For intensivists, treatment options are limited since no parenteral drug is available and no drug has been proven to be effective once life threatening disease occurs. Currently four antiviral drugs are available for the treatment of influenza. These are available only for oral administration while one is available as an inhalation agent. These drugs include amantadine, rimantadine, oseltamivir, and zanamivir. ()
Amantadine and rimantadine should no longer be used for the treatment of influenza due to the high incidence of resistance. Resistance was uncommon (below 2% in 1995–2002) in community isolates until recently. In 2005–6 the resistance frequency in A (H3N2) 92 % in the United States.[67
The neuraminidase inhibitors currently available include zanamivir (Relenza) and oseltamivir (Tamiflu). Both are sialic acid analogues that inhibit the viral neuraminidases by competitively binding with the active enzyme site of influenza A and B viruses. The neuraminidase is critical for viral release from infected cells after replication.
Oseltamivir is administered enterally as a prodrug (oseltamivir phosphate). Esterases in the liver, gastrointestinal tract, and blood cleave this to the active oseltamivir carboxylate. The bioavailability is estimated to be 80%, and the time to maximum plasma concentrations is 3 to 4 hours. Administration with food may delay absorption slightly but does not decrease overall bioavailability. Following oral administration of oseltamivir, the plasma half-life is 7 to 9 hours, and is eliminated primarily unchanged through the kidney.
Oral oseltamivir can be associated with nausea and emesis. Gastrointestinal complaints are usually mild in intensity and ameliorated by administration with food.
Zanamivir is currently available only as a powder for inhalation (Rotadisk). About 4% to 17% of inhaled zanamivir is systemically absorbed. Zanamivir has a half-life of 2.5–5.1 hours. Zanamivir is very well tolerated but bronchospam has been reported and is of special concern in the ICU.[68
Prospective data supporting the use of oseltamivir in the treatment of human influenza comes from four adult studies. Two of these studies evaluated experimentally induced influenza and the other two evaluated community acquired influenza.[37
] For zanamivir, there have been four adult studies. One of these studies evaluated experimentally induced influenza and three evaluated community acquired influenza.[71
The adult acute treatment trials for oseltamivir and zanamivir studied those who presented within 36 hours of developing fever, respiratory symptoms and constitutional symptoms. Treatment with oseltamivir was associated with decreased duration and severity of illness.[37
] Duration decreased by about one day when a dose of 75 mg bid was given. There was no greater clinical benefit from the higher dose of oseltamivir. Oseltamivir treatment resulted in decreased nasal viral titers in both studies compared to placebo, but in only one study was this suggested to be dose dependent. The mortality was nil in all treatment groups including placebo.
Treatment with zanamivir also reduced the symptoms of influenza. Inhaled zanamivir improved symptoms 1.5–1.9 days faster than placebo.[71
] There was no benefit to intranasal topical zanamivir in addition to inhaled zamamivir [73
The earlier the administration of both of these agents and the shorter the duration of fever, the greater the benefit of drug intervention.[76
] Oseltamivir has also been shown to reduce lower respiratory tract complications such as bronchitis and pneumonia.[78
The studies above were performed in a healthy ambulatory population. No subjects with community acquired influenza died in these studies despite more than 30,000 people dying each year from influenza in the US. The optimal antiviral therapy for lower respiratory tract manifestations is not clear. In one study 41 hospitalized patients with influenza pneumonia were treated with rimantadine +/− nebulized zanamivir: the mortality was 8% but there was no comparison group.[35
] Oseltamivir has not been studied prospectively in patients hospitalized with severe lower respiratory tract disease due to influenza. Clinical studies to address this question are underway. Thus, there is no clear evidence that oseltamivir improves outcomes in this population, but most clinicians would use oral oseltamivir if patients had any severe manifestations of influenza.
Currently no parenteral agent is available for the treatment of influenza. However, new injectable neuraminidase inhibitors (peramivir and zanamivir), and novel agents such as polymerase inhibitors (T-705) are in human clinical trials.
Treatment of Pandemic Influenza
Treatment of pandemic influenza will need to be guided by sensitivities of the circulating strain. Treatment recommendations of sporadic cases of avian influenza in humans are to use oseltamivir at currently licensed doses.[79
] Zanamivir is efficacious in animal models but there is no experience with this agent in the treatment of humans with avian influenza. Amantidine and rimantidine should be avoided due to high prevalence of resistance in some clades.[79
] ICU management during a pandemic would need to emphasize strict epidemiologic control to avoid nosocomial spread, prompt initiation of antibacterial therapy when appropriate, and well thought out triage.
In spite of the profound impact of HIV on cell mediated immunity, HIV does not appear to be a risk factor for more frequent or more severe disease with influenza.[80
] In one population series, an excess mortality due to influenza was been reported in the HIV population in the pre-HAART era compared to the general population.[83
] It has not been shown that those with HIV have any different spectrum of disease with influenza.
Patients with leukemia, organ transplantation, and hematopoietic stem cell transplantation (HSCT) do appear to have a more severe disease with influenza. Influenza virus infection in the immunocompromised is associated with a higher rate of viral pneumonia and higher attributable mortality.[84
] Viral shedding is also prolonged to an average of 11 days[85
], which is associated with the development of resistance.[86
] For this reason, standard dose and duration of antivirals may not be adequate in this population. Some authors have advocated higher use of oseltamivir (150mg bid) in the immunocompromised host.[84
Antiviral Impact on Complications
Additional analysis of the controlled studies have shown that oseltamivir treatment was associated with significant reductions in bronchitis and pneumonia, antibiotic use, and all-cause hospitalizations in the month after influenza diagnosis.[78
] Zanamivir as also been shown to reduce complications and secondary antibiotic use, particularly in the high risk patients (immunocompromised, or having underlying respiratory, cardiovascular, or endocrine disorders).[73
Intensivists need to be prepared to manage both seasonal influenza and pandemic influenza. Parenteral antiviral agents are needed, and studies need to be performed to determine if these agents provide benefit to severely ill patients.
Intensivists can diminish the impact of influenza on their patients and their staff. Immunization for health car workers ought to be considered as a mandatory condition of employment for those without a medical or ethical contraindication, and immunizations should be completed by early Fall. Strict adherence to isolation procedures should be emphasized regularly. Recognition of treatment complications of influenza such as bacterial pneumonia should be prompt.
Intensivists also have an obligation to participate in hospital, regional and national programs to coordinate and develop services for a pandemic, which will eventually occur. The media and some health care organizations seem to have developed “flu fatigue” i.e., they are less engaged in pandemic preparation since no large outbreak has occurred. A pandemic will occur. Intensivists and the global society must be prepared.