Severe influenza cases in paediatric intensive care units in Germany during the pre-pandemic seasons 2005 to 2008

Influenza belongs to the most frequent vaccine-preventable diseases. Clinical manifestations of influenza infections range from illness with asymptomatic, atypical (i.e., gastro-intestinal) or oligosymptomatic disease to severe toxic progression resulting in death [1, 2]. Elderly people and infants account for the highest morbidity [1, 3, 4].

Complications of influenza may occur at any age, affecting most severely patients with chronic underlying diseases, as chronic pulmonary diseases, diseases of the circulatory system, metabolic diseases, or immunodeficiency. The most severe complication is peracute fatality in adolescents and young adults caused by acute circulatory failure due to myocarditis or fulminant necrotising influenza-associated pneumonia. A frequently reported complication is a secondary bacterial pneumonia. Other known complications include encephalitis, otitis, and neuromuscular diseases [1, 3, 4].

Surveillance studies from several industrialized countries reported an incidence of paediatric hospitalisations associated with seasonal influenza of 11-154/100,000 children < 5 years of age, and an incidence of 1-13/100,000 children treated for influenza in paediatric intensive care units (PICUs) [5‐7]. For the influenza season 2003-2004, 153 influenza-associated deaths among children were reported in the United States; 47% of those occurred in children without underlying chronic disease [8].

In Germany, only limited epidemiological data on hospitalisations and complications of seasonal influenza in children is available. In the population-based PRIDE study, conducted in 11 paediatric practices and 4 hospitals on children < 3 years of age from November 1999 to October 2001, annual incidence of influenza-associated hospitalisations was estimated as 120/100,000 [9]. In another population-based study conducted 1996-2001 in two paediatric hospitals, incidence was calculated as 123/100,000 children < 6 years of age, and 53/100,000 in children < 17 years of age [10]. However, both studies were too small to detect rare severe influenza-associated complications and fatalities resulting in PICU admittance.

The objective of this study was the nation-wide detection of severe influenza virus infections and fatalities in children, and to identify possible risk factors for complications. These data are important in the current discussion of a possible extension of yearly influenza vaccination from a risk-based strategy to general vaccination of all children. The study was conducted before the occurrence of the new influenza A (H1N1) 2009 pandemic in Germany.

We describe the results from a nation-wide surveillance study on severe paediatric seasonal influenza cases in Germany during three pre-pandemic influenza seasons between 2005 and 2008. A total of 20 laboratory-confirmed influenza-associated PICU cases (14 influenza type A, 5 type B, 1 type unknown), including two fatalities, were reported. This number was surprisingly low and corresponded to an estimated annual incidence for PICU-admitted children with seasonal influenza of 0.1/100,000 children < 5 years of age. In contrast, for the same age group incidences of PICU admissions associated with seasonal influenza were 4/100,000 in USA and 1-13/100,000 in South Australia [5, 7]. Apart from country-specific differences in access to health care as well as in criteria for ICU hospitalisation, the lower incidence found in our study may also be due to the weak to moderate influenza activity during the observation period in Germany [11]. Another important explanation is possible under-diagnosis of influenza in the hospitals, as not all physicians perform influenza testing of children admitted with severe acute respiratory infection. Low participation in the voluntary reporting system due to frequent changes of the medical staff in the PICUs is a further possible reason. Hence, the low reported incidence for PICU-admitted influenza cases in this study may underestimate the true incidence of severe paediatric influenza cases in Germany. With regard to fatal paediatric cases it should be noted that our study was not designed to capture influenza-associated fatalities that occurred outside PICUs, e.g. at home or during emergency treatment. For comparison, the national mortality register reported a total of 25 influenza-associated (ICD-10 code J10) deaths in children < 15 years of age during the years 2006 to 2008.

Our study showed that in Germany children < 1 year of age and children with chronic underlying diseases are the main paediatric risk groups for severe seasonal influenza infections. Influenza-associated pneumonia, secondary bacterial infections, ARDS and encephalitis/encephalopathy were frequent complications. The observed clinical characteristics were similar to the results from the U.S. and other countries [2, 4, 8, 12‐17]. However, children in our study were older (median 7.5 years) than in an ICU study in the U.S. (median 1.5 years) [12]. Fatalities also were reported only in two older children (8 and 14 years of age), whereas the majority of reported paediatric fatalities in the U.S. and Australia are below 5 years of age [14, 17]. In our study, ARDS occurred in 25% of the PICU children, in contrast to a retrospective chart review in an U.S. children's hospital with 27 PICU children diagnosed with seasonal influenza 2008/2009 [18], which reported only 4% of ARDS.

In the current study, 10 (50%) patients were treated with oseltamivir, whereby in 5 (25%) patients treatment was started several days after the appearance of influenza symptoms or ICU admission. Antiviral treatment is most beneficial when started within 2 days after onset of symptoms. Nevertheless, oseltamivir treatment initiated later than 2 days after the first influenza symptoms is still considered useful in children with influenza pneumonia or to reduce viral shedding in the hospital [19]; it also seems to reduce the risk of secondary bacterial super-infections, although the mechanisms are not fully understood [13]. In our study, co-infection with more than one bacterial species was found only in patients that did not receive oseltamivir treatment.

In total, 35% of the patients suffered from bacterial co-infection, including one fatality associated with Streptococcus pneumoniae. Patients with bacterial or fungal co-infections stayed twice as long (median 18 days) at the PICU than other influenza patients, thus indicating the high influence of those co-infections on the morbidity. Staphylococcus aureus was the most frequently observed bacterial species. The data from Germany indicate a similar situation as observed on severe paediatric influenza cases (fatalities) in the USA, which showed bacterial co-infections in 34% of patients in 2007, most frequently with Staphylococcus aureus [13].

In Germany, influenza vaccination in children is currently recommended for risk groups, defined by chronic underlying diseases. In 2005, a regional survey in children < 24 months of age showed that 5% of all children had been vaccinated against influenza [20]. Among the severe cases reported in our study no child had been vaccinated. Eleven (55%) belonged to risk groups with chronic underlying disease, including eight (40%) of at least two years of age for whom influenza vaccines are considered to be efficacious [21]. One risk group child was below 6 months of age and, hence, too young to be immunized. Two other risk group children were under two years of age; for this age group, the efficacy of the inactivated influenza vaccines licensed in Germany is unclear, and data on safety are insufficient thus far [21]. Forty-five% of the patients with severe influenza were previously healthy children, who would not be covered by a risk-based vaccination strategy. A recommendation to vaccinate healthy children routinely against seasonal influenza is not widespread in Europe, but has been argued to have potential community benefits [22].

Renewed interest in paediatric influenza arose with the occurrence of the new pandemic influenza A (H1N1) 2009 in Germany from April 2009 onwards [23]. An ongoing ESPED study on children with severe pandemic influenza A (H1N1) 2009 reported 93 cases below 15 years of age from 55 PICUs during a single season (August 2009 to April 2010), including 15 fatalities (11 within PICUs) [24]. This high number of cases reported in the ongoing ESPED study may be partly due to an increased awareness in physicians regarding the new subtype of influenza with unclear severity at the start of the pandemic, resulting in more frequent laboratory testing and diagnosis of influenza [5, 24]. Additionally, the higher number of PICU admissions may be due to a truly higher severity of the pandemic influenza A (H1N1) 2009 subtype in children compared to previous seasonal influenza subtypes [e.g., [18, 25]], although not all studies report such a difference in severity [26, 27], or found a difference only regarding risk groups [28]. Thus, a comparison of both ESPED studies on the absolute number of severe influenza cases [24] has to be regarded with caution, and may underestimate the importance of severe seasonal influenza caused by non-pandemic influenza virus subtypes in children in Germany. Further prospective, laboratory-confirmed surveillance in PICUs is needed to clarify the complication rates associated with influenza virus A and B and their different subtypes and lineages.

Almost half of the children with severe complications associated with seasonal influenza were previously healthy children, for whom there is currently no recommendation to vaccinate against influenza. Fifty% were children with chronic diseases for whom vaccination had been recommended but had not been followed. In these children the severe course of disease might have been prevented by vaccination. Oseltamivir treatment was often started several days after start of influenza symptoms or PICU admission, indicating that influenza is often diagnosed too late for effective antiviral patient treatment. The general incidence of influenza-associated severe disease in German PICUs was very low, but under-diagnosis and under-reporting during these pre-pandemic influenza seasons may be likely. Therefore prospective studies providing influenza subtype screening on PICU admissions of children with respiratory disease are needed to assess more accurately the burden of severe influenza-associated complications. These studies are necessary to provide data and evidence for the discussion on influenza prevention by general routine vaccination in children.