Jeff: That’s wild. How do they even know that?
Nachi: Not sure, but also worth noting -- an estimated 50 million people died during that pandemic.
Jeff: Clearly a deadly disease. Sadly, that wasn’t the last major outbreak… fifty years later the 1968 hong kong influenza pandemic, H3N2, took between 1 and 4 million lives.
Nachi: And just last year we saw the 2017-2018 influenza epidemic with record-breaking ED visits. This was the deadliest season since 1976 with at least 80,000 deaths.
Jeff: The reason for this is multifactorial. The combination of particularly mutagenic strains causing low vaccine effectiveness, along with decreased production of IV fluids and antiviral medication because of the hurricane, all played a role in last winter’s disastrous epidemic.
Nachi: Overall we’re looking at a rise in influenza related deaths with over 30,000 deaths annually in the US attributed to influenza in recent years. The ED plays a key role in outbreaks, since containment relies on early and rapid identification and treatment.
Jeff: In addition to the mortality you just cited, influenza also causes a tremendous strain on society. The CDC estimates that epidemics cost 10 billion dollars per year. They also estimate that an epidemic is responsible for 3 million hospitalized days and 31 million outpatient visits each year.
Nachi: It is thought that up to 20% of the US population has been infected with influenza in the winter months, disproportionately hitting the young and elderly. Deaths from influenza have been increasing over the last 20 years, likely in part due to a growing elderly population.
Jeff: And naturally, the deaths that we see from influenza also disproportionately affect the elderly, with up to 90% occurring in those 65 or older.
Nachi: Though most of our listeners probably know the difference between an influenza epidemic and pandemic, let’s review it anyway. When the number of cases of influenza is higher than what would be expected in a region, an epidemic is declared. When the occurrence of disease is on a worldwide spectrum, the term pandemic is used.
Jeff: I think that’s enough epidemiology for now. Let’s get started with the basics of the influenza virus. Influenza is spread primarily through direct person-to-person contact via expelled respiratory secretions. It is most active in the winter months, but can be seen year-round.
Nachi: The influenza virus is a spherical RNA-based virus of the orthomyxoviridae family. The RNA core is associated with a nucleoprotein antigen. Variations of this antigen have led to the the 3 primary subgroups -- influenza A, B, and C, with influenza A being the most common.
Jeff: Influenza B is less frequent, but is more frequently associated with epidemics. And Influenza C is the form least likely to infect humans -- it is also milder than both influenza A or B.
Nachi: But back to Influenza A - it can be further classified based on its transmembrane or surface proteins, hemagglutinin and neuraminidase - or H and N for short. There are actually 16 different H subtypes and 9 different N subtypes, but only H1, H2, H3, and N1 and N2 have caused epidemic disease.
Jeff: Two terms worth learning here are antigen drift and anitgen shift. Antigen drift refers to small point mutations to the viral genes that code for H and N. Antigen shift is a much more radical change, with reassortment of viral genes. When cells are infected by 2 or more strains, a new strain can emerge after genetic reassortment.
Nachi: With antigen shift, some immunity may be maintained within a population infected by a similar subtype previously. With antigen drift, there is loss of immunity from prior infection.
Jeff: The appearance of new strains of influenza typically involves an animal host, like pigs, horses, or birds. This is why you might be hear a strain called “swine flu”, “equine flu”, or “avian flu”. Close proximity with these animals facilitates co-infection and genetic reassortment.
Nachi: I think that’s enough basic biology for now, let’s move on to pathophysiology. When inhaled, the influenza virus initially infects the epithelium of the upper respiratory tract and alveolar cells of the lower respiratory tract. Viral replication occurs within 4 to 6 hours. Incubation is 18 to 72 hours. Viral shedding is usually complete roughly 7 days after infection, but can be longer in children and immunocompromised patients.
Jeff: As part of the infectious process and response, there can be significant changes to the respiratory tract with inflammation and epithelial cell necrosis. This can lead to viral pneumonia, and occasionally secondary bacterial pneumonia.
Nachi: The secondary bacterial pathogens that are most common include Staph aureus, Strep pneumoniae, and H influenzae.
Jeff: Despite anything you may read on the internet, vaccines work and luckily influenza happens to be a pathogen which we can vaccinate against. As such, there are 3 methods approved by the FDA for producing influenza vaccines -- egg-based, cell-based, or recombinant influenza vaccine. Once the season’s most likely strains have been determined, the virus is introduced into the medium and allowed to replicate. The antigen is then purified and used to make an injection or nasal spray.
Nachi: It isn’t easy to create vaccines for all strains. H3N2, for example, is particularly virulent, volatile, and mutagenic, which leads to poor prophylaxis against this particular subgroup.
Jeff: In fact, a meta-analysis on vaccine effectiveness from 2004-2015 found that the pooled effectiveness against influenza B was 54%, against the H1N1 pandemic in 2009 was 61%, and against the H3N2 virus was 33%. Not surprisingly, H3N2 dominant seasons are currently associated with the highest rates of influenza cases, hospitalizations, and death.
Nachi: Those are overall some low percentages. So should we still be getting vaccinated? The answer is certainly a resounding YES.. Despite poor protection from certain strains, vaccine effectiveness is still around 50% and prevents severe morbidity and mortality in those patients.
Jeff: That’s right. The 2017-2018 vaccine was only 40% effective, but this still translates to 40% less severe cases and a subsequent decrease in hospitalizations and death.
Nachi: But before we get into actual hospitalization, treatment, and preventing death, let’s talk about the differential. We’re not just focusing on influenza here, but any influenza like illness, since they can be hard to distinguish. The CDC defines “influenza-like illness” as a temperature > 100 F, plus cough or sore throat, in the absence of a known cause other than influenza.
Jeff: Therefore, influenza should really be considered on the differential of any patient who presents to the ED with a fever and URI symptoms. The differential when considering influenza might also include mycoplasma pneumoniae, strep pneumoniae, adenovirus, RSV, rhinovirus, parainfluenza virus, legionella, and community acquired MRSA.
Nachi: With the differential in mind, let’s move on to prehospital care. For the prehospital setting, there isn’t much surprising here. Stabilize and manage the respiratory status with all of your standard tools - oxygen for those with mild hypoxia and advanced airway maneuvers for those with respiratory distess.
Jeff: Of note, EMS providers should use face masks themselves and place them on patients as well. As community paramedicine and mobile integrated health becomes more common, this is one potential area where EMS can potentially keep patients at home or help them seek treatment in alternate destinations to avoid subjecting crowded ED’s to the highly contagious influenza virus.
Nachi: It’s also worth noting, that most communities have strategic plans in the event of a major influenza outbreak. Local, state, and federal protocols have been designed for effective care delivery.
Jeff: Alright, so now that the EMS crew, wearing proper PPE of course, has delivered the patient, who is also wearing a mask, to the ED, we can begin our ED H&P. Don’t forget that patients present with a range of symptoms that vary by age. A typical history is 2-5 days of fever, nasal congestion, sore throat, and myalgias. You might see tachycardia, cough, dyspnea, and chills too.
Nachi: Van Wormer et al conducted a prospective analysis of subjective symptoms to determine correlation with lab confirmed influenza. They found the most common symptoms were cough in 92%, fatigue in 91%, and nasal congestion in 84%, whereas sneezing was actually a negative predictor for influenza.
Jeff: Sneezing, really? Can’t wait to get the Press-Gany results from the sneezing patient I discharge without testing for influenza based on their aggressive sneezes!
Nachi: Aggressive sneezes…? I can’t wait to see your scale for that.
Jeff: Hopefully I’ll have it in next month’s annals. In all seriousness, I’m not doing away with flu swabs just yet. In another retrospective study, Monto et al found that the best multivariate predictors were cough and fever with a positive predictive value of 79%.
Nachi: Yet another study in children found that the predominant symptoms were fever in 95%, cough in 77%, and rhinitis in 78%. This study also suggested that the range of fever was higher in children and that GI symptoms like vomiting and diarrhea were more common in children than adults.
Jeff: Aside from symptomatology, there are quite a few diagnostic tests to consider including viral culture, immunofluoresence, rt-pcr, and rapid antigen testing. The reliability of testing varies greatly depending on the type of test, quality of the sample, and the lab. During a true epidemic, formal testing might not be indicated as the decision to treat is based on treatment criteria like age, comorbidities, and severity of illness.
Nachi: We’ll get to treatment in a few minutes, but diving a bit deeper into testing - there are 3 major categories of tests. The first detects influenza A only. The second detects either A or B, but cannot distinguish between them; and the third detects both influenza A and B and is subtype specific. The majority of rapid testing kits will distinguish between influenza A and B, but not all can distinguish between them. Fluorescent antibody testing by DFA is relatively rapid and yields results within 2 to 4 hours.
Jeff: Viral culture and RT-PCR remain the gold standard, but both require more time and money, as well as a specialized lab. As a result, rapid testing modalities are recommended. Multiple studies have shown significant benefit to the usefulness of positive results on rapid testing. It’s safe to say that at a minimum, rapid testing helps decrease delays in treatment and management.
Nachi: Looking a bit further into the testing characteristics, don’t forget that the positive predictive value of testing is affected by the prevalence of influenza. In periods of low influenza activity (as in the summer), a rapid test will have low PPV and high NPV. The test is more likely to yield false positive results -- up to 50% according to one study when prevalence is below 5%.
Jeff: And conversely, in periods of high influenza activity, a rapid test will have higher PPV and lower NPV, and it is more likely to produce a false negative result.
Nachi: In one prospective study of patients who presented with influenza-like illness during peak season, rapid testing was found to be no better than clinical judgement. During these times, it’s probably better to reserve testing for extremely ill patients in whom diagnostic closure is particularly important. And since the quality of the specimen remains important, empiric treatment of critically ill patients should still be considered.
Jeff: Which is a perfect segway into our next topic - treatment, which is certainly the most interesting section of this article. To start off -- for mild to moderate disease and no underlying high risk conditions, supportive therapy is usually sufficient.
Nachi: Antiviral therapy is reserved for those with a predicted severe disease course or with high risk conditions like long-standing pulmonary disease, pregnancy, immunocompromise, or even just being elderly.
Jeff: Note to self, avoid being elderly.
Nachi: Good luck with that. Anyway, early treatment with antivirals has been shown to reduce influenza-related complications in both children and adults.
Jeff: Once you’ve decided to treat the patient, there are two primary classes of antivirals -- adamantane derivatives and neuraminidase inhibitors. Oh and then there is a new single dose oral antiviral that was just approved by the FDA… baloxavir marboxil (or xofluza), which is in a class of its own -- a polymerase endonuclease inhibitor.
Nachi: The oldest class, the adamantane derivatives, includes amantadine and rimantadine. Then the newer class of neuraminidase inhibitors includes oseltamavir (which is taken by mouth), zanamavir (which is inhaled), and peramivir (which is administered by IV).
Jeff: Oseltamavir is currently approved for patients of all ages. A 2015 meta analysis showed that the intention-to-treat infected population had a shorter time to alleviation of all symptoms from 123 hours to 98 hours. That’s over a day less of symptoms, not bad! There were also fewer lower respiratory tract complications requiring antibiotics and fewer admissions for any cause. Really, not bad!
Nachi: Zanamavir is approved for patients 7 and older -- or for children 5 or older for disease prevention. Zanamavir has been associated with possible bronchospasm and is contraindicated in patients with reactive airway disease.
Jeff: Peramivir, the newest drug in this class, is given as a single IV dose for patients with uncomplicated influenza who have been sick for 2 days or less. Peramavir is approved for patients 2 or older. This is a particularly great choice for a vomiting patient.
Nachi: And as you mentioned before, just last month, the FDA approved baloxavir, a single dose antiviral. It’s effective for influenza type A or B. Note that safety and efficacy have not been established for patients less than 12 years old, weighing less than 40 kg, or pregnant or lactating patients.
Jeff: Unfortunately, there has been some pretty notable antiviral resistance in the recent past, moreso with the adamantane class, but recently also with the neuraminidase inhibitors. In 2007-2008, an oseltamivir-resistant H1N1 strain emerged globally. Luckily, cross-resistance between baloxavir and the adamantanes or neuraminidase inhibitors isn’t expected, as they target different viral proteins, so this may be an answer this year, and in the future.
Nachi: Let’s talk chemoprophylaxis for influenza.. Chemoprophylaxis with oseltamavir or zanamavir can be considered for patients who are at high risk for complications and were exposed to influenza in the first 2 weeks following vaccination, patients who are at high risk for complications and cannot receive the vaccination, and those who are immunocompromised.
Jeff: Chemoprophylaxis is also recommended for pregnant women. For postexposure prophylaxis for pregnant women, the current recommendation is to administer oseltamivir.
Nachi: We should also discuss the efficacy of treatment with antivirals. This has been a hotly debated topic, especially with regards to cost versus benefit… In a meta-analysis, using time to alleviation of symptoms as the primary endpoint, oseltamavir resulted in an efficacy of 73% (with a wide 95% CI from 33% to 89%). And this was with dose of 150mg/day in a symptomatic influenza patient.
Jeff: Similarly zanamavir given at 10mg/day was 62% effective, but again with a wide 95% CI from 15% to 83%. And, of note, other studies have looked into peramivir, but have found no significant benefits other than the route of delivery.
Nachi: In another 2014 study by Muthuri et al., neuraminidase inhibitors were associated with a reduction in mortality -- adjusted OR = 0.81 (with a 95% CI 0.70 to 0.93). Also when comparing late treatment with early treatment (that is, within 2 days of symptom onset), there was a reduction in mortality risk with adjusted OR 0.48 (95%CI 0.41-0.56). These associations with reduction in mortality risk were less pronounced and less significant in children.
Jeff: Mortality benefit, not bad! They further found an increase in mortality hazard ratio with each day’s delay in initiation of treatment up to 5 days, when compared to treatment initiated within 2 days.
Nachi: But back to the children for a second -- another review of neuraminidase inhibitors in children < 12 years old found duration of clinical symptoms was reduced by 36 hours among previously healthy children taking oseltamivir and 30 hours by children taking zanamivir.
Jeff: I think that’s worth summarizing - According to this month’s author’s review of the best current evidence, use of neuraminidase inhibitors is recommended, especially if started within 2 days, for elderly patients and those with comorbidities.
Nachi: Seems like there is decent data to support that conclusion. But let’s not forget that these medications all have side effects.
Jeff: These drugs actually tend to be well tolerated.The most frequently noted side effect of oseltamavir is nausea and vomiting, while zanamavir is associated with diarrhea.
Nachi: Amazing. Let’s talk disposition for your influenza patient.
Jeff: Disposition will depend on many clinical factors, like age, respiratory status, oxygen saturation, comorbid conditions, and reliability of follow up care. Admission might be needed not only to manage the viral infection, but also expected complications.
Nachi: If you’re discharging a patient, be sure to engage in shared decision making regarding risks and benefits of available treatments. Ensure outpatient follow up and discuss return to er precautions.
Jeff: Also, the CDC recommends that these patients stay home for at least 24 hours after their fever has broken.
Nachi: With that -- Let’s summarize the key points and clinical pearls from this month’s issue
Even though influenza vaccine effectiveness is typically only 50%, this still translates to a decrease in influenza-related morbidity and mortality.
The CDC defines influenza-like illness as a temperature > 100 F with either cough or sore throat, in the absence of a known cause other than influenza.
When influenza is suspected in the prehospital setting, patients and providers should wear face masks to avoid spreading the virus.
In the emergency department, standard isolation and droplet precautions should be maintained for suspected or confirmed infections.
The most common symptoms of influenza in adults are cough, fatigue, nasal congestion, and fever. Sneezing is a negative predictor in adults.
In children, the most common presenting symptoms are fever, cough, and rhinitis. Vomiting and diarrhea is also more common in children than adults.
Rapid testing and identification results in decreased delays in treatment and management decisions.
During peak flu season, clinical judgement may be as good as rapid testing, making rapid testing less necessary.
Rapid testing may be more beneficial in times of lower disease prevalence.
Empiric treatment of critically ill patients should be considered even if rapid testing is negative.
For mild to moderate disease and no underlying high-risk conditions, supportive therapy is usually sufficient.
For more ill patients or those at substantial risk for complications, consider antiviral treatment.
Oseltamivir is approved for patients of all ages, and reduces the length of symptoms by one day.
When treating influenza, peramivir is an ideal agent for the vomiting patient.
Baloxavir is a new single-dose antiviral agent approved by the FDA in October 2018. It works in a novel way and is effective for treatment of influenza A and B.
Chemoprophylaxis with oseltamivir or zanamivir should be considered in patients who are immunocompromised or patients who are at elevated risk for complications and cannot receive the vaccination.
Consider oseltamivir as post exposure prophylaxis in pregnant women.
Neuraminidase inhibitors are associated with decreased duration of symptoms and complications, especially if started within 2 days of symptom onset.
Jeff: So that wraps up episode 23 - Influenza: Diagnosis and Management in the Emergency Department.
Nachi: Additional materials are available on our website for Emergency Medicine Practice subscribers. For our subscribers: be sure to go online to get your CME credit for this issue, which includes 3 pharmacology CME credits.
Jeff: Also, for our NP and PA listeners, we have a special offer this month: You can get a full year of access to Emergency Medicine Practice for just $199--including lots of pharmacology, stroke, and trauma CME--and so much more! To get this special deal, go to www.ebmedicine.net/APP.
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Jeff: And the address for this month’s credit is ebmedicine.net/E1218. As always, the you heard throughout the episode corresponds to the answers to the CME questions. Lastly, be sure to find us on iTunes and rate us or leave comments there. You can also email us directly at firstname.lastname@example.org with any comments or suggestions. Talk to you next month!