# How to manage antivirals in critically ill patients with influenza?

Pierre Bay, Ignacio Martin-Loeches, Anne-Fleur Haudebourg, Minh Lê, Gilles Peytavin, Marie-Anne Rameix-Welti, Slim Fourati, Nicolas de Prost

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Pierre Bay, Ignacio Martin-Loeches, Anne-Fleur Haudebourg, Minh Lê, Gilles Peytavin, et al.. How to manage antivirals in critically ill patients with influenza?. Clinical Microbiology and Infection, 2025, 31 (7), pp.1157-1165. 10.1016/j.cmi.2025.04.002. pasteur-05489198

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Narrative review

How to manage antivirals in critically ill patients with influenza?

Pierre Bay <fnref n="1" />, <fnref n="2" />, <fnref n="3" />, <fnref n="4" />, Ignacio Martin-Loeches <fnref n="5" />, Anne-Fleur Haudebourg <fnref n="1" />, <fnref n="2" />, <fnref n="3" />, Minh P. Lê <fnref n="6" />, <fnref n="7" />, Gilles Peytavin <fnref n="6" />, <fnref n="7" />, Marie-Anne Rameix-Welti <fnref n="8" />, <fnref n="9" />, Slim Fourati <fnref n="2" />, <fnref n="3" />, <fnref n="4" />, <fnref n="10" />, Nicolas de Prost <fnref n="1" />, <fnref n="2" />, <fnref n="3" />, <fnref n="4" />, *

ARTICLE INFO

Article history:

Received 30 January 2025

Received in revised form

19 March 2025

Accepted 1 April 2025

Available online 7 April 2025

Editor: L. Leibovici

Keywords:

Antiviral

Influenza

Intensive care unit

Neuraminidase inhibitors

Oseltamivir

A B S T R A C T

**Background:** Influenza is a significant cause of morbidity and mortality, particularly in critically ill patients. The availability of effective antiviral therapies is pivotal in mitigating the severity and complications associated with influenza.

**Objectives:** This review evaluates the antivirals available for the treatment of severe influenza in critically ill patients, focusing on the strength of recommendations and levels of evidence derived from clinical trials, observational studies, and guidelines. The aim is to provide clinicians with evidence-based insights to optimize antiviral strategies in the intensive care unit setting.

**Sources:** A comprehensive literature search was conducted using PubMed, Embase, and Cochrane Library databases for studies published up to January 2025. Keywords included "antiviral therapy," "influenza," "critically ill patients," "oseltamivir," "peramivir," "zanamivir," "lanimavir," "baloxavir," and "favipiravir." Additional references were identified from the bibliographies of relevant articles.

**Content:** The following topics are covered: antivirals available for treating influenza and evidence supporting their use in critically ill patients, pharmacokinetic issues of enteral oseltamivir administration in critically ill patients, and neuraminidase inhibitors resistance.

**Implications:** Neuraminidase inhibitors constitute the vast majority of antivirals currently prescribed for influenza. The most commonly prescribed neuraminidase inhibitor to date is oseltamivir. Although its efficacy in nonsevere cases of influenza is well established, the evidence for its efficacy in critically ill patients is based on less robust studies, as no randomized controlled trials have been conducted in this population. Limited data on oseltamivir pharmacokinetics is available in critically ill patients. The selection of A(H1N1)pdm09 resistant variants to oseltamivir is particularly problematic in critically ill patients hospitalized in intensive care units. Data on other antivirals, such as neuraminidase inhibitors (i.e. zanamivir, peramivir and laninamivir) or baloxavir marboxil in critically ill patients are scarce. Further research is needed to develop new drugs and assess their efficacy in critically ill patients and to better assess the effect of oseltamivir in this population. Pierre Bay, Clin Microbiol Infect 2025;31:1157 © 2025 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

<footnote n="1">¹) Assistance Publique-Hôpitaux de Paris, CHU Henri Mondor-Albert Chenevier, Service de Médecine Intensive Réanimation, Créteil Cedex, France</footnote>

<footnote n="2">²) Groupe de Recherche Clinique CARMAS, Université Paris Est-Crétel, Créteil, France</footnote>

<footnote n="3">³) INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France</footnote>

<footnote n="4">⁴) INSERM U955, Team Viruses, Hepatology, Cancer, Créteil, France</footnote>

<footnote n="5">⁵) Department of Intensive Care Medicine, Multidisciplinary Intensive Care Research Organization, (MICRO), St James' Hospital, Dublin, Ireland</footnote>

<footnote n="6">⁶) Service de Pharmacologie, DMU Biologie et Génomique Médicale (BioGeM), Hôpital Bichat-Claude Bernard, Paris, France</footnote>

<footnote n="7">⁷) INSERM UMR 1137, IAME, Paris, France</footnote>

<footnote n="8">⁸) Centre National de Référence Virus des Infections Respiratoires, Institut Pasteur, Université Paris Cité, Paris, France</footnote>

<footnote n="9">⁹) M3P, Institut Pasteur, Université Paris-Saclay, Université de Versailles St. Quentin, Université Paris Cité, UMR 1173 (21), INSERM, Assistance Publique des Hôpitaux de Paris, Paris, France</footnote>

<footnote n="10">¹⁰) Department of Virology, Hôpitaux Universitaires Henri Mondor, Assistance Publique – Hôpitaux de Paris, Créteil, France</footnote>

<footnote>* Corresponding author. Nicolas de Prost, Service de Médecine Intensive Réanimation, Hôpital Henri Mondor, 1, rue Gustave Eiffel, 94010, Créteil, France.
E-mail address: nicolas.de-prost@aphp.fr (N. de Prost).</footnote>
## Introduction

Influenza continues to be a global health concern, with annual epidemic outbreaks causing significant morbidity and mortality, particularly in vulnerable populations such as critically ill patients. The availability of effective antiviral therapies is pivotal in mitigating the severity and complications associated with influenza in this vulnerable population. However, the effectiveness of these antivirals varies according to several parameters, such as clinical settings, time of intervention and the class of antivirals. This review evaluates the antivirals available for the treatment of severe influenza in critically ill patients, focusing on the strength of recommendations and levels of evidence derived from clinical trials, observational studies, and guidelines. The aim is to provide clinicians with evidence-based insights to optimize antiviral strategies in the intensive care unit (ICU) setting.

### Clinical case vignette

Case 1: A 42-year-old woman with no previous medical history other than severe obesity developed respiratory symptoms and fever in December. After 4 days, her clinical condition worsened, and she presented to the emergency department with acute hypoxemic respiratory failure and fever. She was immediately admitted to the ICU. A chest x-ray showed bilateral alveolar infiltrates, and arterial blood gases revealed profound hypoxemia. The patient required immediate endotracheal intubation and protective invasive mechanical ventilation. Refractory hypoxemia persisted and the patient was eventually placed on veno-venous extracorporeal membrane oxygenation (ECMO). The nasopharyngeal swab at admission was positive for influenza A (H1N1). There was no documented bacterial coinfection. Oseltamivir (75 mg twice a day in powder for suspension) was administered via a gastric tube.

Case 2: A 58-year-old man with diabetes mellitus and end-stage renal disease developed cough and progressive shortness of breath 1 month after a kidney transplantation. His immunosuppressive medications included corticosteroids, mycophenolate mofetil and tacrolimus. His clinical condition deteriorated, and he presented to the emergency department with acute hypoxemic respiratory failure. A chest x-ray showed bilateral lung infiltrates. A nasopharyngeal swab was negative for influenza and a bronchoscopy with bronchoalveolar lavage was performed and ultimately positive for influenza A (H1N1). There was no documented bacterial coinfection. The patient was admitted to the ICU as his respiratory status deteriorated, eventually requiring endotracheal intubation and invasive mechanical ventilation. Oseltamivir (75 mg twice a day in powder for suspension) was initiated via a gastric tube.

### Search strategy

A comprehensive literature search was conducted using PubMed, Embase, and Cochrane Library databases for studies published up to January 2025. Keywords included "antiviral therapy," "influenza," "critically ill patients," "oseltamivir," "peramivir," "zanamivir," "lanimavir," "baloxavir," and "favipiravir". Studies included randomized controlled trials, observational studies, and guideline recommendations.

### General considerations on the management of critically ill patients with influenza

Respiratory viruses are the most common cause of severe community-acquired pneumonia, and influenza is one of the most commonly identified viruses [1]. The reference standard for influenza diagnosis is the detection of viral RNA (by PCR or other nucleic

acid amplification test), which is the most accurate technique compared with antigen-based assays, serology, or viral culture [2]. These tests are usually performed using a nasopharyngeal swab but can give false-negative results in influenza pneumonia (≈ 10%) due to differences in virus shedding along the respiratory tract. If the initial test is negative but clinical suspicion remains high (especially during peak influenza season), lower respiratory tract samples should be obtained, as viral load is generally higher and shedding is more prolonged in the lower airways.

Critically ill patients with influenza often have coinfections. The estimated prevalence of bacterial coinfection ranges from 11–23% [3], with the most common pathogens being *Streptococcus pneumoniae*, *Staphylococcus aureus*, *Haemophilus influenzae*, and Enterobacterales. This justifies the use of empiric antibiotic therapy in all critically ill patients with influenza pneumonia. Over the past decade, influenza-associated pulmonary aspergillosis has emerged as a concern, affecting patients without classic risk factors for aspergillosis and associated with a poor outcome. The prevalence of influenza-associated pulmonary aspergillosis reaches 15% in intubated patients [4] and can be detected as early as admission to the ICU. This highlights the need for systematic and early screening on admission to the ICU.

Currently, corticosteroid therapy is not recommended by international guidelines [5–7]. Although no randomized controlled trials (RCTs) have specifically evaluated corticosteroids as adjunctive immunomodulatory therapy in severe influenza, retrospective studies—summarized in a meta-analysis [8]—have suggested an association with increased mortality when corticosteroids are administered. Ongoing trials are investigating the effect of steroids (NCT06528444, NCT02735707) on the outcome of hospitalized patients with influenza.

### Review of antivirals and their evidence in critically ill patients

Antiviral drugs targeting influenza act on various viral enzymes involved in different phases of the viral replication cycle (Fig. 1) [9,10].

### Neuraminidase inhibitors

Neuraminidase inhibitors (NAIs) constitute the vast majority of antivirals currently prescribed for influenza. Neuraminidase is a tetrameric viral enzyme with sialidase activity that facilitates the release of virions from the host cell. By inhibiting the highly conserved catalytic site located in the distal globular region of neuraminidase, these drugs block the late stage of the viral cycle, resulting in the aggregation of newly synthesized viral particles.

### Oseltamivir

Although its efficacy in nonsevere cases of influenza is well established [11], and data supporting its efficacy in hospitalized patients is accumulating from large observational cohorts [12,13] and meta-analyses [14], the evidence for its efficacy in critically ill patients is based on less robust studies than those conducted in the outpatient setting, as no RCTs have been conducted in this population. However, several observational studies have consistently suggested a benefit of oseltamivir treatment in ICU patients with severe influenza pneumonia [15–20]. These studies, summarized in Table 1 [15–20], suggest that the mortality benefit of oseltamivir is dependent on early administration: most reports showed improved outcomes when treatment was initiated within 2 days of symptom onset. This threshold should be interpreted with caution, as accurate determination of symptom onset can be challenging, and patients are often admitted to the ICU 3–5 days after symptom
<figure><img src="image_3.png" /><figcaption>**Fig. 1.** Summary of the mechanisms of action of antivirals used in managing severe influenza. The figure represents an influenza A virus particle or virion. Influenza viruses are enveloped negative-sense RNA viruses with genomes comprising eight single-stranded RNA segments located inside the virus particle. The three largest RNA segments encode the three subunits of the viral RNA-dependent RNA polymerases (PB1, PB2, and PA) that are responsible for RNA synthesis and replication in infected cells; Two RNA segments encode the viral glycoproteins haemagglutinin (HA) and neuraminidase, which is responsible for releasing viruses and helping viral spread. Neuraminidase inhibitors (NAIs, such as oseltamivir, peramivir, and zanamivir) are shown in blue in the table; They block the neuraminidase enzyme on the surface of the influenza virus, preventing the release of new viral particles from infected cells; Polymerase complex inhibitors, shown in green, include cap-dependent endonuclease inhibitors (Baloxavir Marboxil), which inhibit viral RNA transcription by disrupting the cap-snatching mechanism crucial for viral replication and RNA polymerase inhibitors (Favipiravir), which target the RNA-dependent RNA polymerase, thereby halting the replication of viral RNA. *The dates indicate the date of EMA approval for each drug; Adapted from Krammer et al. [10]. EMA, European Medical Agency; ICU, ICU, intensive care unit.</figcaption></figure>

onset [15,16,18]. The key takeaway is that earlier administration is critical, without rigidly adhering to the 2-day threshold. The majority of these studies involved patients infected with influenza A(H1N1)pdm09, but there is insufficient evidence to suggest that viral subtype has a significant effect on oseltamivir efficacy. Therefore, international guidelines recommend initiating oseltamivir as soon as possible in hospitalized patients with severe influenza, with a low level of evidence (Table 2) [5–7,17–19]. The usual recommended dose is 75 mg twice a day for 5 days, adjusted for renal insufficiency. In patients under haemodialysis, a 30 mg dose after each session provides sufficient drug exposure [21]. The duration of treatment is often debated as ~25% of ICU patients have persistent viral shedding by day 5, particularly those who are immunocompromised or mechanically ventilated [22,23]. Extending treatment to 10 days may be reasonable for immunocompromised patients or those with persistent clinical symptoms and viral shedding on day 5 [6]. It should also encourage genotyping for viral resistance and tailoring treatment to the viral genotype if viral shedding persists at day 5. Compared with the classic dose, higher doses (150 mg twice a day) have not shown faster reduction of nasal viral load or clinical superiority [24,25]. Oseltamivir is generally well tolerated, with rare nonsevere gastrointestinal side effects and neuropsychiatric toxicity, especially in cases of overdose [26].

## Other neuraminidase inhibitors

Data on other NAIs (i.e. zanamivir, peramivir, and laninamivir) in critically ill patients are scarce. Zanamivir is available in intravenous and inhaled formulations. Although efficacy data are available

<table><thead><tr><th>Antiviral</th><th>Mechanism of Action</th><th>Clinical Considerations</th><th>EMA approval</th></tr></thead><tbody><tr><td>Oseamtivir</td><td>NAI: Blocks viral release from cells</td><td>1<sup>st</sup> line therapy; enteral administration only; early initiation is critical; safe and effective for most patients:.</td><td>• Yes<br>• Adults and children > 1 years<br>• 2002</td></tr><tr><td>Peramivir</td><td>NAI: Blocks viral release from cells</td><td>IV administration suitable for patients with impaired enteral absorption; limited data in ICU settings.</td><td>• Yes<br>• Adults and children > 2 years<br>• 2021</td></tr><tr><td>Zanamivir</td><td>NAI: Blocks viral release from cells</td><td>Inhaled and IV formulation; effective for oseltamivir-resistant strains.</td><td>• Yes<br>• Adults and children > 6 months<br>• In case of suspected resistance<br>• 2014</td></tr><tr><td>Baloxavir Marboxil</td><td>Cap-dependent endonuclease inhibitor: Disrupts RNA transcription</td><td>Novel mechanism; single-dose option; ICU-specific data limited but promising for combination therapies.</td><td>• Yes<br>• Adults and children > 1 years<br>• 2023</td></tr><tr><td>Favipiravir</td><td>RNA polymerase inhibitor: Inhibits RNA replication</td><td>Limited clinical data; requires further study to define its role in critically ill patients.</td><td>• No</td></tr></tbody></table>

in critically ill patients, a RCT in hospitalized patients failed to demonstrate clinical superiority over oseltamivir [27]. Zanamivir may be an interesting option in cases of oseltamivir resistance, a topic discussed later [28]. Peramivir is another intravenous NAI that offers a valuable option for patients unable to tolerate oral or inhaled medications. Its once-daily i.v. administration is particularly advantageous in ICU patients with compromised enteral absorption. Although specific evidence in critically ill patients is limited, data from hospitalized populations demonstrate its efficacy in reducing viral load and symptom severity [29–31]. Peramivir is often reserved for scenarios where oseltamivir cannot be administered (e.g. allergy, no enteral administration possible). In addition, it has been reported to have superior virological activity against influenza B [30]. Laninamivir, administered via a single nasal inhalation, has demonstrated noninferiority to oseltamivir in outpatient studies [32]. However, no efficacy data exist for severe influenza cases.

## Polymerase complex inhibitors

The viral polymerase complex, consisting of PB1, PB2, and PA subunits, is essential for viral RNA replication and transcription via a cap-snatching mechanism. Three antivirals have been developed that target this complex: favipiravir, pimodivir, and baloxavir marboxil. Development of pimodivir (targeting PB2) was discontinued due to lack of efficacy [33]. Favipiravir is a nucleosid analogue, which targets the RNA-dependant RNA polymerase PB1 and has broader antiviral activity but offers limited clinical benefit [34]. Baloxavir marboxil, which targets the PA subunit and inhibits polymerase endonuclease activity, has demonstrated more rapid
<table><caption>**Table 1**

Characteristics of studies investigating the effect of oseltamivir in critically ill patients</caption><thead><tr><th>Author, year, reference</th><th>Country</th><th>Type of study</th><th>Number of patients</th><th>Type of influenza virus</th><th>Intervention</th><th>Primary end point</th><th>Effect</th></tr></thead><tbody><tr><td>Rodríguez et al. [15], 2011</td><td>Spain n = 148 centres</td><td>Prospective study</td><td>657</td><td>A(H1N1)pdm09</td><td>Oseltamivir ≤2 days from ICU admission (whole cohort: n = 147, 22%/patients on IMV: n = 79, 20%)</td><td>ICU mortality</td><td>Among 385 patients on IMV: MV analysis OR 0.44; 95% CI, 0.21–0.87, p 0.02<br>PS analysis: 0.44; 95% CI, 0.22–0.90; p < 0.001</td></tr><tr><td>Louie et al. [16], 2012</td><td>USA California</td><td>Retrospective study</td><td>1950</td><td>A(H1N1)pdm09</td><td>NAI (n = 1676 (90%), oseltamivir 99.7%)</td><td>Survival</td><td>Crude analysis: 75% vs. 58%, p < 0.001</td></tr><tr><td>Canadell et al. [17], 2015</td><td>Spain n = 148 centres</td><td>Prospective study</td><td>1058</td><td>A(H1N1)pdm09</td><td>Oseltamivir ≤2 days from onset of symptoms (n = 153, 24%)</td><td>ICU mortality</td><td>MV analysis HR = 0.57; 95% CI, 0.431–0.77; p < 0.001</td></tr><tr><td>Hernu et al. [18], 2017</td><td>France n = 12 centres</td><td>Prospective study</td><td>201</td><td>A H1N1 50% (n = 100)<br>Other type A 35% (n = 35)<br>Type B 15% (n = 30)</td><td>Oseltamivir ≤2 days from onset of symptoms (n = 40, 20%)</td><td>In-hospital mortality</td><td>MV analysis: OR 0.26; 95% CI, 0.08–0.79, p 0.02<br>PS-matched analysis: 4 (10%) vs. 13 (33%), p 0.027</td></tr><tr><td>Lytras et al. [19], 2019</td><td>Greece nationwide</td><td>Retrospective study</td><td>1330</td><td>A(H1N1)pdm09<br>56% (n = 751)<br>A H3N2 21% (n = 276)<br>Type B 13% (n = 175)<br>Other type A 10% (n = 128)</td><td>Oseltamivir ≤2 days from onset of symptoms (n = 529, 25%)</td><td>ICU mortality</td><td>Bayesian models: lower mortality in patients with influenza A/H3N2, RR 0.69; 95% CI, 0.49–0.94</td></tr><tr><td>Moreno et al. [20], 2021</td><td>Spain n = 184 centres</td><td>Retrospective study</td><td>2124</td><td>A(H1N1)pdm09<br>72% (n = 1533)<br>A H3N2 16% (n = 336)<br>Type B 7% (n = 148)<br>Other type A 5% (n = 107)</td><td>Oseltamivir ≤2 days from onset of symptoms (n = 529, 25%)</td><td>ICU mortality</td><td>MV analysis: OR 0.69; 95% CI, 0.51–0.95, p 0.02<br>PS-matched analysis: (19.1% vs. 24.6%; p 0.01</td></tr></tbody></table>

ICU, intensive care unit; IMV, invasive mechanical ventilation; MV, multivariate; NAI, neuraminidase inhibitor; PS, propensity-score.

<table><caption>**Table 2**

Position of international guidelines on oseltamivir use in severe influenza</caption><thead><tr><th>Guidelines</th><th>Recommendation</th><th>Strength/quality of evidence</th></tr></thead><tbody><tr><td>ATS & IDSA 2019 [18]</td><td>"We recommend that anti-influenza treatment, such as oseltamivir, be prescribed for adults with CAP who test positive for influenza in the inpatient setting, independent of duration of illness before diagnosis"</td><td><ul><li>Strong recommendation, moderate quality of evidence</li></ul></td></tr><tr><td>ERS, ESICM, ESCMID & ALAT 2023 [19]</td><td>"We suggest the use of oseltamivir for patients with sCAP due to influenza confirmed by PCR"<br>"When PCR is not available to confirm influenza, we suggest the use of empirical oseltamivir during the influenza season"</td><td><ul><li>Conditional recommendation, very low quality of evidence</li><li>Conditional recommendation, very low quality of evidence</li></ul></td></tr><tr><td>WHO 2022 [17]</td><td>"In persons with suspected or confirmed influenza virus infection with or at risk of severe illness (i.e. including seasonal influenza, pandemic influenza and zoonotic influenza), we suggest administering oseltamivir as soon as possible (vs. not administering oseltamivir)"</td><td><ul><li>Conditional recommendation, low-quality evidence</li></ul></td></tr></tbody></table>

CAP, community-acquired pneumonia; sCAP, severe community-acquired pneumonia. ATS: American Thoracic Society; IDSA: Infectious Diseases Society of America; ERS: European Respiratory Society; ESICM: European Society for Intensive Care Medicine; ESCMID: European Society of Clinical Microbiology and Infectious Diseases; ALAT: Asociacion Latinoamericano de Torax.

antiviral effects and similar clinical efficacy compared with that of oseltamivir in a phase III trial for nonsevere influenza [35]. However, its use in clinical trials was associated with frequent emergence of resistance, leading to treatment failure [36]. Although ICU-specific data are limited, its unique mechanism and single-dose administration make it a promising candidate for combination therapy, potentially reducing resistance. A phase III trial investigating the effect of oseltamivir plus baloxavir versus oseltamivir alone in hospitalized patients with severe influenza found no clinical superiority for the combination strategy [37]. However, resistance rates (to both oseltamivir and baloxavir) were lower than previously reported, and viral clearance was faster with combination therapy. This strategy may be particularly relevant for high-risk populations, such as immunocompromised patients with severe influenza. ICU-specific data are urgently needed.

### Pharmacokinetic issues of enteral oseltamivir administration in critically ill patients

Oseltamivir is administered orally (hard capsules or powder for suspension) in the form of an inactive prodrug, oseltamivir phosphate (OP). Following oral administration of OP, oseltamivir is rapidly absorbed from the gastrointestinal tract and converted by hepatic esterases into the active metabolite oseltamivir carboxylate (OC). Approximately 80% of an oral dose of OP reaches the systemic circulation as OC. OC reaches maximum plasma concentrations after 3 to 4 hours. Steady-state plasma concentrations of OC are reached within 2–3 days of twice-daily dosing. OP and OC are mainly eliminated by renal excretion [38,39]. In healthy volunteers and uncomplicated infected subjects, the pharmacokinetics of OC show little inter-individual variability [40].
However, many pharmacokinetic processes can be compromised in critically ill patients [41,42]. Impaired intestinal perfusion, intestinal wall oedema, gastroparesis and ileus associated with critical illness and shock make the enteric absorption and drug availability unpredictable. Although bioequivalence studies have evaluated the extended-release formulation, data on nasogastric tube administration remains limited [43]. Fluid shifts and volume resuscitation can increase the volume of distribution of many drugs, thereby decreasing drug concentrations in plasma and peripheral tissues, particularly in patients with sepsis or septic shock. Mechanical ventilation, renal replacement therapy, and ECMO support may contribute to both inter-patient and intra-patient variability in drug pharmacokinetics [41].

In addition, the pharmacokinetics of OC may be influenced by drug interactions. OP is the substrate of carboxylesterase and transporters, such as organic anion transporters, P-glycoprotein, and multidrug resistance-associated protein [44]. For instance, clopidogrel has been shown to inhibit the hydrolysis of OP by 90% in vitro, rendering the antivirals therapeutically ineffective [45]. An exposure-response relationship has been reported between plasma OC concentration-time curve from 0 to 24 hours and a composite symptom score [46]. To our knowledge, no toxicity-exposure relationship has yet been described.

The paucity of data on OC pharmacokinetics in critically ill patients is due to the fact that plasma OC measurements are not a standard part of routine hospital practice. A study in 34 critically ill patients suggested good oseltamivir bioavailability, measured after at least 48 hours of treatment administered via a nasogastric tube [47]. However, this study included mildly ill patients, measured OC plasma concentrations after 48 hours of treatment, and did not adjust oseltamivir dose for renal function, which may limit its generalizability. A RCT comparing oseltamivir with intravenous zanamivir found no superiority of zanamivir [27]. However, this

study did not exclusively include critically ill patients, with only 46% of patients on mechanical ventilation. A subsequent pilot study found that two out of 15 critically ill patients had undetectable plasma OC concentrations measured 48 hours after initiation, suggesting impaired OP absorption, which could be detected by the paracetamol absorption test [48].

## Neuraminidase inhibitors resistance

Influenza viruses with reduced sensitivity to NAIs typically carry resistance-associated substitutions (RAS) in the viral neuraminidase (NA), which directly or indirectly alter the binding of the inhibitor. Zanamivir is closer to the transition state of the NA substrate than oseltamivir, which explains why more RAS have been described for the latter drug. The most common RAS to oseltamivir is NA:H275Y in A(H1N1) viruses and NA:R292K in A(H3N2) viruses. Zanamivir, often used as a second-line therapy, maintains activity against NA:H275Y-A(H1N1) viruses but its activity is partially altered against NA:R292K-A(H3N2) viruses. Besides these RASs, several other substitutions have been occasionally associated with resistance to NAIs. A comprehensive mutational profile is regularly updated by the WHO expert working group on surveillance of influenza antiviral susceptibility (WHO - Anti-Viral Working Group) and are summarized at the website virusfrenchresistance.org (Fig. 2).

## Frequency of naturally occurring RAS to NAIs

Naturally occurring RAS to NAIs are limited because most of them reduce NA activity and thus affect viral fitness. Of note, A(H1N1) naturally resistant to oseltamivir emerged and spread worldwide during the 2007–2009 influenza seasons (A/Brisbane/59/2007 carrying NA-H275Y). Since the emergence of the A(H1N1) pdm09 pandemic and the disappearance of the A/Brisbane/59/

<figure><img src="image_4.png" /><figcaption>**Fig. 2.** Detection of resistance associated substitutions (RASs) in sequenced A(H1N1)pdm09 in France during the last influenza seasons. All N1 sequences from France available in GISAID on January 25, 2025 were analysed to detect RASs described to be associated with reduced susceptibility to neuraminidase inhibitors (NAIs). The percentages are shown in the histogram. The curve indicates the number of sequences analysed. The curve indicates the number of analysed sequences. Fold change in susceptibility associated with the mutation: H275Y: Oseltamivir: highly reduced inhibition (HRI) (221–1637); Zanamivir: no inhibition (NI) (1–6); I223R: Oseltamivir: reduced inhibition (RI) (11); Zanamivir: NI (2); I223R: Oseltamivir: NI/RI (9–15); Zanamivir: NI (3); I223V: Oseltamivir: NI (6); Zanamivir: NI (2); S247G: Oseltamivir: RI (15); Zanamivir: NI (1); S247N: Oseltamivir: NI (4–8); Zanamivir: NI (2–5).</figcaption></figure>
2007 variant, the transmission of oseltamivir-resistant A(H1N1) pdm09 viruses carrying H275Y has been limited to date (prevalence less than 1%) [49]. In France, this mutation is found in 36 of the 5826 sequences deposited in the GISAID database since 2009. However, several recent reports highlight the need to actively continue to monitor resistance: for instance, an outbreak of influenza A(H1N1)pdm09 viruses harbouring NA-H275Y has been reported in Japan in September 2024 [50]. In addition, the incidence of A(H1N1)pdm09 H1N1 viruses harbouring NA:1223V or NA:S247N RASs both decreasing susceptibility to oseltamivir increased worldwide since late 2023 [51,52]. The frequency of A(H3N2) and B/Victoria-lineage viruses harbouring naturally occurring RAS to any NAI remains very low (<0.1% and <1% respectively) [49]. The potential threat of an H5N1 pandemic is currently rising. Although the efficacy of NAIs against H5N1 has been reassuring so far, the emergence of some NAI-resistant strains underscores the need for continued surveillance [53]. In addition, other antivirals such as baloxavir may have greater clinical benefit against currently circulating H5N1 when compared with to oseltamivir, as suggested in a mouse model [54].

### Frequency of acquired RAS during treatment with NAIs in critically ill patients in intensive care

During clinical trials, the incidence of oseltamivir-resistant virus was around 1–2% in adults and higher in children, with a Japanese study showing up to 16% (7/43). The selection of A(H1N1)pdm09 resistant variants to oseltamivir is particularly problematic in critically ill patients hospitalized in ICUs. NA-H275Y RAS is frequently acquired in patients with persistent viral replication during treatment, as it has been documented in Australia (57% influenza A-H1N1 breakthrough infections harboured the NA-H275Y) [55] or in a French multicentre study during the 2017/2018 influenza epidemic (23% of influenza A-H1N1 breakthrough infections harboured the NA-H275Y) [28]. The high incidence of resistant viruses in critically ill patients, as in children, is likely due to highly active viral replication in this population with specific clinical conditions (e.g. immunosuppression), which increases viral genetic variability, favouring the emergence and selection of RASs [56,57]. In these cases, switching to zanamivir or a polymerase inhibitor baloxavir [58] or even dual therapy with these two drugs [59] have shown promising results, although more data are needed to assess their efficacy.

Zanamivir is rarely prescribed as a first-line therapy in critically ill patients; a randomized clinical trial comparing oseltamivir with zanamivir (i.v.) in a population of hospitalized patients showed that

resistance to zanamivir was low for A H3N2 viruses (n = 2/153), while no RAS were detected for A H1N1 (n = 0/122) and B viruses (n = 0/52) [27].

First-line dual therapy (NAI + baloxavir) has not yet been shown to be a clear way to reduce the emergence of resistance [37]. However, this option seems interesting in critically ill patients to reduce viral persistence and should be further evaluated in the future.

Finally, the turnaround time for detecting RAS to NAIs by sequencing needs to be optimised to allow for timely switching to an alternative antiviral if necessary. The development and integration of specific PCRs targeting candidate mutations (such as A-H1N1 H275Y) into technologies such as rapid multiplex PCR should also facilitate resistance screening in clinical practice.

### Case vignette: treatment course and outcome

**Case 1:** The patient was still febrile and on ECMO on day 7. Bronchoscopy with bronchoalveolar lavage (BAL) was performed and influenza PCR in BAL fluid was negative. Oseltamivir treatment was discontinued on day 7. Klebsiella pneumoniae ventilator-associated pneumonia was diagnosed on BAL fluid culture with a favourable outcome after antibiotic treatment. The patient was successfully decannulated on day 12 and extubated on day 18 of ICU admission.

**Case 2:** As the patient remained severe with acute respiratory distress syndrome criteria and was immunosuppressed, a 10-day course of oseltamivir treatment was administered. On day 10, the patient was still febrile. An influenza PCR in BAL fluid was still positive, and the NA-H275Y oseltamivir resistance mutation was found. Intravenous treatment with zanamivir was initiated. The patient also developed influenza-associated pulmonary aspergillosis, which was treated with voriconazole, and died on ICU day 28.

### Research agenda and perspectives

Severe influenza is a major public health problem and the evidence for currently available antivirals remains weak. Further research is therefore needed, not only to develop new drugs and assess their efficacy in critically ill patients, but also to fill gaps in knowledge about the benefit of NAIs in this population (Table 3). The question of whether randomized, placebo-controlled trials, testing oseltamivir in critically ill patients is often raised and could provide stronger evidence. However, although some authors agree that such trials would be warranted in hospitalized non-ICU

<table><caption>**Table 3**
Research agenda on antiviral treatment strategies in severe influenza</caption><thead><tr><td>Domain</td><td>Research aim</td></tr></thead><tbody><tr><td>Development of new antivirals</td><td><ul><li>Clinical endpoints</li><li>Virological endpoint (viral load kinetics and resistance)</li><li>Pharmacological endpoint</li></ul></td></tr><tr><td>Development of monoclonal antibodies</td><td><ul><li>Clinical endpoints</li><li>Virological endpoint (viral load kinetics and resistance)</li><li>Pharmacological endpoint</li></ul></td></tr><tr><td>Clinical studies on currently available antivirals</td><td><ul><li>Oseltamivir</li><li>Peramivir</li><li>Baloxavir marboxil</li><li>Combination therapies</li></ul></td></tr><tr><td>Pharmaco-epidemiologic studies in critically ill patients</td><td><ul><li>Clinical endpoints</li><li>Virological endpoint (viral load kinetics and resistance)</li><li>Pharmacological endpoint</li></ul></td></tr><tr><td>Resistance</td><td><ul><li>Rates of baloxavir marboxil-induced resistances in critically ill or immunosuppressed patients</li><li>Effect of combination therapies to decrease baloxavir marboxil-induced resistances in critically ill patients</li><li>Pharmacological endpoint (reservoir disposition concomitantly with resistance)</li></ul></td></tr></tbody></table>
patients, they would be considered unethical in patients at high risk of poor outcome, including immunosuppressed or ICU patients [60]. Instead, high-quality prospective studies using methods to minimize bias, ideally combining clinical, virological and pharmacological endpoints, should be conducted in the most severely ill patients [61]. Antiviral resistance should be carefully analysed, particularly in immunosuppressed or critically ill patients in studies assessing new drugs or antiviral combination strategies.

Similar to what has been developed for other respiratory viral infections, antibody-based therapies may emerge, with the ongoing development of monoclonal antibodies mostly directed against highly conserved viral epitopes such as in the hemagglutinin stalk or in the neuraminidase [62–64]. Immune plasma has been shown to be well tolerated but did not improve the respiratory status of hospitalized adults and children [65]. However, further studies using high-quality plasma and targeting high-risk populations, including immunosuppressed patients would be needed.

The role of adjunctive therapies, particularly corticosteroids, remains poorly defined and is not currently recommended [17–19] due to an increased risk of mortality. Whether patients with well-controlled viral replication, achieved by optimal antiviral administration and an inappropriate immune response could benefit from pharmacological interventions aimed at attenuating the immune and inflammatory response (e.g. corticosteroids) remains uncertain.

## Conclusions

Severe influenza is a therapeutic challenge for clinicians. Current therapeutic management mostly rely on enteral oseltamivir administration. However, impaired enteral absorption and oseltamivir resistances may limit its efficacy in the most severe patients. Other antivirals are available (zanamivir, peramivir, laninamivir, and baloxavir marboxil) but data supporting their use in critically ill patients are scarce. Further research studies are required in this subgroup to optimize patient care.

## Author contributions

P.B. contributed to the conception and design of the work, writing review, systematic search execution, literature review, drafted the work and approved the submitted version. I.M.-L., A.-F.H., M.P.L., G.P., and M.-A.R.-W. contributed to the conception and design of the work, writing review and approved the submitted version. S.F. contributed to the conception and design of the work, data acquisition, drafted the work, writing review and approved the submitted version. N.d.P. contributed to the conception and design of the work, writing review, systematic search execution, literature review, drafted the work and approved the submitted version.

## Transparency declaration

### Potential conflict of interest

I.M.-L. has served as a speaker for MSD, Gilead, and Mundipharma, which are out of the scope of the manuscript's content. A.-F.H. has served as a speaker for Dräger, Air Liquide Medical Systems, Fisher & Paykel and Medtronic. M.P.L. received travel grants from ViiV Healthcare and Gilead Sciences. G.P. has served as speaker or adviser for Gilead Sciences, Merck, Takeda and ViiV Healthcare, outside the submitted work. S.F. has served as a speaker for GlaxoSmithKline, AstraZeneca, MSD, Sanofi, Pfizer, Cepheid and Moderna. N.d.P. has served as an adviser or speaker for Moderna and AstraZeneca.

The other authors and investigators have no conflict of interest to disclose.

## Financial report

This work was supported by the EMERGEN consortium—ANRS Maladies Infectieuses Emergentes (ANRS0153).

## Access to data

Non-applicable.

## Acknowledgements

The authors thank Dr Pierre-André Natella, Ms Nolwenn Bombenger, and Mr Mohamed Ader.

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