Adjuvant Treatment With a Mammalian Target of Rapamycin Inhibitor, Sirolimus, and Steroids Improves Outcomes in Patients With Severe H1N1 Pneumonia and Acute Respiratory Failure*

Abstract

In patients with severe H1N1 pneumonia, early adjuvant treatment with corticosteroids and an mTOR inhibitor was associated with improvement in outcomes, such as hypoxia, multiple organ dysfunction, virus clearance, and shortened liberation of ventilator and ventilator days.

Adjuvant Immunosuppression in the Management of Severe Influenza

“…The study should also collect data on immune responses. This study could then confirm the findings of the study by Wang et al (8) and provide more details about the potential mechanism of action of the intervention. If possible, the study should avoid the use of steroids, unless the animal data suggest that it is required for the beneficial effects of the intervention.…”

“…In this issue of Critical Care Medicine, Wang et al (8) have investigated the role of the addition of sirolimus and corticosteroids to traditional antiviral therapy in the management of laboratory-confirmed influenza A/H INI pdm infection with lower airway involvement. In this single center, prospective, controlled study, the investigators provided standard oseltamivir 75 mg twice daily for 10 days to all patients with polymerase chain reaction (PCR)-confirmed influenza A/ HlNl pdm and respiratory failure requiring ventilatory support.…”

Mitogenic stimulation accelerates influenza-induced mortality by increasing susceptibility of alveolar type II cells to infection

“…In addition, rapamycin blocked both KGFenhanced IL-6 production and KGF-enhanced mortality. It is interesting to note that a small randomized clinical trial of corticosteroids + rapamycin vs. corticosteroids alone in patients with severe H1N1 IAV demonstrated benefit from the combination therapy (41). It is tempting to speculate that rapamycin and other PI3K/Akt/mTOR pathway inhibitors might have prophylactic or therapeutic utility in IAV.…”

Mycophenolic acid, an immunomodulator, has potent and broad-spectrum in vitro antiviral activity against pandemic, seasonal and avian influenza viruses affecting humans

“…A short course of corticosteroid has been shown to hasten clinical improvement or reduce treatment failure in doubleblind randomized placebo-controlled trials (Blum et al, 2015;Torres et al, 2015). The rapamycin inhibitor sirolimus, an immunomodulator frequently used in transplant recipients, was shown to improve the outcome of patients in addition to corticosteroid in a randomized controlled trial involving patients with severe A(H1N1) pneumonia ( Wang et al, 2014a). Since the C max achieved by MMF or mycophenolate sodium is much higher than the IC 50 against influenza viruses, a much lower dose of these drugs with minimal immunomodulatory activity should be sufficient for antiviral activity in humans.…”