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Critical care management of adults with community-acquired severe respiratory viral infection

Critical care management of adults with community-acquired severe respiratory viral infection With the expanding use of molecular assays, viral pathogens are increasingly recognized among critically ill adult patients with community-acquired severe respiratory illness; studies have detected respiratory viral infections (RVIs) in 17–53% of such patients. In addition, novel pathogens including zoonotic coronaviruses like the agents causing Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS) and the 2019 novel coronavirus (2019 nCoV ) are still being identified. Patients with severe RVIs requiring ICU care present typically with hypoxemic respiratory failure. Oseltamivir is the most widely used neuraminidase inhibitor for treatment of influenza; data sug- gest that early use is associated with reduced mortality in critically ill patients with influenza. At present, there are no antiviral therapies of proven efficacy for other severe RVIs. Several adjunctive pharmacologic interventions have been studied for their immunomodulatory effects, including macrolides, corticosteroids, cyclooxygenase-2 inhibitors, sirolimus, statins, anti-influenza immune plasma, and vitamin C, but none is recommended at present in severe RVIs. Evidence-based supportive care is the mainstay for management of severe respiratory viral infection. Non-invasive ventilation in patients with severe RVI causing acute hypoxemic respiratory failure and pneumonia is associated with a high likelihood of transition to invasive ventilation. Limited existing knowledge highlights the need for data regarding supportive care and adjunctive pharmacologic therapy that is specific for critically ill patients with severe RVI. There is a need for more pragmatic and efficient designs to test different therapeutics both individually and in combination. Keywords: Acute respiratory distress syndrome, Influenza, Neuraminidase inhibitor, Antiviral therapy, Coronavirus, Antiviral therapy Introduction severe respiratory viral infections (RVIs) include influ - enza A and B  viruses, picornaviruses (rhinovirus, enter- ovirus [e.g., enterovirus D68]), human coronaviruses With the expanding use of molecular assays, viral patho- (229E, NL63, OC43, HKU1), respiratory syncytial virus gens are increasingly detected among critically ill adult (RSV), human metapneumovirus, parainfluenza virus, patients with respiratory illness; studies have reported a and adenovirus (Tables 1 and 2). Novel pathogens includ- prevalence between 17% and 53% of patients (Table  1), ing zoonotic coronaviruses like the agents causing Severe depending on study design, sample type, duration of ill- Acute Respiratory Syndrome (SARS), Middle East Res- ness, and assay methods. Common viruses that can cause piratory Syndrome (MERS) and the 2019 novel coronavi- rus (2019 nCoV) are still being identified (Table 2). *Correspondence: Arabi@ngha.med.sa Establishing causation between viruses detected in Intensive Care Department, King Abdulaziz Medical City, P.O. Box 22490, respiratory specimens and the clinical illness is some- Riyadh 11426, Saudi Arabia Full author information is available at the end of the article times difficult, because (1) detection of some agents 316 (e.g., picornaviruses) in the upper respiratory tract may Take‑home message indicate asymptomatic or mild infection, (2) upper res- piratory tract samples may be negative despite positive Evidence-based supportive care is the mainstay for management of lower respiratory tract ones, and (3) secondary bac- severe respiratory viral infection. terial and less often fungal infections are commonly Early treatment with neuraminidase inhibitors is associated with reduced mortality in severe influenza. co-identified [1 ]. However, it is generally believed There is a need for pragmatic and efficient trial designs, to test a that most respiratory viruses by themselves can cause variety of investigational therapeutics, individually and in combina- severe illness, especially so in the elderly, persons with tion. co-morbidities (particularly immunosuppression), and occasionally in previously healthy persons, in addition 1950 patients admitted to ICUs with influenza A(H1N1) to predisposing to secondary infections [2]. pdm09, which showed a trend toward improved survival The objective of this narrative review is to out - for those treated earliest [9]. Nevertheless, the Clinical line current knowledge on the management of adults Practice Guidelines by the Infectious Diseases Society of requiring ICU admission for community-acquired America (IDSA) recommends oseltamivir for all hospital- severe acute respiratory infection (SARI) due to RVIs. ized patients with influenza, regardless of illness duration This review focuses on viral pathogens transmitted via prior to hospitalization [10]. the respiratory route. Respiratory infections with other In observational studies of critically ill patients viral pathogens, such as cytomegalovirus and herpes with influenza, higher compared to standard doses of simplex viruses, are not discussed in this review. oseltamivir did not demonstrate benefit [11–13]. An RCT of standard versus double-dose oseltamivir in hos- Antiviral therapy pitalized children and adults found no advantage with Generally available antiviral agents for different RVIs respect to virologic and clinical endpoints [14]. Addition- are summarized in Table  3 [3]. Very few randomized- ally, a study demonstrated accumulation of oseltamivir in controlled trials have been completed in patients hos- patients on both extracorporeal membrane oxygenation pitalized for severe RVIs; recently completed trials of and continuous venovenous hemodiafiltration leading to nitazoxanide in SARI patients and of the RSV inhibitor 4-to 5-fold increase in plasma levels [15]. The IDSA rec - presatovir in adult RSV patients yielded negative results ommends against the routine use of higher doses of US [4, 5]. Antiviral therapeutics for influenza have been stud - Food and Drug Administration-approved NAI drugs for ied most extensively and  are discussed briefly below. A the treatment of seasonal influenza [10]. number of other antiviral agents for influenza, RSV, and Duration of treatment is traditionally 5 days, but treat- other RVIs are advancing in clinical study [6]. Controlled ment duration is often extended to 10  days for severely studies of lopinavir/ritonavir combined with interferon- ill patients with ARDS or pneumonia or those who are beta in hospitlized MERS patients (NCT02845843) and immunocompromised [10]. This approach is supported of lopinavir/ritonavir and interferon-alpha 2b in hospital- by data showing slow influenza viral clearance from ized 2019-nCoV patients (ChiCTR2000029308)  are cur- the lower respiratory tract in critically ill patients with rently in progess. influenza A(H1N1)pdm09 [16]. Of concern is the recent observation of emergence of oseltamivir resistance in Neuraminidase inhibitors 23% of 22 critically ill A(H1N1)pdm09 patients, and its Among the neuraminidase inhibitors (NAIs), oral association with persistent virus detection and much oseltamivir is the most widely available agent. In an indi- higher mortality [17]. vidual participant data meta-analysis of hospitalized Nebulized zanamivir solution has been administered patients with influenza A(H1N1)pdm09 virus infection to mechanically ventilated patients on compassionate (n = 29 234 patients from 78 studies), NAI treatment use basis, but the commercial formulation contains lac- (almost exclusively oseltamivir) was associated with a tose and should not be used for nebulization, because its reduction in mortality compared with no treatment, use has been associated with blockage of the ventilator including in the subgroup of ICU patients. Early treat- circuit. ment (within 2  days of symptom onset) was associated Peramivir is the only intravenous influenza anti - with a reduction in mortality compared with later treat- viral agent currently approved by the US Food and ment [7]. Observational data also indicate reduction in Drug Administration (FDA). Intravenous zanamivir influenza A(H5N1)-associated mortality with timely has been recently approved by the European Medi- oseltamivir treatment before the onset of respiratory cines Agency  (EMA) (Table  3). These agents appear to failure [8]. The importance of timing of oseltamivir treat - have comparable activity to oseltamivir in hospitalized ment has been demonstrated in an observational study of 317 Table 1 Prevalence of communityacquired respiratory viral infections (RVIs) in critically ill patients Study Population Patients Samples Country Assays Overall Influenza Picorna Human Res Human Parainflu Adenovirus (N) preva viruses coronavi piratory metap enza virus lence or (rhinovirus, ruses (229E, syncytial neumovi RVI enterovirus) NL63, virus rus OC43, HKU1) Daubin IMV for > 48 h 187 TA France Viral culture, IFA, 32 (17%) Influenza A 7 (4%) Rhinovirus 19 1 (0.5%) 2 (1%) 0 (0%) 1 (0.5%) 1 (0.5%) 2006 NAAT (10%) Enterovirus 2 (1%) Cameron COPD exacerba- 105 PS Australia IFA, viral culture, 46 (43%) Influenza A 14 Rhinovirus 7 3 (3%) 7 (7%) 3 (3%) 11 (10%) 0 (0%) 2006 tion requiring NAAT, serology (13%) (7%) NIV or IMV Influenza B 6 (6%) Enterovirus 2 (2%) Schnell Acute respiratory 70, 47 (67%) PS, BAL France IFA, NAAT 34 (49%) Influenza A 11 Rhinovirus 6 5 (7%) 4 (6%) 4 (6%) 1 (1%) 3 (4%) 2014 failure mechani- (16%) (9%) cally Influenza B 2 (3%) ventilated Legoff 2005 Acute pneumonia 41 BAL France Viral culture, IFA, 13 (32%) Influenza A 7 0 (0%) 0 (0%) 2 (5%) 0 (0%) 2 (5%) 2 (5%) admitted to ICU NAAT (17%) Influenza B 1 (2%) Wiemken Severe CAP 468, 84% PS USA NAAT 106 (23%) Influenza 38 (8%) Rhinovirus 40 0 (0%0 8 (2%) 15 (3%) 4 (1%) 1 (0.2%) 2013 admitted to ICU adults (9%) Karhu 2014 Severe CAP 49 PS, BAL, Finland NAAT 24 (49%) 1 (2%) Rhinovirus 15 2 (4%) 1 (2%) 0 (0%) 1 (2%) 4 (8%) TA (30%) Enterovirus 2 (4%) Tramuto ILI admitted to 233 PS, BAL Italy NAAT 102 (44%) 57 (24%) Rhinovirus 7 11 (5%) 8 (3%) 16 (7%) 16 (7%) 0 (0%) 2016 ICU (3%) Enterovirus 14 (6%) Choi 2019 Severe CAP 1559 PS, BAL Republic NAAT Not reported 109 (7.0%) Rhinovirus 56 (4%) 52 (3%) 50 (3%) 71 (5%) Not reported admitted to ICU of Korea 120 (8%) Shorr 2018 Severe CAP and 364 sputum, USA NAAT 65 (18%) Influenza A 12 Rhinovirus/ Not reported 11 (3%) 8 (2%) 7 (2%) 6 (2%) HCAP requiring TA, BAL (3%) Enterovirus IMV Influenza B 1 20 (5%) (0.3%) Legoff 2018 Hematology 747 PS France NAAT 163 (22%) 20 (3%) 92 (12%) 22 (3%) 18 (2%) 4 (0.5%), 12 (2%) 5 (0.6%) patients admit- ted to ICU 318 influenza patients, although one RCT comparing two dose levels of intravenous zanamivir to oral oseltamivir found trends toward shorter illness duration in the subset of ICU patients given higher dose intravenous zanamivir [18]. One the other hand, one RCT failed to demonstrate a clinical benefit with intravenous peramivir in hospital - ized patients with influenza [19]. Because its spectrum of activity includes most oseltamivir-resistant viruses, intravenous zanamivir is indicated for treatment of severe influenza A or B when the patient’s influenza virus is known or suspected to be resistant to anti-influenza antivirals other than zanamivir, and/or other antivirals, including inhaled zanamivir, are not suitable (Table 3). Baloxavir Two phase III trials in non-hospitalized patients with influenza found that single-dose baloxavir was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing viral replication [20, 21]. Baloxavir is inhibitory for strains resistant to current agents. However, high frequencies of emergence of variants with reduced susceptibility have been observed during monotherapy. A double-blind RCT comparing oseltamivir to the combination of oseltami- vir and baloxavir is currently in progress in hospitalized patients (NCT03684044). Data on baloxavir’s pharma- cokinetics and optimal dose regimen in critical influenza illness leading to ICU admission are needed [20]. At pre- sent, baloxavir is approved in the US, Japan, and over ten other countries. Adjunctive pharmacologic interventions A wide variety of agents have been proposed for manag- ing immunopathologic host responses that contribute to the pathogenesis of severe RVIs [6]. As summarized below, those that have progressed to clinical study include macrolides, corticosteroids, cyclo-oxygenase2 inhibitors, mTOR inhibitors like sirolimus, statins, and high-dose vitamin C. However, until further evidence becomes available, these agents should not be used for managing severe RVIs unless there is another indication or as part of a clinical trial. Macrolides Macrolide antibiotics, due to putative anti-inflamma - tory and possible antiviral effects, have been studied in patients with RVIs but with inconsistent results. In an open-label RCT of hospitalized patients with influenza (n = 107), early combination therapy with clarithro- mycin, naproxen, and oseltamivir was associated with reduced mortality and hospital length of stay compared to oseltamivir monotherapy [22]. On the other hand, in a multicenter observational study (n = 733), macrolides Table 1 (continued) Study Population Patients Samples Country Assays Overall Influenza Picorna Human Res Human Parainflu Adenovirus (N) preva viruses coronavi piratory metap enza virus lence or (rhinovirus, ruses (229E, syncytial neumovi RVI enterovirus) NL63, virus rus OC43, HKU1) Voiriot 2016 Severe CAP 174 PS, TA, France NAAT 93 (53%) Influenza A 32 Rhinovirus/ 14 (8%) 9 (5%) 12 (7%) 3 (2%) 3 (2%) admitted to ICU BAL (18%) Influenza Enterovirus B 6 (3%) 22 (13%) Arabi 2018 Severe acute 222 PS, TA, Saudi NAAT 43 (19%) Influenza A 29 Rhinovirus 9 5 (2%) 1 (0.5%) 1 (0.5%) 1 (0.5%) 1 (0.5%) respiratory BAL Arabia (13%) Influenza (4%) infection admit- B 3 (1%) Enterovirus 0 ted to ICU (0%) Overall prevalence is reported here for influenza, picornaviruses (rhinovirus, enterovirus), human coronaviruses (229E, NL63, OC43, HKU1), respiratory syncytial virus, human metapneumovirus, parainfluenza virus, and adenovirus. Please refer to the online supplement for references. Studies varied in the approach for sampling and in the used assays; in some studies, specimen collection and assays were standardized across all patients, while in other studies, sampling and assays were performed selectively. All percentages represent % of patients; some patients had more than one viral pathogen isolated IMV invasive mechanical ventilation, TA tracheal aspirate, IFA immunofluorescence assay, NAAT (nucleic acid amplification test) includes commercial and in-house PCR, RT-PCR, and PCR multiplex, COPD chronic obstructive pulmonary disease, NIV non-invasive ventilation, PS nasopharyngeal specimen including nasopharyngeal or oropharyngeal aspirates or swabs, BAL bronchoalveolar lavage, CAP community-acquired pneumonia, ILI influenza-like illness, HCAP healthcare-associated pneumonia Multiple publications exist from the same cohort. We included the most recent one (Supplementary references) 319 Table 2 Common and uncommon community‑acquired respiratory viruses that may cause severe respiratory viral infec ‑ tion Virus Epidemiologic and clinical features Additional infection control precautions Common respiratory viruses Influenza A and influenza B Only influenza type A viruses are known to have caused pandemics Droplet Currently circulating seasonal influenza A viruses in humans: subtype A(H1N1)pdm09 and A(H3N2) strains Currently circulating influenza B viruses: A/Victoria-like, A/Yamagata-like strains May be associated with acute myocardial infarction, myocarditis, rhabdo- myolysis, acute renal failure, encephalopathy/encephalitis, and other non- pulmonary complications Picornaviruses (rhinovirus, enterovirus) Frequently detected in critically ill patients with severe acute respiratory Droplet infection. Human coronaviruses (229E, NL63, OC43, HKU1) Contact May cause severe illness in the elderly, persons with co-morbidities including Respiratory syncytial virus Contact immunosuppression. Human metapneumovirus Contact Parainfluenza (1-4) Contact Adenoviruses Droplet + contact Uncommon and emerging viruses Avian influenza A/H5N1, A/H5N6, A/H7N9 and Residence in or travel to Southeast and East Asia Airborne + contact other subtypes Exposure to poultry or visit to poultry market MERS-CoV Residence in or travel to the Arabian Peninsula Airborne + contact Exposure to dromedary camel (in endemic areas) Nosocomial transmission risk to other patients and to healthcare workers SARS-CoV No cases have been reported since 2004 Airborne + contact Nosocomial transmission risk to other patients and to healthcare workers 2019 Novel coronavirus (2019 nCoV ) As of February 4, 2020, 20630 cases were reported from China and 23 other Droplet + contact countries and wherever pos- sible airborne Measles Incomplete vaccination Airborne Characteristic rash. Progressive giant cell pneumonia without rash may occur in immunocompromised (Hecht’s pneumonia) Hantaviruses (e.g., Sin Nombre, Andes) Residence in or travel to affected areas of North, Central, or South America Standard Exposure to rodent excretions particularly when cleaning buildings Varicella-zoster virus Incomplete vaccination, pregnancy Airborne + contact Often with characteristic rash Please refer to the online supplement for references Infection control precautions are based on the Centers for Disease Control and Prevention at: https ://www.cdc.gov/infec tionc ontro l/guide lines /isola tion/appen dix/ type-durat ion-preca ution s.html#M, https ://www.cdc.gov/coron aviru s/mers/infec tion-preve ntion -contr ol.html, https ://www.cdc.gov/infec tionc ontro l/guide lines /isola tion/appen dix/stand ard-preca ution s.html, https ://www.cdc.gov/flu/profe ssion als/infec tionc ontro l/healt hcare setti ngs.htm (all accessed on Dec 10-2019) All suspected or confirmed RVIs require minimum of standard precautions. Eye protection is a reasonable addition to droplet isolation as the ocular route of infection has been documented for several common respiratory viruses Data on the novel coronavirus are based on the WHO interim report as of February 4, 2020 Other viral pathogens with respiratory routes of acquisition were not associated with improved survival in critically ill Platform Trial for Community-Acquired Pneumonia, patients with influenza A(H1N1)pdm09 [23]. In patients NCT02735707). with MERS (n = 349), macrolide therapy is not associated with a reduction in 90-day mortality or improvement in Corticosteroids MERS-CoV RNA clearance [24]. A study of clarithro- Data on the use of corticosteroids in severe RVIs are mycin combined with the cyclooxygenase inhibitor largely observational. Several studies demonstrated the flufenamic acid in hospitalized patients with influenza is association of corticosteroid use with mortality, bacterial underway (NCT03238612). In addition, macrolides are and fungal infection and the emergence of antiviral resist- also examined in one of the domains of the REMAP-CAP ance in influenza-associated pneumonia or ARDS [25]. trial (Randomized, Embedded, Multifactorial Adaptive A study (n = 607) that accounted for time-dependent 320 Table 3 Antiviral agents for communityacquired respiratory viral infections (RVIs) and relevance to critically ill patients Mechanism Target Virus Resistance Formulation Applicability to critically ill patients of action Amantadine M2 ion channel Influenza A High levels of resistance Oral Not recommended blockers Rimantadine M2 ion channel Influenza A High levels of resistance Oral Not recommended blockers Oseltamivir Neuraminidase Influenza A and B Uncommon (1-3% of Oral Needs dose adjustment in patients with renal impairment inhibitor(NAI) circulating isolates) but No dose adjustment is necessary in patients with mild to moderate hepatic impair- higher for treatment- ment emergent in critically ill Extemporaneous formulation possible or gastric delivery in intubated patients and immunocompro- mised Zanamivir NAI Influenza A and B Rare Intravenous; nebu- Inhibitory for most strains resistant to oseltamivir lized solution Nebulized formulation (investigational) with limited use in severely ill patients (investigational); Limited systemic absorption and distribution to extrapulmonary sites of inhaled inhaled dry pow- commercial product der (commercial Lactose-containing powder commercial preparation with lactose carrier should formulation) not be given nebulized as it may cause ventilator circuit obstruction Intravenous formulation similar in efficacy to oseltamivir in hospitalized patients. Intravenous zanamivir is approved by the European Medicines Agency (EMA) Peramivir NAI Influenza A and B Uncommon (see Intravenous Intravenous formulation (multiple doses) similar in efficacy to oseltamivir in hospi- oseltamivir above) talized patients Peramivir is approved by the FDA and EMA for uncomplicated influenza Laninamivir NAI Influenza A and B Rare Inhaled, single Not suitable for mechanically ventilated patients. dose, long acting Approved in Japan only Favipiravir Polymerase Influenza A, B and other RNA Not seen in clinical strains Oral Under study in hospitalized patients in combination with NAIs inhibitor (PB1 viruses Teratogenicity risk transcriptase), PK altered in critically ill with reduced drug exposure– appropriate dose regimen viral mutagen uncertain Approved only for stockpiling in Japan Baloxavir Polymerase Influenza A, B Treatment-emergence Oral Under study (multiple-dose) in combination with NAIs in hospitalized patients inhibitor (PA resistance common Not studied and PK uncertain in critically ill patients cap-dependent with monotherapy Inhibitory for strains resistant to M2Is and/or NAIs endonuclease) At present, baloxavir is approved in the US, Japan, and over eight other countries Nitazoxanide Host-directed and Influenza and other RVIs Not seen in clinical strains Oral Not effective in hospitalized SARI patients. Not recommended. influenza HA Ribavirin Host-directed RSV, influenza, measles other Not seen in clinical strains Aerosolized, oral, Aerosol formulation approved in RSV-infected children but of uncertain value. effects, RVIs intravenous All 3 formulations have been used in treating RSV-infected HSCT and SOT patients transcriptase (investigational) Anecdotal use of systemic ribavirin in severe measles and other paramyxovirus inhibitor, viral infections mutagen Not recommended in combination with interferons for MERS Teratogenicity risk Aerosol delivery presents risk of healthcare worker exposure 321 patient-level confounders found no independent influ - ence of corticosteroids on mortality of influenza [26]. The IDSA recommends against corticosteroid adjunctive therapy in patients with influenza unless clinically indi - cated for other reasons [10]. In a study of patients hospi- talized with RSV (n = 50), corticosteroid therapy was not associated with significant differences in peak viral load, duration of RSV shedding, nasal cytokines, or lympho- cyte subsets, although antibody responses to RSV were slightly blunted [27]. In one randomized-controlled trial that included 16 non-ICU SARS patients, “early” (< 7 days of illness) hydrocortisone therapy was associated with a higher subsequent plasma viral load [28]. In a study on MERS patients (n = 309), corticosteroid therapy was not associated with significant change in 90-day mortality after adjustment for time-varying confounders, but was associated with delayed MERS-CoV RNA clearance [29]. Cyclooxygenase‑2 inhibitors Cyclooxygenase-2 may modulate excessive pro-inflam - matory responses in severe influenza [30]. In addition to the above study of naproxen–clarithromycin added to oseltamivir [23], preliminary results from a RCT (n = 120) showed that the combination of celecoxib-oseltamivir compared to oseltamivir alone reduced mortality and cytokine levels, although not viral titers, in hospitalized influenza A(H3N2) patients without increased adverse effects [31]. Sirolimus Inhibitors of the mTOR pathway like sirolimus com- bined with oseltamivir have shown inconsistent effects in murine models of severe influenza [32, 33]. Sirolimus also can modulate inflammatory responses through its immunosuppressive properties [34]. In a small RCT (n = 28), treatment with sirolimus compared to no siroli- mus in patients with influenza A(H1N1) pneumonia receiving invasive mechanical ventilation (in addition to oseltamivir and corticosteroids) resulted in improvement in hypoxia, multiple organ dysfunction and virus clear- ance, and in shorter duration of mechanical ventilation [34]. Further study of sirolimus without systemic corti- costeroids is planned among patients hospitalized with influenza (NCT03901001). Statins Because of the putative anti-inflammatory effects, statins have been proposed as adjunctive therapy in influenza (NCT02056340), although large clinical trials in patients in ARDS have not demonstrated clinical benefit [35]. A secondary analysis of data from RCTs using latent class analysis suggested that patients with ARDS may be clas- sified into hyper-inflammatory and hypo-inflammatory Table 3 (continued) Mechanism Target Virus Resistance Formulation Applicability to critically ill patients of action Cidofovir DNA polymerase Adenovirus Intravenous Anecdotal use in severe adenovirus infections and in immunocompromised inhibitor patients Acyclovir DNA polymerase VZV, HSV Uncommon except in Intravenous, oral Intravenous recommended in VZV pneumonia; addition of systemic corticoster- inhibitor immunocompromised oids recommended by some experts Please refer to the online supplement for references SARI severe acute respiratory infection, RSV respiratory syncytial virus, HSCT hematopoietic stem-cell transplantation, SOT solid-organ transplantation, MERS Middle East Respiratory Syndrome, VZV varicella-zoster virus, HSV herpes simplex virus, NAI neuraminidase inhibitors, EMA European Medicines Agency, FDA Food and Drug Agency 322 subphenotypes, and treatment with simvastatin com- with influenza pneumonia and can be especially virulent pared to placebo was associated with improved survival [10]. The recent 2019 ATS/IDSA clinical practice guide - in the hyper-inflammatory but not in the hypo-inflam - lines recommend standard antibacterial therapy to be matory subphenotype [36]. Further studies are needed initially prescribed for adults with community-acquired to examine whether adjunctive pharmacologic interven- pneumonia who test positive for influenza [10]. The tions would be beneficial in targeted subphenotypes of guidelines provide details on when to consider empiric severe RVI. therapy for methicillin resistant Staphylococcus aureus and Pseudomonas aeruginosa and provide guidance for de-escalation of antibacterial therapy in patients with Immune therapy confirmed influenza [10]. Clinicians should be aware Studies in which various antibody immunotherapies of the reports of invasive pulmonary aspergillosis in have been added to neuraminidase inhibitor treatment severely ill influenza patients especially those with under - in hospitalized influenza patients have yielded incon - lying conditions or receiving corticosteroids, although up sistent results. A small randomized-controlled trial to 30% of patients with influenza-associated aspergillosis (n = 35) demonstrated that treatment of severe influenza had been previously healthy [41]. A(H1N1)pdm09 patients with hyperimmune globulin (H-IVIG) containing high titers of virus-specific neu - Supportive care tralizing antibodies within 5 days of symptom onset was Patients with severe RVI present typically with pneumo- associated with a lower viral load and reduced mortality nia, acute respiratory distress syndrome (ARDS), decom- compared to low-titer IVIG [37]. Two recent phase III pensated heart failure, or exacerbation of chronic lung trials have been completed in seasonal influenza patients. disease; leading frequently to acute hypoxemic, and less The FLU-IVIG RCT found no overall effect of anti-influ - commonly hypercapnic, respiratory failure. Except for enza hyperimmune IVIG compared to placebo on the several influenza and novel coronavirus studies noted primary outcome measured by a six-point ordinal scale below, most of the data regarding supportive care strat- of clinical status on day 7, although antiviral and clini- egies come from studies that have not documented spe- cal benefits were noted in the subgroup of patients with cific RVIs. In many ARDS trials, patients with pneumonia influenza B virus infection [38]. The second trial of high- constituted a majority of enrolled patients; but detailed titer versus low-titer anti-influenza immune plasma was description of etiologic pathogens is often lacking. Given terminated for futility because of the lack of effect on the the high prevalence of viral pathogens as outlined ear- same primary outcome [39]. A placebo-controlled, rand- lier, it is likely that severe RVIs constitute a considerable omized trial of the anti-hemagglutinin stem monoclonal proportion. There are general pathophysiologic and clini - antibody MHAA4549A did not demonstrate benefit over cal similarities between ARDS and pneumonia caused oseltamivir alone [6]. The results from these recent trials by severe RVIs and those due to other pathogens or eti- suggest that polyclonal antibody therapies may not sig- ologies, and therefore, the extrapolation of findings from nificantly improve outcomes in severe seasonal influenza unselected populations to patients with severe RVIs can A, although their possible value in treating severe RVI by be justified in the absence of specific data. At the same novel influenza strains remains to be determined. time, there are important differences that may lead to heterogeneity in response to treatment. Vitamin C The recent CITRIS-ALI trial demonstrated that 96-h infusion of vitamin C compared with placebo in a rela- Non‑invasive ventilation tively small number (n = 167) of patients with sepsis and Data on non-invasive ventilation (NIV) in severe RVI are ARDS did not improve the primary outcome of organ limited. In patients with severe RVI resulting in chronic dysfunction scores or alter markers of inflammation and obstructive pulmonary disease (COPD) exacerbations vascular injury. However, mortality, which was one of the or cardiogenic pulmonary edema, NIV may be effec - forty-six pre-specified secondary endpoints, was signifi - tive in reducing the need of endotracheal intubation and cantly lower with vitamin C [40]. Results of other ongo- decreasing ventilator-associated complications and mor- ing larger trials are awaited, and data on severe RVI are tality [42]. needed. However, NIV in patients with severe RVI causing acute hypoxemic respiratory failure and pneumonia is Antibacterial therapy of uncertain benefit. Observational studies reported Co-infections with bacterial pathogens occur often with variable results for NIV in patients with severe influenza RVI. Co-infection with Staphylococcus aureus is common A(H1N1)pdm09 with some reporting NIV failure in up 323 to 85% [43]. In one multicenter observational study of strategy with low tidal volumes (6  ml/kg predicted body 1898 critically ill patients with acute hypoxemic respira- weight) and plateau pressures < 30 to 35 cmH O. In adults tory failure due to influenza, 806 underwent initial NIV, with acute lung injury or ARDS due to various causes, an and 56.8% of them required conversion to invasive ven- individual patient data meta-analysis of 2299 patients tilation. Patients with SOFA ≥ 5 had a higher risk of NIV from three trials (50% with pneumonia) found that higher failure. Similar to other studies, NIV failure was associ- positive end-expiratory pressure (PEEP) levels were asso- ated with increased ICU mortality compared with inva- ciated with improved survival among the subgroup of sive mechanical ventilation [44]. patients with ARDS (defined by PaO /FiO ≤ 200 mmHg) 2 2 Data from uncontrolled studies suggested that NIV [51]. A recent RCT of over 1000 patients with moderate- might have been effective and safe in the management of to-severe ARDS (55% with pneumonia) demonstrated some patients with SARS [45], while others highlighted that prolonged and high-pressure recruitment maneu- concerns of increased SARS transmission risk to health- vers was associated with increased 28-day mortality [52]. care workers [46]. In a multicenter cohort of 302 MERS Titration of PEEP to achieve optimal oxygenation, per- critically ill patients, NIV was used initially in 35% of haps without aggressive recruitment maneuvers, remains patients, but the vast majority of them (92.4%) required a reasonable strategy for most patients. conversion to invasive mechanical ventilation; however, NIV was not independently associated with 90-day mor- High‑frequency oscillatory ventilation (HFOV) tality [47]. HFOV ventilates the lung with tidal volumes lower than A recent single-center RCT in patients with unselected anatomical dead space while achieving relatively high patients with ARDS (n = 83, 45% pneumonia) showed mean airway pressures [53]. In patients with influenza that treatment with helmet NIV resulted in significant A(H1N1)pdm09 influenza, HFOV has been used as a reduction of intubation rates and in 90-day mortal- rescue therapy for those not responding to conventional ity [48]. Further studies in patients with severe RVI are ventilation [53]. Two randomized clinical trials showed needed, as helmet NIV may be more effective than tra - that HFOV in moderate-to-severe ARDS was not associ- ditional masks and may be associated with less risk of ated with improved outcomes compared to conventional transmission due to aerosol generation. ventilation [54, 55]. However, a meta-analysis of 1552 Based on available evidence, NIV in severe RVI may be patients (55% with pneumonia) found that the HFOV used in selected patients in early stages and milder forms treatment effect depended on baseline severity of hypox - of acute hypoxemic respiratory failure, excluding those emia, with harm  among patients with mild-moderate in shock or multiorgan failure, with the recognition that ARDS but possibly decreased mortality in patients with for patients who do not show signs of early recovery, NIV very severe ARDS [56].  Therefore, while HFOV is not may well delay but not avoid invasive ventilation [42]. recommended for routine use in ARDS, there may still be a role as rescue therapy [53]. High‑flow nasal cannula Prone positioning High-flow nasal cannula has emerged as an alternative to A multicenter RCT (n = 474, 60% with pneumonia) dem- NIV to prevent intubation in patients with acute hypox- onstrated that early application of prone positioning emic respiratory failure. In one trial (n = 310, 72% com- (at least 16  h per session) in patients with severe ARDS munity-acquired pneumonia), treatment with high-flow (PaO /FiO < 150 mmHg, with an F iO ≥ 0.6, PEEP of ≥ 5 2 2 2 oxygen, standard oxygen, or NIV did not result in sig- cmH O, and a tidal volume close to 6  ml/kg predicted nificantly different intubation rates; however, there was body weight) resulted in decreased mortality [57]. Prone a significant difference in favor of high-flow nasal can - positioning in patients with avian A(H7N9) influenza- nula in 90-day mortality [49]. A small cohort of patients related severe ARDS has been associated with improved with severe RVI with influenza A(H1N1)pdm09 (n = 25) oxygenation, sustained after returning to a supine posi- showed that high-flow nasal cannula was associated with tion, and with decreased carbon dioxide retention [58]. avoidance of intubation in 45% of patients, although almost all patients with higher severity of illness and Neuromuscular blockers shock were eventually intubated [50]. In patients with severe ARDS, in one trial (n = 339, 38% community-acquired pneumonia), early administration of a neuromuscular blocking agent improved the adjusted Invasive ventilation 90-day survival and increased the time off the ventila - Based on current evidence, patients with ARDS due to tor without increasing muscle weakness [59]. How- severe RVI should be managed with lung-protective ever, in a recent larger trial that enrolled patients with 324 mortality and may sometimes require ECMO or other moderate-to-severe ARDS (n = 1006, 59% pneumonia), types of supportive care [69, 70]. treated with a strategy involving high PEEP, there was no significant difference in mortality at 90 days between Infection prevention and control patients who received an early, continuous cisatracurium Table  2 summarizes infection control precautions for infusion and those who were treated with a usual-care different RVIs as recommended by the Centers for Dis - approach with lighter sedation targets [60]. Specific data ease Control and Prevention (please refer to Table 2 foot- on neuromuscular blockade in severe RVI are lacking. note for CDC references). In patients presenting with severe RVIs, contact plus droplet precautions are rec- Extracorporeal membrane oxygenation (ECMO) ommended; droplet precautions may be discontinued The latest RCT for ECMO (EOLIA) included 249 patients when adenovirus and influenza have been ruled out. For with severe ARDS, 18% with viral etiologies, and found patients with a history of recent travel (10–21  days) to that ECMO did not reduce mortality at day 60 [61]. Yet, countries with active outbreaks of SARS, MERS, or avian a post hoc Bayesian analysis found that the interpreta influenza, airborne plus contact precautions and eye pro - tion of benefit versus no benefit in this trial is critically tection are recommended. dependent upon the range of prior assumptions reflect Aerosol-generating procedures, such as bronchoscopy, ing varying degrees of skepticism and enthusiasm of pre- endotracheal intubation, and open suctioning of the res- vious evidence for the benefit of ECMO—clinicians with piratory tract, tracheotomy, manual ventilation before more enthusiasm for the benefit of ECMO may be justi intubation, nebulizer treatment, high-flow nasal cannula, fied in considering it for certain patients [62]. non-invasive ventilation, and chest compressions, have Indeed, observational studies reported lower hospital been implicated with transmission of infectious agents mortality among patients with ARDS related to influ to healthcare personnel. However, these findings were enza A(H1N1)pdm09 with transfer to an ECMO center identified from limited studies, mainly during the SARS compared with matched non-ECMO-referred patients outbreak [71]. Nevertheless, it is recommended dur- [63]. A case–control study also suggested survival benefit ing aerosol-generating procedures on patients with sus- for ECMO in patients with severe MERS [64]. ECMO is pected or proven infections transmitted by aerosols (for likely to be associated with better outcomes when used example influenza, MERS, SARS) to wear a fit-tested N95 among patients with limited organ failures and good pre mask in addition to gloves, gown, and face/eye protec- morbid functional status, and should be considered for tion. Closed-circuit suctioning may reduce the exposure patients who fail other evidence-based oxygenation strat to aerosols. Performing these procedures in an airborne egies according to individual patient characteristics and a isolation room when feasible is recommended. potential risk–benefit determination. RCTs comparing N95 respirators to medical masks in health care personnel working in outpatient and ward Cardiovascular management settings have not shown significant differences in pro - Timely adequate fluid resuscitation is an essential ele - tection from laboratory-confirmed influenza or other ment of the management of patients with severe RVI RVIs [72, 73]. The relevance of these observations to and shock. However, in those with ARDS (n = 1000, 47% the ICU setting is uncertain, given the frequent use of pneumonia), a conservative strategy of fluid manage aerosol-generating procedures in critically ill patients. ment improved lung function and shortened the duration Cloth masks are clearly inferior to medical masks in pro- of mechanical ventilation without increasing non-pul tecting HCWs from RVIs [74]. Other aspects of preven- monary-organ failures [65]. In addition, aggressive fluid tion strategies to prevent transmission when caring for administration may worsen ventricular function. This patients with severe RVIs include annual influenza vac - may be particularly relevant for patients with severe RVI. cination of healthcare workers, adherence to standard Myocardial involvement is not uncommon with severe precautions, including hand hygiene, during the care of influenza A or B virus infection, and multiple studies any patient and appropriate management of ill healthcare have shown an association between influenza and acute workers (please refer to Table  2 footnote for CDC refer- myocardial infection and myocarditis [66–68]. Echocar ences). Recently, antiseptic hand rubbing using ethanol- diographic findings often include right- and left-ventric - based disinfectants (EBDs) was found to be less effective ular dysfunction [66]. Therefore, clinical assessment of than hand washing with running water in inactivating fluid responsiveness is important along with quantifica influenza virus in undried mucus under experimental tion of right- and left-ventricular size and function using conditions; [75] also nonenveloped viruses like adenovi- echocardiography and/or dynamic minimally invasive rus which are not easily inactivated by EBDs. The impli - cardiovascular monitoring, if available. Myocarditis has cations of these observations for clinical practice remain associated with longer duration of vasoactive agents and 325 to be determined but hand washing with soap and water Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- or hand rubbing with EBD for longer than 30  s may be lished maps and institutional affiliations. warranted. 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Depart- Keijzers G, Khalili H, Knight M, Kudo K, Kusznierz G, Kuzman I, Kwan AM, ment of Medicine, Division of Infectious Diseases and International Health, Amine IL, Langenegger E, Lankarani KB, Leo YS, Linko R, Liu P, Madanat University of Virginia School of Medicine, Charlottesville, VA, USA. F, Mayo-Montero E, McGeer A, Memish Z, Metan G, Mickiene A, Mikic D, Mohn KG, Moradi A, Nymadawa P, Oliva ME, Ozkan M, Parekh D, Paul M, Funding Polack FP, Rath BA, Rodriguez AH, Sarrouf EB, Seale AC, Sertogullarindan B, None. Siqueira MM, Skret-Magierlo J, Stephan F, Talarek E, Tang JW, To KK, Torres A, Torun SH, Tran D, Uyeki TM, Van Zwol A, Vaudry W, Vidmar T, Yokota RT, Compliance with ethical standards Zarogoulidis P, Investigators PC, Nguyen-Van-Tam JS (2014) Eec ff tiveness of neuraminidase inhibitors in reducing mortality in patients admitted to Conflicts of interest hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of Dr. Arabi is the principal investigator on a clinical trial for lopinavir/ritonavir individual participant data. Lancet Respir Med 2:395–404 and interferon in Middle East respiratory syndrome (MERS) and that he was a 8. Adisasmito W, Chan PK, Lee N, Oner AF, Gasimov V, Aghayev F, Zaman non-paid consultant on antiviral active for MERS-coronavirus (CoV ) for Gilead M, Bamgboye E, Dogan N, Coker R, Starzyk K, Dreyer NA, Toovey S (2010) Sciences and SAB Biotherapeutics. Dr. Hayden’s institution received funding Eec ff tiveness of antiviral treatment in human influenza A(H5N1) infec- from GlaxoSmithKline (Data Safety Monitoring Board [DSMB] member for tions: analysis of a Global Patient Registry. J Infect Dis 202:1154–1160 influenza randomized-controlled trial [RCT ]), Celltrion (DSMB chair for influ- 9. Louie JK, Yang S, Acosta M, Yen C, Samuel MC, Schechter R, Guevara H, enza RCT ), and Vaccitech (DSMB chair for influenza RCTs); he received hono - Uyeki TM (2012) Treatment with neuraminidase inhibitors for critically ill raria from World Health Organization (consultant on influenza and emerging patients with influenza A (H1N1)pdm09. Clin Infect Dis 55:1198–1204 viral infections) and the University of Alabama (Scientific Advisory Board 10. Uyeki TM, Bernstein HH, Bradley JS, Englund JA, File TM, Fry AM, Graven- member for National Institutes of Health-sponsored Antiviral Discovery and stein S, Hayden FG, Harper SA, Hirshon JM, Ison MG, Johnston BL, Knight Development Consortium); he disclosed that he has been a non-paid consult- SL, McGeer A, Riley LE, Wolfe CR, Alexander PE, Pavia AT (2019) Clinical ant on antivirals active for MERS-CoV for Gilead Sciences, SAB Biotherapeutics, practice guidelines by the infectious diseases society of America: 2018 and Regeneron, and for multiple companies on influenza therapeutics; Cidara, update on diagnosis, treatment, chemoprophylaxis, and institutional Shionogi, Seqirus, and resTORbio have made charitable contributions to the outbreak management of seasonal influenzaa. Clin Infect Dis 68:895–902 Ford Haitian Orphanage and School for his consulting time; Shionogi and 11. 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Kwong JC, Schwartz KL, Campitelli MA, Chung H, Crowcroft NS, Karnau- chow T, Katz K, Ko DT, McGeer AJ, McNally D, Richardson DC, Rosella LC, http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Intensive Care Medicine Pubmed Central

Critical care management of adults with community-acquired severe respiratory viral infection

Intensive Care Medicine , Volume 46 (2) – Feb 10, 2020

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© Springer-Verlag GmbH Germany, part of Springer Nature 2020
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10.1007/s00134-020-05943-5
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Abstract

With the expanding use of molecular assays, viral pathogens are increasingly recognized among critically ill adult patients with community-acquired severe respiratory illness; studies have detected respiratory viral infections (RVIs) in 17–53% of such patients. In addition, novel pathogens including zoonotic coronaviruses like the agents causing Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS) and the 2019 novel coronavirus (2019 nCoV ) are still being identified. Patients with severe RVIs requiring ICU care present typically with hypoxemic respiratory failure. Oseltamivir is the most widely used neuraminidase inhibitor for treatment of influenza; data sug- gest that early use is associated with reduced mortality in critically ill patients with influenza. At present, there are no antiviral therapies of proven efficacy for other severe RVIs. Several adjunctive pharmacologic interventions have been studied for their immunomodulatory effects, including macrolides, corticosteroids, cyclooxygenase-2 inhibitors, sirolimus, statins, anti-influenza immune plasma, and vitamin C, but none is recommended at present in severe RVIs. Evidence-based supportive care is the mainstay for management of severe respiratory viral infection. Non-invasive ventilation in patients with severe RVI causing acute hypoxemic respiratory failure and pneumonia is associated with a high likelihood of transition to invasive ventilation. Limited existing knowledge highlights the need for data regarding supportive care and adjunctive pharmacologic therapy that is specific for critically ill patients with severe RVI. There is a need for more pragmatic and efficient designs to test different therapeutics both individually and in combination. Keywords: Acute respiratory distress syndrome, Influenza, Neuraminidase inhibitor, Antiviral therapy, Coronavirus, Antiviral therapy Introduction severe respiratory viral infections (RVIs) include influ - enza A and B  viruses, picornaviruses (rhinovirus, enter- ovirus [e.g., enterovirus D68]), human coronaviruses With the expanding use of molecular assays, viral patho- (229E, NL63, OC43, HKU1), respiratory syncytial virus gens are increasingly detected among critically ill adult (RSV), human metapneumovirus, parainfluenza virus, patients with respiratory illness; studies have reported a and adenovirus (Tables 1 and 2). Novel pathogens includ- prevalence between 17% and 53% of patients (Table  1), ing zoonotic coronaviruses like the agents causing Severe depending on study design, sample type, duration of ill- Acute Respiratory Syndrome (SARS), Middle East Res- ness, and assay methods. Common viruses that can cause piratory Syndrome (MERS) and the 2019 novel coronavi- rus (2019 nCoV) are still being identified (Table 2). *Correspondence: Arabi@ngha.med.sa Establishing causation between viruses detected in Intensive Care Department, King Abdulaziz Medical City, P.O. Box 22490, respiratory specimens and the clinical illness is some- Riyadh 11426, Saudi Arabia Full author information is available at the end of the article times difficult, because (1) detection of some agents 316 (e.g., picornaviruses) in the upper respiratory tract may Take‑home message indicate asymptomatic or mild infection, (2) upper res- piratory tract samples may be negative despite positive Evidence-based supportive care is the mainstay for management of lower respiratory tract ones, and (3) secondary bac- severe respiratory viral infection. terial and less often fungal infections are commonly Early treatment with neuraminidase inhibitors is associated with reduced mortality in severe influenza. co-identified [1 ]. However, it is generally believed There is a need for pragmatic and efficient trial designs, to test a that most respiratory viruses by themselves can cause variety of investigational therapeutics, individually and in combina- severe illness, especially so in the elderly, persons with tion. co-morbidities (particularly immunosuppression), and occasionally in previously healthy persons, in addition 1950 patients admitted to ICUs with influenza A(H1N1) to predisposing to secondary infections [2]. pdm09, which showed a trend toward improved survival The objective of this narrative review is to out - for those treated earliest [9]. Nevertheless, the Clinical line current knowledge on the management of adults Practice Guidelines by the Infectious Diseases Society of requiring ICU admission for community-acquired America (IDSA) recommends oseltamivir for all hospital- severe acute respiratory infection (SARI) due to RVIs. ized patients with influenza, regardless of illness duration This review focuses on viral pathogens transmitted via prior to hospitalization [10]. the respiratory route. Respiratory infections with other In observational studies of critically ill patients viral pathogens, such as cytomegalovirus and herpes with influenza, higher compared to standard doses of simplex viruses, are not discussed in this review. oseltamivir did not demonstrate benefit [11–13]. An RCT of standard versus double-dose oseltamivir in hos- Antiviral therapy pitalized children and adults found no advantage with Generally available antiviral agents for different RVIs respect to virologic and clinical endpoints [14]. Addition- are summarized in Table  3 [3]. Very few randomized- ally, a study demonstrated accumulation of oseltamivir in controlled trials have been completed in patients hos- patients on both extracorporeal membrane oxygenation pitalized for severe RVIs; recently completed trials of and continuous venovenous hemodiafiltration leading to nitazoxanide in SARI patients and of the RSV inhibitor 4-to 5-fold increase in plasma levels [15]. The IDSA rec - presatovir in adult RSV patients yielded negative results ommends against the routine use of higher doses of US [4, 5]. Antiviral therapeutics for influenza have been stud - Food and Drug Administration-approved NAI drugs for ied most extensively and  are discussed briefly below. A the treatment of seasonal influenza [10]. number of other antiviral agents for influenza, RSV, and Duration of treatment is traditionally 5 days, but treat- other RVIs are advancing in clinical study [6]. Controlled ment duration is often extended to 10  days for severely studies of lopinavir/ritonavir combined with interferon- ill patients with ARDS or pneumonia or those who are beta in hospitlized MERS patients (NCT02845843) and immunocompromised [10]. This approach is supported of lopinavir/ritonavir and interferon-alpha 2b in hospital- by data showing slow influenza viral clearance from ized 2019-nCoV patients (ChiCTR2000029308)  are cur- the lower respiratory tract in critically ill patients with rently in progess. influenza A(H1N1)pdm09 [16]. Of concern is the recent observation of emergence of oseltamivir resistance in Neuraminidase inhibitors 23% of 22 critically ill A(H1N1)pdm09 patients, and its Among the neuraminidase inhibitors (NAIs), oral association with persistent virus detection and much oseltamivir is the most widely available agent. In an indi- higher mortality [17]. vidual participant data meta-analysis of hospitalized Nebulized zanamivir solution has been administered patients with influenza A(H1N1)pdm09 virus infection to mechanically ventilated patients on compassionate (n = 29 234 patients from 78 studies), NAI treatment use basis, but the commercial formulation contains lac- (almost exclusively oseltamivir) was associated with a tose and should not be used for nebulization, because its reduction in mortality compared with no treatment, use has been associated with blockage of the ventilator including in the subgroup of ICU patients. Early treat- circuit. ment (within 2  days of symptom onset) was associated Peramivir is the only intravenous influenza anti - with a reduction in mortality compared with later treat- viral agent currently approved by the US Food and ment [7]. Observational data also indicate reduction in Drug Administration (FDA). Intravenous zanamivir influenza A(H5N1)-associated mortality with timely has been recently approved by the European Medi- oseltamivir treatment before the onset of respiratory cines Agency  (EMA) (Table  3). These agents appear to failure [8]. The importance of timing of oseltamivir treat - have comparable activity to oseltamivir in hospitalized ment has been demonstrated in an observational study of 317 Table 1 Prevalence of communityacquired respiratory viral infections (RVIs) in critically ill patients Study Population Patients Samples Country Assays Overall Influenza Picorna Human Res Human Parainflu Adenovirus (N) preva viruses coronavi piratory metap enza virus lence or (rhinovirus, ruses (229E, syncytial neumovi RVI enterovirus) NL63, virus rus OC43, HKU1) Daubin IMV for > 48 h 187 TA France Viral culture, IFA, 32 (17%) Influenza A 7 (4%) Rhinovirus 19 1 (0.5%) 2 (1%) 0 (0%) 1 (0.5%) 1 (0.5%) 2006 NAAT (10%) Enterovirus 2 (1%) Cameron COPD exacerba- 105 PS Australia IFA, viral culture, 46 (43%) Influenza A 14 Rhinovirus 7 3 (3%) 7 (7%) 3 (3%) 11 (10%) 0 (0%) 2006 tion requiring NAAT, serology (13%) (7%) NIV or IMV Influenza B 6 (6%) Enterovirus 2 (2%) Schnell Acute respiratory 70, 47 (67%) PS, BAL France IFA, NAAT 34 (49%) Influenza A 11 Rhinovirus 6 5 (7%) 4 (6%) 4 (6%) 1 (1%) 3 (4%) 2014 failure mechani- (16%) (9%) cally Influenza B 2 (3%) ventilated Legoff 2005 Acute pneumonia 41 BAL France Viral culture, IFA, 13 (32%) Influenza A 7 0 (0%) 0 (0%) 2 (5%) 0 (0%) 2 (5%) 2 (5%) admitted to ICU NAAT (17%) Influenza B 1 (2%) Wiemken Severe CAP 468, 84% PS USA NAAT 106 (23%) Influenza 38 (8%) Rhinovirus 40 0 (0%0 8 (2%) 15 (3%) 4 (1%) 1 (0.2%) 2013 admitted to ICU adults (9%) Karhu 2014 Severe CAP 49 PS, BAL, Finland NAAT 24 (49%) 1 (2%) Rhinovirus 15 2 (4%) 1 (2%) 0 (0%) 1 (2%) 4 (8%) TA (30%) Enterovirus 2 (4%) Tramuto ILI admitted to 233 PS, BAL Italy NAAT 102 (44%) 57 (24%) Rhinovirus 7 11 (5%) 8 (3%) 16 (7%) 16 (7%) 0 (0%) 2016 ICU (3%) Enterovirus 14 (6%) Choi 2019 Severe CAP 1559 PS, BAL Republic NAAT Not reported 109 (7.0%) Rhinovirus 56 (4%) 52 (3%) 50 (3%) 71 (5%) Not reported admitted to ICU of Korea 120 (8%) Shorr 2018 Severe CAP and 364 sputum, USA NAAT 65 (18%) Influenza A 12 Rhinovirus/ Not reported 11 (3%) 8 (2%) 7 (2%) 6 (2%) HCAP requiring TA, BAL (3%) Enterovirus IMV Influenza B 1 20 (5%) (0.3%) Legoff 2018 Hematology 747 PS France NAAT 163 (22%) 20 (3%) 92 (12%) 22 (3%) 18 (2%) 4 (0.5%), 12 (2%) 5 (0.6%) patients admit- ted to ICU 318 influenza patients, although one RCT comparing two dose levels of intravenous zanamivir to oral oseltamivir found trends toward shorter illness duration in the subset of ICU patients given higher dose intravenous zanamivir [18]. One the other hand, one RCT failed to demonstrate a clinical benefit with intravenous peramivir in hospital - ized patients with influenza [19]. Because its spectrum of activity includes most oseltamivir-resistant viruses, intravenous zanamivir is indicated for treatment of severe influenza A or B when the patient’s influenza virus is known or suspected to be resistant to anti-influenza antivirals other than zanamivir, and/or other antivirals, including inhaled zanamivir, are not suitable (Table 3). Baloxavir Two phase III trials in non-hospitalized patients with influenza found that single-dose baloxavir was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing viral replication [20, 21]. Baloxavir is inhibitory for strains resistant to current agents. However, high frequencies of emergence of variants with reduced susceptibility have been observed during monotherapy. A double-blind RCT comparing oseltamivir to the combination of oseltami- vir and baloxavir is currently in progress in hospitalized patients (NCT03684044). Data on baloxavir’s pharma- cokinetics and optimal dose regimen in critical influenza illness leading to ICU admission are needed [20]. At pre- sent, baloxavir is approved in the US, Japan, and over ten other countries. Adjunctive pharmacologic interventions A wide variety of agents have been proposed for manag- ing immunopathologic host responses that contribute to the pathogenesis of severe RVIs [6]. As summarized below, those that have progressed to clinical study include macrolides, corticosteroids, cyclo-oxygenase2 inhibitors, mTOR inhibitors like sirolimus, statins, and high-dose vitamin C. However, until further evidence becomes available, these agents should not be used for managing severe RVIs unless there is another indication or as part of a clinical trial. Macrolides Macrolide antibiotics, due to putative anti-inflamma - tory and possible antiviral effects, have been studied in patients with RVIs but with inconsistent results. In an open-label RCT of hospitalized patients with influenza (n = 107), early combination therapy with clarithro- mycin, naproxen, and oseltamivir was associated with reduced mortality and hospital length of stay compared to oseltamivir monotherapy [22]. On the other hand, in a multicenter observational study (n = 733), macrolides Table 1 (continued) Study Population Patients Samples Country Assays Overall Influenza Picorna Human Res Human Parainflu Adenovirus (N) preva viruses coronavi piratory metap enza virus lence or (rhinovirus, ruses (229E, syncytial neumovi RVI enterovirus) NL63, virus rus OC43, HKU1) Voiriot 2016 Severe CAP 174 PS, TA, France NAAT 93 (53%) Influenza A 32 Rhinovirus/ 14 (8%) 9 (5%) 12 (7%) 3 (2%) 3 (2%) admitted to ICU BAL (18%) Influenza Enterovirus B 6 (3%) 22 (13%) Arabi 2018 Severe acute 222 PS, TA, Saudi NAAT 43 (19%) Influenza A 29 Rhinovirus 9 5 (2%) 1 (0.5%) 1 (0.5%) 1 (0.5%) 1 (0.5%) respiratory BAL Arabia (13%) Influenza (4%) infection admit- B 3 (1%) Enterovirus 0 ted to ICU (0%) Overall prevalence is reported here for influenza, picornaviruses (rhinovirus, enterovirus), human coronaviruses (229E, NL63, OC43, HKU1), respiratory syncytial virus, human metapneumovirus, parainfluenza virus, and adenovirus. Please refer to the online supplement for references. Studies varied in the approach for sampling and in the used assays; in some studies, specimen collection and assays were standardized across all patients, while in other studies, sampling and assays were performed selectively. All percentages represent % of patients; some patients had more than one viral pathogen isolated IMV invasive mechanical ventilation, TA tracheal aspirate, IFA immunofluorescence assay, NAAT (nucleic acid amplification test) includes commercial and in-house PCR, RT-PCR, and PCR multiplex, COPD chronic obstructive pulmonary disease, NIV non-invasive ventilation, PS nasopharyngeal specimen including nasopharyngeal or oropharyngeal aspirates or swabs, BAL bronchoalveolar lavage, CAP community-acquired pneumonia, ILI influenza-like illness, HCAP healthcare-associated pneumonia Multiple publications exist from the same cohort. We included the most recent one (Supplementary references) 319 Table 2 Common and uncommon community‑acquired respiratory viruses that may cause severe respiratory viral infec ‑ tion Virus Epidemiologic and clinical features Additional infection control precautions Common respiratory viruses Influenza A and influenza B Only influenza type A viruses are known to have caused pandemics Droplet Currently circulating seasonal influenza A viruses in humans: subtype A(H1N1)pdm09 and A(H3N2) strains Currently circulating influenza B viruses: A/Victoria-like, A/Yamagata-like strains May be associated with acute myocardial infarction, myocarditis, rhabdo- myolysis, acute renal failure, encephalopathy/encephalitis, and other non- pulmonary complications Picornaviruses (rhinovirus, enterovirus) Frequently detected in critically ill patients with severe acute respiratory Droplet infection. Human coronaviruses (229E, NL63, OC43, HKU1) Contact May cause severe illness in the elderly, persons with co-morbidities including Respiratory syncytial virus Contact immunosuppression. Human metapneumovirus Contact Parainfluenza (1-4) Contact Adenoviruses Droplet + contact Uncommon and emerging viruses Avian influenza A/H5N1, A/H5N6, A/H7N9 and Residence in or travel to Southeast and East Asia Airborne + contact other subtypes Exposure to poultry or visit to poultry market MERS-CoV Residence in or travel to the Arabian Peninsula Airborne + contact Exposure to dromedary camel (in endemic areas) Nosocomial transmission risk to other patients and to healthcare workers SARS-CoV No cases have been reported since 2004 Airborne + contact Nosocomial transmission risk to other patients and to healthcare workers 2019 Novel coronavirus (2019 nCoV ) As of February 4, 2020, 20630 cases were reported from China and 23 other Droplet + contact countries and wherever pos- sible airborne Measles Incomplete vaccination Airborne Characteristic rash. Progressive giant cell pneumonia without rash may occur in immunocompromised (Hecht’s pneumonia) Hantaviruses (e.g., Sin Nombre, Andes) Residence in or travel to affected areas of North, Central, or South America Standard Exposure to rodent excretions particularly when cleaning buildings Varicella-zoster virus Incomplete vaccination, pregnancy Airborne + contact Often with characteristic rash Please refer to the online supplement for references Infection control precautions are based on the Centers for Disease Control and Prevention at: https ://www.cdc.gov/infec tionc ontro l/guide lines /isola tion/appen dix/ type-durat ion-preca ution s.html#M, https ://www.cdc.gov/coron aviru s/mers/infec tion-preve ntion -contr ol.html, https ://www.cdc.gov/infec tionc ontro l/guide lines /isola tion/appen dix/stand ard-preca ution s.html, https ://www.cdc.gov/flu/profe ssion als/infec tionc ontro l/healt hcare setti ngs.htm (all accessed on Dec 10-2019) All suspected or confirmed RVIs require minimum of standard precautions. Eye protection is a reasonable addition to droplet isolation as the ocular route of infection has been documented for several common respiratory viruses Data on the novel coronavirus are based on the WHO interim report as of February 4, 2020 Other viral pathogens with respiratory routes of acquisition were not associated with improved survival in critically ill Platform Trial for Community-Acquired Pneumonia, patients with influenza A(H1N1)pdm09 [23]. In patients NCT02735707). with MERS (n = 349), macrolide therapy is not associated with a reduction in 90-day mortality or improvement in Corticosteroids MERS-CoV RNA clearance [24]. A study of clarithro- Data on the use of corticosteroids in severe RVIs are mycin combined with the cyclooxygenase inhibitor largely observational. Several studies demonstrated the flufenamic acid in hospitalized patients with influenza is association of corticosteroid use with mortality, bacterial underway (NCT03238612). In addition, macrolides are and fungal infection and the emergence of antiviral resist- also examined in one of the domains of the REMAP-CAP ance in influenza-associated pneumonia or ARDS [25]. trial (Randomized, Embedded, Multifactorial Adaptive A study (n = 607) that accounted for time-dependent 320 Table 3 Antiviral agents for communityacquired respiratory viral infections (RVIs) and relevance to critically ill patients Mechanism Target Virus Resistance Formulation Applicability to critically ill patients of action Amantadine M2 ion channel Influenza A High levels of resistance Oral Not recommended blockers Rimantadine M2 ion channel Influenza A High levels of resistance Oral Not recommended blockers Oseltamivir Neuraminidase Influenza A and B Uncommon (1-3% of Oral Needs dose adjustment in patients with renal impairment inhibitor(NAI) circulating isolates) but No dose adjustment is necessary in patients with mild to moderate hepatic impair- higher for treatment- ment emergent in critically ill Extemporaneous formulation possible or gastric delivery in intubated patients and immunocompro- mised Zanamivir NAI Influenza A and B Rare Intravenous; nebu- Inhibitory for most strains resistant to oseltamivir lized solution Nebulized formulation (investigational) with limited use in severely ill patients (investigational); Limited systemic absorption and distribution to extrapulmonary sites of inhaled inhaled dry pow- commercial product der (commercial Lactose-containing powder commercial preparation with lactose carrier should formulation) not be given nebulized as it may cause ventilator circuit obstruction Intravenous formulation similar in efficacy to oseltamivir in hospitalized patients. Intravenous zanamivir is approved by the European Medicines Agency (EMA) Peramivir NAI Influenza A and B Uncommon (see Intravenous Intravenous formulation (multiple doses) similar in efficacy to oseltamivir in hospi- oseltamivir above) talized patients Peramivir is approved by the FDA and EMA for uncomplicated influenza Laninamivir NAI Influenza A and B Rare Inhaled, single Not suitable for mechanically ventilated patients. dose, long acting Approved in Japan only Favipiravir Polymerase Influenza A, B and other RNA Not seen in clinical strains Oral Under study in hospitalized patients in combination with NAIs inhibitor (PB1 viruses Teratogenicity risk transcriptase), PK altered in critically ill with reduced drug exposure– appropriate dose regimen viral mutagen uncertain Approved only for stockpiling in Japan Baloxavir Polymerase Influenza A, B Treatment-emergence Oral Under study (multiple-dose) in combination with NAIs in hospitalized patients inhibitor (PA resistance common Not studied and PK uncertain in critically ill patients cap-dependent with monotherapy Inhibitory for strains resistant to M2Is and/or NAIs endonuclease) At present, baloxavir is approved in the US, Japan, and over eight other countries Nitazoxanide Host-directed and Influenza and other RVIs Not seen in clinical strains Oral Not effective in hospitalized SARI patients. Not recommended. influenza HA Ribavirin Host-directed RSV, influenza, measles other Not seen in clinical strains Aerosolized, oral, Aerosol formulation approved in RSV-infected children but of uncertain value. effects, RVIs intravenous All 3 formulations have been used in treating RSV-infected HSCT and SOT patients transcriptase (investigational) Anecdotal use of systemic ribavirin in severe measles and other paramyxovirus inhibitor, viral infections mutagen Not recommended in combination with interferons for MERS Teratogenicity risk Aerosol delivery presents risk of healthcare worker exposure 321 patient-level confounders found no independent influ - ence of corticosteroids on mortality of influenza [26]. The IDSA recommends against corticosteroid adjunctive therapy in patients with influenza unless clinically indi - cated for other reasons [10]. In a study of patients hospi- talized with RSV (n = 50), corticosteroid therapy was not associated with significant differences in peak viral load, duration of RSV shedding, nasal cytokines, or lympho- cyte subsets, although antibody responses to RSV were slightly blunted [27]. In one randomized-controlled trial that included 16 non-ICU SARS patients, “early” (< 7 days of illness) hydrocortisone therapy was associated with a higher subsequent plasma viral load [28]. In a study on MERS patients (n = 309), corticosteroid therapy was not associated with significant change in 90-day mortality after adjustment for time-varying confounders, but was associated with delayed MERS-CoV RNA clearance [29]. Cyclooxygenase‑2 inhibitors Cyclooxygenase-2 may modulate excessive pro-inflam - matory responses in severe influenza [30]. In addition to the above study of naproxen–clarithromycin added to oseltamivir [23], preliminary results from a RCT (n = 120) showed that the combination of celecoxib-oseltamivir compared to oseltamivir alone reduced mortality and cytokine levels, although not viral titers, in hospitalized influenza A(H3N2) patients without increased adverse effects [31]. Sirolimus Inhibitors of the mTOR pathway like sirolimus com- bined with oseltamivir have shown inconsistent effects in murine models of severe influenza [32, 33]. Sirolimus also can modulate inflammatory responses through its immunosuppressive properties [34]. In a small RCT (n = 28), treatment with sirolimus compared to no siroli- mus in patients with influenza A(H1N1) pneumonia receiving invasive mechanical ventilation (in addition to oseltamivir and corticosteroids) resulted in improvement in hypoxia, multiple organ dysfunction and virus clear- ance, and in shorter duration of mechanical ventilation [34]. Further study of sirolimus without systemic corti- costeroids is planned among patients hospitalized with influenza (NCT03901001). Statins Because of the putative anti-inflammatory effects, statins have been proposed as adjunctive therapy in influenza (NCT02056340), although large clinical trials in patients in ARDS have not demonstrated clinical benefit [35]. A secondary analysis of data from RCTs using latent class analysis suggested that patients with ARDS may be clas- sified into hyper-inflammatory and hypo-inflammatory Table 3 (continued) Mechanism Target Virus Resistance Formulation Applicability to critically ill patients of action Cidofovir DNA polymerase Adenovirus Intravenous Anecdotal use in severe adenovirus infections and in immunocompromised inhibitor patients Acyclovir DNA polymerase VZV, HSV Uncommon except in Intravenous, oral Intravenous recommended in VZV pneumonia; addition of systemic corticoster- inhibitor immunocompromised oids recommended by some experts Please refer to the online supplement for references SARI severe acute respiratory infection, RSV respiratory syncytial virus, HSCT hematopoietic stem-cell transplantation, SOT solid-organ transplantation, MERS Middle East Respiratory Syndrome, VZV varicella-zoster virus, HSV herpes simplex virus, NAI neuraminidase inhibitors, EMA European Medicines Agency, FDA Food and Drug Agency 322 subphenotypes, and treatment with simvastatin com- with influenza pneumonia and can be especially virulent pared to placebo was associated with improved survival [10]. The recent 2019 ATS/IDSA clinical practice guide - in the hyper-inflammatory but not in the hypo-inflam - lines recommend standard antibacterial therapy to be matory subphenotype [36]. Further studies are needed initially prescribed for adults with community-acquired to examine whether adjunctive pharmacologic interven- pneumonia who test positive for influenza [10]. The tions would be beneficial in targeted subphenotypes of guidelines provide details on when to consider empiric severe RVI. therapy for methicillin resistant Staphylococcus aureus and Pseudomonas aeruginosa and provide guidance for de-escalation of antibacterial therapy in patients with Immune therapy confirmed influenza [10]. Clinicians should be aware Studies in which various antibody immunotherapies of the reports of invasive pulmonary aspergillosis in have been added to neuraminidase inhibitor treatment severely ill influenza patients especially those with under - in hospitalized influenza patients have yielded incon - lying conditions or receiving corticosteroids, although up sistent results. A small randomized-controlled trial to 30% of patients with influenza-associated aspergillosis (n = 35) demonstrated that treatment of severe influenza had been previously healthy [41]. A(H1N1)pdm09 patients with hyperimmune globulin (H-IVIG) containing high titers of virus-specific neu - Supportive care tralizing antibodies within 5 days of symptom onset was Patients with severe RVI present typically with pneumo- associated with a lower viral load and reduced mortality nia, acute respiratory distress syndrome (ARDS), decom- compared to low-titer IVIG [37]. Two recent phase III pensated heart failure, or exacerbation of chronic lung trials have been completed in seasonal influenza patients. disease; leading frequently to acute hypoxemic, and less The FLU-IVIG RCT found no overall effect of anti-influ - commonly hypercapnic, respiratory failure. Except for enza hyperimmune IVIG compared to placebo on the several influenza and novel coronavirus studies noted primary outcome measured by a six-point ordinal scale below, most of the data regarding supportive care strat- of clinical status on day 7, although antiviral and clini- egies come from studies that have not documented spe- cal benefits were noted in the subgroup of patients with cific RVIs. In many ARDS trials, patients with pneumonia influenza B virus infection [38]. The second trial of high- constituted a majority of enrolled patients; but detailed titer versus low-titer anti-influenza immune plasma was description of etiologic pathogens is often lacking. Given terminated for futility because of the lack of effect on the the high prevalence of viral pathogens as outlined ear- same primary outcome [39]. A placebo-controlled, rand- lier, it is likely that severe RVIs constitute a considerable omized trial of the anti-hemagglutinin stem monoclonal proportion. There are general pathophysiologic and clini - antibody MHAA4549A did not demonstrate benefit over cal similarities between ARDS and pneumonia caused oseltamivir alone [6]. The results from these recent trials by severe RVIs and those due to other pathogens or eti- suggest that polyclonal antibody therapies may not sig- ologies, and therefore, the extrapolation of findings from nificantly improve outcomes in severe seasonal influenza unselected populations to patients with severe RVIs can A, although their possible value in treating severe RVI by be justified in the absence of specific data. At the same novel influenza strains remains to be determined. time, there are important differences that may lead to heterogeneity in response to treatment. Vitamin C The recent CITRIS-ALI trial demonstrated that 96-h infusion of vitamin C compared with placebo in a rela- Non‑invasive ventilation tively small number (n = 167) of patients with sepsis and Data on non-invasive ventilation (NIV) in severe RVI are ARDS did not improve the primary outcome of organ limited. In patients with severe RVI resulting in chronic dysfunction scores or alter markers of inflammation and obstructive pulmonary disease (COPD) exacerbations vascular injury. However, mortality, which was one of the or cardiogenic pulmonary edema, NIV may be effec - forty-six pre-specified secondary endpoints, was signifi - tive in reducing the need of endotracheal intubation and cantly lower with vitamin C [40]. Results of other ongo- decreasing ventilator-associated complications and mor- ing larger trials are awaited, and data on severe RVI are tality [42]. needed. However, NIV in patients with severe RVI causing acute hypoxemic respiratory failure and pneumonia is Antibacterial therapy of uncertain benefit. Observational studies reported Co-infections with bacterial pathogens occur often with variable results for NIV in patients with severe influenza RVI. Co-infection with Staphylococcus aureus is common A(H1N1)pdm09 with some reporting NIV failure in up 323 to 85% [43]. In one multicenter observational study of strategy with low tidal volumes (6  ml/kg predicted body 1898 critically ill patients with acute hypoxemic respira- weight) and plateau pressures < 30 to 35 cmH O. In adults tory failure due to influenza, 806 underwent initial NIV, with acute lung injury or ARDS due to various causes, an and 56.8% of them required conversion to invasive ven- individual patient data meta-analysis of 2299 patients tilation. Patients with SOFA ≥ 5 had a higher risk of NIV from three trials (50% with pneumonia) found that higher failure. Similar to other studies, NIV failure was associ- positive end-expiratory pressure (PEEP) levels were asso- ated with increased ICU mortality compared with inva- ciated with improved survival among the subgroup of sive mechanical ventilation [44]. patients with ARDS (defined by PaO /FiO ≤ 200 mmHg) 2 2 Data from uncontrolled studies suggested that NIV [51]. A recent RCT of over 1000 patients with moderate- might have been effective and safe in the management of to-severe ARDS (55% with pneumonia) demonstrated some patients with SARS [45], while others highlighted that prolonged and high-pressure recruitment maneu- concerns of increased SARS transmission risk to health- vers was associated with increased 28-day mortality [52]. care workers [46]. In a multicenter cohort of 302 MERS Titration of PEEP to achieve optimal oxygenation, per- critically ill patients, NIV was used initially in 35% of haps without aggressive recruitment maneuvers, remains patients, but the vast majority of them (92.4%) required a reasonable strategy for most patients. conversion to invasive mechanical ventilation; however, NIV was not independently associated with 90-day mor- High‑frequency oscillatory ventilation (HFOV) tality [47]. HFOV ventilates the lung with tidal volumes lower than A recent single-center RCT in patients with unselected anatomical dead space while achieving relatively high patients with ARDS (n = 83, 45% pneumonia) showed mean airway pressures [53]. In patients with influenza that treatment with helmet NIV resulted in significant A(H1N1)pdm09 influenza, HFOV has been used as a reduction of intubation rates and in 90-day mortal- rescue therapy for those not responding to conventional ity [48]. Further studies in patients with severe RVI are ventilation [53]. Two randomized clinical trials showed needed, as helmet NIV may be more effective than tra - that HFOV in moderate-to-severe ARDS was not associ- ditional masks and may be associated with less risk of ated with improved outcomes compared to conventional transmission due to aerosol generation. ventilation [54, 55]. However, a meta-analysis of 1552 Based on available evidence, NIV in severe RVI may be patients (55% with pneumonia) found that the HFOV used in selected patients in early stages and milder forms treatment effect depended on baseline severity of hypox - of acute hypoxemic respiratory failure, excluding those emia, with harm  among patients with mild-moderate in shock or multiorgan failure, with the recognition that ARDS but possibly decreased mortality in patients with for patients who do not show signs of early recovery, NIV very severe ARDS [56].  Therefore, while HFOV is not may well delay but not avoid invasive ventilation [42]. recommended for routine use in ARDS, there may still be a role as rescue therapy [53]. High‑flow nasal cannula Prone positioning High-flow nasal cannula has emerged as an alternative to A multicenter RCT (n = 474, 60% with pneumonia) dem- NIV to prevent intubation in patients with acute hypox- onstrated that early application of prone positioning emic respiratory failure. In one trial (n = 310, 72% com- (at least 16  h per session) in patients with severe ARDS munity-acquired pneumonia), treatment with high-flow (PaO /FiO < 150 mmHg, with an F iO ≥ 0.6, PEEP of ≥ 5 2 2 2 oxygen, standard oxygen, or NIV did not result in sig- cmH O, and a tidal volume close to 6  ml/kg predicted nificantly different intubation rates; however, there was body weight) resulted in decreased mortality [57]. Prone a significant difference in favor of high-flow nasal can - positioning in patients with avian A(H7N9) influenza- nula in 90-day mortality [49]. A small cohort of patients related severe ARDS has been associated with improved with severe RVI with influenza A(H1N1)pdm09 (n = 25) oxygenation, sustained after returning to a supine posi- showed that high-flow nasal cannula was associated with tion, and with decreased carbon dioxide retention [58]. avoidance of intubation in 45% of patients, although almost all patients with higher severity of illness and Neuromuscular blockers shock were eventually intubated [50]. In patients with severe ARDS, in one trial (n = 339, 38% community-acquired pneumonia), early administration of a neuromuscular blocking agent improved the adjusted Invasive ventilation 90-day survival and increased the time off the ventila - Based on current evidence, patients with ARDS due to tor without increasing muscle weakness [59]. How- severe RVI should be managed with lung-protective ever, in a recent larger trial that enrolled patients with 324 mortality and may sometimes require ECMO or other moderate-to-severe ARDS (n = 1006, 59% pneumonia), types of supportive care [69, 70]. treated with a strategy involving high PEEP, there was no significant difference in mortality at 90 days between Infection prevention and control patients who received an early, continuous cisatracurium Table  2 summarizes infection control precautions for infusion and those who were treated with a usual-care different RVIs as recommended by the Centers for Dis - approach with lighter sedation targets [60]. Specific data ease Control and Prevention (please refer to Table 2 foot- on neuromuscular blockade in severe RVI are lacking. note for CDC references). In patients presenting with severe RVIs, contact plus droplet precautions are rec- Extracorporeal membrane oxygenation (ECMO) ommended; droplet precautions may be discontinued The latest RCT for ECMO (EOLIA) included 249 patients when adenovirus and influenza have been ruled out. For with severe ARDS, 18% with viral etiologies, and found patients with a history of recent travel (10–21  days) to that ECMO did not reduce mortality at day 60 [61]. Yet, countries with active outbreaks of SARS, MERS, or avian a post hoc Bayesian analysis found that the interpreta influenza, airborne plus contact precautions and eye pro - tion of benefit versus no benefit in this trial is critically tection are recommended. dependent upon the range of prior assumptions reflect Aerosol-generating procedures, such as bronchoscopy, ing varying degrees of skepticism and enthusiasm of pre- endotracheal intubation, and open suctioning of the res- vious evidence for the benefit of ECMO—clinicians with piratory tract, tracheotomy, manual ventilation before more enthusiasm for the benefit of ECMO may be justi intubation, nebulizer treatment, high-flow nasal cannula, fied in considering it for certain patients [62]. non-invasive ventilation, and chest compressions, have Indeed, observational studies reported lower hospital been implicated with transmission of infectious agents mortality among patients with ARDS related to influ to healthcare personnel. However, these findings were enza A(H1N1)pdm09 with transfer to an ECMO center identified from limited studies, mainly during the SARS compared with matched non-ECMO-referred patients outbreak [71]. Nevertheless, it is recommended dur- [63]. A case–control study also suggested survival benefit ing aerosol-generating procedures on patients with sus- for ECMO in patients with severe MERS [64]. ECMO is pected or proven infections transmitted by aerosols (for likely to be associated with better outcomes when used example influenza, MERS, SARS) to wear a fit-tested N95 among patients with limited organ failures and good pre mask in addition to gloves, gown, and face/eye protec- morbid functional status, and should be considered for tion. Closed-circuit suctioning may reduce the exposure patients who fail other evidence-based oxygenation strat to aerosols. Performing these procedures in an airborne egies according to individual patient characteristics and a isolation room when feasible is recommended. potential risk–benefit determination. RCTs comparing N95 respirators to medical masks in health care personnel working in outpatient and ward Cardiovascular management settings have not shown significant differences in pro - Timely adequate fluid resuscitation is an essential ele - tection from laboratory-confirmed influenza or other ment of the management of patients with severe RVI RVIs [72, 73]. The relevance of these observations to and shock. However, in those with ARDS (n = 1000, 47% the ICU setting is uncertain, given the frequent use of pneumonia), a conservative strategy of fluid manage aerosol-generating procedures in critically ill patients. ment improved lung function and shortened the duration Cloth masks are clearly inferior to medical masks in pro- of mechanical ventilation without increasing non-pul tecting HCWs from RVIs [74]. Other aspects of preven- monary-organ failures [65]. In addition, aggressive fluid tion strategies to prevent transmission when caring for administration may worsen ventricular function. This patients with severe RVIs include annual influenza vac - may be particularly relevant for patients with severe RVI. cination of healthcare workers, adherence to standard Myocardial involvement is not uncommon with severe precautions, including hand hygiene, during the care of influenza A or B virus infection, and multiple studies any patient and appropriate management of ill healthcare have shown an association between influenza and acute workers (please refer to Table  2 footnote for CDC refer- myocardial infection and myocarditis [66–68]. Echocar ences). Recently, antiseptic hand rubbing using ethanol- diographic findings often include right- and left-ventric - based disinfectants (EBDs) was found to be less effective ular dysfunction [66]. Therefore, clinical assessment of than hand washing with running water in inactivating fluid responsiveness is important along with quantifica influenza virus in undried mucus under experimental tion of right- and left-ventricular size and function using conditions; [75] also nonenveloped viruses like adenovi- echocardiography and/or dynamic minimally invasive rus which are not easily inactivated by EBDs. The impli - cardiovascular monitoring, if available. Myocarditis has cations of these observations for clinical practice remain associated with longer duration of vasoactive agents and 325 to be determined but hand washing with soap and water Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- or hand rubbing with EBD for longer than 30  s may be lished maps and institutional affiliations. warranted. Received: 20 October 2019 Accepted: 16 January 2020 Published online: 10 February 2020 Future directions for research The Global Influenza Programme has published the updated WHO Public Health Research Agenda for Influ - References enza, in which research priorities were identified for 1. Karhu J, Ala-Kokko TI, Vuorinen T, Ohtonen P, Syrjala H (2014) Lower several domains including patient management [76]. respiratory tract virus findings in mechanically ventilated patients with Existing knowledge highlights the need for data regard- severe community-acquired pneumonia. Clin Infect Dis 59:62–70 2. Hasvold J, Sjoding M, Pohl K, Cooke C, Hyzy RC (2016) The role of human ing supportive care and adjunctive pharmacologic ther- metapneumovirus in the critically ill adult patient. J Crit Care 31:233–237 apy that is specific for critically ill patients with severe 3. Zumla A, Memish ZA, Maeurer M, Bates M, Mwaba P, Al-Tawfiq JA, Den- RVI. 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Depart- Keijzers G, Khalili H, Knight M, Kudo K, Kusznierz G, Kuzman I, Kwan AM, ment of Medicine, Division of Infectious Diseases and International Health, Amine IL, Langenegger E, Lankarani KB, Leo YS, Linko R, Liu P, Madanat University of Virginia School of Medicine, Charlottesville, VA, USA. F, Mayo-Montero E, McGeer A, Memish Z, Metan G, Mickiene A, Mikic D, Mohn KG, Moradi A, Nymadawa P, Oliva ME, Ozkan M, Parekh D, Paul M, Funding Polack FP, Rath BA, Rodriguez AH, Sarrouf EB, Seale AC, Sertogullarindan B, None. 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Dr. Hayden’s institution received funding Eec ff tiveness of antiviral treatment in human influenza A(H5N1) infec- from GlaxoSmithKline (Data Safety Monitoring Board [DSMB] member for tions: analysis of a Global Patient Registry. J Infect Dis 202:1154–1160 influenza randomized-controlled trial [RCT ]), Celltrion (DSMB chair for influ- 9. Louie JK, Yang S, Acosta M, Yen C, Samuel MC, Schechter R, Guevara H, enza RCT ), and Vaccitech (DSMB chair for influenza RCTs); he received hono - Uyeki TM (2012) Treatment with neuraminidase inhibitors for critically ill raria from World Health Organization (consultant on influenza and emerging patients with influenza A (H1N1)pdm09. Clin Infect Dis 55:1198–1204 viral infections) and the University of Alabama (Scientific Advisory Board 10. Uyeki TM, Bernstein HH, Bradley JS, Englund JA, File TM, Fry AM, Graven- member for National Institutes of Health-sponsored Antiviral Discovery and stein S, Hayden FG, Harper SA, Hirshon JM, Ison MG, Johnston BL, Knight Development Consortium); he disclosed that he has been a non-paid consult- SL, McGeer A, Riley LE, Wolfe CR, Alexander PE, Pavia AT (2019) Clinical ant on antivirals active for MERS-CoV for Gilead Sciences, SAB Biotherapeutics, practice guidelines by the infectious diseases society of America: 2018 and Regeneron, and for multiple companies on influenza therapeutics; Cidara, update on diagnosis, treatment, chemoprophylaxis, and institutional Shionogi, Seqirus, and resTORbio have made charitable contributions to the outbreak management of seasonal influenzaa. Clin Infect Dis 68:895–902 Ford Haitian Orphanage and School for his consulting time; Shionogi and 11. 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