Influenza

In most cases influenza infection in humans is uncomplicated and self-limiting within a few days or weeks, but for some patients the disease is fatal. Approximately one third of influenza infections are mild or asymptomatic, to the extent that infected persons do not even see a doctor (Hayward, 2010; Hayward, 2014). Our model assumes a mean duration of five days (Nicholson, 2003).

Wielders et al. (2010) included four different outcomes and their long-term sequelae following acute illness. These were pneumonia, otitis media, acute respiratory distress syndrome (ARDS) and sepsis. The frequency of other post-infectious complications following an influenza infection is low and these were therefore disregarded in the current study. From a clinical perspective, the acute manifestations of the disease often occur in concomitance as complicated cases

Based on information derived from the General Practice Research Database (GPRD), Meier et al. (2000) estimated the number of patients consulting a doctor with symptoms of influenza-like illness (ILI) who developed complications. The percentages were based on subjects who had at least one clinical diagnosis of influenza or influenza-like-illness (ILI) recorded in the GPRD between 1991 and 1996. In addition to the wide range of national case definitions, estimated consultation rates will also vary among countries due to differences in consultation behaviour, estimation procedure (estimation of incidence, given that many surveillance systems are based on sentinel reporting), vaccination coverage (although vaccination has a limited impact on the number of consultations) and obligatory doctor visits for absence from work or school (Harbers, 2005; Meijer et al., 2006). Therefore, doctor consultations were not considered to be indicative of acute complicated influenza disease.

Given very little specific information on the ratio of complicated/uncomplicated acute disease, no distinction was made between these and the variability was accounted for by including all possible manifestations in the disability weight (mild, moderate and severe): 0.051 (0.007–0.125).

Case fatality ratio

Research has shown that clinicians often attribute influenza-related deaths to a pre-existing underlying condition rather than to influenza (Zucs et al., 2005). Therefore, it is difficult to identify true mortality due to influenza only. Distinguishing further between mortality due to influenza with or without complications such as cardiac problems or pneumonia is even more difficult. Therefore in the current study only one category of death was considered, encompassing all causes which, in the model, occur shortly after infection.

For the Netherlands, it was estimated that during the period 1967–1989 the overall impact of influenza on mortality was greater than registered mortality by a factor of 3.6 (Sprenger et al., 1993). Using this multiplication factor for more recent data may overestimate the number of deaths due to influenza, because in many Member States today vaccination coverage is considerably higher than in the period 1967–1989. In the study by Sprenger et al. almost half of the non-registered influenza deaths were registered as deaths from heart disease, approximately 25% from lung disease and approximately 30% from other diseases (Sprenger et al., 1993). Recently, time series analysis has also been used to estimate mortality attributable to influenza and other respiratory pathogens (van den Wijngaard et al., 2010).

In about 0.1% of all influenza cases the disease will be fatal (Flu.gov, 2012). This includes both uncomplicated and complicated influenza cases.

Approximately 90% of persons with influenza as cause of death were aged ≥ 65 years (Webster, 2013). Therefore, given that the case fatality proportion for influenza is age-dependent, we modelled the age-specific risk according to the observed mortality data in Estonia, Germany and the Netherlands (see Table 3) (CBS, 2009).

Risk of complications

The most vulnerable populations in terms of complications following influenza are children aged under one 1 year and adults over 65 years, pregnant woman, and people of any age with comorbid illnesses (Rothberg et al., 2008).

The most common complications of influenza are secondary bacterial infections, especially otitis media and pneumonia (van Steenbergen, et al., 2006). It is estimated that 0.65% of influenza cases develop otitis media and 0.36% pneumonia (Meier et al., 2000). Secondary bacterial pneumonia most often complicate the condition 4–14 days after primary seasonal influenza infection (Rothberg et al., 2008). Neurological complications such as encephalopathy (Reye’s syndrome), encephalomyelitis, transverse myelitis, aseptic meningitis, focal neurological disorders, and Guillain-Barrι syndrome most often appear in small children (Rothberg et al., 2010). The incidence of neurological complications among <5 years was estimated to be 4 per 100 000 (Newland, 2007).

Wielders et al. (2010) assumed that about 1.23% of all influenza cases develop pneumonia. Earlier, van Lier et al. (2007) assumed that this fraction was 0.36%. In most cases the disease will be self-limiting within a few days, and only in a few cases will it be fatal. According to Murray et al. (1996) long-term outcomes of pneumonia in developed countries are very rare and can be disregarded when estimating disease burden.

Wielders et al. (2010) assumed that 0.65% of influenza cases will develop otitis media as a complication of influenza. Most affected persons will fully recover, but 0.006% of otitis media cases will develop deafness as a life-long disability (Murray, 1996). Given the very low risk, we considered this complication as negligible.

A few cases will develop sepsis during an influenza infection, estimated at 0.0097% of all cases (Wielders, 2010). In some cases the disease will be fatal but again, since there was no detailed information available on the percentage, we assumed that fatal cases would be included in the death estimate related to influenza. Long-term disability was estimated to occur in 82% of patients surviving sepsis (Korosec Jagodic, 2006). However, given the fact that sepsis is caused by bacteria giving rise to super-infections possibly related to other factors, the long-term sequelae of sepsis are not considered to be part of the burden of influenza infections.

Acute respiratory distress syndrome (ARDS) and life-long disability

Following Wielders et al. (2010), we assumed that 0.023% of influenza cases will develop ARDS as a complication of influenza. We assumed that the risk of developing ARDS changes according to age (Manzano, 2005). Wielder’s study, however, does not consider cases <15 years and in order to account for these, we also included a study on younger populations (Zimmerman, 2009). We combined the ARDS incidence from the two studies, added them together and estimated the age-group risk of developing ARDS (see Table 4).

In a few cases the disease will be fatal. However, having no detailed information on the specific risk, we assumed that fatal cases would be included in the death estimate related to influenza. Around 30–55% (Hopkins, 1999; Mikkelsen, 2012) of patients surviving ARDS will have developed disabilities related to cognitive impairments at one year follow-up. Therefore, in our model, we estimated that 0.007–0.013% of all symptomatic influenza cases will develop cognitive sequelae assumed to be permanent.

Model input summary

Table 1. Transition probabilities used in the outcome tree

Health outcome
(Health state)

Distribution of health states in health outcome

Transition probability

Source/assumption

Permanent disability due to ARDS

 

0.007–0.013%
Age dep. (Table 4)

Wielders, 2010; Manzano, 2005; Hopkins, 1999; Mikkelsen, 2012

Fatal cases

 

0.10%
Age dep. (Table 3)

Flu.gov, 2012; observed cases

Table 2. Disability weights and duration

Health outcome
(Health state)

Disability Weight (DW) (Haagsma, 2015)

Duration

DW

Label

In years

Source

Symptomatic infection

0.051 (0.007–0.125)

Infectious disease, acute episode, from mild to severe

0.014

Nicholson, 2003

Permanent disability due to ARDS

0.056 (0.044–0.067)

Motor plus cognitive impairments, mild

Remaining life expectancy

Hopkins, 1999; Mikkelsen, 2012

Table 3. Age group distribution of 0.1% risk of fatal cases

Age

%

0

0.58

01-04

0.51

05-09

0.24

10-14

0.27

15-19

0.24

20-24

0.33

25-29

0.31

30-34

0.33

35-39

0.75

40-44

1.15

45-49

1.56

50-54

1.53

55-59

2.21

60-64

3.23

65-69

4.54

70-74

5.22

75-79

11.42

80-84

18.72

85+

46.85

Source: based on all reported fatal influenza cases in Estonia, Germany and the Netherlands for the years 2005–2007.

Table 4. Age group distribution of 0.007–0.013% risk of developing ARDS

Age

%

0-14

7.21

15-29

2.59

30-44

7.66

45-59

12.17

60-74

28.73

≥75

41.63

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