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Summary IFITM3 and TLR3 SNPs are associated with fatal clinical outcome of Chinese patients with avian (H7N9) or pandemic (H1N1pdm09) influenza virus infections, and the risks are cumulative. Our findings pose important public health and clinical implications in the at-risk populations., Background. We examined associations between single-nucleotide polymorphisms (SNPs) of IFITM3, TLR3, and CD55 genes and influenza clinical outcomes in Chinese. Methods. A multicenter study was conducted on 275 adult cases of avian (H7N9) and pandemic (H1N1pdm09) influenza. Host DNA was extracted from diagnostic respiratory samples; IFITM3 rs12252, TLR3 rs5743313, CD55 rs2564978, and TLR4 rs4986790/4986791 were targeted for genotyping (Sanger sequencing). The primary outcome analyzed was death. Results. IFITM3 and TLR3 SNPs were in Hardy–Weinberg equilibrium; their allele frequencies (IFITM3/C-allele 0.56, TLR3/C-allele 0.88) were comparable to 1000 Genomes Han Chinese data. We found over-representation of homozygous IFITM3 CC (54.5% vs 33.2%; P = .02) and TLR3 CC (93.3% vs 76.9%; P = .04) genotypes among fatal cases. Recessive genetic models showed their significant independent associations with higher death risks (adjusted hazard ratio [aHR] 2.78, 95% confidence interval [CI] 1.29–6.02, and aHR 4.85, 95% CI 1.11−21.06, respectively). Cumulative effects were found (aHR 3.53, 95% CI 1.64−7.59 per risk genotype; aHR 9.99, 95% CI 1.27−78.59 with both). Results were consistent for each influenza subtype and other severity indicators. The CD55 TT genotype was linked to severity. TLR4 was nonpolymorphic. Conclusions. Host genetic factors may influence clinical outcomes of avian and pandemic influenza infections. Such findings have important implications on disease burden and patient care in at-risk populations.

A prospective study among adults hospitalized for polymerase chain reaction–confirmed respiratory syncytial virus infections (n = 123) showed frequent occurrence of lower respiratory-tract complications causing respiratory insufficiency (52.8%), requirement for assisted ventilation (16.3%), and intensive care unit admission/death (12.2%). High viral RNA concentration was detected at time of hospitalization, including in patients who presented later than 2 days of illness (day 1–2, 7.29 ± 1.47; day 3–4, 7.28 ± 1.41; day 5–8, 6.66 ± 1.87 log10 copies/mL). RNA concentration was independently associated with risk of complications and respiratory insufficiency (adjusted odds ratio 1.40 per log10 copies/mL increase, 95% confidence interval, 1.03–1.90; P = .034). Our data indicate the need and provide a basis for clinical research on antiviral therapy in this population.

Introduction − Macrolides can ameliorate inflammation in respiratory diseases, providing clinical benefits. Data in influenza is lacking. Method − A randomized, open-label, multicenter trial among adults hospitalized for laboratory-confirmed influenza was conducted. Study treatments of oseltamivir and azithromycin (500 mg/day), or oseltamivir alone, both for 5 days, were allocated at 1:1 ratio. The primary outcome was plasma cytokine/chemokine concentration change over time (Day 0–10); secondary outcomes were viral load and symptom score changes. Generalized Estimating Equation (GEE) models were used to analyze longitudinal data. Results − Fifty patients were randomized to the oseltamivir-azithromycin or oseltamivir groups, with comparable baseline characteristics (age, 57 ± 18 years; A/H3N2, 70%), complications (72%), and viral load. Pro-inflammatory cytokines IL-6 (GEE: β −0.037, 95%CI-0.067,-0.007, P = 0.016; reduction from baseline −83.4% vs −59.5%), CXCL8/IL-8 (β −0.018, 95%CI-0.037,0.000, P = 0.056; −80.5% vs −58.0%), IL-17 (β −0.064, 95%CI-0.117,-0.012, P = 0.015; −74.0% vs −34.3%), CXCL9/MIG (β −0.010, 95%CI-0.020,0.000, P = 0.043; −71.3% vs −56.0%), sTNFR-1, IL-18, and CRP declined faster in the oseltamivir-azithromycin group. There was a trend toward faster symptom resolution (β −0.463, 95%CI-1.297,0.371). Viral RNA decline (P = 0.777) and culture-negativity rates were unaffected. Additional ex vivo studies confirmed reduced induction of IL-6 (P = 0.017) and CXCL8/IL-8 (P = 0.005) with azithromycin. Conclusion − We found significant anti-inflammatory effects with adjunctive macrolide treatment in adults with severe influenza infections. Virus control was unimpaired. Clinical benefits of a macrolide-containing regimen deserve further study. [ClinicalTrials.gov NCT01779570]

Background We aimed to study the pathogenic roles of High-Mobility Group Box 1 (HMGB1) / Receptor-for-Advanced-Glycation-End-products (RAGE) signaling and pro-inflammatory cytokines in patients with active pulmonary tuberculosis (PTB). Methods A prospective study was conducted among non-HIV adults newly-diagnosed with active PTB at two acute-care hospitals (n = 80); age-and-sex matched asymptomatic individuals (tested for latent TB) were used for comparison (n = 45). Plasma concentrations of 8 cytokines/chemokines, HMGB1, soluble-RAGE, and transmembrane-RAGE expressed on monocytes/dendritic cells, were measured. Gene expression (mRNA) of HMGB1, RAGE, and inflammasome-NALP3 was quantified. Patients’ PBMCs were stimulated with recombinant-HMGB1 and MTB-antigen (lipoarabinomannan) for cytokine induction ex vivo. Results In active PTB, plasma IL-8/CXCL8 [median(IQR), 6.0(3.6–15.1) vs 3.6(3.6–3.6) pg/ml, P

An open-label trial on intravenous peramivir was conducted among adult patients hospitalised for influenza-associated lower respiratory tract complications (LRTCs). Virus culture and quantitative reverse transcription PCR (qRT-PCR) were performed serially until Day 10. Peramivir treatment was associated with viral RNA decline as well as culture and RNA negativity, which occurred at rates comparable with those of oseltamivir: by Day 5, viral load decline -2.5 log10 copies/mL [βinteraction -0.071, standard error (SE) 0.121, 95% confidence interval (CI) -0.309 to 0.167]; culture-negative, 94% (vs. 95%); and RNA-negative, 44% (vs. 36%). Extended treatment of >5 days was required in 69% of cases because of slow clinical resolution and viral clearance in LRTCs. Peramivir was well tolerated. These data are useful for future trial design in this unique population.

Background Influenza virus infections are causing substantial morbidity and mortality, despite availability of antiviral treatments. Macrolides have been shown to ameliorate inflammation in respiratory diseases and provide clinical benefits. Data in influenza, however, are scarce. We aimed to assess the anti-inflammatory effects of macrolide treatment in patients with influenza, and its effects on viral clearance and symptom resolution. Methods In this open-label, multicentre, randomised controlled trial, we recruited adults admitted to hospital for laboratory-confirmed influenza in Hong Kong. Key inclusion criteria were age 18 years or older, influenza A and B virus infections confirmed by PCR or immunofluorescence assays, and presentation within 4 days from illness onset. Patients were randomly assigned (1:1) using a computer-generated sequence to oseltamivir (75 mg twice daily) plus azithromycin (500 mg per day) or oseltamivir (75mg twice daily) alone, both given orally for 5 days. The primary outcome was change in plasma cytokine and chemokine concentration over time (day 0–10), analysed by intention to treat. Generalised estimating equation (GEE) models were used to analyse longitudinal data, and were adjusted for potential confounders. Ethics approvals were obtained from the institutional review bodies of all participating institutes. All patients provided written informed consent. This trial is registered with ClinicalTrials.gov, number NCT01779570. Findings During the influenza seasons beginning from 2013–14 through to 2015–16, 50 patients were randomly assigned to the oseltamivir-azithromycin (n=25) or oseltamivir (n=25) groups, with similar baseline characteristics (mean age 54·7 years [SD 18·5] in the oseltamivir-azithromycin group vs 58·6 years [18·1] in the oseltamivir group; 16 [64%] of 25 patients in the oseltamivir-azithromycin group were men vs 15 [60%] of 25 in the oseltamivir group). Three key pro-inflammatory cytokines declined faster in the oseltamivir-azithromycin group than in the oseltamivir group: interleukin (IL)-6 (GEE β=–0·037 [95% CI −0·067 to −0·007], p=0·016; change from baseline −83·4% vs −59·5%), IL-17 (β=–0·064 [–0·117 to −0·012], p=0·015; −74·0% vs −34·3%), and CXCL9 (β=–0·010 [–0·020 to 0·000], p=0·043; −71·3% vs −56·0%). Non-significant differences in the following cytokines were observed between treatment groups: CXCL8 (β=–0·018 [–0·037 to 0·000], p=0·056; −80·5% vs −58·0%), sTNFR-1 (β=–0·003 [–0·006 to 0·000], p=0·084; −40·1% vs −24·8%), IL-18 (β=–0·006 [–0·015 to 0·003], p=0·197; −29·1% vs 30·2%), and C-reactive protein (β=–0·033 [–0·088 to 0·022], p>0·10; −77·5% vs −48·2%). Two serious adverse events (SAEs) occurred in the oseltamivir-azithromycin group (Pseudomonas aeruginosa pneumonia, post-influenza vestibular neuronitis onset after stopping treatment for 1 week) versus one SAE in the oseltamivir group (increased ascites; p>0·99); all SAEs were considered unrelated to treatment. Other common adverse events were gastrointestinal or hepatic symptoms (five [20%] of 25 in the oseltamivir-azithromycin group vs four [16%] of 25 in the oseltamivir group; p>0.99) and dizziness or hearing symptoms (two [8%] vs two [8%]; p>0·99). All events were transient and reversible, and no participants died in this study. Interpretation We found significant anti-inflammatory effects with adjunctive macrolide treatment in adults with severe influenza infection. The clinical benefits of a macrolide-containing regimen deserve further study. Funding Research Grant Council of the Government of the Hong Kong Special Administrative Region, China (468112).

Background Whether host genetic factors determine clinical severity of influenza virus infections is unclear. This study examined the effects of single nucleotide polymorphisms (SNPs) of IFITM3, TLR3, CD55 , and TLR4 genes on outcomes of avian influenza A (H7N9) and pandemic influenza A (H1N1) pdm09 in Chinese patients. Methods This multicentre cohort study took place in four centres in Hong Kong, Beijing, Guangdong, and Shanghai and included adults prospectively diagnosed with H7N9 and H1N1 pdm09 infections during three respective seasonal outbreaks (H7N9, 2013–15; H1N1 pdm09 , 2011–14). The inclusion criteria were PCR-confirmed H7N9 or H1N1 pdm09 virus infection, age 18 years or older, and Chinese ethnicity. Host DNA was extracted from diagnostic respiratory samples, and IFITM3 (rs12252), TLR3 (rs5743313), CD55 (rs2564978), and TLR4 (rs4986790/4986791) were genotyped by Sanger sequencing. The data were tested to see whether they deviated from the Hardy-Weinberg equilibrium, and were compared with the 1000 Genomes data. The primary outcome for analysis was mortality. The effects of the SNPs were examined under different genetic models (recessive, additive, and dominant). The joint effect of significant loci was tested by computing the genetic risk score. All identifying patient information was removed from the dataset, and only anonymous data were used for analysis; individual consent was not required. Ethics approvals were obtained from the institutional review boards of all participating institutes. Findings Our cohort consisted of 275 adults with H7N9 and H1N1 pdm09 infections, of whom 33 died. In patients who died, we found over-representation of the homozygous IFITM3 CC genotype (18 [54%] of 33 patients with available data who died vs 70 [33%] of 211 with available data who survived; p=0·017) and the TLR3 CC genotype (28 [93%] of 30 vs 160 [77%] of 208; p=0·039). Recessive genetic models, adjusted for age, comorbidity, and antiviral treatment, showed that these genotypes had a significant association with increased risk of death ( IFITM3 CC genotype, adjusted hazard ratio [HR] 2·78 [95% CI 1·29–6·02]; and TLR3 CC genotype, adjusted HR 4·85 [1·11–21·06]). Cumulative effects were found (adjusted HR 3·53 [95% CI 1·64–7·59] per risk genotype; adjusted HR 9·99 [1·27–78·59] with both genotypes). The case-fatality rate in patients with a genetic risk score of 2, 1, and 0 was 23%, 11%, and 3%, respectively. Results were similar for each influenza subtype and other severity indicators such as development of acute respiratory failure. The population-attributable risk for mortality was 35·5% (95% CI 9·9–69·8) for IFITM3 CC and 74·6% (21·7–100) for TLR3 CC (combined effect, 83·6% [52·3–100]), owing to their high prevalence among Chinese people. A SNP of CD55 (genotype TT) was linked to severity of influenza as indicated by an increased risk for hospital admission (adjusted odds ratio [OR] 2·77, 95% CI 1·21–6·36; p=0·02); TLR4 was shown to be non-polymorphic in this cohort. Interpretation Host genetic factors might influence clinical outcomes of avian and pandemic influenza. Our findings could have important implications on public health and health-care planning, patient care, and design of clinical trials. Funding Health and Medical Research Fund (RRG-09) of the Hong Kong Special Administrative Region, China.