Methodology

The Flu Tool relies on a baseline set of multipliers, derived from the peer-reviewed literature, that extrapolate from flu-related hospitalization and/or death data (depending on the data that the user enters into the tool) to estimate other levels of the Burden of Disease (BoD) pyramid. Data to inform multipliers and other assumptions were gathered through a series of systematic literature reviews that included data extracted from studies published in all six WHO regions. Data were included from studies published from January 1, 2000 to August 31, 2024.

The tool uses data from systematic reviews of the peer-reviewed literature in 3 ways:

1. To determine multipliers (and 95% confidence intervals [95% CIs]) for estimating deaths or hospitalizations (depending on the user-supplied data), critically ill (e.g., intensive care unit [ICU]) hospitalizations, medically attended mild/moderate cases, and medically unattended mild/moderate cases.
2. To determine expansion factors that account for under-detection and under-reporting of flu-related hospitalizations and deaths. These expansion factors function similarly to the multipliers described above, but rather than using reported hospitalization or death data to estimate other flu severity levels (e.g., critical (ICU-level) hospitalizations, mild/moderate cases), expansion factors use reported hospitalization or death data to estimate the true number of hospitalized cases or flu deaths, respectively (i.e., the same level of severity).
3. To determine proportions of flu-related hospitalizations by syndrome (i.e., clinical presentation). While flu typically presents as a respiratory disease, it can also present with other primary clinical manifestations as well, including circulatory disease and symptoms that are neither respiratory nor circulatory. Flu surveillance typically focuses on respiratory symptoms, so flu cases that present with non-respiratory symptoms are more likely to be excluded from reported surveillance data.

The Flu Tool allows users to select the year/flu season for which to estimate flu burden, as well as the ability to compare results between seasons. The format of the season—i.e., single-year season for Southern Hemisphere countries vs two-year season for Northern Hemisphere countries (e.g., 2020-2021) vs hybrid season for tropical countries (near the Equator)—is determined based on the reporting format used for the WHO Global Influenza Programme FluNET database.

The Flu Tool incorporates data from a literature review focused on understanding the proportions of flu-related hospitalizations that have a respiratory, circulatory, or non-respiratory/non-circulatory primary clinical presentation (or syndrome). The purpose of this analysis is to provide data on flu-related hospitalizations without the traditional respiratory presentation in order to improve understanding of the burden of other clinical manifestations. Data from the peer-reviewed literature were limited and could not be broken down by age group due to small sample sizes, so we used data from all ages from the combined literature to calculate estimates for the proportions described above.

From the literature review, it was determined that, on average, 81.94% of all flu-related hospitalizations exhibit respiratory disease, 4.61% a primary circulatory presentation, and 13.45% have other non-respiratory, non-circulatory presentations (e.g., gastrointestinal). To determine the expected number of respiratory, circulatory, and non-respiratory/non-circulatory cases, the tool divides the number of flu-related hospitalizations calculated in the tool (including the expansion factor, if selected) by 81.94%, in order to estimate the total number of flu-related hospitalizations. The tool then multiplies that total by 4.61% and 13.45% to calculate the number of circulatory and non-respiratory, non-circulatory hospitalizations, respectively.

These estimates are intended to be approximate and should be considered notional due to the limited size and number of studies from which the underlying data were extracted.

The Flu Tool represents uncertainty through the display of 95% confidence intervals (95% CIs), which are applied to the multipliers and expansion factors calculated using the methods detailed above. The tool also allows (but does not require) users to enter 95% CIs with their hospitalization or death data. Users who elect to enter custom multipliers must also enter accompanying 95% CIs.

Uncertainty is propagated through the tool primarily using the normal Delta Method. For example, to compute the expected number of deaths given a starting number of user-entered hospitalizations (with an accompanying 95% CI) and a tool-generated multiplier (with 95% CI), the following Delta Method using a normal approximation is applied:

Step 1: Compute SEs from CIs

Step 2: Point estimate of deaths

Step 3: Variance of deaths (delta method)

Step 4: Standard error

Step 5: 95% CI (Normal approximation)