Pediatrics Update: "Flu" Season: Here We Go Again . . .

The "flu" season is about to begin. Are you prepared?

In this review, we provide the most recent statistics concerning the burden of this illness, summarize the newest vaccine recommendations, and discuss the potential for vaccine shortage.

MICROBIOLOGY

Influenza is caused by orthomyxoviruses, mainly influenza A and B viruses, which invade the respiratory tract. Hemagglutinin (HA) and neuraminidase (NA) are 2 surface glycoproteins of the influenza virus that aid in viral replication. HA allows the virus to attach to the respiratory epithelial cells, and NA causes the viruses to be released and dispersed from the infected cell.¹ Point mutations that occur during viral replication lead to antigenic drift (minor antigenic variations within the same subtype) in either HA or NA.

Although antibodies to surface proteins--especially HA--develop, protection against a new variant is not guaranteed. Antigenic drift occurs continuously in both influenza A and B viruses. As a result, circulating influenza viruses are constantly changing--hence, the need to modify the vaccine developed for each influenza season. Antigenic shift (a major antigenic variation leading to the emergence of a new HA or NA) has occurred rarely only in influenza A virus. Three distinct HA subtypes (H1, H2, and H3) and 2 NA subtypes (N1 and N2) have been recognized as the cause of global epidemics.²

EPIDEMIOLOGY

Less severe than the previous season, the 2004-2005 flu season in the United States spanned from October to May and peaked in mid-February.³ Influenza A (H3N2) predominated. In October 2004, it became mandatory to report deaths associated with laboratory-confirmed influenza infection in persons younger than 18 years. Between January and June 2005, 36 pediatric deaths were reported to the CDC from 16 states.³ Many of the casualties were otherwise healthy children: this emphasizes the need to prevent this illness. Nevertheless, vaccine coverage data reveal that only half of children aged 6 to 23 months, one third of high-risk children aged 2 to 17 years, and two thirds of adults 65 years or older received the influenza vaccine.⁴

SIGNS AND SYMPTOMS

In children, influenza manifests primarily with a sudden onset of systemic and respiratory symptoms. High fever, headache, malaise, myalgias, rhinitis, and cough are common findings, as are nausea, vomiting, and abdominal pain. Signs and symptoms that accompany the potential respiratory complications of influenza--such as croup, acute otitis media, bronchiolitis, secondary bacterial pneumonia, and sinusitis--may be present. Acute otitis media and lower respiratory tract disease are most common in children younger than 2 years.⁵ Nonrespiratory complications include myositis, myocarditis, encephalitis, and febrile seizures; patients may display typical features of these conditions.

Influenza can take 1 to 2 weeks or longer to resolve completely. Particularly worrisome symptoms include high fever that persists beyond the first week, respiratory distress, cyanosis, evidence of dehydration, and mental status changes.

DIAGNOSIS

Findings from the history and physical examination and the presence of influenza in the community provide ample support for an influenza diagnosis. However, influenza cannot be differentiated from viral syndromes caused by such pathogens as respiratory syncytial virus and parainfluenza virus based on the clinical scenario alone. A definitive diagnosis may forestall the need for additional tests in a young child and can provide the option to administer anti-flu medications while avoiding unnecessary use of antibiotics. Detection techniques for influenza A and B include viral culture, serology, rapid antigen testing, and polymerase chain reaction and immunofluorescence.⁶ In the clinic or office setting, rapid antigen tests are probably the most useful. A number of these commercial tests are available. The sensitivity and specificity of these tests vary; the site from which to obtain a specimen (eg, throat vs nasopharynx) also differs depending on the specific test, as does the type of virus detected (influenza A, influenza B, or both).

TREATMENT

General measures. The most important treatment measures in children include maintenance of hydration and administration of analgesics and antipyretics. Salicylates are contraindicated in children with influenza because of the risk of Reye syndrome.

Antiviral agents. These drugs may be considered for children at high risk for complications--such as those with chronic pulmonary, cardiac, renal, or liver disease; immunodeficiency; hemoglobinopathy; or diabetes mellitus. Children younger than 18 years who are receiving long-term aspirin therapy and all children in the first 2 years of life are considered to be at increased risk for influenza complications.⁶ Antiviral therapy may also be considered for an older and otherwise healthy child who has particularly severe symptoms.

For maximal efficacy, antiviral medications must be administered within 48 hours of symptom onset--and preferably within 30 to 36 hours of confirmation of an influenza diagnosis. Antiviral medications reduce the duration of symptoms by about 1 day.^6,7 Whether antivirals prevent influenza-related complications has not been established, however.

Table 1 provides an overview of drug prophylaxis and treatment with antiviral agents. Amantadine and rimantadine are ion channel blockers; oseltamivir and zanamivir are NA inhibitors. The ion channel blockers inhibit the transmembrane M2 protein found in influenza A virus. This protein facilitates viral replication by allowing hydrogen ions to pass into the virion.⁸ Because M2 protein is present only in influenza A virus, the ion channel blockers are not effective in the treatment of influenza B. The NA inhibitors effectively treat both influenza A and B.

Amantadine and oseltamivir are approved for use in children as young as 1 year. The inhaled agent zanamivir is approved for children 7 years and older. Rimantadine is indicated for the treatment of influenza A in patients aged 13 years and older.

The principal side effects of all the oral medications include GI disturbances, such as nausea and vomiting. The ion channel blockers may cause dizziness, jitteriness, and sleep disturbances. Zanamivir can exacerbate asthma.⁷ As with any medical intervention, the risks versus benefits of the antivirals must be evaluated for each patient.

PREVENTION

Wash hands. The best means of preventing influenza is to control its spread in day-care centers, schools, and workplaces. Respiratory secretions from persons with influenza are most infectious 24 hours before the onset of symptoms and during the entire symptomatic period. Influenza is spread by droplets (via sneezing or coughing) or by direct contact with articles contaminated with respiratory secretions. Boone and Gerba⁹ found that influenza A was detected in over 50% of fomites sampled from homes and day-care centers during the flu season. Measures such as wearing a mask and frequent hand washing with soap or an alcohol-based sanitizer by the patient and close contacts may prevent the spread of infection. Frequent cleaning of toys and other contact surfaces should be routine in day-care centers.

Get immunized. Any person older than 6 months who has no contraindications should be vaccinated against influenza. Vaccination is appropriate in the general population to prevent and control influenza epidemics. Protection from influenza can be achieved either by annual immunization of at-risk persons or by chemoprophylaxis. In most cases, however, chemoprophylaxis is not a substitute for vaccination.

There are 2 types of influenza vaccines available in the United States:

• Trivalent inactivated influenza vaccine (TIV).

• Live, attenuated influenza vaccine (LAIV).

TIVs are used in persons older than 6 months. LAIV is indicated for use only in healthy persons between the ages of 5 and 49 years.⁸ The 2005-2006 trivalent vaccine virus strains are A/California/7/2004 (H3N2)-like, A/New Caledonia/20/99 (H1N1)-like, and B/Shanghai/361/2002-like antigens.¹⁰

TIV. The 2 TIV vaccines currently available in the United States are Fluzone and Fluvirin. Because the efficacy of Fluvirin has not been established in children younger than 4 years, it is not licensed for this age group.^2,8 (Fluarix--a newly approved flu vaccine--is also available, but it is indicated for persons 18 years and older.) In the United States, only the split-virus (disrupted virus particles) influenza vaccines are licensed; both of these can be obtained in thimerosal-free formulations.

Table 2 outlines the dosing schedule for influenza vaccines. Children younger than 9 years who have never been vaccinated against influenza should receive 2 doses 4 weeks apart. It is difficult to estimate the efficacy of influenza vaccines because there are a number of variables involved. If the end point is influenza confirmed by positive culture, efficacy varies between 30% and 95%--depending on the season and the population studied.^2,8,11

The most common side effects associated with TIV are soreness at the injection site and fever. Less frequent adverse events include headache, myalgia, chills, nausea, and lethargy. The 2 absolute contraindications for TIV are anaphylactic reactions to egg or chicken protein and hypersensitivity to thimerosal or to the other components of the vaccines. It is not known whether TIV increases the recurrence of Guillain-Barré syndrome (GBS); therefore, a history of GBS is a relative contraindication for TIV.⁸ Also, there is no causal relationship between influenza vaccines and demyelinating disorders.¹² There are conflicting data on the safety of TIV in children with HIV infection. However, most experts believe that the benefits of vaccination with TIV far outweigh the risk of complications in children infected with HIV.⁸

LAIV. FluMist, the only live, attenuated vaccine available in the United States, must be stored frozen and should be used within 30 minutes once the vaccine is warmed to room temperature. It is administered intranasally, 0.25 mL in each nostril. Children younger than 9 years who have never received influenza vaccine should be given 2 doses 6 weeks apart (see Table 2). The most common side effects are mild increases in headaches, nasal congestion, runny nose, and cough.

In children younger than 5 years, LAIV has been associated with an increased incidence of asthma and reactive airway disease; it is therefore not currently recommended for this age group.⁸ Rarely, a live-attenuated virus strain can be transmitted to a nonimmunized contact.¹³

The intranasal vaccine is contraindicated in persons younger than 5 years and in those older than 49 years. It is also contraindicated in persons with a history of anaphylactic reaction to egg or chicken protein and in those taking salicylates. It is also contraindicated in those who have a known or suspected immunodeficiency or a history of GBS, asthma, or any condition considered to confer a high risk of severe influenza. A multicenter trial showed that after a single dose, the intranasal vaccine was 86.9% effective against influenza A (H3N2) and 91.3% effective against influenza B. After 2 doses, it was 96% effective against influenza A (H3N2) and 90.5% effective against influenza B.¹⁴

There are no data on the efficacy of concurrent administration of LAIV and the recommended childhood vaccines. Inactivated vaccines can be administered simultaneously with LAIV. Live vaccines can either be administered on the same day as LAIV or 4 weeks apart.

Candidates for vaccination

Healthy children younger than 2 years and children with certain chronic disorders have an elevated rate of hospitalization for influenza and its complications. Therefore, the American Academy of Pediatrics recommends annual influenza vaccination for all healthy children between the ages of 6 and 24 months and for all children older than 6 months with chronic cardiopulmonary, hematologic/oncologic, immunologic, metabolic, or renal disorders. Annual influenza vaccination is also recommended for household contacts and out-of-home caregivers of children younger than 2 years, women in their second or third trimester of pregnancy, and all health care professionals.⁸

Changes to recommendations for this season include the specification that persons with any condition that can compromise respiratory function or handling of secretions should be vaccinated and that health care facilities should be encouraged to provide vaccine to workers in ways that maximize uptake.⁴

If there is a Vaccine Shortage

In the 2004-2005 influenza season, the United States experienced a vaccine shortage from the suspension of vaccine production by a British manufacturer. This suspension resulted in a loss of nearly half the projected US influenza vaccine supply for the past season.⁴ As of the time of publication of this article, it is unknown whether a shortage will occur this season. We refer you to the CDC's Web site (www.cdc.gov/flu) for the most up-to-date information about the status of the vaccine supply.

If there is an inadequate supply, the CDC has defined a tiered use of the inactivated vaccine (Table 3).¹⁵ The highest priority group includes persons 65 years or older with comorbid conditions and residents of long-term-care facilities. Healthy persons aged 2 years to 49 years are considered lowest priority. The use of LAIV is encouraged in all eligible patients to increase the availability of inactive vaccine for the priority group.

Chemoprophylaxis. Chemoprophylaxis is an important adjuvant to TIV in the control and prevention of influenza. Chemoprophylaxis does not interfere with the immune response to TIV.²

Amantadine and rimantadine are approved for prophylaxis against influenza A in children older than 1 year. Oseltamivir is approved for prophylaxis against influenza A and B for children older than 13 years.

Chemoprophylaxis is indicated for:

• High-risk children for 2 weeks after TIV administration and healthy children if TIV is given after influenza circulation has been documented.

• High-risk children in whom TIV is contraindicated.

• Nonimmunized close contacts of high-risk children.

• Immunocompromised children who may not respond to TIV.

• High-risk children in a closed setting (eg, a hospital or boarding school).

• High-risk children during times when the vaccine strains poorly match the circulating influenza virus strains.

THE BOTTOM LINE

Flu season is upon us. We have safe and effective vaccines available to prevent the spread of influenza. Therefore, it is incumbent on us to be aware of the status of the vaccine supply, to vaccinate high-priority patients, and to offer vaccination to all other eligible patients if vaccine is available.

References:

REFERENCES:

1.

Glezen WP, Cherry JD. Influenza viruses. In: Feigin RD, Cherry JD, eds.

Pediatric Infectious Diseases.

Vol 2. 3rd ed. Philadelphia: WB Saunders Company; 1992:1688-1691.

2.

American Academy of Pediatrics. Influenza. In: Pickering LK, ed.

Red Book

:

2003 Report of the Committee on Infectious Diseases.

26th ed. Elk Grove Village, Ill: American Academy of Pediatrics; 2003: 382-386.

3.

Centers for Disease Control and Prevention. Update: influenza activity--United States and worldwide, 2004-2005 season.

MMWR.

2005;54:631-634.

4.

Centers for Disease Control and Prevention. Influenza Vaccine Bulletin #1. 2005-2006 Flu season. Available at:

www.cdc.gov/flu

. Accessed September 7, 2005.

5.

Neuzil KM, Zhu Y, Griffin MR, et al. Burden of interpandemic influenza in children younger than 5 years: a 25-year prospective study.

J Infect Dis.

2002; 185:147-152.

6.

Centers for Disease Control and Prevention. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP).

MMWR.

2004;53(RR-06):1-40.

7.

Stiver G. The treatment of influenza with antiviral drugs.

CMAJ.

2003;168:49-56.

8.

Committee on Infectious Diseases. Policy statement. Recommendations for influenza immunization of children.

Pediatrics.

2004;113:1441-1447.

9.

Boone SA, Gerba CP. The occurrence of influenza A virus on household and day care center fomites.

J Infect.

2005;51:103-109.

10.

Harper SA, Fukuda K, Uyeki TM, et al. Preven-tion and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP).

MMWR.

2005;54(RR-8):1-40.

11.

Hurwitz ES, Haber M, Chang A, et al. Studies of the 1996-1997 inactivated influenza vaccine among children attending day care: immunologic response, protection against infection, and clinical effectiveness.

J Infect Dis.

2000;182:1218-1221.

12.

Institute of Medicine.

Immunization Safety Review Committee Meeting: Influenza Vaccines and Neurological Complications.

Washington, DC: National Academics Press; 2003.

13.

Vesikari T, Karvonen A, Korhonen I, et al. A randomized double-blind placebo-controlled trial of the safety, transmissibility and phenotypic stability of live attenuated cold-adapted influenza vaccine (CAIV) in children attending day care. Presented at: 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2001; Chicago. Abstract 37359.

14.

Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children.

N Engl J Med.

1998;338:1405-1412.

15.

Centers for Disease Control and Prevention. Tiered use of inactivated influenza vaccine in the event of a vaccine shortage.

MMWR.

2005;54(30): 749-750.