Influenza treatment - anything to add?

Every Influenza season, clinicians face tough question about how best to treat severe cases requiring hospitalization. While the roles of vaccines and anti-virals are well established, other therapies have been proposed. In this blog post, I will take an in-depth look at some of these therapies:

1. What is the role of corticosteroids in treating influenza?

2. Should antibiotics - particularly macrolides - be used for severe influenza infections?

3. What evidence exists for other therapies in influenza-related ARDS?

1. What is the role of corticosteroids in treating influenza?

Corticosteroids have been successfully studied in Covid-acute respiratory distress syndrome (ARDS) (1) and in severe community-acquired pneumonia (2), making their use in severe influenza seem logical. Theoretically, their use could reduce lung inflammation and prevent fibrosis in ARDS (3). Animal studies have supported this idea, showing decreased lung damage and mortality with corticosteroids (4). However human data suggest that corticosteroids offer no clear benefit in influenza pneumonia, and several observational studies even link their use to increased mortality (3-6). Yet, some remarks should be made about the available data:

• The absence of benefit is not duet to lack of use. For instance, in a large Spanish cohort, about 30% of the severe influenza cases received corticosteroids between 2009 and 2014 (7).

  
  

• Likewise, a lack of benefit is not a reflection of lack of publications. One meta-analysis, for example examined corticosteroids in influenza-related ARDS and severe pneumonia. It included in total 6637 patients from 19 studies, of which all but one were observational (4). No mortality benefit was observed by administering corticosteroids in severe influenza.

  
  

• As most data come from observational studies, some biases are introduced. First of all, sicker patients were more likely to receive corticosteroids (4), yet even after adjusting for illness severity, no benefit was demonstrated (4). This could resemble an observation seen in ARDS in general. In this case, a systematic review of observational studies also linked steroids to increased mortality whereas randomized controlled trials suggest a survival benefit (8). Additionally, there is wide variability in timing and dosing of corticosteroids, which may affect outcomes (6). A large, multicenter cohort study, for instance, found increased hospital mortality with earlier use and higher cumulative doses of corticosteroids (3).

  
  

• To date, only one randomized trial has investigated the effect of corticosteroids for influenza. Wirz et al. included 24 influenza patients as part of a larger trial about the effect of corticosteroids in community-acquired pneumonia (9). Unfortunately, the small sample size of influenza cases in this study precluded firm conclusions (10). Since 2023, the RECOVERY trial has begun investigating corticosteroids in influenza. Currently, around 900 participants have been enrolled (11).

  
  

• The best summary of the current evidence may come from a 2019 Cochrane review (10): “The currently available evidence is insufficient to determine the effectiveness of corticosteroids for people with influenza.”

My view: Currently, I would avoid routinely administering corticosteroids in Influenza unless there is separate indication, such as COPD or asthma exacerbation. Hopefully, new guidance is coming soon by means of the renewed RECOVERY trial or other studies.

2. Should antibiotics - particularly macrolides - be used for severe influenza infections?

Many authors have proposed adding a macrolide to antiviral therapy for moderate to severe influenza infections, citing three main arguments:

1. Potential antiviral effect

In vitro, macrolides have demonstrated to reduce the replication of several viruses, including rhinovirus, respiratory syncytial virus and influenza A (12). However, caution is warranted: while azithromycin demonstrated antiviral activity against SARS-CoV-2 in vitro, large randomized controlled trials found no clinical benefit in Covid-19 infections (13).

2. Anti-inflammatory effect

Macrolides are well-known for their anti-inflammatory properties (13), which is one of the reasons why they are often combined with beta-lactams in severe community-acquired pneumonia. (13). Similarly, in influenza, one randomized controlled trial found that azithromycin administration led to a faster reduction in certain pro-inflammatory cytokines (14).

3. Antibacterial effect

Bacterial co-infections are common in hospitalized influenza patients. A systematic review of 27 studies (3215 patients) reported bacterial co-infection rates ranging from 11 to 35% (15). Additionally, another study found bacterial pneumonia in 55% of autopsies from fatal cases during the 2009 H1N1 influenza outbreak. These findings align with a retrospective analysis of a Japanese database: azithromycin use increased with the severity of influenza pneumonia. Moreover, in mechanically ventilated patients, macrolides were associated with a significant reduction in 30-day mortality (although no mortality difference was observed at 90 days)(13). Lastly, a randomized controlled trial compared oseltamivir alone to oseltamivir combined with clarithromycin and naproxen. The combination therapy resulted in lower mortality and shorter hospital stays (17).

My view: While the potential antiviral and anti-inflammatory effects of macrolides in influenza pneumonia are intriguing, the current evidence is insufficient to support their routine use. However, given the high risk of bacterial co-infections in severe influenza pneumonia, I maintain a lower threshold for starting antibiotics in these cases.

3. What evidence exists for other therapies in influenza-related ARDS?

In recent years, the Covid-19 pandemic has resulted in many novel therapies in ARDS. Both IL-6 pathway inhibitors (such as tocilizumab) and Janus Kinase inhibitors (such as barcitinib and ruxolitinib) have been shown to reduce mortality in Covid-19 related ARDS (19,20). However, evidence for their use in influenza-related ARDS remains limited, with only anecdotal reports available to date (18). Until specific evidence is published regarding influenza-related ARDS, the potential benefits of adjunctive immunomodulators remain uncertain.

References:

1. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management (Accessed on August 04, 2025).

 2. Dequin PF, Meziani F, Quenot JP, et al. Hydrocortisone in Severe Community-Acquired Pneumonia. N Engl J Med. 2023 May 25;388(21):1931-1941.

 3. Tsai MJ, Yang KY, Chan MC, et al. Impact of corticosteroid treatment on clinical outcomes of influenza-associated ARDS: a nationwide multicenter study. Ann Intensive Care. 2020 Feb 27;10(1):26.

 4. Zhou Y, Fu X, Liu X, Huang C, et al. Use of corticosteroids in influenza-associated acute respiratory distress syndrome and severe pneumonia: a systemic review and meta-analysis. Sci Rep. 2020 Feb 20;10(1):3044.

 5. Li G, Chen D, Gao F, et al. Efficacy of corticosteroids in patients with acute respiratory distress syndrome: a meta-analysis. Ann Med. 2024 Dec;56(1):2381086.

 6. Nedel WL, Nora DG, Salluh JI, et al. Corticosteroids for severe influenza pneumonia: A critical appraisal. World J Crit Care Med. 2016 Feb 4;5(1):89-95.

 7. Moreno G, Rodríguez A, Reyes LF, et al. Corticosteroid treatment in critically ill patients with severe influenza pneumonia: a propensity score matching study. Intensive Care Med. 2018 Sep;44(9):1470-1482.

 8. Li G, Chen D, Gao F, et al. Efficacy of corticosteroids in patients with acute respiratory distress syndrome: a meta-analysis. Ann Med. 2024 Dec;56(1):2381086.

 9. Wirz SA, Blum CA, Schuetz P, et al. Pathogen- and antibiotic-specific effects of prednisone in community-acquired pneumonia. Eur Respir J. 2016 Oct;48(4):1150-1159.

 10. Lansbury LE, Rodrigo C, Leonardi-Bee J, et al. Corticosteroids as Adjunctive Therapy in the Treatment of Influenza: An Updated Cochrane Systematic Review and Meta-analysis. Crit Care Med. 2020 Feb;48(2):e98-e106.

11. RECOVERY dexamethasone for influenza https://www.recoverytrial.net/ (Accessed on August 04, 2025).

 12. Bustos-Hamdan A, Bracho-Gallardo JI, Hamdan-Partida A, et al. Repositioning of Antibiotics in the Treatment of Viral Infections. Curr Microbiol. 2024 Oct 26;81(12):427.

 13. Tokito T, Kido T, Muramatsu K, et al. Impact of Administering Intravenous Azithromycin within 7 Days of Hospitalization for Influenza Virus Pneumonia: A Propensity Score Analysis Using a Nationwide Administrative Database. Viruses. 2023 May 10;15(5):1142.

 14. Lee N, Wong CK, Chan MCW, et al. Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: A randomized controlled trial. Antiviral Res. 2017 Aug;144:48-56.

15. Klein EY, Monteforte B, Gupta A, et al. The frequency of influenza and bacterial coinfection: a systematic review and meta-analysis. Influenza Other Respir Viruses. 2016 Sep;10(5):394-403.

16. Gill JR, Sheng ZM, Ely SF, et al. Pulmonary pathologic findings of fatal 2009 pandemic influenza A/H1N1 viral infections. Arch Pathol Lab Med. 2010 Feb;134(2):235-43.

 17. Hung IFN, To KKW, Chan JFW, et al. Efficacy of Clarithromycin-Naproxen-Oseltamivir Combination in the Treatment of Patients Hospitalized for Influenza A(H3N2) Infection: An Open-label Randomized, Controlled, Phase IIb/III Trial. Chest. 2017 May;151(5):1069-1080.

 18. Marwah V, Jyothis, MC, Choudhary, R, et al. Successful Management of Cytokine Storm Induced Acute Respiratory Distress Syndrome Secondary to H1N1 Influenza with Tocilizumab. Medical Journal of Dr. D.Y. Patil Vidyapeeth 16(4):p 648-650, Jul–Aug 2023.

 19. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Shankar-Hari M, Vale CL, et al. Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis. JAMA. 2021 Aug 10;326(6):499-518.

 20. Ahari NM, Mahmoodpoor A,  Soleimanpour H, et al. Evaluation of the Effects of Baricitinib and Ruxolitinib in Acute Respiratory Distress Syndrome (ARDS) Patients: A Meta-Analysis Study. Pharmaceutical Sciences, 2025 Feb, 31(2): 127-134.