial apoptosis and was attenuated by caspase inhibition with zVAD.fmk. At 48 h, the animals exposed to hyperthermia and LPS had an enhanced lung inflammatory response. In murine lung epithelial cell lines (MLE-15, LA-4) and in primary type II alveolar epithelial cells, FRH enhanced apoptosis in response to TNF-alpha but not Fas ligand. The increase in apoptosis was caspase-8 dependent and associated with suppression of NF-kappaB activity. The FRH-associated NF-kappaB suppression was not associated with persistence of IkappaB-alpha, suggesting that FRH-mediated suppression of NF-kappaB occurs by means other than alteration of IkappaB-alpha kinetics. These data show for the first time that FRH promotes lung injury in part by increasing lung epithelial apoptosis. The enhanced apoptotic response might relate to FRH-mediated suppression of NF-kappaB activity in the alveolar epithelium with a resultant increase in susceptibility to TNF-alpha-mediated cell death.

Non-decompensated cirrhosis as a risk factor for invasive aspergillosis: a case report and review of the immune dysfunction of cirrhosis.

Invasive aspergillosis is a frequently insidious syndrome that carries a poor prognosis even when promptly and appropriately treated. Those patients that are identified as possessing risk factors for invasive aspergillosis are more likely to receive early therapy. Patients with profound immunosuppression, such as those with hematologic malignancy, iatrogenic immunosuppression for solid organ transplant, and advanced AIDS, are clearly at risk for invasive aspergillosis. Recently, invasive aspergillosis has been reported in patients with subtle immune dysfunction such as those with critical illness and advanced cirrhosis. However, patients with early cirrhosis also possess risk for invasive mycoses. We report a case of non-decompensated cirrhosis as the predisposition to invasive aspergillosis and review the immune dysfunction of cirrhosis that creates this risk.