Treating influenza in children and adolescents

October 2001

---Philip A. Brunell, MD

Until recently, influenza virus has been viewed as a scourge of the elderly with most efforts directed at preventing morbidity in this group.

The effect of influenza infection on infants and children has also been recognized for many years, and recent publications have confirmed this (NEJM. 2000;342,225; NEJM. 2000; 342,232). Yet, pediatric influenza infections have not received as much attention as the disease in the elderly. One of reasons for the inattention is likely due to the difference in the symptomatology produced by influenza in the elderly as compared with preschoolers. In the latter group it often does not produce a unique syndrome as it does in older children and adults, and is not the dominant respiratory illness. In contrast, it is one of many respiratory viruses that affect young patients. In this age group, it may produce a variety of respiratory symptoms.

At long last, a new type of vaccine, a live-attenuated intranasal vaccine, has been developed but has not yet been approved. As a result, there has been renewed interest in the immunization of children to reduce morbidity from influenza in older people.

A new class of antiviral drugs, neuraminidase inhibitors, has been found to be effective in adults and in children. In contrast to the older M2 ion channel inhibitors, which are effective only against A strains, the neuraminidase inhibitors are effective against both A and B strains of influenza virus. This may make it feasible to offer specific therapy for the treatment of influenza. This may, in turn, reduce the use of antibacterial drugs, and thus, resistance as a consequence of their widespread and often inappropriate use.

These new antiviral drugs, zanamivir (Relenza, GlaxoSmithKline) and oseltamivir (Tamiflu, Roche) are approved for treatment of children older than 12 and 1 year, respectively. Both must be used within the first day or so of symptoms to be efficacious. In pediatric trials, the duration of symptoms was decreased by zanamivir by an average of 1.25 days [Pediatr Infect Dis J. 2000;19:410]. Zanamivir given within 36 hours of the introduction of influenza into a household to children older than 5 years was effective in preventing spread to family members. Symptoms were reduced by 2.5 days in index cases who were treated [NEJM. 2000;343:1282].

However, this drug has not been approved for pediatric prophylaxis. Oseltamivir is approved for prophylaxis in children older than 12 years on the basis of efficacy studies (JAMA. 2001;285:748).

The neuraminidase inhibitors cost considerably more than the older drugs, amantadine and rimantadine. In contrast to the first-generation influenza drugs, they have not been associated with as much resistance. Amantadine caused some central nervous system adverse events and oseltamivir some emesis. Zanamivir has been reported to reduce air flow and cause bronchospasm in some patients with reactive airway disease and should be used with caution in these patients. We do not have a direct comparison of the newer with the older anti-influenza drugs, but rimantadine was reported to be superior to acetaminophen in the treatment of influenza A in children [Pediatrics. 1987;80:275]. We do not have similar data for the new antiviral drugs. There is a substantial difference in price between the older and the new drugs and between the antiviral drugs and acetaminophen.

Diagnostic tests

Rapid diagnostic office tests, eg, Quickvue Influenza Test, Zstat Flu, should enable office practitioners to make a specific diagnosis and prescribe one of the new antiviral drugs. The tests are said to have great specificity and reasonable sensitivity but evaluation of these tests in children has been difficult to find. In an abstract at the 2001 Pediatric Academic Societies meeting (K. Edwards), Quickvue was reported to have a sensitivity of about 75% for A strains and a specificity of >95%. Although the test detects both A and B strains, the latter were not evaluated in this report.

To minimize expense, one should use these tests for those who are candidates for treatment with the antiviral drugs rather that testing everyone with a respiratory illness. It also has been suggested that at a time when there are a substantial number of positive tests children with illnesses compatible with influenza might be treated without testing. One of the ways to track the path of influenza virus is to access www.cdc.gov/ncidod/diseases/flu/weekly or call (888) 232-3228 or your local health department.

Influenza vaccine supplies

The delayed delivery of influenza vaccine this season has probably done more to stimulate immunization that any organized campaign. In recent years there has been more interest in the immunization of children because of greater appreciation of the morbidity that this virus causes in children. The rate of hospitalization in the very young is second only to the oldest age group. Even in the absence of complications, influenza is a severe illness. Severe croup can result from influenza virus, and bacterial otitis media (OM) is a common complication. Probably the greatest impetus to the immunization of children is the need to prevent illnesses that are likely to keep them from school and day care and their parents from work.

What has been the reticence to recommend routine use of influenza vaccine for children? In contrast to other vaccines, influenza vaccine must be given annually. For children 6 months to 8 years of age, they must receive 2 doses the first time they are immunized against influenza virus. Thus, it adds one injection to an already crowded schedule. What is more, it is much less effective than the routine childhood vaccines.

Recent studies in a day care center indicated that its efficacy was only 45% and 31% against types B and H3N2, respectively [NEJM.2000;284:1677]. Fortunately, the split vaccines, which are used in children, are less reactive than the older vaccines, which gave this vaccine a bad reputation for reactions. It is prepared in eggs and so it should be used with this in mind. This may be important when immunizing children with asthma, for whom it is often recommended.

Parents need to understand that influenza vaccine protects against influenza and will not prevent or modify most respiratory illnesses that occur during the fall and winter. It is not a “cold vaccine.” It will not prevent respiratory syncytial virus, parainfluenza or rhinoviruses that cause similar illnesses. In a study of influenza during an epidemic in a day care center, those immunized did not have a significant decrease in respiratory illness, although there was a reduction in laboratory-proven influenza infections [J Infect Dis. 2000;182:1218]. It tends to modify influenza in those who are infected. It has been shown to prevent OM associated with influenza virus infection, as has treatment with oseltamivir (Pediatr Infect Dis J. 2001;20:127). These effects have been recorded during epidemics of influenza. Parents must understand that influenza vaccine in not a vaccine against “ear infections” year round. The attack prevented during the influenza season may be a single episode during a year in which a child may experience several attacks of OM.

It is necessary to monitor the changes in the antigen composition of circulating influenza viruses to be certain to match the vaccine with the strain that is expected to be prevalent in the coming epidemic. To accomplish this, a decision must be made months ahead of the “influenza season” to enable manufacturers to produce the vaccine in time.

It is recommended that the early deliveries of vaccine be used to immunize those at increased risk. Immunization of those not at high risk should be delayed until November when there should be adequate supplies of vaccine. Immunization can be continued after this time, if necessary, as most epidemics in recent years have occurred after the first of the year. The optimal time to immunize, however, is in October or early November.

Intranasal vaccine

There has been considerable experience with an investigational “cold-adapted” intranasal influenza vaccine (FluMist, Aviron/Wyeth Lederle). By growing influenza virus in the laboratory at lower temperatures, it becomes attenuated. In addition, it will grow in the lower temperature of the nose in preference to the lungs and produce local immunity in the nasal mucosa. This vaccine is in large-scale trial at this time. It has the obvious advantage of not requiring an injection. In addition, it appears to be less restricted in terms of strain specificity. Thus if the match of the vaccine strain with the circulating strain is not a close one, one may still expect to have some protection. There is also data indicating that protection may extend beyond a single influenza season (J Pediatr. 2000;136:168).

The first submission of this vaccine to FDA did not result in approval. However, it will be back. If the intranasal vaccine fulfills its early promise, routine immunization of children against influenza may become a reality. At that time it will be appropriate to address the issue of protecting older individuals against influenza by immunization of children. Interest in this possibility has been fueled by a report that mortality from influenza in the elderly in Japan was impacted by routine immunization of school children (NEJM. 2001;344:889). See also Pediatric Annals November 2000 issue on influenza in children. In fact, much of what has appeared about infants and children in recent years is the possibility that immunization of this group might reduce morbidity in older individuals.

In the meantime, children should be immunized if they may be in contact with individuals at high risk or are at increased risk of complications if they should develop influenza (see Red Book). In 2001, the use of the available vaccines together with newer rapid diagnostic tests and in conjunction with old and new antiviral drugs may increase our ability to reduce morbidity from influenza in pediatric patients.