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Critical Care Management of Adults with Community-Acquired Severe Intensive Care Med https://doi.org/10.1007/s00134-020-05943-5 NARRATIVE REVIEW Critical care management of adults with community-acquired severe respiratory viral infection Yaseen M. Arabi1,2,3* , Robert Fowler4,5,6 and Frederick G. Hayden7 © 2020 Springer-Verlag GmbH Germany, part of Springer Nature 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 identifed. Patients with severe RVIs requiring ICU care present typically with hypoxemic respiratory failure. Oseltamivir is the most widely used neuraminidase inhibitor for treatment of infuenza; data sug- gest that early use is associated with reduced mortality in critically ill patients with infuenza. At present, there are no antiviral therapies of proven efcacy for other severe RVIs. Several adjunctive pharmacologic interventions have been studied for their immunomodulatory efects, including macrolides, corticosteroids, cyclooxygenase-2 inhibitors, sirolimus, statins, anti-infuenza 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 specifc for critically ill patients with severe RVI. There is a need for more pragmatic and efcient designs to test diferent therapeutics both individually and in combination. Keywords: Acute respiratory distress syndrome, Infuenza, Neuraminidase inhibitor, Antiviral therapy, Coronavirus, Antiviral therapy Introduction severe respiratory viral infections (RVIs) include infu- enza A and B viruses, picornaviruses (rhinovirus, enter- With the expanding use of molecular assays, viral patho- ovirus [e.g., enterovirus D68]), human coronaviruses gens are increasingly detected among critically ill adult (229E, NL63, OC43, HKU1), respiratory syncytial virus patients with respiratory illness; studies have reported a (RSV), human metapneumovirus, parainfuenza virus, prevalence between 17% and 53% of patients (Table 1), and adenovirus (Tables 1 and 2). Novel pathogens includ- depending on study design, sample type, duration of ill- ing zoonotic coronaviruses like the agents causing Severe ness, and assay methods. Common viruses that can cause Acute Respiratory Syndrome (SARS), Middle East Res- piratory Syndrome (MERS) and the 2019 novel coronavi- rus (2019 nCoV) are still being identifed (Table 2). *Correspondence: [email protected] 3 Intensive Care Department, King Abdulaziz Medical City, P.O. Box 22490, Establishing causation between viruses detected in Riyadh 11426, Saudi Arabia respiratory specimens and the clinical illness is some- Full author information is available at the end of the article times difcult, because (1) detection of some agents (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 infuenza. co-identifed [1]. However, it is generally believed There is a need for pragmatic and efcient 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 to predisposing to secondary infections [2]. 1950 patients admitted to ICUs with infuenza A(H1N1) Te objective of this narrative review is to out- pdm09, which showed a trend toward improved survival line current knowledge on the management of adults for those treated earliest [9]. Nevertheless, the Clinical requiring ICU admission for community-acquired Practice Guidelines by the Infectious Diseases Society of severe acute respiratory infection (SARI) due to RVIs. America (IDSA) recommends oseltamivir for all hospital- Tis review focuses on viral pathogens transmitted via ized patients with infuenza, regardless of illness duration the respiratory route. Respiratory infections with other prior to hospitalization [10]. viral pathogens, such as cytomegalovirus and herpes In observational studies of critically ill patients simplex viruses, are not discussed in this review. with infuenza, higher compared to standard doses of oseltamivir did not demonstrate beneft [11–13]. An Antiviral therapy RCT of standard versus double-dose oseltamivir in hos- Generally available antiviral agents for diferent RVIs pitalized children and adults found no advantage with are summarized in Table 3 [3]. Very few randomized- respect to virologic and clinical endpoints [14]. Addition- controlled trials have been completed in patients hos- ally, a study demonstrated accumulation of oseltamivir in pitalized for severe RVIs; recently completed trials of patients on both extracorporeal membrane oxygenation nitazoxanide in SARI patients and of the RSV inhibitor and continuous venovenous hemodiafltration leading to presatovir in adult RSV patients yielded negative results 4-to 5-fold increase in plasma levels [15]. Te IDSA rec- [4, 5]. Antiviral therapeutics for infuenza have been stud- ommends against the routine use of higher doses of US ied most extensively and are discussed briefy below. A Food and Drug Administration-approved NAI drugs for number of other antiviral agents for infuenza, RSV, and the treatment of seasonal infuenza [10]. other RVIs are advancing in clinical study [6]. Controlled Duration of treatment is traditionally 5 days, but treat- studies of lopinavir/ritonavir combined with interferon- ment duration is often extended to 10 days for severely beta in hospitlized MERS patients (NCT02845843) and ill patients with ARDS or pneumonia or those who are of lopinavir/ritonavir and interferon-alpha 2b in hospital- immunocompromised [10]. Tis approach is supported ized 2019-nCoV patients (ChiCTR2000029308) are cur- by data showing slow infuenza viral clearance from rently in progess. the lower respiratory tract in critically ill patients with infuenza A(H1N1)pdm09 [16]. Of concern is the recent Neuraminidase inhibitors observation of emergence of oseltamivir resistance in Among the neuraminidase inhibitors (NAIs), oral 23% of 22 critically ill A(H1N1)pdm09 patients, and its oseltamivir is the most widely available agent. In an indi- association with persistent virus detection and much vidual participant data meta-analysis of hospitalized higher mortality [17]. patients with infuenza A(H1N1)pdm09 virus infection Nebulized zanamivir solution has been administered to mechanically ventilated patients on compassionate (n = 29 234 patients from 78 studies), NAI treatment (almost exclusively oseltamivir) was associated with a use basis, but the commercial formulation contains lac- reduction in mortality compared with no treatment, tose and should not be used for nebulization, because its including in the subgroup of ICU patients. Early treat- use has been associated with blockage of the ventilator ment (within 2 days of symptom onset) was associated circuit. with a reduction in mortality compared with later treat- Peramivir is the only intravenous infuenza anti- ment [7]. Observational data also indicate reduction in viral agent currently approved by the US Food and infuenza A(H5N1)-associated mortality with timely Drug Administration (FDA). Intravenous zanamivir oseltamivir treatment before the onset of respiratory has been recently approved by the European Medi- failure [8]. Te importance of timing of oseltamivir treat- cines Agency (EMA) (Table 3). Tese agents appear to ment has been demonstrated in an observational study of have comparable activity to oseltamivir in hospitalized Table 1 Prevalence of community‑acquired respiratory viral infections (RVIs) in critically ill patients Study Population Patients Samples Country Assays Overall Infuenza Picorna‑ Human Res‑ Human Parainfu‑ 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%) Infuenza 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%) Infuenza A 14 Rhinovirus 7 3 (3%) 7 (7%) 3 (3%) 11 (10%) 0 (0%) 2006 tion requiring NAAT, serology (13%) (7%) NIV or IMV Infuenza B 6 (6%) Enterovirus 2 (2%) Schnell Acute respiratory 70, 47 (67%) PS, BAL France IFA, NAAT 34 (49%) Infuenza A 11 Rhinovirus 6 5 (7%) 4 (6%) 4 (6%) 1 (1%)
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