Respiratory tract infections are the leading cause of illness in infancy and early childhood. Medical help is not sought for the majority of these infections, but lower respiratory tract infections (LRTIs) are the most common reason for consultation with a doctor and for hospitalization in this age group. The main viruses responsible for LRTIs are respiratory syncytial virus (RSV), parainfluenza viruses and influenza viruses. 1, 2
The burden of disease resulting from influenza infections has long been underestimated in Germany, and influenza vaccination of children is only recommended for those with underlying cardiac or pulmonary disease. However, children have a central role in the spread of annual influenza epidemics, as demonstrated by the results of mass vaccination of schoolchildren in Japan. 3 The possibility of treating and preventing influenza infections with the newly developed neuraminidase inhibitors provides another reason to assess the epidemiology of influenza in infants and children.
The aim of this paper is to summarize the national data on the disease burden of influenza in children in Germany, to enable informed decision-making on influenza-related issues.
MATERIALS AND METHODS
The data in this report are derived from three separate sources.
The reporting system of the Deutsche Arbeitsgemeinschaft Influenza (AGI), a sentinel for acute respiratory illness (ARI)
Offices of general practitioners and pediatricians report the numbers of patients seen with ARI as a percentage of their total patient number. These figures are combined with the numbers of influenza virus isolates reported from the German virologic laboratories that receive specimens from the sentinel physicians and other physicians in charge of severely ill patients. The AGI data can then be used to determine the magnitude of the influenza epidemic in a given winter, as well as the types of viruses causing the outbreak. These data are available online (http://influenza.rki.de/agi) and in a booklet published yearly at the end of the winter season (AGI, Marburg, Germany).
Data from a prospective hospital-based study, Paediatric Infectious
Disease (PID)-ARI-net. This study by Weigl et al. 4 reports patients from Kiel, the capital of the northernmost federal state in Germany. Between 1996 and 2001, nasopharyngeal aspirates of hospitalized children (0 to 16 years) were tested by a nine-valent multiplex PCR. 5 The incidence rates were based on population data from the Kiel area.
Data from the Paediatric Respiratory Infection in Germany (PRIDE) study
This population-based prospective multicenter study recruited children from 11 pediatric practices and from the referral children’s hospitals in Hamburg, Bochum, Dresden and Freiburg. Between November 1999 and October 2001, children younger than 3 years were enrolled in the study if they presented with clinical signs of laryngotracheitis (croup), bronchitis, bronchiolitis or pneumonia. 6 Three groups of patients were registered: (1) outpatients who visited one of the pediatric practices with any of the defined LRTIs; (2) inpatients who had been hospitalized because of one of the LRTIs; and (3) nosocomial cases in children who had been hospitalized for >48 h when they developed symptoms of an LRTI. Nasopharyngeal secretions from these children were tested by a hexavalent multiplex PCR. 7, 8 The population at risk was calculated as the total number of children 0 to 3 years of age who would consult one of the PRIDE practices in case of any illness. The rates of nosocomial infections were calculated for total person-days at risk, which was estimated by the mean duration of hospitalization in the respective age group.
The investigators from Kiel were the founders of the PID-ARI-net, and they are now joined with the investigators participating in the PRIDE study. The network is currently active in Kiel, Mainz and Freiburg, and the data are available online (http://www.pid-ari.net).
The data reported by PID-ARI-net and PRI.DE are from seasons of interpandemic influenza activity between 1996 and 2001. Overall, for the 0- to 5-year age group, the network showed a doubling of consultation rates in the sentinel offices and a tripling of hospital admissions because of ARI during the influenza season when compared with the rest of the year.
In the PID-ARI-net study, a total of 3469 children were hospitalized with ARI during the study period. A nasopharyngeal specimen was obtained from 60.5% of these children. RSV was the most frequently detected virus, occurring in 9.5% of all hospitalized children. Influenza A virus infection was diagnosed in 122 (3.5% of all) children, and influenza B was diagnosed in 14 (0.4%) children (influenza B was searched for in 3 years only). The clinical diagnoses recorded in the 136 children with confirmed influenza were: “flu” (47%); pneumonia (26%); bronchitis (13%); wheezy bronchitis (12%); and croup (1%).
The PRIDE study registered 2924 hospitalizations of children. A nasopharyngeal specimen was obtained in 64.9% of the cases. In children from whom a nasopharyngeal specimen was available, influenza A virus was detected in 73 (4.0%) cases and influenza B virus in 4 (0.2%) cases. RSV was detected in 38.0% of the children. Table 1 shows the viral etiology of the LRTIs in the hospitalized children.
The hospitalization rate because of influenza was 123 per 100 000 children in the PID-ARI-net study (for children aged 0–5 years only) and 120 per 100 000 children in the PRIDE population. The mean duration of hospitalization in the PRIDE study was 6.3 days (5 to 95%; range, 1 to 14 days). In both studies premature birth and underlying cardiac or pulmonary disease were risk factors for hospitalization (relative risks in the range of 2 to 4), but the vast majority of hospitalized children were previously healthy.
In the PID-ARI-net study 10 children were diagnosed with a nosocomial infection caused by influenza A virus and 2 children were diagnosed with influenza B virus. Of a total of 141 nosocomial cases of LRTI found in the PRIDE study, 2 were caused by influenza A virus. In children 0 to 3 years of age, the risk of contracting a nosocomial influenza infection was 1.5/100 000 patient-days.
In the PRIDE study 2386 children with LRTI were seen in pediatric offices, and 60.7% of them made a nasopharyngeal specimen available. Influenza A virus was found in 53 (3.7%) children and influenza B virus in 1 (0.1%). RSV was the most prevalent virus detected (20.9%). The etiologic viruses in outpatient children with various LRTIs are shown in Table 1.
The yearly incidence rate for any visit to a doctor because of influenza-associated LRTI was 1.1 per 100 children younger than 3 years. The corresponding rate for any LRTI in this age group was 28.7 per 100 children.
In the German health care system, children are generally treated by pediatricians, rather than by general practitioners. This allows a nearly complete record of children with respiratory illnesses to be registered with pediatricians as sentinels. To enable comparison with studies in other countries, the PRIDE study used generally accepted definitions for the clinical diagnoses of LRTI. 6 A retrospective cohort in Tennessee 9 showed an outpatient visit rate attributable to influenza of ∼10 to 15 per 100 in children 0 to 3 years of age. This is 10 times the rate found in the PRIDE study (1.1 per 100). The PRIDE data are in line with a prospective study of children in an immunization program, in which the rates of influenza-positive emergency contacts in children younger than 5 years were 0.8 per 100 for LRTI and 9.5 per 100 for any other influenza illness. 10 The low rates observed in the PRIDE study can be explained by the absence of severe influenza epidemics and the use of LRTI as an inclusion criterion. Obviously the total number of influenza-infected children, including those presenting with an “influenza-like illness” only, would be substantially higher, and many children with a mild disease are also less likely to be seen by a doctor. Therefore the PRIDE data can be regarded as a conservative estimate of the burden of influenza in outpatient children.
The hospitalization rates for influenza (mainly for children 0 to 5 years of age) have been reported to be in the range of 120/100 000 in otherwise healthy children, 11, 12 and up to 470/100 000 in those with predisposing conditions. 2, 9, 12 The data from PRIDE and PID-ARI-net fit well in the first group. The duration of hospitalization in children with influenza corresponds to that of children with RSV. However, the length of hospital stay for RSV infection worldwide is not so much dependent on the severity of disease as on the country where the patient lives. 13
The national health care system in Germany and the attitudes of parents and patients may also have accounted for the low consultation rates registered in the PRIDE study. Even if these data cannot be directly generalized to other countries, they are helpful in estimating the influenza disease burden in Germany.
In conclusion influenza illness in German children results in rates of hospitalization that are similar to those observed in other countries, and the rates of outpatient visits because of influenza-associated LRTI are also in the range reported in the literature. However, a more refined search would reveal many more cases of influenza presenting with influenza-like illness. Influenza presents a significant health risk to all children, and a more complete evaluation of any means of treatment or prevention is warranted.
1. Cooney MK, Fox JP, Hall CE. The Seattle virus watch: VI. Observations of infections with and illness due to parainfluenza, mumps and respiratory syncytial viruses and Mycoplasma pneumoniae
. Am J Epidemiol 1975; 101: 532–51.
2. Glezen WP, Keitel WA, Taber LH, Piedra PA, Clover RD, Couch RB. Age distribution of patients with medically-attended illnesses caused by sequential variants of influenza A/H1N1: comparison to age-specific infection rates, 1978–1989. Am J Epidemiol 1991; 133: 296–304.
3. Reichert TA, Sugaya N, Fedson DS, Glezen WP, Simonsen L, Tashiro M. The Japanese experience with vaccinating schoolchildren against influenza. N Engl J Med 2001; 344: 889–96.
4. Weigl JA, Puppe W, Schmitt HJ. The incidence of influenza-associated hospitalizations in children
in Germany. Epidemiol Infect 2002; 129: 525–33.
5. Weigl JA, Puppe W, Grondahl B, Schmitt HJ. Epidemiological investigation of nine respiratory pathogens in hospitalized children
in Germany using multiplex reverse-transcriptase polymerase chain reaction. Eur J Clin Microbiol Infect Dis 2000; 19: 336–43.
6. Denny FD, Clyde WA. Acute lower respiratory tract infections in nonhospitalized children
. J Pediatr 1986; 108: 635–46.
7. Kehl SC, Henrickson KJ, Hua W, Fan J. Evaluation of the Hexaplex assay for detection of respiratory viruses in children
. J Clin Microbiol 2001; 39: 1696–701.
8. Liolios L, Jenney A, Spelman D, Kotsimbos T, Catton M, Wesselingh S. Comparison of a multiplex reverse transcription-PCR-enzyme hybridization assay with conventional viral culture and immunofluorescence techniques for the detection of seven viral respiratory pathogens. J Clin Microbiol 2001; 39: 2779–83.
9. Neuzil KM, Mellen BG, Wright PF, Mitchel EF Jr, Griffin MR. The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children
. N Engl J Med 2000; 342: 225–31.
10. 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: 147–52.
11. 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.
12. Mullooly JP, Barker WH. Impact of type A influenza on children
: a retrospective study. Am J Public Health 1982; 72: 1008–16.
13. Behrendt CE, Decker MD, Burch DJ, Watson PH. International variation in the management of infants hospitalized with respiratory syncytial virus: International RSV Study Group. Eur J Pediatr 1998; 157: 215–20.