Patients included
A total of 28,096 hospitalized patients at 46 participating hospitals in 13 countries were screened for eligibility (Table 1). Six of the sites included in the GIHSN during the 2017–2018 influenza season (Paris [France], Ivory Coast, Kazakhstan, Peru, Poland, and Tunisia) were not included in this analysis because they recruited fewer than 40 patients. Of the 27,096 screened patients, 12,803 (47.3%) met selection criteria and were included in the analysis (Figure 1). The most common reasons for exclusion were admission outside the epidemic season for the site, not having the required symptoms, or having had symptoms for >7 days.
Table 1. Characteristics of included sites
Coordinating site
|
Number of hospitals
|
Included patients
|
Inclusion period (calendar week and year of influenza season)
|
Influenza transmission zone a
|
St. Petersburg (Russian Federation)
|
7
|
3,101
|
Week 2 to 21, 2018
|
Eastern Europe
|
Spain (Valencia)
|
4
|
2,841
|
Week 45, 2017 to week 20, 2018
|
South West Europe
|
Moscow (Russian Federation)
|
1
|
1,247
|
Week 3 to 19, 2018
|
Eastern Europe
|
South Africa (Johannesburg)
|
2
|
1,123
|
Week 15 to 42, 2018
|
Southern Africa
|
Canada (Halifax)
|
14
|
1,026
|
Week 50, 2017 to week 17, 2018
|
North America
|
Mexico (Mexico City)
|
6
|
701
|
Week 42, 2017 to week 13, 2018
|
Central America Caribbean
|
India (Srinagar)
|
1
|
609
|
Week 41, 2017 to week 9, 2018
|
Southern Asia
|
Serbia (Novi Sad)
|
4
|
590
|
Week 52, 2017 to week 15, 2018
|
South West Europe
|
Romania (Bucharest)
|
1
|
492
|
Week 49, 2017 to week 16, 2018
|
Eastern Europe
|
China (Shanghai)
|
1
|
399
|
Week 49, 2017 to week 11, 2018
|
Eastern Asia
|
Kenya (Nairobi)
|
2
|
386
|
Week 4 to 32, 2018
|
Eastern Africa
|
Czech Republic (Prague)
|
1
|
117
|
Week 52, 2017 to week 12, 2018
|
Eastern Europe
|
Lyon (France)
|
1
|
98
|
Week 50, 2017 to week 13, 2018
|
South West Europe
|
Argentina (Buenos Aires)
|
1
|
73
|
Week 30 to 39, 2018
|
Temperate South America
|
All sites
|
46
|
12,803
|
|
|
a World Health Organization influenza transmission zone [14]
Just over half (51.0%) of the 12,803 included patients were male (Table 2). Overall, 43.3% of the included patients were aged <15 years and 26.4% were aged ≥65 years. Overall, more than half of the patients (58.6%) did not report any chronic conditions. Of patients with comorbidities or underlying diseases, the most common was cardiovascular disease (23.8% [3,048/12,803]). Twenty percent of adult patients (1,300/6,516) were considered obese based on a body-mass index >30 kg/m2. Other comorbidities reported for >10% of patients included COPD (12.4% [1,592/12,803]) and diabetes (11.6% [1,490/12,803]). In addition, 21.8% (1,546/7,082) of adult patients were current smokers. As assessed by the Barthel Index, 83.4% (2,617/3,140) of patients aged ≥65 years had mild or minimal functional impairment. Over half of the included patients (56.2%) had consultations with a general practitioner within the previous 3 months, and 29.2% had been hospitalized in the previous 12 months. The overall influenza vaccination rate was 14.3%, and antivirals were used by 19.9%.
Influenza vaccination rates increased with age from as low as 1.1% in patients aged <1 year to as high as 49.0% in patients aged ≥85 years, whereas no clear trend was observed for antiviral use (Additional file 4). As expected, chronic conditions increased with age (from 2.9% in patients <1 year to 89.2% in patients ≥80 years).
Influenza vaccination rates varied from 0.0% (Kenya) to 42.9% (France), and rates of antiviral use varied from 0.0% (Kenya and Serbia) to 93.7% (China) (Additional file 5 and Additional file 6). Demographics varied considerably between sites due to differences in the populations treated at the participating hospitals. For example, the site in China included only children, whereas the sites in Canada, Czech Republic, and France included only adults.
Table 2. Characteristics of included patients (N=12,803)
Characteristic
|
Category
|
n (%)
|
Age range (y)
|
<1
|
2,063 (16.1)
|
1 to <5
|
2,586 (20.2)
|
5 to <15
|
900 (7.0)
|
15 to <50
|
2,452 (19.2)
|
50 to <65
|
1,425 (11.1)
|
65 to <75
|
1,241 (9.7)
|
75 to <85
|
1,255 (9.8)
|
≥85
|
881 (6.9)
|
Sex
|
Female
|
6,269 (49.0)
|
Male
|
6,534 (51.0)
|
Chronic conditions
|
0
|
7,506 (58.6)
|
1
|
2,499 (19.5)
|
>1
|
2,798 (21.9)
|
Pregnant a
|
Yes
|
263 (2.1)
|
Hospitalized in the last 12 months b
|
Yes
|
3,417 (29.2)
|
Underlying chronic conditions
|
Cardiovascular disease
|
3,048 (23.8)
|
COPD
|
1,592 (12.4)
|
Diabetes
|
1,490 (11.6)
|
Renal disease
|
745 (5.8)
|
Neoplasms
|
669 (5.2)
|
Asthma
|
655 (5.1)
|
Neuromuscular disease
|
487 (3.8)
|
Immunological disorders
|
392 (3.1)
|
Autoimmune diseases
|
230 (1.8)
|
Cirrhosis
|
206 (1.6)
|
Rheumatological disease
|
135 (1.1)
|
Obesity c
|
Yes
|
1,300 (20.0)
|
Consultations with a general practitioner in the last 3 months
|
0
|
4,848 (43.8)
|
1
|
2,187 (19.7)
|
>1
|
4,043 (36.5)
|
Smoking habits d
|
Never smoker
|
3,583 (50.6)
|
Past smoker
|
1,953 (27.6)
|
Current smoker
|
1,546 (21.8)
|
Functional status impairment (Barthel score) e
|
Total (0-15)
|
172 (5.5)
|
Severe (20-35)
|
129 (4.1)
|
Moderate (40-55)
|
222 (7.1)
|
Mild (60-90)
|
831 (26.5)
|
Minimal (95-100)
|
1,786 (56.9)
|
Influenza vaccination ≥14 days from symptom onset
|
Yes
|
1,818 (14.2)
|
Antiviral use during the current episode
|
Yes
|
2,544 (19.9)
|
|
|
Abbreviation: COPD, chronic obstructive pulmonary disease
a Proportion of females (N=6,269)
b N=11,690
c Assessed for patients aged ≥18 years only, defined as a body mass index >30 kg/m2, N=6,516
d Assessed for patients aged ≥18 years only, N=7,082
e Assessed for patients aged ≥65 years only, N=3,140
Influenza strain circulation in hospitalized patients
Of the 12,803 included patients, 4,306 (33.6%) tested positive for influenza virus infection by RT-PCR (Figure 1).
In the influenza transmission zones of North America (Canada), Eastern Europe (Moscow, St. Petersburg, Czech Republic, and Romania), East Asia (China), and South West Europe (Spain, Serbia, and France), influenza was first detected during the last few weeks of 2017 or first few weeks of 2018, after which circulation reached a single peak and then tapered off by week 10 to 15 of 2018 (Figure 2). Influenza B/Yamagata-like, A/H1N1pdm09, and A/H3N2 viruses dominated and co-circulated in Eastern and South West Europe. In Eastern Asia, all strains co‑circulated, but influenza A/H1N1pdm09 virus was dominant. Even within these transmission zones, however, strain circulation varied substantially (Figure 3). For example, influenza B/Yamagata-like virus was common at all sites within the East Europe transmission zone, but influenza A/H3N2 virus was common only at the St. Petersburg and Moscow sites (Figure 3 and Additional file 7). Likewise, within the South West Europe transmission zone, influenza B/Yamagata-like virus was common at all sites, but influenza A/H3N2 virus was common only in Spain (Figure 3 and Additional file 8). Influenza A and B strains also co-circulated in North America (Canada), but subtyping was mostly unavailable at the time of the current analysis.
In the Central American Caribbean transmission zone (Mexico), the timing of seasonal influenza was similar to that of the Northern Hemisphere transmission zones. However, strain circulation differed, with influenza A/H3N2 (67.2%) virus dominating and little influenza B detected. In the Temperate South America transmission zone (Argentina), influenza circulated earlier (weeks 30 to 39 of 2017), with influenza B/Yamagata-like (49.0%) and A/H1N1pdm09 (45.1%) viruses dominating.
In contrast to the influenza transmission zones in the Northern Hemisphere, two distinct peaks of influenza activity were detected in Southern Africa (South Africa) and Southern Asia (India). In Southern Africa, a first peak, dominated by influenza A/H1N1pdm09 virus, occurred between weeks 18 and 28 of 2017, and a second, dominated by influenza A/H3N2 virus, between weeks 30 and 42 of 2017. In Southern Asia, a first peak, dominated by influenza A/H1N1pdm09 virus, occurred between week 41 of 2017 and week 1 of 2018 and a second, dominated by influenza A/H3N2 virus, between weeks 3 and 9 of 2018. No discernable peak of influenza circulation was detected in Eastern Africa (Kenya), although influenza A/H1N1pdm09 virus dominated.
Overall, across all regions of the GIHSN, influenza B/Yamagata-like virus (26.1% of influenza-positive patients) and influenza A/H3N2 (25.6%) were the most frequently detected strains, closely followed by A/H1N1pdm09 (21.1%). Influenza B/Victoria-like virus was detected in 2.3% of influenza-positive patients, unsubtyped influenza A virus in 12.2%, and influenza B of unknown lineage in 12.7%. Except in Mexico and South Africa, influenza B/Yamagata-like was the dominant B lineage detected in all countries where lineage was determined.
Complicated hospitalization in influenza-positive patients
Of the 4,306 influenza-positive patients, 458 (10.6%) had a complicated hospitalization, as defined by admission to an ICU, need for mechanical ventilation, or death during hospitalization (Figure 4). Most complicated hospitalizations were in patients aged ≥50 years. Age distributions of ICU admission (n=355) and mechanical ventilation (n=221) were similar, whereas death (n=166) continuously increased with age (Additional file 9).
COPD was associated with complicated hospitalization in influenza-positive admissions aged 50 to <65 years (OR, 2.94 [95% CI, 1.37–6.31]) and ≥65 years (1.69 [95% CI, 1.10–2.60]) (Figure 5). Prescription of antivirals during the current influenza episode was associated with complicated hospitalization in influenza-positive admissions aged 15 to <50 years (OR, 7.73 [95% CI, 2.68–22.33]) and 50 to <65 years (OR, 2.78 [95% CI, 1.12–6.92]). Other factors associated with complicated hospitalization included diabetes in influenza-positive admissions aged 15 to <50 years (OR, 3.90 [95% CI, 1.18–12.92]); male sex (OR, 2.63 [95% CI, 1.27–5.44]) and hospitalization during the last 12 months (OR, 2.90 [95% CI, 1.38–6.06]) in influenza-positive admissions aged 50 to <65 years; and current smoking in influenza-positive admissions aged ≥65 years (OR, 2.18 [95% CI, 1.23‑3.87]). No factors were found to be associated with complicated hospitalization among influenza-positive patients aged <15 years. The frequency of complicated hospitalization did not differ between influenza A and B for any age group. The frequency of complicated hospitalization also did not differ between A/H1N1pdm09 and A/H3N2 for any age group (data not shown). All factors examined in relation to complicated hospitalization are provided in Additional file 10.
Length of hospital stay
The mean length of hospital stay in influenza-positive admissions was lowest in admissions aged <15 years (approximately 6 days) and highest in admissions aged 65–74 years (approximately 9 days) (Figure 6). COPD (coefficient, 3.22 [95% CI, 1.18–5.27]) and diabetes (coefficient, 2.77 [95% CI, 0.59–4.94]) were associated with a longer hospital stay and influenza B (vs. A) with a shorter hospital stay (coefficient, −1.82 [−3.61–−0.03]) in influenza-positive admissions aged 50 to <65 years, and other chronic conditions (coefficient, 1.20 [95% CI, 0.06–2.33]) were associated with a longer hospital stay in influenza-positive admissions aged 15 to <50 years (Figure 7). Hospitalization during the previous 12 months was associated with a longer hospital stay in influenza‑positive admissions aged <15 years (coefficient, 0.96 [95% CI, 0.41–1.52]). No factors associated with a longer hospital stay were identified in influenza-positive admissions aged ≥65 years. Length of hospital stay did not differ between influenza A and B for any age group. The length of hospital stay also did not differ between A/H1N1pdm09 and A/H3N2 for any age group (data not shown).