Cover article

First of two parts

Influenza:
Update on strategies for management

By Michele Cheung, MD, and Jay M. Lieberman, MD

Advances in rapid diagnostic tests and antiviral therapy for influenza have given pediatricians new options for identifying and fighting this old and resilient foe.

"[The soldiers'] faces soon wear a bluish cast; a distressing cough brings up the blood stained sputum. In the morning the dead bodies are stacked about the morgue like cord wood. This picture was painted on my memory cells at the division hospital, Camp Devens, in the fall of 1918, when the deadly influenza virus demonstrated the inferiority of human inventions in the destruction of human life."

Colonel Victor C. Vaughan¹

The 1918 influenza pandemic killed more than 20 million people around the world; more people died from the flu than were killed in World War I. Young adults in particular were struck hard, and deaths in this age group caused the average life expectancy in the United States to drop by over 10 years in 1918 (Figure 1).² No one knows why the so-called Spanish flu killed otherwise healthy young adults, or when the next flu pandemic will occur. But it will.

Influenza continues to be a major cause of acute respiratory illness, pneumonia, and hospitalization in people of all ages and socioeconomic status. Every winter, physicians' offices, clinics, urgent care centers, and emergency departments fill with children and adults suffering from the flu. Advances in rapid diagnostic tests and antiviral medications have changed our approach to these patients. In this article, the first of a two-part review of influenza, we discuss the latest management strategies. In the "Influenza: Update on strategies for prevention" article, we focus on the newest strategies for preventing influenza.

Why pediatricians should care about flu

Influenza affects 10% to 20% of the US population each year, resulting in more than 110,000 hospitalizations and 10,000 to 40,000 deaths.^3,4 Estimates of the magnitude of illnesses and complications caused by influenza vary because the diagnosis is often clinical, patients are not always hospitalized, and symptoms overlap with other diseases. One estimate, extrapolated from studies of the impact of influenza in Houston, Texas, suggests that approximately 65 million individuals are symptomatic and 30 million seek medical care for influenza each year in the US.⁵ Approximately 90% of deaths occur in the elderly, but influenza also takes its toll on children.

Certain children and adolescents are at high risk of complications from influenza (Table 1), including those who have a chronic pulmonary disease such as asthma or hemodynamically significant cardiac disease. Moreover, the highest rates of influenza infection are among school-age children and young adults, although the highest hospitalization rates are among infants and the elderly.

During annual epidemics, 10% to 40% of healthy children are infected with influenza, with 1% of infections resulting in hospitalization.⁶ Although studies on pediatric hospitalizations for influenza are often confounded by co-circulating respiratory viruses such as respiratory syncytial virus (RSV), recent data suggest that the risk of hospitalization for otherwise healthy infants and young children infected with influenza is comparable to that of high-risk adults and the elderly.⁷ In another study, the hospitalization rate for acute respiratory disease for otherwise healthy children under 2 years of age was approximately 200 per 100,000 person-months during months when influenza activity predominated over RSV activity.⁸ This approaches the hospitalization rate seen in children age 5 to 17 years with chronic health conditions and is 12 times the rate for healthy 5- to 17-year-olds. Extrapolation of these data suggests that 8,400 to 11,700 children between 6 and 24 months of age are hospitalized for influenza annually in the US.⁸

Influenza also has an impact on outpatient management of children during flu season. Each year, influenza accounts for an average of six to 15 additional outpatient visits and three to nine additional courses of antibiotics for every 100 children.⁷

Furthermore, children often introduce influenza into the home and transmit it to the elderly. In families with young children, as many as one in three family members become infected with influenza.⁹

The flu virus at a glance

First isolated in 1933, influenza viruses are enveloped RNA viruses that belong to the family Orthomyxoviridae. There are three types of influenza viruses: A, B, and C. Only A and B are associated with epidemic human disease. Influenza A viruses are further subtyped based on differences in two surface glycoproteins, hemagglutinin (H) and neuraminidase (N) (Figure 2, available in the print edition, adapted from Neuzil KM, Mellen BG, Wright PF, et al: The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med 2000;342:225 and Simonsen L, Fukada K, Schonberger LB, et al: The impact of influenza epidemics on hospitalizations. J Infect Dis 2000;181:831).¹⁰ Influenza B viruses also contain hemagglutinin and neuraminidase but are not subtyped because these proteins change less rapidly than in flu A. Hemagglutinin is required for the virus to attach to host-cell membranes; neuraminidase is an enzyme involved in viral penetration and release of virus from infected cells.

The virus spreads mainly by small, aerosolized particles but also by direct contact with respiratory secretions. Person-to-person transmission occurs readily, and a single person can infect a large number of susceptible people.¹⁰ The incubation period is one to four days, and a person is infectious from approximately one day before to five days after symptom onset. Children and immunocompromised hosts shed virus for a longer period.

Influenza is prevalent in the US in the late fall, winter, and early spring (October through March), although virus circulates year-round in other parts of the world. Detection of influenza in the US during the summer is uncommon and may herald the introduction of an imported or novel strain. (See "Surveillance and the pediatrician's role".)

Clinical manifestations and complications

Influenza can have protean manifestations in children, but "classic" flu is characterized by the abrupt onset of fever (38º C to 40º C), chills, cough, rhinorrhea, sore throat, malaise, myalgias, headache, and anorexia. The sensitivity and specificity of clinical definitions for influenza compared with viral culture range from 63% to 78% and 55% to 71%, respectively, depending on the definition, level of influenza activity, and other respiratory viruses co-circulating in the community.³

In children, influenza may also manifest as croup, bronchiolitis, conjunctivitis, or a nonspecific febrile illness. Young infants, in particular, may present with a sepsis-like syndrome. Affected children may have gastrointestinal complaints such as nausea, vomiting, diarrhea, and abdominal pain.

Acute illness is self-limited, usually lasting several days, although residual symptoms such as cough and malaise can linger for weeks. Immunocompromised people may have a prolonged course.

Viral respiratory tract infections often precede acute otitis media, and influenza is an important predisposing factor for ear infection in children. Otitis media may occur in 20% or more of children 6 years of age or younger who are infected with influenza.¹¹ Concomitant bacterial infection is found in about two thirds of otitis media cases in which a respiratory virus is isolated from the middle ear fluid.¹² For this reason, children with influenza who present with acute otitis media should be treated with an antibiotic.

In addition to displaying common upper respiratory tract and constitutional symptoms, patients with influenza may experience complications or unusual manifestations. Influenza is associated with exacerbations of asthma, cystic fibrosis, and other chronic lung conditions. Lower respiratory tract complications, including pneumonia, bronchiolitis, and wheezing, occur in up to 25% of children with influenza.⁶ Pneumonia can result from primary viral infection or secondary bacterial superinfection by microorganisms such as Staphylococcus aureus, group A ß-hemolytic streptococci, Streptococcus pneumoniae, and Haemophilus influenzae.

Myositis is seen more commonly in children than in adults and may occur during early convalescence, particularly from influenza B infection. Patients with myositis may present with acute onset of muscular pain and tenderness, refusal to walk, and elevated serum creatine kinase.⁶ Influenza-related myocarditis can result in cardiac muscle damage, arrhythmias, and cardiomyopathy.

Encephalitis, transverse myelitis, and Guillain-Barré syndrome (GBS) are potential neurologic complications of influenza. Influenza may also be a common cause of febrile seizures in young children. In a study of children hospitalized for viral respiratory illnesses in Hong Kong, influenza A was associated with an increased incidence of febrile seizures and of repeated seizures when compared with parainfluenza or adenovirus infection.¹³ During months of peak influenza activity, influenza A accounted for up to 44% of admissions for febrile seizures.

Finally, Reye syndrome can occur as a complication of influenza. This complication has, however, become very rare since recognition of its association with aspirin use prompted warnings against using this medication in children.

Not just a clinical diagnosis anymore

The diagnosis of flu is usually made clinically, although testing for influenza can be useful in some situations. Currently available methods for diagnosis include rapid tests, culture, polymerase chain reaction (PCR), and serology.

With children who are at high risk of complications of influenza, rapid diagnostic testing may help the clinician evaluate the patient early in the illness, when antiviral therapy may be beneficial. Rapid testing of hospitalized children with acute respiratory illness can assist in infection control issues and possible cohorting of patients. It can also guide prophylaxis of high-risk contacts and assist in the control of institutional outbreaks. In the nontoxic febrile infant who does not have another source, a positive rapid test may help guide decisions regarding initiation of antibiotics or further diagnostic work-up. Finally, rapid diagnostics can contribute to influenza surveillance.

In a study of the effect of rapid influenza A diagnosis on emergency department (ED) management of febrile infants and toddlers, patients diagnosed with influenza A while still in the ED were less likely to be given ceftriaxone or have a urinalysis or complete blood count performed than were patients with influenza A whose results were reported after discharge.¹⁴ Another study revealed that patients with a positive rapid test for influenza A were less likely to receive antibiotics and, if admitted to the hospital, received antibiotics for a shorter duration.¹⁵

Influenza is a predisposing factor for invasive bacterial infections such as meningococcemia, and a positive rapid test for influenza does not rule out serious bacterial infection in a toxic-appearing child. However, the incidence of serious bacterial infections in children with viral respiratory syndromes is low,^14–16 and confirmation of influenza in a nontoxic child with no obvious bacterial focus of infection should allow the clinician to withhold antibiotics while monitoring the patient closely.

Appropriate specimens for rapid diagnostic testing in children include nasopharyngeal swabs, throat swabs, and nasal washings. Several rapid diagnostic tests, costing about $15 to $20 each, have been marketed over the past several years (Table 2).^10,17 The cited sensitivities and specificities of these tests vary based on the product, patient population, specimens used, and comparison detection method.

TABLE 2
Rapid diagnostic tests

In a head-to-head analysis of Directigen Flu A, Flu OIA, QuickVue, and ZstatFlu in a pediatric practice, the first three products appeared to have similar sensitivity (93% to 95%) and specificity (76% to 84%) to each other when compared with viral culture as the gold standard.¹⁸ ZstatFlu was the least sensitive (72%) of the four and appeared to be more cumbersome and time-consuming. The sensitivities seen in this study are higher than those reported by the manufacturers, while the specificities were lower. According to the authors, the higher sensitivities may reflect higher titer viral shedding seen in pediatric patients (compared with adults), while the lower specificities may be due to less sensitive culture results because of storage and testing practices.

In general, the relatively high sensitivity of rapid diagnostic tests in children along with the ease of use, rapid turnaround, and noninvasiveness give these tests a potential role in the work-up and management of high-risk children with fevers and respiratory symptoms, hospitalized patients with febrile respiratory illness, and febrile infants without another source. A negative rapid test result does not rule out influenza, however, and viral culture remains the gold standard for diagnosis. Culture also allows isolation of the virus for typing and identification by public health laboratories. This is especially important in patients with recent travel history or severe disease, who may have a new or particularly virulent strain. Conventional culture results are not available for several days, however, so they cannot guide clinicians' decisions to initiate antiviral therapy. In general, viral cultures should be obtained in highly suspicious cases with negative rapid testing, in patients with severe or unusual manifestations of disease, and for surveillance purposes.

Reverse transcriptase–PCR detects influenza RNA in clinical specimens and can be used to type and subtype strains of influenza viruses. Influenza PCR is available only in research and public health laboratories, however. Diagnosis of influenza by serology requires acute and convalescent specimens, resulting in a delay in diagnosis of at least 10 to 14 days after the initial specimen is taken. Therefore, the role of PCR and serology in the diagnosis of influenza for the clinician is extremely limited.

To treat or not to treat

Influenza is usually a self-limited disease, and treatment is primarily supportive. Antipyretics such as acetaminophen may be used for fever control, but salicylates such as aspirin should be avoided in children and adolescents because of the risk of Reye syndrome.

Antiviral therapy is not warranted for most pediatric patients with influenza, since disease is usually self-limited and the treatment effect is modest and because of the cost and potential side effects of antivirals. However, antiviral therapy is indicated for:

• children and nonpregnant adolescents at high risk of complications
  (Table 1)
• children and adolescents with severe influenza

Antiviral therapy may also be considered for:

• patients with special family, school, or social situations, such
  as upcoming important examinations, trips, or athletic competitions
• patients who are contacts of high-risk people, as treatment may reduce
  the risk of transmission

If antiviral therapy is warranted, it should be initiated within the first 48 hours of illness for the greatest benefit. High-risk or severely ill patients seen after the first 48 hours of illness may still benefit from antiviral therapy. Treatment should be continued for five days (or for 24 to 48 hours after acute symptoms resolve) in immunocompetent patients. Immunocompromised patients may require prolonged therapy.

Four anti-influenza drugs are available: amantadine, rimantadine, oseltamivir, and zanamivir (Table 3). When initiated within the first two days of illness, treatment may decrease fever and the severity of symptoms and reduce duration of illness by one to one-and-a-half days. Treatment can also decrease the likelihood of transmission of virus to others.^19–21 Antivirals may also prevent influenza-associated otitis media and antibiotic usage, as suggested by a study of oral oseltamivir in children in which investigators observed a 44% decrease in the incidence of ear infections compared with placebo.²⁰

"Older" antivirals. The adamantanes, amantadine hydrochloride and rimantadine hydrochloride, are effective against only influenza A. They work by blocking the function of a channel protein (M2) that is necessary for initiation of viral replication. Both drugs are given orally, are well absorbed, and are excreted in the urine. Amantadine is approved by the US Food and Drug Administration (FDA) for treatment of patients 1 year and older. Because of its catecholamine effect, it has been associated with adverse neurologic effects such as insomnia, anxiety, and depression in about 10% to 15% of patients, especially in those with impaired renal function. Hallucinations and seizures can occur with high plasma concentrations. Rimantadine causes central nervous system side effects in only about 2% of users. Both amantadine and rimantadine are associated with mild gastrointestinal upset. Side effects are concentration-related and resolve upon cessation of therapy. Although rimantadine is approved by the FDA for treatment only of patients 13 years and older, it may be considered for treatment of younger patients as well.^3,22

Resistance to amantadine and rimantadine develops rapidly in 25% to 35% of treated individuals. Resistant viruses do not cause more severe illness, but the development of resistance has possible consequences for close contacts of individuals who are treated.

"Newer" antivirals. Zanamivir and oseltamivir are neuraminidase inhibitors and, unlike the adamantanes, have the advantage of being active against influenza B in addition to flu A. Zanamivir is available as a powder for oral inhalation and is approved for treatment of children at least 7 years of age. Administration of zanamivir requires active participation by the recipient and understanding of the inhalation maneuver. Zanamivir has few side effects, although bronchospasm and reduced flow rates have been reported in persons with underlying lung disease.²² Therefore, zanamivir should be used with caution in children and adolescents with asthma or other underlying pulmonary diseases.

Oseltamivir is available orally as a capsule or solution and is approved for treatment of children as young as 1 year of age. The most common adverse effects associated with oseltamivir are nausea and vomiting (in about 10% to 20% of users), but only infrequently does this lead to drug discontinuation.

Resistance to neuraminidase inhibitors has been reported but is less common than with the adamantanes.²² In one study of children treated with 15 days of oseltamivir, 5.5% of influenza A-positive patients developed variants with in vitro resistance near the end of therapy.²⁰ There did not appear to be any clinical consequences of resistance in these patients, although potential consequences for contacts are unknown. Animal studies suggest that strains resistant to neuraminidase inhibitors are less infectious and less pathogenic than wild-type influenza virus.²³ The clinical relevance of resistance to neuraminidase inhibitors is unclear and is an area that calls for further investigation.

Choosing among antivirals. The choice of antiviral must take into consideration the influenza type as well as the drug's costs, side effects, and safety profile. For treatment of influenza A infection, the adamantanes are as effective as the neuraminidase inhibitors and much less expensive, with amantadine being less costly but rimantadine having a better safety profile. Therefore, the adamantanes, especially rimantadine, can be safely and effectively used for treatment of influenza A infection. For acute influenza infections of unknown type or for treatment of influenza B, the neuraminidase inhibitors are recommended. Oseltamivir is easier to administer than zanamivir and is approved for young children, but has more frequent gastrointestinal side effects.

All the antivirals except for zanamivir are approved for influenza prophylaxis as well as treatment, although, in the case of rimantadine and oseltamivir, the approved ages for prophylactic use differ from those for treatment. Antivirals should not be used as a substitute for immunization unless a contraindication to vaccination exists. For a more detailed discussion of the prophylactic use of antiviral medications, see the article that follows.

Nipping the bug in the bud

Pediatricians today have more tools to fight influenza than they did in the past. Rapid diagnostic tests can facilitate the work-up and management of high-risk children with fevers and respiratory symptoms, hospitalized patients with febrile respiratory illness, and febrile infants without another source. Antivirals can be used to shorten the duration and severity of illness in children and adolescents at high risk of complications of influenza and those with severe disease, and can be considered in other select patients. Applying the latest diagnostic and treatment options judiciously can reduce morbidity, help prevent the spread of influenza in institutions, and decrease antibiotic usage in febrile children with respiratory symptoms.

REFERENCES

1. Kolata G: Flu: The Story of the Great Influenza Pandemic of 1918 and the Search for the Virus That Caused It. New York: Farrar, Straus and Giroux, 1999

2. Taubenger J, Reid A, Fanning T: The 1918 influenza virus: A killer comes into view. Virology 2000;274:241

3. CDC: Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 2001;50(RR-4):1

4. Cifu A, Levinson W: Influenza. JAMA 2000;284:2847

5. Poland GA, Couch R: Intranasal influenza vaccine: Adding to the armamentarium for influenza control (editorial). JAMA 1999;282:182

6. American Academy of Pediatrics: Influenza, in Pickering L (ed): 2000 Red Book: Report of the Committee on Infectious Diseases. Elk Grove Village, Ill., American Academy of Pediatrics, 2000, p 351

7. Neuzil KM, Mellen BG, Wright PF, et al: The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med 2000;342:225

8. Izurieta HS, Thompson WW, Kramarz P, et al: Influenza and the rates of hospitalization for respiratory disease among infants and young children. N Engl J Med 2000;342:232

9. Couch RB: Influenza: Prospects for control. Ann Intern Med 2000;133:992

10. Cox NJ, Subbarao K: Influenza. Lancet 1999;354: 1277

11. Belshe RB, Mendelman PM, Treanor JJ, et al: The efficacy of live-attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine in children. N Engl J Med 1998;338:1405

12. Heikkinen T: The role of respiratory viruses in otitis media. Vaccine 2001;19:S51

13. Chiu SS, Tse CY, Lau YL, et al: Influenza A infection is an important cause of febrile seizures. Pediatrics 2001;108:E63

14. Sharma V, Dowd D, Slaughter A, et al: Effect of rapid diagnosis of influenza virus type A on the emergency department management of febrile infants and toddlers. Arch Pediatr Adolesc Med 2002;156:41

15. Noyola D, Demmler G: Effect of rapid diagnosis on management of influenza A infections. Pediatr Infect Dis J 2000;19:303

16. Greenes D, Harper M: Low risk of bacteremia in febrile children with recognizable viral syndromes. Pediatr Infect Dis J 1999;18:258

17. Rapid Diagnostic Tests for Influenza. The Medical Letter on Drugs and Therapeutics 1999;41:121

18. Rodriguez WJ, Schwartz RH, Thorne MM: Evaluation of diagnostic tests for influenza in a pediatric practice. Pediatr Infect Dis J 2002;21:193

19. Hayden FG, Treanor JJ, Fritz RS, et al: Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: Randomized controlled trials for prevention and treatment. JAMA 1999;282:1240

20. Whitley RJ, Hayden FG, Reisinger KS, et al: Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 2001;20:127

21. CDC: Prevention and Control of Influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2002;51:1

22. CDC: Neuraminidase inhibitors for treatment of influenza A and B infections. MMWR Morb Mortal Wkly Rep 1999;48;RR-14:1

23. Mendel D, Sidwell R: Influenza virus resistance to neuraminidase inhibitors. Drug Resist Updates 1998;1:184

DR. CHEUNG is attending physician, pediatric infectious diseases, Miller Children's Hospital, Long Beach, Calif., and assistant clinical professor of pediatrics, University of California, Irvine.

DR. LIEBERMAN is chief, pediatric infectious diseases, Miller Children's Hospital, Long Beach, Calif., and associate professor of clinical pediatrics, University of California, Irvine. He is a member of the speakers' bureau with Aventis Pasteur and Wyeth-Lederle, and a recipient of a research grant from MedImmune.

Surveillance and the pediatrician's role

The identification of circulating strains of influenza and the detection of novel influenza viruses are possible through the surveillance efforts of local, state, national, and global public health agencies. Influenza surveillance in the US is coordinated by the Centers for Disease Control and Prevention (CDC) and includes data from laboratories, sentinel physicians, vital registrars, and state epidemiologists. Additional data on hospital admissions for influenza and pneumonia, school or work absences, usage of antivirals for influenza, and emergency room visits for influenza-like illnesses may be collected at a local level.

Surveillance allows clinicians to know when influenza is present in their community, whether it is influenza A or B or both, and whether circulating strains match vaccine strains. Therefore, surveillance is important to make appropriate recommendations for use of rapid diagnostics and antivirals, predict health-care resource needs (such as hospital beds and staffing), determine strain components for upcoming flu season vaccine, identify outbreaks and epidemics, monitor for bioterrorism, and plan for and detect pandemics.

Because children are heavily involved in the transmission of influenza, pediatricians and family practitioners are on the front line for monitoring influenza-like illnesses in the community. We encourage primary health-care providers to participate in influenza surveillance and to contact Alicia Postema, epidemiologist in the influenza branch at the CDC (404-639-3747), for information about becoming a sentinel physician.

 

Jay Lieberman, Michele Cheung. Influenza: Update on strategies for management. Contemporary Pediatrics October 2002;19:82.