Seasonal influenza epidemics are important causes of mortality and morbidity. Cytokine dysregulation, with high levels of pro-inflammatory cytokines, occurs in patients with severe influenza A(H1N1)pdm09 virus infection, A(H5N1) infection, and A(H7N9) infection. We aim to investigate the effects of adjunctive sirolimus in adults hospitalized with influenza A or B infections involving the lower respiratory tract.

The investigators aim to investigate the effects of adjunctive sirolimus in adults hospitalized with influenza A or B infections involving the lower respiratory tract. Patients will be randomized to either oseltamivir and adjunctive sirolimus or oseltamivir alone and assessed with reference to normalization of respiratory status (SaO2 ≥93% or respiratory rate ≤20/min on room air) as the primary endpoint,10 cytokines/chemokines and pro-inflammatory mediator changes, viral clearance, symptom resolution, ICU admission/death, day 28 mortality; safety profiles will also be assessed.

The investigators hypothesize that addition of sirolimus to oseltamivir would improve respiratory status and other endpoints more effectively than oseltamivir alone through reduction of inflammatory responses without affecting viral clearance.

Inclusion Criteria:

• influenza A and B virus infections confirmed by PCR and/or immunofluorescence assays, hospitalized for the management of severe manifestations of influenza, initiation of oseltamivir, clinical evidence of lower respiratory tract infection (e.g. shortness of breath, tachypnea, oxygen desaturation, crepitations on auscultation, infiltrations or consolidations on chest radiograph) and written informed consent (by the subjects, or from their next of kin if the subjects are unable to provide written consent at the time of enrollment)

Exclusion Criteria:

• use of other immunosuppressants (e.g. post-chemotherapy, post-transplant, autoimmune diseases) other than systemic corticosteroids
• patients with known immuno-compromised conditions (e.g. active haematological malignancies, HIV/AIDS patients who are on antiretroviral therapy and CD4 cell count < 200)
• pregnancy/lactation
• hepatic failure
• patients with surgery done/planned within 1 month
• patients who have received macrolide antibiotics and NSAID for 1 week prior to enrolment due to their immuno-modulating effects
• patients on drugs that may interact and alter sirolimus level (rifampicin, azole antifungals, phenytoin, diltiazem, verapamil, nicardipine, metoclopramide, phenobarbital, carbamazepine) will be excluded for safety purposes
• Use of investigational anti-influenza antivirals and blood products