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Influenza - 2/5/2013

posted Feb 5, 2013, 6:06 AM by Rohit Das   [ updated Feb 5, 2013, 6:35 AM by Purnema Madahar ]

Thought it would be fitting to write about Influenza at some point this month…over the past 5-6 weeks, influenza has become an epidemic in New York City, Boston and several other areas in the U.S. Influenza is a very interesting, complicated virus that has caused significant morbidity and mortality over at least the past four centuries, if not longer, so definitely worth talking about…

·         What is the epidemiology of influenza and its burden on the health care system?

·         What is the difference between influenza pandemics and epidemics, from both a population and molecular perspective? 

·         What are the key clinical manifestations? How is it diagnosed?

·         What are the main complications of influenza, and how is it best treated?

·         What are the different types of vaccines and what is their efficacy?

What is the epidemiology of influenza and its burden on the health care system?

·     Before getting into some recent numbers, I’d like to touch on some history. Outbreaks of febrile, respiratory illnesses have been documented for about 400 years. We began to have a scientific understanding of Influenza in 1933, when Influenza A was isolated from ferrets. Influenza B was discovered subsequently in 1939, and Influenza C (yes, there’s a “C”) in 1950. After discovery of the virus, vigorous work was done on development of inactivated vaccines, which began to be implemented in 1940…the first live vaccine was not licensed until 2003. Oseltamivir, the drug we primarily use to treat influenza A and B, was FDA approved in 2000.

·         In temperate climates, like ours, influenza exclusively occurs in the winter months, and has an attack rate of approximately 10-20% in the unvaccinated population, but has been reported to be as high as 40-50%. Influenza generally follows a “U” shaped epidemic curve – that is, attack rates are highest in the young population, whereas mortality rates are highest in the elderly population…some numbers – studies show that influenza leads to around 15 million excess respiratory illness per year in those <20 years of age, and around 4 million excess respiratory illnesses in older individuals.

·      The mortality due to influenza is tabulated as “Pneumonia-Related and Influenza-Related Excess Death,” which essentially is a comparative calculation assessing the mortality difference due to an epidemic as compared to expected seasonal baseline calculations. Over the last 20 years or so, this number has ranged from 2,000 to 12,000, with the worst years being when Influenza A strains predominate. “All-Cause Excess Deaths” are also tabulated, and range from 8,000 to 40,000, again correlating with Influenza A predominance. Both of these estimates are probably underestimates to a degree.

·         Morbidity related to influenza is also a big issue – each case of influenza is associated with, on average, 5-6 days of restricted activity, 3-4 days of bed disability and 3 days lost from work or school. Only a small proportion of the economic impact of influenza is due to direct medical costs (10-15%); the majority is actually due to decreased productivity (40-50%).

What is the difference between influenza pandemics and epidemics, from both a population and molecular perspective? 

·         Some nomenclature – influenza is of the Orthomyxo-something or other virus family, and is classified as influenza A, B or C based on significant antigenic differences. Viruses are then named by their type, place of initial isolation, strain designation, and year of isolation (e.g., the eight strain isolated in Puerto Rico in 1934 was called A/Puerto Rico/8/34…yea, confusing…). Infuenza A strains are then subtyped based on their hemagglutinin antigen (of which 16 have been identified) and neuraminidase (of which 9 have been identified).

·        Epidemics and pandemics of influenza refer mainly to Influenza A and it’s subtle and sometimes not-so-subtle antigenic changes. Though influenza B and C do undergo antigenic drift (shall go over this), their clinical impact is nowhere near as significant as influenza A. Influenza B can cause severe disease in at-risk patients, and Influenza C is a non-seasonal illness that rarely, if ever, leads to complications.

·       Epidemics are defined as disease incidence, within a given population during a given time, which substantially exceeds what is “expected” for that population during that given time. Epidemics are limited to one location, which can be a city, town, country, etc., and typically maintain the expected seasonality. Pandemics, from a population and clinical standpoint, are on a much larger scale – they involve large parts of the world, are characterized by extremely rapid transmission, occur outside typical seasonality, have high attack rates that are age-independent, and lead to significant mortality, particularly in young healthy individuals. The last pandemic was in March 2009, at which time a novel swine H1N1 Influenza A virus emerged that involved nearly 200 countries and killed at least 12,000 people. The largest documented pandemic EVER was in 1918-1919, which led to over 21 million deaths worldwide (of which around 600,000 were in the U.S.).

·    So...why does Influenza A have the ability to cause epidemics and pandemics? The answer lies in its ability to change the structure of its immunologically active antigens – specifically hemagglutinin (HA - mediates host-cell membrane attachment) and neuraminidase (NA – helps with releasing virions from infected cells by cleaving sialic acid containing membrane glycoproteins); the antibodies we develop against HA are particularly important for our immune response, as they neutralize influenza’s infectivity. So, when populations are exposed to an influenza virus, they develop immunity via anti-HA and anti-NA antibodies – the epidemiologic and clinical impact of subsequent infection is then determined by how much the virus’s antigenicity has changed…so how does it change???

o   Antigenic drift – all influenza viruses, as mentioned, are capable of this phenomenon. Best studied for the HA antigen, what this refers to is gradual accumulation of amino acid changes in one or more of the five antigenic sites on HA. As the virus drifts over time, antigenic variants become selected for (because we develop immunity to viruses that haven’t drifted…), and ultimately lead to epidemic level disease. It’s thought that at least 2 of the antigenic sites on HA need to be altered to have a clinical impact. This process…gradual antigenic drift, accumulation of viruses with antigen variants, and epidemic influenza, occurs regularly in 1-3 year intervals between pandemics.

o   Antigenic shift – this is the real deal. Antigenic shift heralds pandemic influenza, and essentially represents influenza A viruses that have “new” HA or NA antigens that have little to no serologic relationship between the HA and NA of “old” influenza A viruses. We thus have no immunity against them, therefore leading to pandemics. Pandemics are not as predictable as epidemics, but historically, seem to be occurring every 10-30 years. Since influenza A can harbor itself in many different species (us, swine, birds, marine mammals…even recently isolated from dogs and cats), it’s thought that reassortment of human and non-human (especially avine) influenza A strains is what leads to pandemic disease.


What are the key clinical manifestations on uncomplicated Influenza? How is it diagnosed?

·      Influenza incubates for 1-2 days before typically causing abrupt onset of symptoms, and many patients can pinpoint the hour of onset. Systemic symptoms predominate initially – fever, headaches, myalgia, fatigue…etc. Upper respiratory symptoms are also usually present at onset, but often overshadowed by the systemic complaints (which is a key differentiating factor from other viral URIs). Older patients may not manifest respiratory symptoms at all.

·     On exam, fever is the most important finding – it is usually high, peaks within 12 hours of onset of symptoms, and subsides over an average of 3 days (though can be as long as 8 days). In uncomplicated cases, lung findings are found in only 10-15% of cases.

·         In the setting of an outbreak, diagnosis can be made very accurately based on clinical grounds alone. In a pooled retrospective study of nearly 4000 patients, the combination of fever and cough within 48 hours of symptom onset had a PPV of around 85% - yet another reinforcement of the predictive power of high pre-test probability and a good history.

·      Otherwise, the main diagnostic test we use is a rapid antigen assay for Influenza A and B antigens. A pooled meta analysis has calculated the sensitivity of the assay to be around 54%, with a specificity of around 98%. The sensitivity of the test is very dependent on the time course of the illness – since viral shedding peaks in the first 24-48 hours, sensitivity is highest in that timeframe, and rapidly declines thereafter. PCR is a more accurate test, but generally takes time to come back and is therefore not helpful for initial management.


What are the main complications of influenza, and how is it best treated?

·         There are two main pulmonary complications of influenza:

o   Primary Viral Pneumonia – this mostly occurs in patients with cardiovascular comorbidities. It presents initially much like uncomplicated influenza, but has a rapidly worsening course with persistent fever, dyspnea and marked hypoxia/ARDS. Imaging will reveal diffuse bilateral infiltrates (like ARDS), but no consolidation. Though a rare complication, mortality is very high.

o   Secondary Bacterial Pnuemonia – the classic history here is influenza like symptoms initially, a period of improvement for 4-10 days, then recurrence of symptoms with a bacterial picture – cough with gunk, fever, and consolidation on chest imaging. This occurs most commonly in older patients with chronic comorbidities. For unclear reasons, community acquired Staph. aureus is a common pathogen, along with your run of the mill bugs.

·         There are case reports of other complications of influenza, including myositis, myopericarditis, Guillan-Barre Syndrome and Reye’s Syndrome (in children, obviously)…

·       So, regarding treatment – the most important thing to realize is that immunocompetent people are very good at treating themselves – within 48 hours, our immune system is efficient at limiting viral replication, and thus the window for benefit is really within the first 36 hours of symptom onset.

o   Oseltamivir is the agent we usually use – it is an inhibitor of the influenza virus neuaraminidase, metabolized in the liver, excreted by the kidney, and pretty commonly leads to GI side effects (around 10% - nausea, diarrhea, abdominal bloating) but is otherwise very well tolerated.

o   Regarding Oseltamivir’s efficacy, studies in uncomplicated influenza patients have shown that if initiated within 36 hours of onset, duration of symptoms decreased by 30-40%, and patients returned to work significantly earlier. In pooled metaanalyses from phase III trials, in high risk patients, Oseltamivir also has been shown to significantly decrease the rate of complications requiring antimicrobials.

o   In 2007-2008, oseltamivir-resistant H1N1 strains were isolated, which reportedly occurred in patients who had NOT received oseltamivir previously. The resistance seemed to be due to a single, sporadic mutation in one amino acid of the NA antigen (H275Y mutation). Fortunately, there is no evidence of ongoing transmission of this strain, and it has not had a significant public health impact…but it has provided an arena for pharmaceutical companies to get busy!!

·         So who gets treatment??…well this daily is already long enough, so I ask that you refer to the 2011 CDC recommendations, page 9, Box 1 for a succinct answer.


What are the different types of vaccines and what is their efficacy?

·         As mentioned above, chemically inactivated influenza vaccines were first licensed and used in 1934. Each year, in February/March, collaborators from the WHO and advisory committees from the CDC and FDA decide which antigenic variants of the three major circulating strains (currently Influenza A H1N1, Influenza A H3N2, and influenza B) are most likely to cause epidemic disease, and concoct the vaccine based on those conclusions. Often, however, new variants emerge after the vaccine is created, and studies show that 80% of epidemics are due to such strains.

·       After vaccination, therapeutic levels of serum antibodies are present by 2-3 weeks, and peak around 2-3 months, but quickly fall thereafter. The reported vaccine efficacy (defined as the decrease in incidence of disease in vaccinated patients as compared to unvaccinated patients) is around 75%, but can be as high as 90% if the vaccine is lucky enough to accurately match the epidemic strain, and can be as low as 55% in older adults and other patients who aren't able to initiate an adequate immune response.

·        There is also a live-attenuated virus, first licensed in 2003, administered via nasal spray, and recommended for the 5 to 49 year-old age group. Since older adults have a low rate of antibody response with the live vaccine, it is not recommended for patients older than 49. Studies comparing the live and inactivated vaccine have shown pretty much equal efficacy. Overall, the live vaccine is best for children, where the magnitude of the immune response is high and the incidence of needle-phobia is especially high…

·         The inactivated vaccine is very safe. Despite what our patients tell us, the incidence of transient low-grade fever, though common (up to 10%) is not significantly higher than placebo. Local soarness (big deal…) occurs in up to 60-80% of patients. Since the vaccine is created in chicken eggs, a hypersensitivity history to eggs is a contraindication.

·         Who gets the vaccine? Well, the third heading of the CDC recommendation reads “Any person who wishes to avoid influenza.” So yea, everyone.


After reading about Influenza, I find it absolutely fascinating. I've attached a textbook chapter to this daily, as I feel this topic is deserving of such depth. Also attached are the CDC guidelines for treatment. Enjoy.

Influenza Viruses, Including Avian Influenza and Swine Influenza
Treanor et. al., Mandell, Douglas and Bennett's Principles and Practice of Infectious Disease, 7th Ed, 2009

Fiore et. al., CDC Recommendations and Reports 2011, Volume 60 (1): 1-18