Flu Season is Here! A Refresher for Osteopathic Family Physicians
Vaccinations and treatments for influenza, a virus that accounts for 36,000 deaths annually
By Jeffrey T. Kirchner, DO
Influenza or the “flu” as it is commonly known has been a scourge to the medical community for hundreds of years. The term “influenza” dates back to 1357 AD, coming from the Italian word meaning “influence”.1 Popular belief at that time blamed the development of flu on the influence of the stars. The great influenza pandemic of 1918-19 resulted in millions of deaths in persons between the ages of 20 and 40 years. Four times as many Americans actually died from influenza than on the battlefields of France. By the time the epidemic ended, the H1N1 strain of influenza A claimed the lives of 25-50 million people, including more than 500,000 in the United States.2
Despite the availability of an influenza vaccine since the early 1950’s, the flu still affects about 95 million people worldwide each year, including 20 million in the United States. The incidence in the United States is highest in young and school age children from three months to 16 years.3 However, the morbidity and mortality due to acute influenza is highest in those over the age of 65 years, and with underlying medical conditions. This illness accounts for an average 226,000 hospitalizations and 36,000 deaths annually – numbers that have not changed for the past 10 years.4 Costs to society in terms of direct medical costs as well as indirect costs due to time missed from work by those affected, are substantial. The influenza vaccine is the most effective way for preventing this illness and its subsequent complications.
Influenza is primarily an acute respiratory illness that produces marked inflammation of the pharynx, nasal mucosa, conjunctiva, and respiratory tract. Influenza tends to occur primarily during cold weather or the winter season, producing large outbreaks and epidemics worldwide.
The disease can be caused by three types of influenza virus - types A, B or C. These single-stranded RNA viruses share similar virologic and structural properties but vary antigenically. Influenza A has two specific hemagglutinin (HA) and neuraminidase (NA) surface proteins which is how the virus is sub-typed. It can cause disease in both humans and birds - both domestic and wild.
It is the H5N1 strain that causes avian influenza and has been the source of significant concern over the past few years.4 Type B is separated into distinct genetic lineages but not subtypes. It is found only in humans and in general is associated with less severe epidemics than type A.
New variants of the influenza virus result from point mutations during replication (antigenic drift). Antibody to one of these subtypes does not confer immunity against new strains. Thus, individuals can become infected with influenza viruses more than once. This is the basis for national global surveillance and the need for changes in the annual production and administration of influenza vaccine.
Antigenic shift refers to an abrupt and major change that produces a novel subtype of influenza A. Such a shift may occur from direct animal-to-human transmission of the virus or a mixing of human and animal influenza A strains that would create a new human subtype. This process is known as genetic reassortment. A global pandemic could occur if three circumstances were met: the introduction of a new influenza A subtype into the human population; the virus causing serious illness in humans; and increased ease of sustained person to person transmission.5
The virus is primarily transmitted from person to person via large-particle respiratory droplet transmissions or less commonly via the inhalation of small-particle aerosols which contain the virus. Contact with virally-contaminated surfaces is another possible mode of transmission. Those at greatest risk for contracting the disease include persons in closed environments such as nursing homes, schools, or prisons. Large inoculums of the virus have been found in the respiratory secretions of those infected. Viral transmission may occur via sneezing, coughing, or simply talking. Adults are noted to be infectious to others from about one day prior to onset of symptoms through day five of the illness. Children and immunocompromised persons can shed the virus for 10 days to several weeks.4
Clinical Manifestations
After an incubation period of one to four days (two on average), infected individuals most commonly present with abrupt onset of fever and cough. The fever may range from 100°-104°F. In some instances, patients can recall the exact time when they began feeling ill. The clinical manifestations of influenza also include myalgias, sore throat, headache, nasal congestion with rhinorrhea, and sneezing. Cervical lymphadenopathy may be present in younger persons. The presence of gastrointestinal symptoms such as nausea and vomiting occurs in children but such symptoms in adults should suggest an alternative diagnosis.3,6
During the flu season, clinical diagnosis for most physicians would seem easy, although this is not always the case. One systematic review of 16 studies determined that clinical findings in patients with “influenza-like” illness are not particularly useful for confirming or excluding the diagnosis.7 However, another study by Monto et al found that a clinical diagnosis can be made with a reasonable degree of certainty during an influenza outbreak.8 This study found that the combination of fever and cough within 48 hours of development of symptoms had a positive predictive value of 79 percent and a sensitivity of 64 percent in adults and adolescents who had laboratory-documented influenza.
A more recent study of pediatric patients, however found the positive predictive value of these same symptoms to be only about 60 percent.9 It must be cautioned that many other respiratory pathogens will cause similar symptoms include rhinovirus, respiratory syncytial virus, coronavirus, adenovirus, and parainfluenza. Additional conditions to consider in the differential diagnosis of persons presenting with “flu-like” symptoms include viral pharyngitis, “atypical” (Mycoplasma or Chlamydial) pneumonia, and infectious mononucleosis. Updated information regarding influenza is provided by the CDC and can be found at www.cdc.gov/flu/weekly/fluactivity.htm.
Complications
The majority of persons infected with the influenza virus will have an uncomplicated clinical course that lasts about three days until signs of improvement are noted. Systemic symptoms tend to abate first followed by diminishing cough and fatigue. However, for others it may take as long as two weeks until they feel completely well. Acute bronchitis is the most commonly recognized complication of acute influenza.3
Sinusitis and otitis media may also occur, especially in children. Febrile seizures are also seen in six to 20 percent of children admitted to the hospital and found to have acute influenza.4
Pneumonia is the most significant complication of influenza, affecting high-risk patients such as those with underlying cardiac or pulmonary disease, immunosuppression or the elderly. It frequently leads to the need for hospitalization and accounts for more than 25 percent of influenza-related deaths.6 Primary influenza pneumonia occurs from direct infection of lung tissue by the virus. It can be quite severe but is relatively uncommon. More notable are secondary bacterial infections. The direct effect of the influenza virus on tracheobronchial epithelium with destruction of cilia is felt to be the key predisposing factor. The most common pathogen is Streptococcus pneumoniae but pneumonia may also be caused by Staphylococcus aureus and Haemophilus influenzae. Other potential but infrequent complications include toxic shock syndrome (secondary to S. aureus), myositis, rhabdomyolysis, pericarditis, and myocarditis. Neurologic sequelae that have been observed include meningitis, encephalitis, transverse myelitis, and Guillain-Barre syndrome.4,6
Diagnosis
As previously noted, making a clinical diagnosis of influenza can sometimes be difficult during the winter season, especially when influenza is known to be present in the community. Diagnostic testing does have a role in certain circumstances. These include confirming a suspected outbreak in the community or nursing home setting, or in what appears to be atypical cases of influenza.3,4 Another scenario where testing may be useful is in a severely ill patient requiring hospitalization. In general, diagnostic testing should be done if it will impact clinical decision making such as administering or withholding specific treatments or institution of infection control measures.
Testing by viral culture is the gold-standard but this may take three days or longer for results. Serologic testing is also available but again requires paired titers obtained 10-14 days apart. Polymerase chain reaction (PCR) testing is very sensitive for detection of low levels of viral RNA in nasal specimens but is limited by cost and false-positive results. The preferred method to diagnose acute influenza is with rapid testing.9 There are currently a large number of FDA-approved and CLIA-waived diagnostic tests for influenza. These are usually performed with a nasal swab and some are able to distinguish between Influenza A and B. The general sensitivity of the rapid tests is reported to be about 70 percent and the specificity about 90 percent, although this data is variable among studies. The tests appear to be most accurate if performed within the first day or two of the appearance of symptoms when there is peak viral-shedding. Nasal sampling also has a better diagnostic yield than using a pharyngeal swab.
Additional diagnostic testing such a chest radiograph, cultures, or blood work in patients thought to have acute influenza should be guided mainly by symptoms and clinical findings. Otherwise, they are rarely beneficial.
Treatment and Prophylaxis
The majority of patients with acute influenza can be treated symptomatically. Hydration to replace fluid loss from fever is important. Acetaminophen or ibuprofen may provide antipyretic and analgesic benefits, reducing the severity of fever and myalgias. However, there is no good evidence that antipyretic therapy reduces the duration of illness.
Antiviral agents are available for treating patients with acute influenza. Prior to the 2005-06 flu season, amantadine and rimantidine were often used. However, resistance to these drugs have precluded their use and they are no longer recommended.4 Two agents, zanamivir (Relenza®) and oseltamivir (Tamiflu®) are approved for uncomplicated cases of influenza A and B. These agents inhibit neuraminidase, a glycolated viral envelope protein required for viral release and transmission in the body. Zanamivir is given as two 10-mg inhalations daily and oseltamivir is dosed 75-mg orally twice daily for five days. Ideally these agents should be given within 48 hours of onset of symptoms, if not sooner. Their primary effect is to shorten the duration of illness by about 24 hours and potentially reduce the risk of serious complications.3 This may be important for elderly and immunocompromised patients. Both drugs are listed as Category C for use in pregnancy which means there is insufficient data to assess clinical safety in this patient population. These agents should only be used in this situation if maternal benefits outweigh risks to the fetus.4 However, the decision to treat with one of these two drugs should be made on an individual basis as they are relatively expensive ($80 - $100 per course of therapy) and have associated toxicities.
Potential side effects of zanamivir are nausea, vomiting, and headache. Oseltamivir may cause bronchospasm and should be used cautiously in persons with a history of asthma, COPD or other lung disease. Zanamivir may be used in children age five and older. Oseltamivir also has a pediatric indication for children age one year and older.
Both of these drugs are also FDA approved for prophylaxis in controlling influenza outbreaks in institutions or households.4 The prophylactic dose of each agent is one-half the therapeutic dose and they may be given as an adjunct to administration of influenza vaccine, or for persons in whom vaccine administration is contraindicated. Zanamivir is only licensed for prophylaxis in children age seven years and older.
Vaccination
The most important component of influenza prevention is appropriate yearly administration of influenza vaccine for all persons indicated per current CDC guidelines. (see Table 1). There is very strong data from prospective studies to show influenza vaccine is cost-effective but also results in decreased rates of hospitalization and mortality, especially in high-risk populations.3 The CDC recommendations have been expanded in recent years and now include children aged six to 59 months, women who are pregnant during flu season, persons who are HIV-infected, healthy household members of at-risk persons, and all adults age 50 years and over. All physicians and nurses should be vaccinated, but historically (and perhaps ironically) healthcare workers have had low vaccinations rates.11
The two vaccines currently available in the United States include the trivalent inactivated vaccine (TIV) and the live-attenuated influenza vaccine (LAIV). Both vaccines contain two strains of influenza A and one strain of influenza B virus. The LAIV can be given via a nasal spray but is currently only approved for healthy, non-pregnant persons aged five to 49 years.
Influenza vaccine should ideally be given in October or November, but can be offered throughout the winter. As influenza season typically does not peak until February or March, it is still reasonable to vaccinate persons well into the winter months. Nursing home patients should not be immunized before October as antibody levels may wane before the end of flu season. Also of note is that children aged six months to eight years who receive the vaccine for the first time should get two doses separated by six weeks.4
There are few contraindications to influenza vaccine. The TIV should not be given to persons with a history of anaphylactic reactions to eggs or other vaccine components. Persons presenting with an acute febrile illness should not be vaccinated until their symptoms abate. The vaccine can safely be given during illness in which fever is absent or mild.4
Dr. Kirchner is a 1985 graduate of the Philadelphia College of Osteopathic Medicine. He completed a rotating internship at the Osteopathic Medical Center of Philadelphia and his residency in Family Practice at Abington Memorial Hospital. He is board-certified by the American Board of Family Medicine and as an HIV specialist by the American Academy of HIV Medicine.
References: