Jonathan S. Olshaker
More people died in the 1918 influenza pandemic than in all of World War I. Today, influenza remains a major killer and causes more morbidity and mortality than the acquired immunodeficiency syndrome (AIDS). In nonpandemic years, 20,000 to 40,000 persons die of influenza-related illness in the United States alone (1); in pandemic years, deaths can exceed 100,000. Influenza infections account for tremendous health care expenditures each year. The Centers for Disease Control and Prevention (CDC) estimates that there are between 114,000 and 146,000 hospitalizations per year, with the highest rates of both hospitalization and death being among the elderly and in children younger than 2 years old (2,3).
Influenza is caused by large RNA viruses belonging to the myxovirus groups. Of the three immunologically distinct groups (A, B, and C), influenza A and B are encountered most frequently. Group A is responsible for the majority of the mortality and significant morbidity. It appears to cause more severe disease than type B, making secondary bacterial infection more likely, and is more common in older populations. The disease is spread by large-particle respiratory droplet transmission through coughing or sneezing. The typical incubation period is 1 to 4 days. Adults can be infectious from the day before symptoms begin through 5 days after illness onset. Children can be infectious for more than 10 days after symptom onset.
CLINICAL PRESENTATION
Influenza is an extremely common respiratory illness, characterized by the abrupt onset of fever, sore throat, headache, myalgias, and nonproductive cough. The malaise is often much more extreme than that seen with most other common respiratory illnesses. During an influenza outbreak, influenza can be diagnosed by clinical criteria with a high degree of certainty, with exceptions being in the elderly and in very young children. Young children can present more atypically, often with otitis media, nausea, vomiting, and less prominent respiratory symptoms. In addition, they can present with febrile seizures and symptoms mimicking bacterial sepsis. Symptoms last from a few days to a week in most patients. More severe illness can result if there is pulmonary involvement due to primary viral or secondary bacterial pneumonia, which is the most common cause of death. The vast majority of severe disease occurs in the elderly, the immunosuppressed, patients with chronic cardiovascular or pulmonary disease, and in young children. In addition, pregnancy can increase the risk for serious complications from influenza.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of influenza includes the myriad respiratory and infectious diseases seen in the emergency department (ED). The clinician’s major task should be to recognize serious illness that requires specific antibiotic treatment or other aggressive interventions.
Prominent severe headache, meningeal signs, or changes in mental status make it mandatory to rule out meningitis. Sore throat, often seen with influenza, may be due to peritonsillar abscess, epiglottitis, or streptococcal pharyngitis. Myalgia may be due to bacteremia or sepsis, particularly in the elderly. A finding of hypotension or marked orthostasis mandates evaluation for sepsis or toxic shock syndrome, particularly if there is evidence of multiple organ system involvement. Cough or difficulty breathing may be due to bacterial or viral pneumonia, acute bronchospasm, or cardiac processes such as congestive heart failure or myocardial ischemia.
Unfortunately, the differentiation of viral from bacterial pneumonia in the patient with influenza is difficult. Antibiotics should be instituted early if there is any suspicion of a bacterial process.
In the spring of April 2009, an outbreak of H1N1 influenza A virus was observed in many countries, including the United States. In June 2009, the World Health Organization raised its pandemic alert to the highest level, indicating widespread transmission of the disease. The pandemic was not declared to be over until August 2010. In the past few years another major public health concern is the possibility of avian influenza turning into a pandemic. Avian flu is an influenza A virus found chiefly in birds, but isolated human cases have been found in Asia, parts of Europe, the Middle East, and Africa, usually after direct contact with infected poultry. In late March and April 2013, human cases of novel avian influenza A H7N9 infection in China were reported to the World Health Organization. The reported case fatality rates have been alarmingly high, exceeding 50%. Current seasonal influenza vaccines provide no protection against human infection with avian influenza A viruses (4).
ED EVALUATION
The initial evaluation of influenza and influenza-like illness should focus on assessment of the airway, breathing, and circulation. Pulse oximetry is a simple noninvasive test that may provide a quick indication of respiratory compromise. Physical examination should focus on the heart and lungs. A thorough examination of the skin should include a search for any cutaneous manifestations of infectious disease, such as purpura or petechiae.
Patients with significant cough, respiratory symptoms, or abnormalities on lung examination should have a chest radiograph. Lumbar puncture and urinalysis may be indicated if suggested by appropriate symptoms. A complete blood cell count, though nonspecific, may lend support to a diagnosis of superimposed bacterial infection. Tests to determine levels of electrolytes, blood urea nitrogen, creatinine, and blood glucose should be ordered in those patients with severe derangements of fluid balance or in those who have chronic medical problems or take medications, such as diuretics, that can affect electrolyte balance. Arterial blood gas analysis and serum lactate may be appropriate when hypoxia or sepsis is suspected. Blood cultures should also be obtained if sepsis is a possibility.
Rapid ED influenza tests are readily available. They are immunoassays that can identify influenza A and B viral nucleoprotein antigens in respiratory specimens. Unfortunately, their poor sensitivity limits their usefulness, particularly in high-risk individuals (5). In a meta-analysis of 159 studies that evaluated rapid antigen tests, the pooled sensitivity was 62.3% and the pooled specificity was 98.2% (6). The sensitivity was lower in adults than children and higher for influenza A than influenza B. Thus, a negative result should be interpreted with caution and treatment should not be delayed in high-risk individuals if influenza is suspected. Small studies have shown that awareness of a positive rapid influenza test result in pediatric ED patients can reduce the number of laboratory tests and radiographs, decrease antibiotic use, and increase the use of antiviral drugs (7,8).
Reverse transcriptase polymerase chain reaction (RT-PCR) is the most sensitive and specific test for a relatively rapid identification of influenza. Its use in the ED is still limited because results may not be available for 4 to 6 hours or even longer.
In the past, viral culture has been considered the gold standard for laboratory diagnosis, but results often take 4 to 12 hours and limit any benefit for initial clinical management.
KEY TESTING
• CXR if significant respiratory symptoms
• CBC for suspected superimposed bacterial infection
• Electrolytes, BUN, creatinine, glucose if dehydrated
• Influenza diagnostic testing (rapid or PCR) to confirm diagnosis
ED MANAGEMENT
The initial treatment for patients with suspected influenza is directed at ensuring adequate oxygenation and hemodynamic stability. Patients with viral or bacterial pneumonia, particularly the elderly or those with chronic obstructive pulmonary disease, can present in extremis with an immediate need for endotracheal intubation and mechanical ventilation. Supplemental oxygen should be given to patients with significant respiratory symptoms or low pulse oximeter readings. Although it is not viewed as standard of care, one study showed that referral to a center where extracorporeal membrane oxygenation was available reduced mortality among patients with severe 2009 influenza H1N1 infection (9).
Patients who are tachycardic, hypotensive, or orthostatic should have a large-bore intravenous line placed and receive initial fluid resuscitation with normal saline. Care should be taken to avoid overhydration, particularly in the elderly or in those with a history of congestive heart failure. Standard bronchodilator therapy is indicated for any accompanying reactive airway disease.
If the patient has a coexisting pneumonia, antibiotics should be instituted in the ED, because it is, as a rule, difficult to differentiate viral pneumonia from bacterial pneumonia. Antibiotics should provide adequate coverage against Haemophilus influenzae and group B Streptococcus, as well as Staphylococcus aureus, which is a relatively common bacterial pathogen associated with influenza outbreaks.
The antiviral agents rimantadine and amantadine previously were found to be effective in reducing the severity and duration of illness in high-risk individuals who had not been vaccinated. However, neither is currently recommended by the CDC for influenza treatment or prophylaxis because of high rates of resistance and side effects.
The Food and Drug Administration has approved a new class of antiviral drugs, neuraminidase inhibitors. Neuraminidase permits the virus to penetrate the surfaces of cells and is necessary for optimal release of virus from infected cells. Inhibitors now available are oseltamivir, given orally, and zanamivir, inhaled through the mouth at a high flow rate. These agents are approved for the treatment of influenza in patients who have been symptomatic for less than 2 days. Initial studies showed only a 1- to 1.5-day decrease in the duration of symptoms, but subsequent research has supported further benefits and indications for these drugs. Both drugs have been shown to be effective in significantly reducing time to alleviation of symptoms, in prophylaxis for close contacts, and in reducing complications in high-risk individuals especially when the drugs are administered within 48 hours of onset of symptoms (10,11). Zanamivir was associated temporally with the termination of a nursing home outbreak that amantadine had failed to control (12). A 2011 meta-analysis concluded that oseltamivir reduced respiratory complications by 28% (13). Other meta-analyses have provided contradictory results regarding reduction in influenza-related respiratory tract complications in healthy adults (14).
The adult dose of oseltamivir for treatment of influenza is 75 mg twice daily for 5 days. Oseltamivir is approved for treatment and prophylaxis in those 1 year of age and older. The pediatric dose of oseltamivir is 30 mg twice daily for ≥15 kg, 45 mg twice daily for 15 to 23 kg, 60 mg twice daily for 23 to 40 kg, and 75 mg twice daily for >40 kg. Treatment should begin within 2 days of onset of symptoms of influenza. The recommended oral dose of oseltamivir for prophylaxis of influenza in adults and adolescents 13 years and older after close contact with an infected individual is 75 mg once daily for at least 7 days. Therapy should begin within 2 days of exposure. Oseltamivir causes nausea and vomiting in about 10% of treated persons, although most continue taking the drug. When taken with food, the incidence of gastrointestinal side effects is reduced. Transient neuropsychiatric events including self-harm and delirium have been reported after oseltamivir use.
Zanamivir is approved for the treatment of those 7 years of age and older and the prophylaxis of those 5 years of age or older. The dose of zanamivir for treatment of influenza in adult and pediatric patients aged 7 years and older is two inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart) for 5 days. Prophylaxis is two inhalations once daily. Zanamivir should be used cautiously in patients with chronic respiratory disease because it can cause bronchospasm and reduction in airflow. A small percentage of patients have difficulty using the inhaler. Understanding proper use should be ensured. The intravenous formulation of zanamivir is being evaluated in clinical trials and is available for compassionate use from its manufacturer.
Treatment with the neuraminidase inhibitors is recommended for the following:
• All patients with high-risk factors (elderly, immunosuppressed, diabetics, adults, and children with other chronic diseases)
• Patients with severe influenza including lower respiratory tract infection
• Pregnant women and women up to 2 weeks postpartum
• Adults 65 years of age and older
• Residents of nursing homes and other care facilities
• Consider for other patients
Prophylaxis recommendations for the neuraminidase inhibitors are as follows:
• Give to high-risk patients who have not been vaccinated.
• Consider for immunosuppressed patients who have been vaccinated.
• Give to high-risk vaccinated patients who received vaccine in poor-match years.
• Give once daily × 6 weeks in season.
• Give × 14 days or until 7 days after onset of last case in nursing home outbreaks.
CRITICAL INTERVENTIONS
• Ensure adequate oxygenation.
• Provide for staphylococcal coverage when treating pneumonia.
• Initiate neuraminidase inhibitors for high-risk patients with influenza.
• Administer influenza vaccine from late September through December to patients at risk for influenza complication and groups capable for influenza transmission.
DISPOSITION
The majority of patients with influenza can be treated as outpatients. Close follow-up should be ensured and the patient should be given specific instructions to return immediately if symptoms progress.
There should be a low threshold for admission for elderly patients, pregnant patients, the immunocompromised, those with chronic pulmonary or cardiac disease, and young children. These patients should be admitted if there is any evidence of pneumonia, which can often progress rapidly. Admission to an intensive care unit should be considered for patients who are hypoxic or show any signs of significant respiratory difficulty.
PREVENTION AND VACCINATION
Influenza vaccines have been shown in numerous studies to be effective in preventing clinical disease (4,15) and extremely cost-effective, especially in persons older than age 65 (16). Each year, a different vaccine preparation is developed, using virus strains believed likely to appear in North America the following winter. The CDC estimated that the effectiveness of the 2012 to 2013 seasonal influenza vaccine in preventing medically attributed infections in all age groups was 56% (4), but as many as 90% of influenza cases can be prevented when there is a good match between vaccine and epidemic strains of the virus (17). Influenza vaccine has also been extremely effective in reducing morbidity and mortality (by up to 80%) in vaccinated individuals who nevertheless develop clinical disease, particularly the elderly and the immunocompromised (18). A number of studies have shown that vaccination reduces influenza-related hospitalizations and deaths in nursing home populations during epidemics (19,20). Also, vaccination clearly lowers cardiovascular mortality and all other case mortality in patients with cardiovascular disease and other high-risk medical conditions (21). A large 2012 cohort study of community dwelling elderly individuals showed vaccination was associated with a reduction in hospitalizations and death during influenza season (15). The World Health Organization says influenza vaccination may limit the number of false alarms for SARS. Adverse effects of the vaccine itself have been minimal and should not deter its use in the high-risk patient.
Despite the overwhelming evidence supporting the benefits and efficacy of influenza vaccines, many high-risk individuals go unvaccinated. Studies have shown poor vaccination rates in both the elderly and younger persons with high-risk medical conditions such as asthma. Vaccination of health care providers has clearly been shown to decrease mortality in patients (22), but unfortunately the rate of vaccination remains unacceptably low.
Emergency physicians can play a major role in educating patients and the general public about the need for vaccinations in high-risk groups. This should occur before the peak influenza season begins. Target groups for vaccination programs are listed in Table 190.1. Of note, the Advisory Committee on Immunizing Practices of the CDC supports the vaccination of all children older than 6 months and clearly recommends vaccination of children 6 months to 4 years old (23). Vaccinations should be offered between late September and early November, depending on when regional influenza activity is expected to begin. Many EDs offer the vaccine on-site. This approach has been shown to be both needed and feasible (24), even for patients presenting with acute asthma attacks requiring prednisone treatment (25). Emergency physicians are also often in a position to recognize the outbreak of influenza in closed environments such as nursing homes.
TABLE 190.1
Influenza Vaccination Target Groups
Stopping, slowing, or otherwise limiting the spread of an avian flu pandemic has recently become a major focus in the United States and globally. Present efforts are directed at poultry containment, rapid identification of human disease, and limitation of exposure to infected individuals. In addition, there has recently been a heightened focus on vaccine development, improvement in surge capacity, and stock piling of neuraminidase inhibitors, which are felt to be of potential benefit in treating avian flu.
Common Pitfalls
• Failure to recognize that the elderly, the very young, the immunosuppressed, pregnant and postpartum patients, and those with chronic cardiac or pulmonary disease are at high risk for complications from influenza or acute worsening of their baseline chronic disease
• Failure to appreciate that young children can present atypically
• Failure to appreciate the role of S. aureus as a pneumonia pathogen during influenza outbreaks
• Failure to start treatment in a high-risk individual because of a negative rapid influenza test
• Failure to be on the alert for nursing home patients with influenza and to notify appropriate officials about potential outbreaks
• Failure of health care workers to be vaccinated themselves
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