Epidemiological trends in notified influenza cases in Australia’s Northern Territory, 2007‐2016

Abstract Background The Northern Territory (NT) of Australia has a mix of climates, sparsely distributed population and a large proportion of the populace are Indigenous Australians, and influenza is known to have a disproportionate impact upon this group. Understanding the epidemiology of influenza in this region would inform public health strategies. Objectives To assess if there are consistent patterns in characteristics of influenza outbreaks in the NT. Methods Laboratory confirmed influenza cases in the NT are notified to the NT Centre for Disease Control. We conducted analyses on notified cases from 2007‐2016 to determine incidence rates (by age group, Indigenous status and area), seasonality of cases and spatial distribution of influenza types. Notified cases were linked to laboratory datasets to update information on influenza type or subtype Results The disparity in Indigenous and non‐Indigenous notification rates varied by age group, with rate ratios for Indigenous versus non‐Indigenous ranging from 1.58 (95% CI:1.39, 1.80) for ages 15‐24 to 5.56 (95% CI: 4.71, 6.57) for ages 55‐64. The disparity between Indigenous and non‐Indigenous notification rates appeared higher in the Central Australia region. Indigenous versus non‐Indigenous hospitalisation and mortality rate ratios were 6.51 (95% CI: 5.91, 7.18) and 5.46 (95% CI: 2.40, 12.71) respectively. Inter‐seasonal peaks during February and March occurred in 2011, 2013 and 2014, and were due to influenza activity in the tropical north of the NT. Conclusions Our results highlight the importance of influenza vaccination across all age groups for Indigenous Australians. An early vaccination campaign targeted against outbreaks in February‐March would be best focused on the tropical north.


| INTRODUC TI ON
Seasonal epidemics of the influenza virus represent a continual global challenge. These epidemics usually occur in the winter months of temperate regions, but in tropical regions, influenza is reported to circulate widely outside this season. 1 Particular groups in the population, such as the elderly and pregnant women, are known to be at higher risk of severe outcomes from influenza infection. 2 The virus has also caused the breakout of pandemics, the most recent being the 2009 H1N1 pandemic. 2 Australia's Northern Territory has several features which are likely to make the epidemiology of influenza in this area unique.

| Data cleaning and analysis
Duplicate notifications were deleted. Notifications for patients who resided outside the Northern Territory were excluded from the calculations of rates but included in analyses that used raw count data. Hospital admissions that occurred >14 days after or more than 3 days before influenza diagnosis were considered not to be influ-

| Ethics approval
Ethical approval for the study was obtained from the Human Research  influenza B 1222 (17.7%) of the cases. The remainder were co-infections (9 cases) or untyped (10 cases). The subtype or lineage of 3756 (54.5%) of cases was known. Notification rates after 2009 were consistently higher than notification rates prior to 2009 (Table S1).

| Notified cases and notification rates
In most years and age groups, Indigenous Australians had higher notification rates than non-Indigenous Australians ( Figure 1). The greatest disparity between Indigenous and non-Indigenous notification rates throughout the study period was for older adults, although children aged between 0 and 4 were also disproportionately affected (Table 1).  Table 2).

| Notification rates by area
Based on raw rate ratios alone, the Central Australia region had the greatest disparity in influenza case notification rate between the Indigenous and non-Indigenous populations. The wide confidence intervals present are likely due to small case numbers.

| Rates of severe outcomes in Indigenous and non-Indigenous Australians
Hospitalisations were 6.51 times higher (95% CI: 5.91, 7.18) amongst Indigenous Australians (with the Indigenous and non-Indigenous rates being 237.01 and 36.40 per 100 000, respectively). Mortality was 5.46 times higher (95% CI: 2.40, 12.71) than that for non-Indigenous Australians (with the Indigenous and non-Indigenous rates being 3.14 and 0.57 per 100 000, respectively). In seasons with multiple peaks, most of the earlier cases occurred in the Top End ( Figure 4B).

| Spatial distribution of influenza A and B
The proportion of type A and type B cases in each SA2 area by year is shown in Figure 5  The increased influenza rates within the Indigenous population seen in this study during both pandemic and non-pandemic periods (Figures 1 and 3) could be associated with increased crowding within Indigenous households, which is more common in remote areas. A study which modelled an influenza-like illness outbreak and incorporated data on household structures found that the illness would impact 90% of the population of a remote Indigenous community, 75% of an urban Indigenous community and 25% of a non-Indigenous urban population. 14 The higher rates of severe outcomes from infection are consistent with previous data that Indigenous populations are disproportionately affected by influenza. A study examining severe influenza A(H1N1)pdm09 cases in the Indigenous and non-Indigenous populations of countries across the Americas and the Pacific found that rates of hospitalisations from A(H1N1)pdm09 were 3.0-to 7.7-fold higher for the Indigenous population compared to the corresponding non-Indigenous population. 15 Furthermore, this study revealed that mortality rates from A(H1N1)pdm09 were between 3.4-and 5.3-fold higher in the Indigenous population again compared to the corresponding non-Indigenous population. 15 Seasonal influenza too has been reported to have had a disproportionate impact upon Indigenous Australians at a national level, with studies reporting that Indigenous hospitalisation rates from influenza were 2.3-3.9 times higher than rates for non-Indigenous Australians. [16][17][18] Genetic factors may contribute to the higher rates of severe outcomes from influenza infection in the Indigenous population. 19 Analysis of HLA types found in Aboriginal Australians found that alleles of the A*24 type, which are thought to be less efficient at presenting conserved regions of the virus, were found at a higher frequency in Aboriginal Australians. 19 The A*24 allele was also detected at higher frequency in Native American populations, indicating this genetic susceptibility to severe influenza outcomes is not merely restricted to Indigenous Australian populations. 19 HLA types efficient at presenting conserved regions of the H7N9 subtype were found at lower frequencies in Aboriginal Australians compared to Caucasians, making this group more vulnerable to a subtype already known to be highly pathogenic. 20 Comorbid medical conditions are reported to be more prominent in the Indigenous population than the non-Indigenous population in this region, 21 and this too may contribute to the higher rates of severe outcomes from influenza infection. For example, it was reported that 40% of Indigenous adults in the Northern Territory had chronic kidney disease compared to only 8.7% of non-Indigenous Australians. 21 In 2015, the prevalence of rheumatic heart disease was reported to be 37 times higher in Indigenous Australians than non-Indigenous Australians in the Northern Territory. 21 The data provide some guidance as to priorities for vaccination There is growing evidence to suggest a decline in the effectiveness of the influenza vaccine over time but the rate at which the effectiveness TA B L E 1 Ratios (95% CI) of Indigenous influenza case notification rate to non-Indigenous influenza case notification rate in the Northern Territory from 2007 to 2016 by age group.

| D ISCUSS I ON
Categories marked ND indicate that there were no notifications for Indigenous or non-Indigenous Australians that year   10, 4.62) of the vaccine declines is unclear. 24 (Table S1). Finally, the resident

ACK N OWLED G EM ENTS
We would like to thank staff at the WHO Collaborating Centre for Reference and Research on Influenza for their work in linking the notification data to the Centre's database. We wish to acknowledge the Aboriginal and Torres Strait Islander communities in Australia who have been affected by influenza.

Dr. Tong reports grants from National Health and Medical Research
Council, during the conduct of the study.

AUTH O R CO NTR I B UTI O N S
Aaron Lawson Weinman: Formal analysis (lead); Investigation