Seasonal influenza represents a significant morbidity burden to an intensive care service . Though the spectrum of clinical disease varies from mild – requiring simple outpatient measures only – there is a proportion of patients who develop significant complications, particularly, refractory respiratory failure [2▪]. Though there are well established risk factors for increasing severity of disease – immunosuppression, pregnancy, extremes of age and chronic disease [2▪] – many of these are unfortunately unmodifiable and both vaccination uptake  and coverage have been suboptimal .
The major determinant of mortality in patients suffering from septic shock is the progression of multiorgan failure (MOF). A relatively unique characteristic of influenza is that while patients in the latter stages can develop MOF, the main organ failure is respiratory with severe and, on many occasions, refractory hypoxemia in the context of acute respiratory distress syndrome (ARDS) .
Noninvasive ventilation (NIV) has been considered an attractive option to provide ventilatory support whilst also avoiding potential ventilator-associated complications (VACs) -- namely ventilator-associated pneumonia (VAP). However, multiple studies have failed to demonstrate the benefit of NIV in severe forms of community-acquired pneumonia (sCAP), particularly in patients with ARDS and septic shock . To date, though no randomized controlled trials (RCT) have been conducted to determine the role of NIV in influenza, observational studies have shed some light upon this clinical conundrum. A multicentre study from Spain involving 148 ICUs found that NIV failure was frequent in patients with influenza infection, with half of the patients who initially received NIV eventually failing. Moreover, NIV failure was associated with increased ICU mortality . Interestingly, the severity of organ failure was helpful for risk stratification as patients with a SOFA at least 5 were at higher risk of NIV failure.
Recently, there has been an explosion in the use of high-flow nasal cannula (HFNC) to support oxygenation in patients with acute respiratory failure. Thus far, however, there has been no study supporting its use in influenza patients. On the basis of recent findings in both immunocompetent and immunosuppressed patients, we would suggest caution in its deployment for this purpose and would advocate restricting its use to patients being closely monitored under critical care supervision.
When severe hypoxemia occurs, invasive mechanical ventilation is the cornerstone of supportive therapy in ICUs worldwide . Patients infected with influenza are commonly affected by the inherent virulence of the virus and the predominant feature is the early development of ARDS characterized by acute lung injury and primary viral pneumonia. The first priority in this instance is to ensure a low tidal volume (6 ml/kg), lung protective ventilatory strategy is adhered to. The aim of this approach is to avoid volutrauma and atelectotrauma and subsequent ventilator-induced lung injury (VILI) during invasive mechanical ventilation, and thereby reduce local production and release of cytokines (biotrauma) .
If inadequate oxygenation persists after conventional invasive mechanical is instituted, lung recruitment strategies may be attempted  in an effort to improve oxygenation. This can be achieved with the use of electrical impedance tomography to guide PEEP titration , as opposed to conventional recruitment maneuvers, which have been called into question after the ART Trial in 2017 . Ventilator--patient dyssynchrony often occurs during invasive mechanical ventilation and can contribute to ineffective gas exchange . Once identified, there are two potential strategies to improve this interaction. Firstly, pharmacotherapy -- increasing depth of sedation and analgesia, with or without the addition of a nondepolarizing muscle relaxant (NDMR). Secondly, manipulation of ventilator settings and mode switching .
Recently, however, the benefit of muscle relaxation is less clear cut following the publication of a large trial showing no benefit in mortality in moderate-to-severe ARDS patients treated with early and continuous NDMR infusion . Prone positioning, on the other hand, can be recommended thanks to demonstrated improvements in oxygenation, lung recruitment and overall survival . We would encourage prompt prone positioning in patients with severe hypoxemia in order to optimize oxygenation, lung compliance and minimize driving pressure. High frequency oscillatory ventilation (HFOV), an advanced ventilatory technique based on dissociating oxygenation and ventilation, has fallen out of favour in adults since the publication of OSCAR  and OSCILLATE  called its benefits into question.
In some circumstances, the above measures are ineffective, and one must resort to a technique that has enjoyed a resurgence in recent years in the treatment of influenza: extracorporeal membrane oxygenation (ECMO). Current technical and design improvements, including latest generation oxygenators that optimize membrane characteristics to facilitate gas exchange, heparin-coated circuits, and magnetically driven centrifugal pumps that minimize haemolysis have made it possible to consider ECMO as an alternative rescue technique in refractory ARDS associated with severe influenza A (H1N1). A recent systematic review and meta-analysis of 494 patients receiving ECMO for severe influenza infection with respiratory failure found that the crude mortality was higher than previous years. Duration of pre-ECMO mechanical ventilation (in days) was the only statistically significant moderator of mortality identified . Therefore, we can only recommend the use of ECMO as a rescue therapy when patients fail to respond to conventional therapies. Patients’ performance status prior to ICU admission might represent the most important discriminator for deciding whether to initiate ECMO or not.
An interesting characteristic of influenza virus infection is the particularly high rate of associated co-infection, which has been shown to be up to 23% in ICU patients. Though the classic association is with Staphylococcus aureus co-infection, there is increasing evidence of an extended repertoire of co-infectious organisms , including Streptococcus pneumoniae, Haemophilus influenzae and Pseudomonas aeruginosa, as well as Aspergillus spp. The latter two, in particular, are associated with a markedly increased mortality, and a retrospective Dutch and Belgian study [21▪] has characterized aspergillus co-infection in influenza as having a mortality rate of up to 51%. The same study also demonstrated an aspergillus infection rate of 14% in immunocompetent patients and 32% in those who were immunocompromised.
Given this strong association it has been recommended that empiric community-acquired organism antibacterial cover be considered on admission until such time as bacterial co-infection can be excluded . However, antimicrobial overuse is not without risk. A recent Spanish CHAID decision tree analysis of a cohort of critically ill influenza-infected patients suggested that in the absence of shock, a low procalcitonin (PCT) level (<0.29 ng/ml) can be used as a marker of the absence of bacterial co-infection, offering a negative predictive value of 94% . Interestingly, the same study failed to achieve similar results with C-reactive protein (CRP), thereby suggesting it not be used as a laboratory marker to exclude co-infection.
A well established class of medications, with an excellent safety profile even in pregnancy , the principle difference between drugs of this class is mode of administration (Fig. 1). Neuraminidase inhibitors prevent the cleavage of neuraminidase on the surface of virus-infected cells, thereby preventing virion separation and further infectious spread . Oseltamivir is an enteral preparation, Peramivir an intravenous formulation and Zanamivir both an inhaled and intravenous option . Oseltamivir is the preferred option because of the larger weight of evidence supporting its use, with predominantly mild gastrointestinal (GI) side effects. Although having little evidence backing its use, Zanamivir may also precipitate bronchospasm, and is therefore, not recommended in the critically ill, particularly those requiring mechanical ventilation .
All of these drugs have activity against influenza A and B [2▪,24]. Moreover, though their benefit is better established following early initiation (<48 h after symptom onset) [25–27], there is an increasing evidence base that delayed initiation may still be worthwhile [28,29].
It is worth noting that much of the evidence base supporting these drugs is not based on an RCT of critically ill patients, but observational studies of both inpatient and outpatient populations and then subsequent meta-analyses demonstrating benefit [25,26]. Though a mortality benefit in ICU has been suggested by a meta-analysis by Doll et al., and in a second by Muthuri et al., disease duration, secondary complications and severity have all been consistently demonstrated to be reduced with therapy. However, the effect sizes are relatively modest, amounting to less than a 24 h reduction in symptomatology.
Pharmacological studies suggest that oseltamivir reaches effective plasma concentrations via the enteral route in critically ill patients on both renal-replacement therapy  and ECMO [2▪,33]. Evidence does not support extra dosing in the obese or critically ill , with no improvement in outcomes with additional drug administered [2▪,35]. As such, the recommended dose is 75 mg twice daily.
Recent work evaluating its use in pregnancy has suggested an increased dose may, however, be required in these patients and has been supported by recent guidelines [36,37▪▪] (105 mg twice daily, though up to 150 mg twice daily may be required). In the absence of renal replacement therapy, a dose reduction in the presence of CrCl less than 60 ml/min has been recommended . Though the optimal duration of therapy is unclear, there is some suggestion that being guided by ongoing laboratory evidence of viral shedding may be a superior approach to the current predefined 5 days of therapy . In the event of the enteral route being unavailable – whether because of malabsorption, gastrointestinal failure, stasis, or another disorder – intravenous peramivir has been shown to be noninferior to enteral oseltamivir in uncomplicated influenza . Trials did not, however, demonstrate any benefit to combination therapy or any superiority of the intravenous preparation [41,42]. The relative advantage of peramivir, namely its single dose infusion, is countered by its significantly higher cost, and currently, there is not sufficient evidence to recommend its routine use in an ICU setting .
Zanamivir has been previously approved as an intravenous formulation for compassionate use on a case-by-case basis only. Laninamivir has only been approved for use in Japan, and is another prodrug administered via the inhalational route . An RCT from 2017, performed in patients aged 16 years or older with severe influenza admitted to 97 hospitals from 26 countries, found that 600 mg intravenous zanamivir not superior to either oseltamivir or 300 mg intravenous zanamivir . This would support the compassionate use of zanamivir for patients who are not clinically improving that has been suggested in some guidelines. Overall NAI resistance is low , but appropriate caution should be maintained, particularly given the previous rapid emergence with regard to adamantines and resistant strains seen during the 2009 pandemic . In this instance, Japan – for example – supports case-by-case use of alternative NAI agents .
There is emerging evidence that combination therapy, whether with other antivirals or other compounds – such as naproxen and clarithromycin – may offer additional clinical benefit over NAI use alone but for the moment this is still hypothesis-generating work . Moreover, Martin-Loeches et al. conducted a propensity-matched score analysis in critically ill patients and could not find any benefit associated with the use of macrolides.
Baloxavir is a novel antiviral agent that first was approved by the Food and Drug Administration (FDA) for use in uncomplicated influenza in 2018. It functions as a viral cap-endonuclease inhibitor and prevents initiation of viral mRNA synthesis . This confers activity against both influenza A and B viruses , even those resistant to NAIs [51,52].
Clinical studies have shown it to be as effective as oseltamivir in treating uncomplicated influenza infections in the outpatient setting [53▪], but as yet no studies have been performed in the critically ill. It is administered as a single oral dose  but has the caveat of rapid emergence of resistant strains, even during the trial period [55,56].
Adverse effects, thus far, have been predominantly gastrointestinal and are reported as mild, not differing significantly from oseltamivir . At present, no evidence supports combination therapy, though a phase 3 clinical trial of baloxavir with oseltamivir versus oseltamivir is currently enroling (NCT03684044). Baloxavir is three-fold as expensive as oseltamivir for a complete treatment course , which in the absence of clinical superiority may be difficult to justify financially. Data for baloxavir is also lacking in special populations -- particularly children -- for use as prophylaxis, as well as during pregnancy.
Examples of this drug class include rimantadine and amantadine. They function as M2 inhibitors, inhibiting the delivery of viral genetic material to the infected cell cytoplasm . This mechanism confers activity solely against Influenza A viruses because of Influenza B having a structurally different M2 protein .
From 2005 onwards, use of this class of medications was recommended against by the Centers for Disease Control and Prevention (CDC) because of both poor tolerability  and emergence of high resistance rates (often in excess of 99%) , and as such will not be addressed further here.
Favipiravir is an oral influenza virus RNA polymerase inhibitor. It is a nucleoside analogue that directly inhibits RNA-dependant RNA-polymerase . As such, this confers activity against both resistant influenza strains, as well as other families of RNA viruses, such as Respiratory Syncitial virus (RSV), enteroviruses, and norovirus . Preclinical studies suggest it may be effective even if administered up to 72 h after symptom onset  – though this can increase to 96 h if used in combination with oseltamivir  -- and is generally well tolerated .
However, concerns over teratogenicity raised in animal studies has limited its licencing in Japan (the only country to approve its use in humans currently) to resistant or re-emerging pandemic influenza, and is not for use in parturients . Moreover, in-vitro data has raised the possibility of relatively rapid emergence of resistant influenza strains through amino acid substitutions in RNA polymerase , though this has not yet been borne out clinically.
At present, there is no large resulted clinical trial to support its use in humans, though several are underway (NCT02026349 – results posted but not yet published/NCT01068912/NCT01728753), and therefore, little evidence to recommend its use, particularly in the critically ill.
Pimodivir is an oral nonnucleoside inhibitor of influenza virus polymerase in advanced stages of development . Promising early work demonstrating antiviral activity in strains resistant to NAIs , has been offset by concerns regarding rapid emergence during therapy of viral polymerase mutations that are associated with pimodivir resistance .
A phase 2b trial has compared pimodivir against placebo in healthy volunteers . The most beneficial dose appeared to be 1200 mg loading followed by 600 mg twice daily. Though there was a reduction in influenza symptomatology, the magnitude of this effect was not dissimilar to that demonstrated in NAIs.
A further trial of pimovidir with or without oseltamivir versus placebo has been recently published . This study demonstrated that pimovidir-treated patients – particularly, those in the 600 mg twice daily arm -- had a significantly lower viral RNA burden over time, with the largest benefit seen in combination with oseltamivir. A large clinical trial in patients at risk of influenza complications is ongoing (NCT03381196) and two other studies (NCT02532283 and NCT03376321) are underway but presently its use in the critically ill cannot be recommended.
Several different monoclonal antibodies against retained segments of haemagglutinin in influenza A are currently under development. Examples include MHAA4549A [73,74], MEDI8852 , and VIS410 .
However, early clinical work comparing these therapies against placebo has thus far has been disappointing. Despite initially promising efficacy, these studies have not yet demonstrated a clinical advantage compared with traditional neuraminidase inhibitors despite the potential for benefit outside the NAI 48 h window and a possibly more favourable pharmacokinetic profile.
Further trials examining these drugs in comparison with oseltamivir are ongoing and may well weigh heavily in future clinical applicability of these therapies (NCT02293863, NCT03040141 and NCT02603952).
Currently, steroid co-administration in influenza treatment is recommended against. Strong signals have emerged from retrospective propensity-matched analyses and meta-analyses of an increased mortality if steroids are included in the treatment regimen [77–79,80▪▪], in the absence of another indication, such as septic shock or a COPD exacerbation [37▪▪].
A recent Cochrane review failed to conclusively demonstrate harm, given the heterogeneity of data available, particularly the absence of an RCT, but still highlighted a strong signal of increase mortality . Moreover, there is an association between steroid administration and postinfluenza secondary infection [82,83], particularly organisms, such as Aspergillus[84,85].
As things stand in the field of influenza therapy, early empiric initiation of an enteral NAI represents the current gold standard of antiviral-directed therapy. It is the treatment choice with the strongest evidence – albeit lacking with respect to critically ill patients – and an excellent safety profile. Unfortunately, the contenders being explored for clinical practice, thus far, are hamstrung by cost, lack of evidence and emerging resistance. In the absence of another indication, it would seem prudent to avoid steroid use in influenza-infected patients, given the poorer outcomes previously demonstrated. Though there are promising developments afoot, prevention is likely better than cure and efforts to improve vaccination programmes are a potential way to overcome the relatively modest clinical effect of our current therapies.
Financial support and sponsorship
This work was supported by the Department of Intensive Care Medicine, St James's Hospital, Dublin, Ireland.
Conflicts of interest
There are no conflicts of interest.
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