Influenza Virus-Related Critical Illness

Prevention, Diagnosis, Treatment

Eric J. Chow; Joshua D. Doyle; Timothy M. Uyeki

Crit Care. 2019;23(214)

Background

Annual seasonal influenza epidemics of variable severity result in significant morbidity and mortality in the United States (U.S.) and worldwide.^[1–3] In temperate climate countries, including the U.S., influenza activity peaks during the winter months whereas in tropical regions influenza activity may be more variable.^[4–6] Most persons with symptomatic influenza virus infection have self-limited uncomplicated upper respiratory tract illness. One study estimated that during 2010–2016, approximately 8.3% of the U.S. population experienced symptomatic influenza each year.^[7] However, complications may result in severe illness, including fatal outcomes. During 2010–2018, an estimated 4.3–23 million medical visits, 140,000–960,000 hospitalizations, and 12,000–79,000 deaths were associated with influenza each year in the U.S..^[8] Another study estimated that 18,000–96,000 influenza-related intensive care unit (ICU) admissions occur annually in the U.S..^[9] There are an estimated 291,000–646,000 respiratory deaths attributed to seasonal influenza each year worldwide.^[2] Here, we review strategies for prevention, diagnosis, and treatment of influenza virus infections in the ICU (Table 1).

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Crit Care. 2019;23(214) © 2019 BioMed Central, Ltd.
Copyright to this article is held by the author(s), licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original citation.

Table 1. Key points: care of patients with severe influenza
Key Points
There are an estimated 291,000–646,000 seasonal influenza-associated respiratory deaths every year worldwide.
Annual influenza vaccination is the primary method of preventing influenza and influenza-related complications, especially in high-risk persons.
Influenza molecular diagnostic testing is recommended for all patients requiring hospitalization with suspected influenza.
Influenza antiviral treatment should be started as soon as possible in hospitalized patients with suspected influenza, including critically ill patients, and should not be delayed while awaiting results of influenza diagnostic tests.
Enterically administered oseltamivir is recommended for influenza patients except for those with contraindications (e.g., gastric stasis, ileus, malabsorption).
Repeat virologic testing in lower respiratory tract specimens may be required to determine therapeutic endpoints in ventilated patients with influenza
Corticosteroids are not recommended for the routine treatment of influenza except when indicated for treatment of underlying medical conditions (e.g., COPD or asthma exacerbation) or septic shock.

Table 2. Groups at high risk for influenza complications*
Risk factors for severe influenza outcomes
Age < 5 years, especially those < 2 years
Age > 65 years
Pregnant women
Extreme obesity (BMI > 40 kg/m²)
Native Americans/Alaskan Natives (may also apply to indigenous people from other countries)
Current or past tobacco use
Children and adolescents receiving aspirin or salicylate-containing medications who might be at risk for Reye syndrome
Underlying chronic medical conditions:
∘ Pulmonary
∘ Cardiovascular
∘ Renal
∘ Hepatic
∘ Neurologic
∘ Hematologic
∘ Metabolic
∘ Immunocompromised state

*From the U.S. Centers for Disease Control and Prevention Advisory Committee on Immunization Practices

Table 3. Influenza diagnostic tests
Influenza testing modality[49, 56]	Method	Time to results	Sensitivity	Specificity	Respiratory specimens*
Influenza testing modality[49, 56]	Method	Time to results	Sensitivity	Specificity	Swab	Wash/fluid	Aspirate
Molecular assay (Rapid)**#	Nucleic acid amplification	10–15 min	Moderate to high	High	NP or nasal	N/A	N/A
Molecular assay**#	Nucleic acid amplification	15–30 min	High	High	NP or throat	NP or BAL/mini BAL	Nasal or endotracheal
Rapid influenza diagnostic Test (RIDT)	Antigen detection	10–15 min	Low to moderate	High	NP, nasal, throat	NP or nasal	NP or nasal
Immunofluorescence assay (direct and indirect)	Antigen detection	1–4 h	Moderate	High	NP	NP	Nasal
Rapid cell culture (shell vials; cell mixtures)	Virus isolation	1–3 days	High	High	NP or throat	NP or BAL/mini BAL	Nasal or endotracheal
Tissue cell viral culture (conventional)	Virus isolation	3–10 days	High	High	NP or throat	NP or BAL/mini BAL	Nasal or endotracheal

*FDA-approved clinical specimens vary by specific test; refer to the manufacturer's package insert for each test's approved specimens
**Recommended for testing hospitalized patients with suspected influenza. Some molecular assays also detect other respiratory pathogens
#Patients with respiratory failure and suspected influenza should have lower respiratory tract specimens collected and tested, including if upper respiratory tract specimens are negative for influenza because a patient may have cleared influenza virus from the upper respiratory tract and continue to have influenza viral replication in the lower respiratory tract
NP nasopharyngeal, BAL bronchoalveolar lavage
Serologic testing is not recommended for diagnosis or clinical management of patients with suspected influenza

Table 4. Antiviral treatment
Antiviral agents and age group [64]	Treatment dosing
Oseltamivir
Adults (including pregnancy)	75 mg twice daily
Children (1 year or older) ≤15 kg	30 mg twice daily
Children > 15–23 kg	45 mg twice daily
Children > 23–40 kg	60 mg twice daily
Children > 40 kg	75 mg twice daily
Term Infants 0–11 months*	See details in footnote
Preterm infants**	See details in footnote
Zanamivir
Adults	10 mg (two 5-mg inhalations), twice daily
Children (≥ 7 years)	10 mg (two 5-mg inhalations), twice daily
Peramivir
Adults	600 mg intravenous infusion once, given over 15–30 min
Children (2–12 years)	One 12 mg/kg dose, up to 600 mg maximum, intravenous, given over 15–30 min
Children (13–17 years)	600 mg intravenous infusion once, given over 15–30 min
Baloxavir marboxil***
Adults and children (12 years or older) ≥40–80 kg	Single dose of 40 mg
Adults and children (12 years or older) ≥80 kg	Single dose of 80 mg

*FDA-approved oral oseltamivir treatment dose for infants 14 days and older and less than 1 year old is 3 mg/kg per dose twice daily. The American Academy of Pediatrics has recommended an oseltamivir treatment dose of 3.5 mg/kg orally twice daily for infants 9–11 months of age
**Current weight-based dosing recommendations are not appropriate for premature infants. Please refer to American Academy of Pediatrics recommendations (https://pediatrics.aappublications.org/content/142/4/e20182367) for further information
***Safety and efficacy of baloxavir marboxil in patients less than 12 years old or weighing less than 40 kg have not been established. There are no data on balosavir treatment of hospitalized patients with influenza, and appropriate dosing frequency is unknown. A phase III clinical trial of baloxavir treatment of hospitalized influenza patients is ongoing: https://clinicaltrials.gov/ct2/show/NCT03684044