Intravenous N-acetylcysteine and Oseltamivir Versus Oseltamivir in Adults Hospitalized With Influenza and Pneumonia

• N-acetyl cysteine (Drug): N-acetyl cysteine will be administered at 100 mg/kg daily as a continuous IV infusion (in 1000ml of 5% dextrose) over 24 hrs and oseltamivir 75 mg bid orally for 5 days. Extension of dosing to 10 days for oseltamivir and the study drug is allowed if there is slow recovery, lack of improvement, or deterioration.
• 5% Dextrose (Drug): 5% dextrose 1 liter given over 24 hrs and oral oseltamivir 75 mg bid for 5 days. Extension of dosing to 10 days for oseltamivir and the study drug is allowed if there is slow recovery, lack of improvement, or deterioration.

Primary outcomes

• Normalization of respiratory status in day [28 days]: oxygen saturation more than 93% or respiratory rate lower than 20/min on room air

Secondary outcomes

• viral ribonucleic acid (RNA) in copies per milliliter [28 days]: All serially collected samples will be subjected to viral ribonucleic acid (RNA) quantification using quantitative reverse transcription PCR (qRTPCR) targeting the matrix (M)-gene ('viral load')
• Interleukin 6 in pg/ml [10 days]
• interleukin-8 in pg/ml [10 days]
• interleukin 17 in pg/ml [10 days]
• Chemokine ligand 9 (CxCL9/MIG) in pg/ml [10 days]
• Soluble tumour necrosis factor receptor-1 (sTNFR-1) in pg/ml [10 days]
• interleukin 18 in pg/ml [10 days]
• CRP in mg/L [10 days]
• phospho-p38 and phospho-ERK (activated MAPKs) in mean fluorescence intensity(MFI) [10 days]
• phospho-inhibitor kB/IkB (NF-kB) in mean fluorescence intensity(MFI) [10 days]
• resolution of symptoms in days [28 days]: A standard questionnaire will be used to collect baseline and serial clinical data. These include clinical manifestations/complications, symptom severity score, vital signs (e.g. temperature, respiratory rate, oxygen saturation), fever duration, requirements for supplemental oxygen therapy and invasive/non-invasive ventilation, duration of hospitalization, death, and occurrence of adverse events.
• ICU admission in days [28 days]
• mortality in days [28 days]
• Incidence of Treatment-Emergent Adverse Events in numbers [28 days]
• a six step ordinal scale of clinical status [7 days]: death, in ICU, ongoing hospitalisation on oxygen, hospital stay not on oxygen, discharged but not returned to normal activities, or discharged and returned to normal activities

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* influenza A and B virus infections confirmed by polymerase chain reaction (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 <93% on room air, crepitations on auscultation, infiltrations or consolidations on chest radiograph)
* 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 immunosuppressants (e.g. post-chemotherapy, post-transplant, autoimmune diseases) other than systemic corticosteroids
* known immuno-compromised conditions (e.g. active haematological malignancies, HIV/AIDS patients who are on antiretroviral therapy and CD4 cell count < 200),
* pregnancy
* lactation,
* end-stage renal failure
* hepatic failure
* cardiac failure
* patients on anticoagulation (except prophylactic dose of low molecular weight heparin),
* patients with scheduled major surgery within 2 weeks (NAC may affect blood clotting),
* patients who have received macrolide antibiotics and NSAID for 1 week prior to enrolment due to their immuno-modulating effects.
* Use of investigational anti-influenza antivirals and blood products

• David SC Hui, MD, Principal investigator, Chinese University of Hong Kong