Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: A randomized controlled trial

Lee, Nelson; Wong, Chun-Kwok; Chan, Michael; Yeung, Esther S.L.; Tam, Wilson W.S.; Tsang, Owen Tak Yin; Choi, Kin Wing; Chan, Paul K.S.; Kwok, Alex Pak Ki; Lui, Grace; Leung, WK; Yung, Irene M. H.; Wong, Ricky W.K.; Cheung, C. Sherman; Hui, David S.

doi:10.1016/j.antiviral.2017.05.008

Cited by 79 publications

(78 citation statements)

References 39 publications

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“…In addition, there is mounting interest in employing the anti-inflammatory activity of macrolide antibiotics to complement other treatment modalities with bacteriocidal, bacteriostatic, or even anti-viral actions. Recently, azithromycin’s effect on inflammation was demonstrated in hospitalized patients with influenza as an adjuvant to oseltamivir [13]. Many of these disorders are mediated, in part, by actions of interleukin 1β (IL-1β) elaborated by the inflammasome.…”

Section: Introductionmentioning

confidence: 99%

Azithromycin decreases NALP3 mRNA stability in monocytes to limit inflammasome-dependent inflammation

et al. 2017

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BackgroundAzithromycin, an antibiotic used for multiple infectious disorders, exhibits anti-inflammatory effects, but the molecular basis for this activity is not well characterized. Azithromycin inhibits IL-1β-mediated inflammation that is dependent, in part, on inflammasome activity. Here, we investigated the effects of azithromycin on the NACHT, LRR, and PYD domains-containing protein 3 (NALP3) protein, which is the sensing component of the NALP3 inflammasome, in human monocytes.MethodsTHP-1 cells were treated with azithromycin alone, LPS alone, or both. NALP3 and IL-1β protein levels were determined by immunoblotting. NLRP3 gene (encoding NALP3) transcript levels were determined by quantitative qPCR. In order to measure NLRP3 transcript decay, actinomycin D was used to impair gene transcription. THP-1 Lucia cells which contain an NF-κB responsive luciferase element were used to assess NF-κB activity in response to azithromycin, LPS, and azithromycin/LPS by measuring luminescence. To confirm azithromycin’s effects on NLRP3 mRNA and promoter activity conclusively, HEK cells were lipofected with luciferase reporter constructs harboring either the 5’ untranslated region (UTR) of the NLRP3 gene which included the promoter, the 3’ UTR of the gene, or an empty plasmid prior to treatment with azithromycin and/or LPS, and luminescence was measured.ResultsAzithromycin decreased IL-1β levels and reduced NALP3 protein levels in LPS-stimulated THP-1 monocytes through a mechanism involving decreased mRNA stability of the NALP3 – coding NLRP3 gene transcript as well as by decreasing NF-κB activity. Azithromycin accelerated NLRP3 transcript decay confirmed by mRNA stability and 3’UTR luciferase reporter assays, and yet the antibiotic had no effect on NLRP3 promoter activity in cells containing a 5’ UTR reporter.ConclusionsThese studies provide a unique mechanism whereby azithromycin exerts immunomodulatory actions in monocytes by destabilizing mRNA levels for a key inflammasome component, NALP3, leading to decreased IL-1β-mediated inflammation.

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Section: Introductionmentioning

confidence: 99%

Azithromycin decreases NALP3 mRNA stability in monocytes to limit inflammasome-dependent inflammation

et al. 2017

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“…There were no deaths recorded by Lee et al The OR estimate derived from the two RCTs (Hung et al, Hung et al) overlapped with the univariable OR from the observational study despite heterogeneity in study populations—for example, ICU and non‐ICU admissions and overall mortality rates of 4.6%‐25.7% (Figure C). Note after statistical adjustment in a multivariable logistic regression model, Martin‐Loeches et al reported no significant mortality benefit from macrolides (OR = 0.87; 95% CI: 0.55‐1.37; P = .5).…”

Section: Resultsmentioning

confidence: 87%

“…Lee et al reported no significant change in viral RNA decline or symptom resolution between treatment groups. However, in a generalised estimating model (GEE) adjusting for comorbidities and disease severity, the azithromycin treatment group had a significantly faster decline in the pro‐inflammatory cytokines CXCL9/MIG and IL‐17 from baseline to Day 10.…”

Section: Resultsmentioning

confidence: 98%

“…Two studies investigated the effect of macrolide therapy alone: one prospective cohort study and one open‐label RCT (Table ). A second open‐label RCT investigated the effect of a macrolide in combination with an NSAID for influenza treatment.…”

Section: Resultsmentioning

confidence: 99%

“…Lee et al and Hung et al enrolled adults hospitalised with seasonal influenza, and administered azithromycin 500 mg for 5 days, or clarithromycin 500 mg and naproxen 200 mg BD for 2 days to their experimental groups, respectively. Hung et al administered celecoxib 200 mg daily for 5 days or placebo to hospitalised adults.…”

Section: Resultsmentioning

confidence: 99%

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Passive immune therapy and other immunomodulatory agents for the treatment of severe influenza: Systematic review and meta‐analysis

Lim

Car

Leo

et al. 2019

Influenza Resp Viruses

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Background A range of immunomodulatory therapies have been proposed as adjuncts to conventional antivirals to suppress harmful inflammation during severe influenza infection. We conducted a systematic review to assess available data of the effect of adjunctive non‐corticosteroid immunomodulatory therapy and potential adverse effects. Method We searched MEDLINE, Embase, Web of Science and clinical trial databases for published and unpublished studies, and screened the references of included articles. We included RCTs, quasi‐RCTs and observational studies of virologically confirmed influenza infections in hospitalised patients. We did not restrict studies by language of publication, influenza type/subtype or age of participants. Where possible, we pooled estimates of effect using random‐effects meta‐analysis models. Results We identified 11 eligible studies for inclusion: five studies (4 RCTs and 1 observational; 693 individuals) of passive immune therapy; four studies (3 RCTs and 1 observational; 1120 individuals) of macrolides and/or non‐steroidal anti‐inflammatory drugs (NSAIDs), one RCT of mTOR inhibitors (38 individuals), and one RCT of statin therapy (116 individuals). Meta‐analysis of RCTs of passive immune therapy indicated no significant reduction in mortality (OR 0.84, 0.37‐1.90), but better clinical outcomes at Day 7 (OR 1.42, 1.05‐1.92). There was a significant reduction in mortality associated with macrolides and/or NSAIDs (OR 0.28; 0.10‐0.77). Conclusions Passive immune therapy is unlikely to offer substantial mortality benefit in treatment of severe seasonal influenza, but may improve clinical outcomes. The effect of other immunomodulatory agents is uncertain, but promising. There is a need for high‐quality RCTs with sufficient statistical power to address this evidence gap.

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CRISPR/Cas9‐mediated knockout of HBsAg inhibits proliferation and tumorigenicity of HBV‐positive hepatocellular carcinoma cells

Song

Zhang

et al. 2018

J of Cellular Biochemistry

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Chronic hepatitis B virus (HBV) infection remains the most common risk factor for hepatocellular carcinoma (HCC). High HBV surface antigen (HBsAg) levels are highly correlated with hepatocarcinogenesis and HBV‐associated HCC development. However, the role and detailed mechanisms associated with HBsAg in HCC development remain elusive. In this study, we designed specific single guide RNAs (sgRNAs) targeting the open reading frames, preS1/preS2/S, of the HBV genome and established HBsAg knockout HCC cell lines using the CRISPR/Cas9 system. We showed that knockout of HBsAg in HCC cell lines decreased HBsAg expression and significantly attenuated HCC proliferation in vitro, as well as tumorigenicity in vivo. We also found that overexpression of HBsAg, including the large (LHBs), middle (MHBs), and small (SHBs) surface proteins promoted proliferation and tumor formation in HCC cells. Moreover, we demonstrated that knockout of HBsAg in HCC cells decreased interleukin (IL)‐6 production and inhibited signal transducer and activator of transcription 3 (STAT3) signaling, while overexpression of HBsAg induced a substantial accumulation of pY‐STAT3. Collectively, these results highlighted the tumorigenic role of HBsAg and implied that the IL‐6‐STAT3 pathway may be implicated in the HBsAg‐mediated malignant potential of HBV‐associated HCC.

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Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: A randomized controlled trial

Cited by 79 publications

References 39 publications

Azithromycin decreases NALP3 mRNA stability in monocytes to limit inflammasome-dependent inflammation

Azithromycin decreases NALP3 mRNA stability in monocytes to limit inflammasome-dependent inflammation

Passive immune therapy and other immunomodulatory agents for the treatment of severe influenza: Systematic review and meta‐analysis

CRISPR/Cas9‐mediated knockout of HBsAg inhibits proliferation and tumorigenicity of HBV‐positive hepatocellular carcinoma cells

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