Sooner is definitely better when it comes to antivirals for influenza, but later is better than nothing, infectious disease specialist Jennifer Babik, MD, told attendees at the University of California San Francisco (UCSF) Management of the Hospitalized Patient conference in October.
“We've always known that treatment of inpatients within 48 hours decreases mortality. The problem is that over 40% of patients hospitalized with flu present outside this classic treatment window,” she said.
Now data suggest that hospitalized patients benefit from starting an antiviral up to 5 days after symptoms start. “In the 2009 H1N1 pandemic, multiple studies showed a mortality benefit for treating after 48 hours,” said Dr. Babik, who is an assistant clinical professor at UCSF.
The patients who were treated earlier did better, however. “One study found that each day that you delay, the risk of death goes up by 20%, so it's quite remarkable. If you suspect influenza, you should consider starting therapy while you're awaiting test results,” she said.
Without those results, it's difficult to know whether a patient has flu, Dr. Babik noted. For example, flu vaccination status is not definitive evidence. “It depends on the flu season how much you can take that into account. We know last year the flu vaccine was only about 10% to 20% effective . . . If it's a year where it's about 80% effective, you might take that into account in your decision making,” she said.
Procalcitonin and symptoms don't answer the question either. “We know that you can have both viral and bacterial [infections], so if you have a procalcitonin, it doesn't mean you don't also have influenza,” Dr. Babik said. “The 2009 pandemic studies showed that people with influenza pneumonia or bacterial superinfection presented the exact same way.”
Of the tests for flu, rapid antigen tests hold the advantage of being widely available. “That's the benefit of them, but they're only 50% to 70% sensitive, so they cannot be used to exclude influenza during influenza season. I don't use a negative point-of-care test in my decision,” Dr. Babik said.
Molecular assays, or polymerase chain reaction (PCR) tests, are 95% sensitive and specific for flu, and some can identify influenza A versus B or flu subtypes. But even their results sometimes have to be viewed with caution, depending on where they're from.
“Upper-tract samples are what we usually use—nasopharyngeal swaps or aspirates. . . . In critically ill patients, it's really important to get lower-tract specimens as well, because we definitely know that people can stop shedding in the upper tract and still be positive in the lower tract. So if you've got high suspicion in your critically ill patient, and your nasopharyngeal PCR is negative, I would not stop therapy until you get a lower-tract sample,” said Dr. Babik.
Therapy is typically a neuraminidase inhibitor: oseltamivir, zanamivir, or the newest option, peramivir. The M2 inhibitors are the other class of antivirals for flu, but there's widespread resistance to them, Dr. Babik noted.
Oseltamivir is the accepted mainstay of treatment, although there is debate about whether a dose higher than the usual 75 mg has benefit. “This [idea] comes from avian influenza animal models where [the higher dose] seems to be more effective,” said Dr. Babik. However, randomized trials of immunocompetent, non-ICU patients found no difference in viral clearance, mortality, duration of fever, use of oxygen, ICU admission, intubation, or length of stay with the higher dose.
No one's published such a study in ICU patients, though. “We don't have a data-driven answer for this. At UCSF, we still use [the higher dose] in our ICU population,” Dr. Babik said.
Zanamivir has generally been the next option. It's an inhaled drug and can't be used in patients who are intubated or have underlying respiratory disease (unless you have a patient with oseltamivir-resistant flu and apply for the IV version under the FDA's emergency investigational new drug program, Dr. Babik noted).
Peramivir is the new kid on the block, approved in December 2014. It's an IV drug, given in a 600-mg dose. So far, it has mainly been used when there's concern that a patient's gastrointestinal system won't absorb oseltamivir, Dr. Babik said. “It's a new drug. I think we're going to see a lot more data coming out about it.”
Peramivir's FDA approval is for a single dose, but back in 2009, when it was an investigational drug, it was being used for 5 to 10 days, Dr. Babik noted. Five days is the standard treatment window for the other flu drugs, but sicker patients may need to take them longer.
“We actually treat for 10 days in our critically ill patients because we know that they shed for longer. You could also consider that in immunocompromised patients. Sometimes we'll keep going if someone is really sick and still has a positive PCR, but there is no data to support that,” she said.
If a patient's not getting better on treatment, that's also the time to consider drug resistance testing. The good news is that oseltamivir resistance is still relatively rare, with only 2% of isolates showing it in the past 2 years, Dr. Babik reported.