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Erschienen in: BMC Public Health 1/2019

Open Access 01.12.2019 | Research article

Influenza epidemiology and influenza vaccine effectiveness during the 2016–2017 season in the Global Influenza Hospital Surveillance Network (GIHSN)

verfasst von: Víctor Baselga-Moreno, Svetlana Trushakova, Shelly McNeil, Anna Sominina, Marta C. Nunes, Anca Draganescu, Serhat Unal, Parvaiz Koul, Jan Kyncl, Tao Zhang, Ainagul Kuatbayeva, Afif Ben-Salah, Elena Burtseva, Joan Puig-Barberà, Javier Díez-Domingo, for the Global Influenza Hospital Surveillance Network (GIHSN)

Erschienen in: BMC Public Health | Ausgabe 1/2019

Abstract

Background

The Global Influenza Hospital Surveillance Network (GIHSN) aims to determine the burden of severe influenza disease and Influenza Vaccine Effectiveness (IVE). This is a prospective, active surveillance and hospital-based epidemiological study to collect epidemiological data in the GIHSN. In the 2016–2017 influenza season, 15 sites in 14 countries participated in the GIHSN, although the analyses could not be performed in 2 sites. A common core protocol was used in order to make results comparable. Here we present the results of the GIHSN 2016–2017 influenza season.

Methods

A RT-PCR test was performed to all patients that accomplished the requirements detailed on a common core protocol. Patients admitted were included in the study after signing the informed consent, if they were residents, not institutionalised, not discharged in the previous 30 days from other hospitalisation with symptoms onset within the 7 days prior to admission. Patients 5 years old or more must also complied the Influenza-Like Illness definition. A test negative-design was implemented to perform IVE analysis. IVE was estimated using a logistic regression model, with the formula IVE = (1-aOR) × 100, where aOR is the adjusted Odds Ratio comparing cases and controls.

Results

Among 21,967 screened patients, 10,140 (46.16%) were included, as they accomplished the inclusion criteria, and tested, and therefore 11,827 (53.84%) patients were excluded. Around 60% of all patients included with laboratory results were recruited at 3 sites. The predominant strain was A(H3N2), detected in 63.6% of the cases (1840 patients), followed by B/Victoria, in 21.3% of the cases (618 patients). There were 2895 influenza positive patients (28.6% of the included patients). A(H1N1)pdm09 strain was mainly found in Mexico. IVE could only be performed in 6 sites separately. Overall IVE was 27.24 (95% CI 15.62–37.27. Vaccination seemed to confer better protection against influenza B and in people 2–4 years, or 85 years old or older. The aOR for hospitalized and testing positive for influenza was 3.02 (95% CI 1.59–5.76) comparing pregnant with non-pregnant women.

Conclusions

Vaccination prevented around 1 in 4 hospitalisations with influenza. Sparse numbers didn’t allow estimating IVE in all sites separately. Pregnancy was found a risk factor for influenza, having 3 times more risk of being admitted with influenza for pregnant women.
Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12889-019-6713-5) contains supplementary material, which is available to authorized users.
Abkürzungen
AOR
Adjusted odds ratio
CI
Confidence interval
GIHSN
Global Influenza Hospital Surveillance Network
IVE
Influenza vaccine effectiveness
OR
Odds ratio
RT-PCR
Reverse transcription-polymerase chain reaction

Background

Influenza is a major public health problem that can cause hospitalisations, and it is related with respiratory failures [1, 2]. The Global Influenza Hospital Surveillance Network (GIHSN) is an international public-private collaboration that started in 2012. The GIHSN goals are to improve understanding of influenza epidemiology, quantifying the circulation of the different types and subtypes of influenza, in order to measure the effectiveness of seasonal influenza vaccines and better inform public health policy decisions. We conduct a prospective, active surveillance, hospital-based epidemiological study that collects epidemiological and virological data from those sites that are included in the network. Each season results are presented in annual meetings and, since 2012, have been published [36], with the agreement of the Principal Investigators of all concerned sites. The implementation and data collection for the last season (2016–2017) was led by the Foundation for the Promotion of Health and Biomedical Research of Valencia Region (FISABIO), a regional public health institution in Valencia, Spain, and funded by the Foundation for Influenza Epidemiology. Fifteen sites in fourteen countries participated in the GIHSN in the season 2016–2017. Among them, there were 12 sites (St. Petersburg, Moscow, Kazakhstan, Czech Rep., Canada, Romania, Turkey, Spain, Tunisia, Suzhou/Shanghai, India and Mexico) from Northern Hemisphere countries not situated in the tropics and three sites (Ivory Coast, Peru and South Africa) from the tropics or the Southern Hemisphere. Since Peru and Ivory Coast only reported two positive cases for influenza in the influenza season, the analysis was performed without the data from these countries, and therefore, results are reported for 13 sites. A common core protocol and standard operating procedures are used for all participating sites, in order to allow comparisons among countries, and analyse results of all sites.

Methods

This study aims to determine the frequency of influenza-related hospitalisations in different countries, by circulating strains and age groups, to study risk factors for influenza-associated hospitalisations and estimate Influenza Vaccine Effectiveness (IVE) by site, age group and strain. Each site had one or more hospitals that recruited patients for the study, between October 2016 and May 2017 in Northern Hemisphere sites, except China, whose patients were recruited between June and September. For Southern Hemisphere sites, patients were recruited between May and November. Patients were included in the study if they presented any of the admission diagnoses included in the protocol, and only if they signed the informed consent to participate in the study. Among them, we selected for the study only those who were residents in the predefined hospital catchment’s area in the previous past 6 months, who were not institutionalised, who hadn’t been discharged from other hospitalisation in the last 30 days, and who had symptoms possibly related to influenza in 7 days or less prior to admission (Fig. 1). We also excluded patients who had previously tested positive for influenza in the current season, and also patients for whom the difference between the date of the onset of symptoms and the date of swabbing was 10 days or more (that is, those admitted after the 7th day after the onset of symptoms+maximum delay in swabbing). For patients 5 years old or more, they must also have complied with the Influenza-Like Illness (ILI) definition, detailed in European Centre for Disease Prevention and Control (ECDC) protocols, according to the decision of the Commission of the European Union of 8 August 2012 [7]. Patients enrolled outside the influenza epidemic period of each of the participating sites were also excluded. Influenza seasons were previously determined by each site, following recommendations of previous studies [8]. This methodology has been used in the GIHSN since the beginning of the network, and has been previously described [9]. For patients under 14 years old, nasal and/or nasopharyngeal swabs were collected, whereas, for patients 14 years old or more, pharyngeal and/or nasopharyngeal swabs were taken. Reverse transcription-polymerase chain reaction (RT-PCR) was used, according to each site’s protocol, in order to detect influenza virus; viral subtyping was performed in order to identify A(H1N1)pdm09, A(H3N2), B/Yamagata-lineage, and B/Victoria-lineage strains in the positive specimens.
We performed a test-negative study [10] in order to compare positives (cases) and negatives (controls) for influenza and estimate Influenza Vaccine Effectiveness (IVE). Odds Ratios were used to estimate IVE, comparing cases and controls of patients depending on the vaccination status. Patients were considered vaccinated if they received an influenza vaccine in the current season, at least 15 days before the onset of symptoms. Patients with contra-indication to influenza vaccination were excluded from the IVE analysis, but were included in the analysis regarding influenza circulation. Vaccination status was ascertained either by recall or by vaccination registries. Adjusted odds ratios (aOR) were calculated using a logistic regression model including sex, occupational social class, obesity status, pregnancy, underlying conditions, general practitioner (GP) consultations in last 3 months, smoking habits, days from onset of symptoms to swabbing as fixed effects, age and epidemiological week of admission using cubic splines, and site as a cluster variable, in order to consider sites variability [11]. IVE was calculated as (1-aOR) × 100. The same factors were used to adjust IVE by strain or age group. The variables relative to the Barthel Index (in patients 65 years old or older) and the previous hospitalisations in the last year were initially considered to be included in the model, but were excluded from the final model as they were not statistically significant considering all variables mentioned above. The model did not include the number of consultations at the GP in the last 3 months to estimate IVE in Canada, as this site did not provide information for this variable. Severe outcomes were also studied, defining them as an influenza positive patient admitted to ICU during the hospitalisation, or with COPD exacerbation, respiratory failure, any cardiovascular complication, shock or death during hospitalisation. Heterogeneity was studied, using the I2 test, and considering that heterogeneity was relevant if I2 ≥ 50% [12, 13].

Results

Included patients: distribution, characteristics and influenza positives and negatives

There were 21,967 eligible admissions between October 1, 2016 and November 9, 2017. However, only 10,140 patients complied with the conditions described above, and had laboratory results, hence only these were included in the analysis. Among them, 2895 (28.6%) tested positive for influenza, and 7245 (71.4%) tested negative for influenza (Table 1). The most common reason of exclusion was the fact that patients didn’t have ILI symptoms in the 7 days previous to admission. It is important to note that 2/3 of all included patients in the GIHSN came from 4 sites (St. Petersburg, Moscow, Canada and Valencia). These 4 sites also have the highest numbers of influenza positive cases, including 77.8% of all influenza positives in the GIHSN, and 84.3% of the A(H3N2) influenza positives among all participant sites. A (H3N2) was the predominant strain this season, being detected in 63.6% of all influenza positive cases (1840 patients), followed by B/Victoria, with 21.3% among the influenza positive cases (618 patients) (Table 1). Influenza A(H3N2) was detected throughout the season, whereas B/Victoria started to increase in the second week of 2017 in the Northern Hemisphere, and in the 31st week of 2017 in the Southern Hemisphere, approximately in the middle of the season in each Hemisphere (Fig. 2).
Table 1
Patients included and excluded in the current analyses, inclusion criteria and influenza laboratory results
Category
St. Pet
Moscow
Kazakhstan
Czech Rep.
Canada
Romania
Turkey
Valencia
Tunisia
Suzhou/ Shanghai
India
Mexico
South Africa
Total
n
%
n
%
n
%
n
%
n
%
N
%
n
%
n
%
n
%
n
%
n
%
n
%
n
%
n
%
Screened admissions
2012
 
2244
 
661
 
201
 
2450
 
902
 
917
 
6913
 
106
 
1264
 
693
 
1480
 
2124
 
21967
 
Exclusion criteria
 Non resident
2
0.1
167
7.4
0
0.0
3
1.5
1
0.0
394
43.7
78
8.5
25
0.4
9
8.5
180
14.2
5
0.7
294
19.9
0
0.0
1158
5.3
 institutionalised
1
0.0
19
0.8
21
3.2
0
0.0
461
18.8
1
0.1
20
2.2
358
5.2
0
0.0
1
0.1
0
0.0
9
0.6
0
0.0
891
4.1
 Previous discharged < 30 days
3
0.1
114
5.1
44
6.7
7
3.5
145
5.9
68
7.5
173
18.9
1131
16.4
5
4.7
65
5.1
33
4.8
216
14.6
0
0.0
2004
9.1
 Unable to communicate
10
0.5
136
6.1
0
0.0
11
5.5
0
0.0
0
0.0
50
5.5
367
5.3
0
0.0
30
2.4
0
0.0
126
8.5
282
13.3
1012
4.6
 Not giving consent
44
2.2
8
0.4
49
7.4
13
6.5
0
0.0
1
0.1
15
1.6
275
4.0
0
0.0
3
0.2
1
0.1
54
3.6
90
4.2
553
2.5
 No ILI symptoms ≥5 years
0
0.0
42
1.9
9
1.4
37
18.4
573
23.4
41
4.5
140
15.3
2164
31.3
0
0.0
0
0.0
0
0.0
108
7.3
215
10.1
3329
15.2
 Admission within 7 days of symptoms onset
4
0.2
124
5.5
279
42.2
8
4.0
137
5.6
4
0.4
3
0.3
335
4.8
4
3.8
301
23.8
2
0.3
216
14.6
170
8.0
1587
7.2
 Previous influenza infection
2
0.1
0
0.0
0
0.0
0
0.0
0
0.0
6
0.7
7
0.8
1
0.0
0
0.0
15
1.2
0
0.0
9
0.6
1
0.0
41
0.2
 Onset of symptoms to swab > 9 days
0
0.0
1
0.0
0
0.0
0
0.0
0
0.0
0
0.0
2
0.2
1
0.0
6
5.7
1
0.1
0
0.0
0
0.0
0
0.0
11
0.1
 Sample inadequate
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
 Sample lost
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
25
23.6
0
0.0
0
0.0
0
0.0
0
0.0
25
0.1
 Recruited outside periods with continuous influenza positive admissions
9
0.4
13
0.6
100
15.1
11
5.5
1
0.0
0
0.0
16
1.7
131
1.9
18
17.0
198
15.7
159
22.9
98
6.6
462
21.8
1216
5.5
 Included with valid laboratory results
1937
96.3
1620
72.2
159
24.1
111
55.2
1132
46.2
387
42.9
413
45.0
2125
30.7
39
36.8
470
37.2
493
71.1
350
23.6
904
42.6
10140
46.2
RT-PCR result
 Influenza negative
1417
73.2
869
53.6
128
80.5
69
62.2
414
36.6
221
57.1
311
75.3
1862
87.6
30
76.9
433
92.1
425
86.2
259
74.0
807
89.3
7245
71.4
 Influenza positive
520
26.8
751
46.4
31
19.5
42
37.8
718
63.4
166
42.9
102
24.7
263
12.4
9
23.1
37
7.9
68
13.8
91
26.0
97
10.7
2895
28.6
Subtype and lineage
 A(H1N1)pdm09
1
0.2
0
0.0
0
0.0
1
2.4
3
0.3
0
0.0
0
0.0
0
0.0
1
11.1
1
2.7
11
16.2
56
61.5
2
2.1
76
2.6
 A(H3N2)
296
56.9
420
55.9
15
48.4
32
76.2
585
51.7
39
23.5
81
79.4
251
95.4
6
66.7
21
56.8
21
30.9
12
13.2
61
62.9
1840
63.6
 A not subtyped
34
6.5
4
0.5
0
0.0
2
4.8
67
5.9
4
2.4
3
2.9
12
4.6
0
0.0
0
0.0
0
0.0
0
0.0
3
3.1
129
4.5
 B/Yamagata lineage
2
0.4
0
0.0
0
0.0
4
9.5
35
3.1
0
0.0
19
18.6
0
0.0
2
22.2
1
2.7
0
0.0
15
16.5
30
30.9
108
3.7
 B/Victoria lineage
187
36.0
299
39.8
0
0.0
1
2.4
4
0.4
74
44.6
2
2.0
0
0.0
0
0.0
14
37.8
37
54.4
0
0.0
0
0.0
618
21.3
 B not subtyped
0
0.0
28
3.7
16
51.6
2
4.8
24
2.1
50
30.1
1
1.0
0
0.0
0
0.0
0
0.0
0
0.0
11
12.1
3
3.1
135
4.7
In the Northern Hemisphere, there was a significant increase in the number of influenza cases in week #49 of 2016, with a peak in the number of positive cases during the second week of 2017 and starting to descend at the eighth week of 2017. Influenza B/Victoria started to increase clearly in the second week of 2017, as A(H3N2) started to descend. 70.3% of all influenza cases were positive for influenza A, whereas 29.7% were positive for influenza B, with a clear different distribution among sites.
A(H3N2) was predominant in all sites, except in Mexico, where the predominant strain was A(H1N1)pdm09, and Romania and India with a predominance of B/Victoria-lineage. Both B lineages circulated during this season, with geographical differences, so in Canada, Czech Republic, Turkey, Tunisia, Mexico and South Africa, B/Yamagata was more often detected, while the B/Victoria was elsewhere. Influenza B cases generally appeared as a second influenza wave (Fig. 3). In Valencia, no cases were positive for influenza B.
Influenza B was mainly observed in the youngest, and was the predominant strain in the age group 5–17 years old. Among the two influenza B lineages, in general B/Victoria was detected more often than B/Yamagata, except in the age group 50–64 years (Fig. 4).
The distribution of influenza cases among the age groups was clearly different among sites, but differences were mainly due to the characteristics of the participating hospitals for each site. Tunisia and Czech Republic only recruited patients 18 years old or older, while Suzhou/Shanghai only enrolled patients under 18 years old. In Moscow, the majority of influenza positives were pregnant women (which represented the 49.4% of the included patients), and therefore, the highest number of influenza positives among the different age groups was situated in the age group 18–49 years old in this site. Influenza positive cases were mainly found in patients 65 years old or older in Valencia and Canada, but 89.8% of the included patients from Canada were 50 years old or older. In St. Petersburg and South Africa, due to the characteristics of the patients of the participating hospitals (mainly children) there were more influenza positive cases in the youngest groups (Fig. 5).
25.8% of the included patients were previously hospitalised in the same year and 36.6% of the included patients had at least one underlying condition, but this percentage varied among sites, in Canada, for example, more than 90% of the included patients had at least one underlying condition, whereas in St. Petersburg, this percentage was lower than 10% and in Turkey was 48.2%, but these percentages could be related to the age distribution of the included patients in each site. Among the different comorbidities, the most common were cardiovascular (20.7% of the included patients), diabetes (10.4%) and chronic obstructive pulmonary disease (COPD) (9.9%). Obesity was also found in more than 14% of the included patients, being more relevant in Canada (29.6%), Valencia (26.3%) and Czech Republic (23.4%). Moscow was the site with the highest number of pregnant women among all sites (800 pregnant in Moscow among 940 pregnant women in all sites), being 49.4% of the included patients in this site. In Kazakhstan, pregnant women represented 22.6% of the included patients. The Barthel Index in those over 65 years showed that almost 90% of these subjects were not dependent or had a mild dependence. 68.3% of the patients who tested negative for influenza were swabbed from 0 to 4 days after symptoms started, but this percentage was 78.4% for influenza positive cases (p-value< 0.0001).
Vaccination coverage differed among sites. Patients were considered as vaccinated if vaccination was at least 15 days before symptoms onset (Table 2). Targeted patients for vaccination criteria were different among sites (Additional file 1: Complementary Table S1). Vaccination coverage was 11.1% among the influenza positives and 18.4% among the influenza negatives overall. Cardiovascular diseases, renal impairment, chronic obstructive pulmonary disease and diabetes were the most common comorbidities among influenza positives (Table 3). Seasonality had also a clear geographical distribution. Sites in higher latitudes had, generally, an earlier start of the influenza season.
Table 2
Characteristics of included patients overall and by site
Characteristic
St. Pet
Moscow
Kazakhstan
Czech Rep.
Canada
Romania
Turkey
Valencia
Tunisia
Suzhou/ Shanghai
India
Mexico
South Africa
Total
N = 1937
N = 1620
N = 159
N = 111
N = 1132
N = 387
N = 413
N = 2125
N = 39
N = 470
N = 493
N = 350
N = 904
N = 10,140
n
%
n
%
n
%
n
%
n
%
n
%
n
%
n
%
n
%
n
%
n
%
n
%
n
%
n
%
Age in years, median (range)
3 (0–87)
24 (0–91)
17 (1–76)
64 (18–90)
76 (17–105)
5 (0–63)
3 (0–95)
68 (0–102)
58 (14–84)
0 (0–13)
60 (0–99)
3 (0–96)
0 (0–91)
20 (0–105)
Age group
 0–1 y
684
35.3
167
10.3
34
21.4
0
0.0
0
0.0
89
23.0
179
43.3
421
19.8
0
0.0
334
71.1
57
11.6
151
43.1
576
63.7
2692
27.0
 2–4 y
483
24.9
156
9.6
33
20.8
0
0.0
0
0.0
87
22.5
39
9.4
108
5.1
0
0.0
96
20.4
19
3.9
50
14.3
146
16.2
1217
12.2
 5–17 y
310
16.0
182
11.2
14
8.8
0
0.0
1
0.1
118
30.5
32
7.7
54
2.5
1
2.6
40
8.5
16
3.2
43
12.3
16
1.8
827
8.3
 18–49 y
388
20.0
1052
64.9
73
45.9
37
33.3
97
8.6
72
18.6
14
3.4
145
6.8
9
23.1
0
0.0
79
16.0
52
14.9
82
9.1
2100
21.1
 50–64 y
49
2.5
34
2.1
2
1.3
20
18.0
156
13.8
21
5.4
45
10.9
227
10.7
12
30.8
0
0.0
100
20.3
21
6.0
48
5.3
735
7.4
 65–74 y
12
0.6
12
0.7
2
1.3
24
21.6
196
17.3
0
0.0
29
7.0
335
15.8
8
20.5
0
0.0
143
29.0
11
3.1
21
2.3
793
8.0
 75–84 y
9
0.5
10
0.6
1
0.6
20
18.0
264
23.3
0
0.0
55
13.3
462
21.7
9
23.1
0
0.0
51
10.3
11
3.1
11
1.2
903
9.0
  ≥ 85 y
2
0.1
7
0.4
0
0.0
10
9.0
246
21.7
0
0.0
20
4.8
373
17.6
0
0.0
0
0.0
28
5.7
11
3.1
4
0.4
701
7.0
Sex
 Male
1050
54.2
607
37.5
76
47.8
64
57.7
541
47.8
205
53.0
224
54.2
1125
52.9
27
69.2
287
61.1
242
49.1
171
48.9
486
53.8
5105
50.3
 Female
887
45.8
1013
62.5
83
52.2
47
42.3
591
52.2
182
47.0
189
45.8
1000
47.1
12
30.8
183
38.9
251
50.9
179
51.1
418
46.2
5035
49.7
Chronic conditions
 0
1758
90.8
1382
85.3
111
69.8
35
31.5
99
8.7
349
90.2
214
51.8
803
37.8
7
17.9
443
94.3
129
26.2
218
62.3
878
97.1
6426
63.4
 1
157
8.1
187
11.5
42
26.4
40
36.0
307
27.1
28
7.2
87
21.1
626
29.5
18
46.2
27
5.7
182
36.9
85
24.3
26
2.9
1812
17.9
  ≥2
22
1.1
51
3.1
6
3.8
36
32.4
726
64.1
10
2.6
112
27.1
696
32.8
14
35.9
0
0.0
182
36.9
47
13.4
0
0.0
1902
18.7
Previously hospitalised (last 12 months)
 No
1447
74.7
1354
83.6
143
89.9
80
72.1
279
72.1
272
65.9
1457
68.6
30
76.9
329
70.0
312
63.3
240
68.6
745
82.4
6688
74.2
 Yes
490
25.3
266
16.4
16
10.1
31
27.9
108
27.9
141
34.1
668
31.4
9
23.1
141
30.0
181
36.7
110
31.4
159
17.6
2320
25.8
Underlying chronic conditions
 Cardiovascular disease
49
2.5
70
4.3
5
3.1
50
45.0
872
77.0
17
4.4
110
26.6
602
28.3
15
38.5
24
5.1
199
40.4
65
18.6
16
1.8
2094
20.7
 Chronic obstructive pulmonary disease
21
1.1
23
1.4
24
15.1
7
6.3
134
11.8
1
0.3
70
16.9
500
23.5
21
53.8
0
0.0
177
35.9
28
8.0
2
0.2
1008
9.9
 Asthma
28
1.4
29
1.8
0
0.0
7
6.3
146
12.9
2
0.5
46
11.1
162
7.6
2
5.1
2
0.4
5
1.0
27
7.7
7
0.8
463
4.6
 Immunodeficiency/organ transplant
13
0.7
1
0.1
1
0.6
4
3.6
114
10.1
8
2.1
18
4.4
29
1.4
1
2.6
0
0.0
17
3.4
16
4.6
0
0.0
222
2.2
 Diabetes
7
0.4
16
1.0
3
1.9
25
22.5
344
30.4
6
1.6
47
11.4
500
23.5
7
17.9
0
0.0
71
14.4
23
6.6
0
0.0
1049
10.3
 Renal impairment
4
0.2
74
4.6
15
9.4
3
2.7
167
14.8
4
1.0
27
6.5
274
12.9
4
10.3
1
0.2
29
5.9
14
4.0
1
0.1
617
6.1
 Neuromuscular disease
56
2.9
29
1.8
6
3.8
6
5.4
182
16.1
0
0.0
31
7.5
57
2.7
1
2.6
0
0.0
45
9.1
13
3.7
0
0.0
426
4.2
 Neoplasm
0
0.0
15
0.9
0
0.0
11
9.9
239
21.1
5
1.3
27
6.5
141
6.6
0
0.0
0
0.0
33
6.7
8
2.3
0
0.0
479
4.7
 Cirrhosis/liver disease
18
0.9
18
1.1
1
0.6
3
2.7
22
1.9
5
1.3
6
1.5
62
2.9
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
135
1.3
 Autoimmune disease
7
0.4
29
1.8
0
0.0
5
4.5
1
0.1
5
1.3
5
1.2
43
2.0
2
5.1
0
0.0
22
4.5
12
3.4
0
0.0
131
1.3
Pregnant (women 15–45 y)
72
3.7
800
49.4
36
22.6
3
2.7
14
1.2
7
1.8
0
0.0
2
0.1
0
0.0
0
0.0
0
0.0
2
0.6
4
0.4
940
9.3
Obese (all ages)
165
8.5
150
9.3
13
8.2
26
23.4
197
29.6
35
9.0
76
18.4
559
26.3
5
12.8
77
16.4
37
7.5
46
13.1
71
9.6
1457
14.4
Outpatient consultations last 3 months
 0
894
46.2
658
40.6
116
73.0
33
29.7
166
42.9
148
35.8
233
11.0
14
35.9
44
9.4
120
24.3
81
23.1
776
85.8
3283
36.4
 1
624
32.2
238
14.7
43
27.0
34
30.6
121
31.3
100
24.2
413
19.4
11
28.2
123
28.3
59
12.0
70
20.0
82
9.1
1928
21.4
  ≥ 2
419
21.6
724
44.7
0
0.0
44
39.6
100
25.8
165
40.0
1479
69.6
14
35.9
293
62.3
314
63.7
199
56.9
46
5.1
3797
42.2
Smoking habits (patients ≥18 y)
 Never smoker
222
48.3
698
62.6
58
74.4
51
45.9
431
43.5
55
59.1
85
52.1
784
50.8
15
39.5
0
198
49.4
57
53.8
102
61.4
2756
52.4
 Past smoker
46
10.0
263
23.6
16
20.5
24
21.6
387
39.1
6
6.5
59
36.2
464
30.1
12
31.6
0
121
30.2
34
32.1
35
21.1
1467
27.9
 Current smoker
192
41.7
154
13.8
4
5.1
36
32.4
172
17.4
32
34.4
19
11.7
294
19.1
11
28.9
0
82
20.4
15
14.2
29
17.5
1040
19.7
Functional status impairment (Barthel score; patients ≥65 y)
 Total (0–15)
0
0.0
0
0.0
0
0.0
0
0.0
14
2.8
0
8
8.3
94
8.0
0
0.0
0
13
5.9
0
0.0
1
5.6
130
6.0
 Severe (20–35)
0
0.0
0
0.0
0
0.0
0
0.0
11
2.2
0
3
3.1
26
2.2
3
17.6
0
3
1.4
3
9.1
1
5.6
50
2.3
 Moderate (40–55)
0
0.0
2
6.9
0
0.0
1
1.9
15
3.0
0
3
3.1
54
4.6
8
47.1
0
8
3.6
1
3.0
1
5.6
93
4.3
 Mild (60–90)
4
18.2
7
24.1
2
66.7
14
25.9
90
17.9
0
35
36.5
261
22.3
4
23.5
0
62
27.9
12
36.4
9
50.0
500
23.1
 Minimal (95–100)
18
81.8
20
69.0
1
33.3
39
72.2
373
74.2
0
47
49.0
735
62.8
2
11.8
0
136
61.3
17
51.5
6
33.3
1394
64.3
Sampling time
 0–2 days
1160
59.9
843
52.0
109
68.6
31
27.9
474
41.9
76
19.6
59
14.3
386
18.2
7
17.9
8
1.7
44
8.9
67
19.1
321
39.1
3585
35.6
 3–4 days
568
29.3
595
36.7
46
28.9
42
37.8
387
34.2
155
40.1
161
39.0
892
42.0
14
35.9
107
22.8
175
35.5
123
35.1
308
37.5
3573
35.5
 5–7 days
209
10.8
179
11.0
4
2.5
37
33.3
259
22.9
144
37.2
181
43.8
655
30.8
18
46.2
264
56.2
274
55.6
141
40.3
140
17.1
2505
24.9
 8–9 days
0
0.0
3
0.2
0
0.0
1
0.9
12
1.1
12
3.1
12
2.9
192
9.0
0
0.0
91
19.4
0
0.0
19
5.4
52
6.3
394
3.9
Influenza vaccination ≥15 days from symptom onset
86
4.4
65
4.0
0
0.0
6
5.4
139
12.3
7
1.8
21
5.1
825
38.8
2
5.1
1
0.2
11
2.2
49
14.0
5
0.6
1217
12.0
Influenza vaccination ≥15 days from symptom onset (age ≥ 65)
2
8.7
5
17.2
0
0.0
6
11.1
124
14.1
0
14
13.5
701
59.9
2
11.8
0
5
2.3
9
27.3
0
0.0
868
33.8
Influenza vaccination ≥15 days from symptom onset (targeted groups)
65
4.5
30
2.2
0
0.0
6
7.0
138
12.7
3
4.4
21
9.0
806
50.3
2
6.1
1
0.4
8
2.1
43
16.0
2
1.5
1125
16.0
Table 3
Characteristics of included patients according to RT-PCR result
 
Influenza negative
Influenza positive
A (H1N1)pdm09
A (H3N2)
A not subtyped
B/Yamagata
B/Victoria
B not subtyped
N = 7245
N = 2895
N = 76
N = 1840
N = 129
N = 108
N = 618
N = 135
Characteristic
n
%
n
%
P vs. negative
n
%
P vs. negative
n
%
P vs. negative
n
%
P vs. negative
n
%
P vs. negative
n
%
P vs. negative
n
%
P vs. negative
Age in years, median (range)
12 (0–105)
28 (0–103)
< 0.001
35 (0–84)
0.083
35 (0–103)
< 0.001
48 (0–102)
< 0.001
13 (0–92)
0.840
18 (0–89)
0.008
7 (0–94)
0.139
Age group
    
< 0.0001
  
0.0001
  
< 0.0001
  
< 0.0001
  
0.0003
  
< 0.0001
  
< 0.0001
 0–1 y
2361
32.8
331
11.9
 
11
14.5
 
220
12.5
 
16
16.0
 
20
19.8
 
47
7.6
 
20
14.9
 
 2–4 y
906
12.6
311
11.2
 
12
15.8
 
162
9.2
 
13
13.0
 
16
15.8
 
86
13.9
 
24
17.9
 
 5–17 y
446
6.2
381
13.7
 
7
9.2
 
143
8.1
 
7
7.0
 
15
14.9
 
176
28.5
 
35
26.1
 
 18–49 y
1305
18.1
795
28.7
 
23
30.3
 
440
25.1
 
15
15.0
 
10
9.9
 
282
45.6
 
26
19.4
 
 50–64 y
540
7.5
195
7.0
 
13
17.1
 
159
9.1
 
3
3.0
 
12
11.9
 
5
0.8
 
4
3.0
 
 65–74 y
565
7.9
228
8.2
 
7
9.2
 
178
10.1
 
15
15.0
 
7
6.9
 
11
1.8
 
10
7.5
 
 75–84 y
631
8.8
272
9.8
 
3
3.9
 
223
12.7
 
16
16.0
 
11
10.9
 
9
1.5
 
12
9.0
 
  ≥ 85 y
441
6.1
260
9.4
 
0
0.0
 
230
13.1
 
15
15.0
 
10
9.9
 
2
0.3
 
3
2.2
 
Sex
    
< 0.0001
  
0.1374
  
< 0.0001
  
0.3877
  
0.6826
  
< 0.0001
  
0.5137
 Male
3766
52.0
1339
46.3
 
33
43.4
 
859
46.7
 
72
55.8
 
54
50.0
 
254
41.1
 
74
54.8
 
 Female
3479
48.0
1556
53.7
 
43
56.6
 
981
53.3
 
57
44.2
 
54
50.0
 
364
58.9
 
61
45.2
 
Chronic conditions
    
< 0.0001
  
0.1801
  
< 0.0001
  
< 0.0001
  
0.0025
  
< 0.0001
  
0.6485
 0
4765
65.8
1661
57.4
 
44
57.9
 
894
48.6
 
51
39.5
 
58
53.7
 
528
85.4
 
92
68.1
 
 1
1240
17.1
572
19.8
 
19
25.0
 
415
22.6
 
27
20.9
 
18
16.7
 
71
11.5
 
24
17.8
 
  ≥2
1240
17.1
662
22.9
 
13
17.1
 
531
28.9
 
51
39.5
 
32
29.6
 
19
3.1
 
19
14.1
 
Previously hospitalised (last 12 months)
    
0.0163
  
0.2604
  
0.9969
  
0.6372
  
0.8445
  
0.0002
  
0.0086
 No
5029
73.6
1659
76.2
 
58
79.5
 
924
73.6
 
44
71.0
 
53
72.6
 
494
80.5
 
94
84.7
 
 Yes
1802
26.4
518
23.8
 
15
20.5
 
331
26.4
 
18
29.0
 
20
27.4
 
120
19.5
 
17
15.3
 
Underlying chronic conditions
 Cardiovascular disease
1298
17.9
796
27.5
< 0.0001
17
22.4
0.3145
627
34.1
< 0.0001
60
46.5
< 0.0001
37
34.3
< 0.0001
30
4.9
< 0.0001
28
20.7
0.3970
 Chronic obstructive pulmonary disease
802
11.1
206
7.1
< 0.0001
8
10.5
0.8806
159
8.6
0.0025
10
7.8
0.2328
10
9.3
0.5513
16
2.6
< 0.0001
7
5.2
0.0301
 Asthma
276
3.8
187
6.5
< 0.0001
6
7.9
0.0656
147
8.0
< 0.0001
14
10.9
< 0.0001
8
7.4
0.0541
8
1.3
0.0013
4
3.0
0.6100
 Immunodeficiency/organ transplant
155
2.1
67
2.3
0.5867
3
3.9
0.2806
49
2.7
0.1758
7
5.4
0.0116
3
2.8
0.6497
2
0.3
0.0020
3
2.2
0.9475
 Diabetes
687
9.5
362
12.5
< 0.0001
11
14.5
0.1405
292
15.9
< 0.0001
33
25.6
< 0.0001
13
12.0
0.3693
5
0.8
< 0.0001
8
5.9
0.1610
 Renal impairment
409
5.6
208
7.2
0.0034
4
5.3
0.8858
161
8.8
< 0.0001
11
8.5
0.1616
7
6.5
0.7089
19
3.1
0.0069
7
5.2
0.8184
 Neuromuscular disease
234
3.2
192
6.6
< 0.0001
2
2.6
0.7690
147
8.0
< 0.0001
15
11.6
< 0.0001
8
7.4
0.0157
12
1.9
0.0775
9
6.7
0.0266
 Neoplasm
311
4.3
168
5.8
0.0012
0
0.0
0.0649
133
7.2
< 0.0001
20
15.5
< 0.0001
7
6.5
0.2670
4
0.6
< 0.0001
5
3.7
0.7377
 Cirrhosis/liver disease
97
1.3
38
1.3
0.9171
0
0.0
0.3099
29
1.6
0.4372
3
2.3
0.3369
1
0.9
0.7103
4
0.6
0.1428
1
0.7
0.5475
 Autoimmune disease
96
1.3
35
1.2
0.6402
1
1.3
0.9944
16
0.9
0.1139
1
0.8
0.5869
4
3.7
0.0341
12
1.9
0.2061
1
0.7
0.5548
Pregnant (women 15–45 y)
459
58.0
481
82.7
< 0.0001
1
10.0
0.0023
272
83.7
< 0.0001
2
28.6
0.1164
1
14.3
0.0198
196
89.9
< 0.0001
9
56.3
0.8866
Obese (all ages)
1083
15.6
374
14.6
0.1967
18
25.4
0.0250
271
17.0
0.1905
13
17.1
0.7231
17
18.3
0.4834
46
7.4
< 0.0001
12
9.6
0.0654
Outpatient consultations last 3 months
    
0.6362
  
0.7448
  
0.0005
  
0.7360
  
0.0061
  
0.0120
  
0.0008
 0
2504
36.7
779
35.8
 
25
34.2
 
388
30.9
 
20
32.3
 
40
54.8
 
262
42.7
 
48
43.2
 
 1
1448
21.2
480
22.0
 
14
19.2
 
287
22.9
 
15
24.2
 
11
15.1
 
121
19.7
 
35
31.5
 
  ≥ 2
2879
42.1
918
42.2
 
34
46.6
 
580
46.2
 
27
43.5
 
22
30.1
 
231
37.6
 
28
25.2
 
Smoking habits (patients ≥18 y)
    
< 0.0001
  
0.0753
  
< 0.0001
  
0.1387
  
0.9041
  
0.1663
  
0.0818
 Never smoker
4106
57.0
1598
57.5
 
42
56.0
 
993
56.7
 
62
53.9
 
57
56.4
 
367
59.5
 
84
64.1
 
 Past smoker
1366
19.0
640
23.0
 
21
28.0
 
459
26.2
 
23
20.0
 
18
17.8
 
98
15.9
 
15
11.5
 
 Current smoker
1728
24.0
542
19.5
 
12
16.0
 
300
17.1
 
30
26.1
 
26
25.7
 
152
24.6
 
32
24.4
 
Functional status impairment (Barthel score; patients ≥65 y)
    
0.0764
  
0.5686
  
0.1750
  
0.9911
  
0.4228
  
0.6788
  
0.0012
 Total (0–15)
106
6.8
24
3.9
 
0
0.0
 
21
4.2
 
3
7.3
 
0
0.0
 
0
0.0
 
0
0.0
 
 Severe (20–35)
35
2.3
15
2.4
 
0
0.0
 
11
2.2
 
1
2.4
 
0
0.0
 
0
0.0
 
3
13.0
 
 Moderate (40–55)
62
4.0
31
5.0
 
0
0.0
 
26
5.2
 
1
2.4
 
0
0.0
 
1
4.5
 
3
13.0
 
 Mild (60–90)
364
23.5
136
22.1
 
4
44.4
 
109
21.9
 
10
24.4
 
6
24.0
 
5
22.7
 
3
13.0
 
 Minimal (95–100)
985
63.5
409
66.5
 
5
55.6
 
330
66.4
 
26
63.4
 
19
76.0
 
16
72.7
 
14
60.9
 
Sampling time
    
< 0.0001
  
0.0051
  
< 0.0001
  
0.0797
  
0.7704
  
< 0.0001
  
0.3919
 0–2 days
2374
33.1
1211
42.0
 
16
21.1
 
830
45.3
 
54
41.9
 
35
32.7
 
237
38.3
 
40
29.6
 
 3–4 days
2521
35.2
1052
36.5
 
22
28.9
 
657
35.9
 
38
29.5
 
41
38.3
 
244
39.5
 
53
39.3
 
 5–7 days
1941
27.1
564
19.5
 
34
44.7
 
303
16.5
 
35
27.1
 
28
26.2
 
132
21.4
 
39
28.9
 
 8–9 days
335
4.7
59
2.0
 
4
5.3
 
42
2.3
 
2
1.6
 
3
2.8
 
5
0.8
 
3
2.2
 
Influenza vaccination ≥15 days from symptom onset
938
13.0
279
9.6
< 0.0001
7
9.2
0.3339
221
12.0
0.2825
10
7.8
0.0806
9
8.3
0.1554
25
4.1
< 0.0001
8
5.9
0.0156
Influenza vaccination ≥15 days from symptom onset (age ≥ 65)
673
39.9
195
22.1
< 0.0001
1
10.0
0.0541
175
24.4
< 0.0001
8
10.7
< 0.0001
6
17.1
0.0064
1
4.6
0.0008
4
15.4
0.0112
Influenza vaccination ≥15 days from symptom onset (targeted groups)
869
18.4
256
11.1
< 0.0001
7
13.0
0.3047
214
13.6
< 0.0001
8
7.2
0.0025
7
11.1
0.1373
14
3.1
< 0.0001
7
9.7
0.0586
Patients with a qualified occupation had a higher risk of being admitted with influenza. Patients with a swab taken 8–9 days after symptoms onset appeared with less risk of being admitted with influenza, suggesting a decrease in the influenza viral load for these patients (Table 4).
Table 4
Subject characteristics and risk of admission with influenza
 
All admissions
Influenza-positive
Crude OR
Heterogeneity by strain (I2)
aOR(*)
N = 10140
N = 2895
     
Characteristic
N
N
%
Value
95% CI
 
Value
95% CI
Age group
 0–1 years
2692
331
12.3
1.00
79.4%
1.00
 2–4 years
1217
311
25.6
2.45
2.06–2.92
75.6%
0.86
0.67–1.09
 5–17 years
827
381
46.1
6.09
5.03–7.38
94.6%
1.59
0.85–2.96
 18–49 years
2100
795
37.9
4.35
3.73–5.06
96.4%
0.65
0.22–1.97
 50–64 years
735
195
26.5
2.58
2.10–3.15
96.6%
0.59
0.25–1.39
 65–74 years
793
228
28.8
2.88
2.37–3.50
95.3%
0.61
0.31–1.22
 75–84 years
903
272
30.1
3.07
2.55–3.71
96.9%
0.50
0.21–1.20
 ≥ 85 years
701
260
37.1
4.21
3.45–5.13
98.4%
0.49
0.19–1.28
Sex
 Male
5105
1339
26,2%
1.00
 
54.0%
1.00
 
 Female
5035
1556
30,9%
1.26
1.15–1.37
46.5%
0.84
0.74–0.95
Smoking habits
 Current smoker
2270
542
23,9%
1.00
 
81.7%
1.00
 
 Past smoker
2006
640
31,9%
1.49
1.30–1.71
88.4%
1.04
0.89–1.22
 Never smoker
5704
1598
28,0%
1.24
1.11–1.39
34.0%
1.09
0.93–1.28
Consultations at the GP (last 3 months)
 No
3283
779
23,7%
1.00
 
95.0%
1.00
 
 Yes
5725
1398
24,4%
1.04
0.94–1.15
92.6%
0.91
0.69–1.18
Occupation / Social class
 Qualified
3810
1255
32,9%
1.00
 
97.1%
1.00
 
  Skilled
1376
355
25,8%
0.71
0.62–0.81
81.9%
0.83
0.72–0.94
  Low or unskilled
3411
591
17,3%
0.43
0.38–0.48
91.5%
0.63
0.50–0.78
Other risk factors
 Comorbidity
3714
1234
33,2%
1.43
1.31–1.56
98.7%
0.90
0.63–1.30
 Cardiovascular disease
2094
796
38,0%
1.74
1.57–1.92
98.7%
1.01
0.72–1.40
 Chronic obstructive pulmonary disease
1008
206
20,4%
0.62
0.52–0.72
92.5%
0.66
0.45–0.98
 Asthma
463
187
40,4%
1.74
1.44–2.11
94.3%
1.31
0.96–1.77
 Immunodeficiency/organ transplant
222
67
30,2%
1.08
0.81–1.45
85.2%
0.57
0.28–1.17
 Diabetes
1049
362
34,5%
1.36
1.19–1.56
98.1%
1.19
1.03–1.37
 Chronic renal impairment
617
208
33,7%
1.29
1.09–1.54
89.2%
1.06
0.89–1.27
 Chronic neuromuscular disease
426
192
45,1%
2.13
1.75–2.59
91.7%
1.08
0.75–1.56
 Active neoplasm
479
168
35,1%
1.37
1.13–1.67
96.8%
0.63
0.42–0.95
 Chronic liver disease
135
38
28,1%
0.98
0.67–1.43
38.8%
1.09
0.79–1.50
 Autoimmune disease
131
35
26,7%
0.91
0.62–1.35
23.8%
1.14
0.84–1.56
 Obesity
1457
374
25,7%
0.92
0.81–1.04
93.3%
0.83
0.69–1.00
 Pregnancy
942
483
51,3%
2.96
2.58–3.40
97.6%
3.02
1.59–5.76
Days from onset of symptoms to swabbing
 0–2 days
3585
1211
33,8%
1.00
 
92.8%
1.00
 
 3–4 days
3573
1052
29,4%
0.82
0.74–0.90
36.9%
1.05
0.99–1.12
 5–7 days
2505
564
22,5%
0.57
0.51–0.64
83.4%
0.82
0.64–1.07
 8–9 days
394
59
15,0%
0.35
0.26–0.46
65.2%
0.60
0.47–0.77
(*)Adjusted Odds Ratios were obtained using the model described in the ‘Methods’ section (pg.6)
Pregnant women had a 3 times higher risk of having influenza at admission than non-pregnant. Also subjects with diabetes had 1.19 times higher risk of being an influenza case. On the other hand, patients with COPD or neoplasm had lower risk of testing positive for influenza. Despite there was a high number of admissions with cardiovascular diseases (CVD), no difference in the risk of influenza was found in these patients. (Fig. 6).
During pregnancy, the risk of testing positive for influenza was higher during the third trimester than in the first trimester, and also if they had any comorbidity in the first trimester (Fig. 7).
There were no significant statistical differences among influenza positives and negatives for those who were admitted to ICU or who received mechanical ventilation or those who died while they were hospitalised, and differences for those with extracorporeal membrane oxygenation could be due to sparse numbers of patients who received extracorporeal membrane oxygenation. Apart from influenza, the main discharge diagnosis was pneumonia, either for influenza-negatives or influenza-positives (Table 5).
Table 5
Influenza severity and complications 232 by RT-PCR results
 
Influenza-negative
Influenza-positive
 
A(H1N1)pdm09
A (H3N2)
A not subtyped
B/Yamagata
B/Victoria
B not subtyped
 
N=7245
N=2895
N=76
N=1840
N=129
N=108
N=618
N=135
Category
n
%
n
%
P vs. negative
n
%
n
%
n
%
n
%
n
%
n
%
P-value for distribution by strain
Severity indicator
 Intensive care unit admission
317
4.4
132
4.6
0.6656
9
11.8
102
5.5
5
3.9
5
4.6
6
1.0
6
4.4
<0.0001
 Mechanical ventilation
225
3.1
75
2.6
0.1728
5
6.6
61
3.3
3
2.3
2
1.9
3
0.5
2
1.5
0.0018
 Extracorporeal membrane oxygenation
89
1.2
9
0.3
0.0000
0
0.0
5
0.3
3
2.3
0
0.0
1
0.2
0
0.0
0.0035
 Death during hospitalisation
183
2.5
69
2.4
0.6904
4
5.3
52
2.8
3
2.3
3
2.8
5
0.8
2
1.5
0.0745
 Length of stay (days), median (interquartile range)
6
(3-8)
5
(3-8)
<0.001
6
(3-10)
5
(3-8)
6
(3-9)
4
(2-6.5)
6
(4-8)
5
(3-7)
0.004
Respiratory diagnoses
    
<0.0001
            
0.3163
 None
2052
28.3
1828
63.1
 
15
19.7
1191
64.7
79
61.2
51
47.2
435
70.4
60
44.4
 
 Pneumonia
2335
32.2
658
22.7
 
58
76.3
362
19.7
37
28.7
40
37.0
112
18.1
55
40.7
 
 COPD exacerbation
192
2.7
91
3.1
 
2
2.6
74
4.0
5
3.9
3
2.8
3
0.5
4
3.0
 
 Respiratory failure
109
1.5
12
0.4
 
1
1.3
9
0.5
1
0.8
0
0.0
0
0.0
1
0.7
 
 Asthma exacerbation
53
0.7
30
1.0
 
0
0.0
29
1.6
0
0.0
0
0.0
1
0.2
0
0.0
 
 Acute respiratory distress syndrome
18
0.2
2
0.1
 
0
0.0
0
0.0
0
0.0
0
0.0
2
0.3
0
0.0
 
 Pneumotorax
1
0.0
0
0.0
 
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
 
 Bronchiolitis
383
5.3
48
1.7
 
0
0.0
29
1.6
1
0.8
0
0.0
12
1.9
6
4.4
 
 Upper respiratory infection
2101
29.0
226
7.8
 
0
0.0
146
7.9
6
4.7
14
13.0
53
8.6
9
6.7
 
Metabolic failure
    
0.1725
            
0.2106
 No
7016
96.8
2827
97.7
 
72
94.7
1803
98.0
126
97.7
106
98.1
604
97.7
127
94.1
 
 Acute renal failure
85
1.2
19
0.7
 
3
3.9
10
0.5
2
1.6
2
1.9
0
0.0
2
1.5
 
 Diabetic coma
8
0.1
1
0.0
 
0
0.0
1
0.1
0
0.0
0
0.0
0
0.0
0
0.0
 
 Fluid/electrolyte/acid-base/balance disorders
136
1.9
48
1.7
 
1
1.3
26
1.4
1
0.8
0
0.0
14
2.3
6
4.4
 
Cardiovascular events
    
<0.0001
            
<0.0001
 None
6674
92.1
2766
95.5
 
69
90.8
1741
94.6
122
94.6
104
96.3
611
98.9
129
95.6
 
 Acute myocardial infarction
6
0.1
1
0.0
 
0
0.0
1
0.1
0
0.0
0
0.0
0
0.0
0
0.0
 
 Arterial or venous embolia
1
0.0
0
0.0
 
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
 
 Carditis
2
0.0
1
0.0
 
0
0.0
0
0.0
0
0.0
0
0.0
1
0.2
0
0.0
 
 Cardiac arrest
1
0.0
1
0.0
 
0
0.0
1
0.1
0
0.0
0
0.0
0
0.0
0
0.0
 
 Malignant hypertension
1
0.0
3
0.1
 
0
0.0
2
0.1
0
0.0
0
0.0
0
0.0
1
0.7
 
 Any cardiovascular condition
560
7.7
123
4.2
 
7
9.2
95
5.2
7
5.4
4
3.7
6
1.0
5
3.7
 
Neurologic events
    
0.4268
            
0.4345
 No
7241
99.9
2894
100.0
 
76
100.0
1839
99.9
129
100.0
108
100.0
618
100.0
135
100.0
 
 Altered mental status
3
0.0
1
0.0
 
0
0.0
1
0.1
0
0.0
0
0.0
0
0.0
0
0.0
 
 Convulsions
1
0.0
0
0.0
 
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
 
Major discharge diagnoses
    
<0.0001
            
<0.0001
 Influenza
241
3.3
2272
78.5
 
40
52.6
1401
76.1
97
75.2
39
36.1
584
94.5
113
83.7
 
 Pneumonia
2427
33.5
238
8.2
 
31
40.8
145
7.9
12
9.3
29
26.9
13
2.1
12
8.9
 
 Other respiratory disease
2683
37.0
177
6.1
 
1
1.3
132
7.2
8
6.2
15
13.9
17
2.8
6
4.4
 
 Cardiovascular
267
3.7
34
1.2
 
1
1.3
31
1.7
1
0.8
1
0.9
0
0.0
1
0.7
 
 Other
1627
22.5
174
6.0
 
3
3.9
131
7.1
11
8.5
24
22.2
4
0.6
3
2.2
 
Probabilities of most common severe outcomes by strain by age and influenza strains are displayed in Fig. 8. This probability had an upward trend up to 80 years old after a shock. The probability point estimates of having any cardiovascular complication increased greatly from 90 years old for those who had influenza. Similar trends were found for each individual strain for these discharge diagnoses.
Vaccination coverage was 9% or higher for targeted groups only in 4 sites (Fig. 9), and only 6 sites had at least 20 patients vaccinated among the patients targeted for vaccination. The IVE analysis was restricted to the sites with the highest vaccination coverage in targeted groups for vaccination having at least 20 patients vaccinated in these groups. These sites were Valencia, Canada, St. Petersburg, Mexico, Moscow and Turkey.
The IVE analysis, therefore, will be carried out in these six sites and globally. Vaccination coverage in pregnant women was 0% in Kazakhstan among the included patients, and in Moscow, only 1.3% (10 out of 800) of the admitted pregnant women received the vaccine at least 15 days before symptoms onset, therefore, adjusted IVE could not be estimated for pregnant women.
Vaccination coverage was higher in patients older than 65 years and in patients with two or more comorbidities. Among immunized women 15 to 45 years old, 19 of 47 were pregnant (40.4%), and among all vaccinated patients, 26.7% were obese.
Of the subjects vaccinated, 78.0% were also vaccinated in season 2015–2016 and 67.2% were vaccinated in season 2014–2015. However, 8.0% of the unvaccinated patients in the current season were vaccinated in the season 2015–2016, and 6.6% in the season 2014–2015 (Table 6).
Table 6
Characteristics of patients included in the primary analysis by vaccination status
Risk variables
 
Unvaccinated
Vaccinated
P value
Category
n
%
n
%
 
Number of patients, n (%)
Controls
6307
70.7
938
77.1
< 0.0001
 
Cases
2616
29.3
279
22.9
 
Age (y)
Median (range)
11.4 (0–105.3)
76.5 (0.6–102.8)
< 0.0001
Age group, n (%) (2)
0–5 months
1254
14.3%
0
0.0%
< 0.0001
 
6–11 months
643
7.3%
13
1.1%
 
1–4 yrs
1948
22.2%
51
4.3%
 
5–17 yrs
760
8.7%
67
5.6%
 
18–49 yrs
1988
22.7%
112
9.4%
 
50–64 yrs
628
7.2%
106
8.9%
 
65–74 yrs
583
6.6%
210
17.6%
 
75–84 yrs
566
6.5%
337
28.2%
 
≥85 y
403
4.6%
299
25.0%
 
Sex, n (%)
Male
4462
50.0%
643
52.8%
0.0641
Female
4461
50.0%
574
47.2%
 
Comorbidities, n (%)
None
6123
68.6%
303
24.9%
< 0.0001
1
1457
16.3%
355
29.2%
 
> 1
1343
15.1%
559
45.9%
 
Pregnant, n (%)
921
69.5%
19
40.4%
< 0.0001
Obesity, n (%)
1148
13.8%
309
26.7%
< 0.0001
Previous hospitalisation within 12 months, n (%)
1914
24.1%
406
37.7%
< 0.0001
GP visit within 3 months, n (%)
None
3074
38.8%
209
19.4%
< 0.0001
1
1740
21.9%
188
17.4%
 
> 1
3116
39.3%
681
63.2%
 
Smoking, n (%)
Current
2112
24.1%
158
13.0%
< 0.0001
Past
1618
18.5%
388
32.0%
 
Never
5037
57.5%
667
55.0%
 
Functional impairment in ≥65 y, n (%)
None or minimal
72
5.4%
58
7.0%
0.4086
Mild
32
2.4%
18
2.2%
 
Moderate
52
3.9%
41
4.9%
 
Severe
309
23.1%
191
23.0%
 
Total
871
65.2%
523
62.9%
 
Sampling interval (days)
Median (range)
3 (0–9)
 
4 (0–9)
 
< 0.0001
Sampling interval, n (%)
≤4 days
6377
72.1%
781
64.2%
< 0.0001
5–7 days
2148
24.3%
357
29.3%
 
8–9 days
315
3.6%
79
6.5%
 
Site, n (%)
St. Pet
1851
20.7%
86
7.1%
< 0.0001
Moscow
1555
17.4%
65
5.3%
 
Kazakhstan
159
1.8%
0
0.0%
 
Czech Republic
105
1.2%
6
0.5%
 
Canada
993
11.1%
139
11.4%
 
Romania
380
4.3%
7
0.6%
 
Turkey
392
4.4%
21
1.7%
 
Valencia
1300
14.6%
825
67.8%
 
Tunisia
37
0.4%
2
0.2%
 
Suzhou/Shanghai
469
5.3%
1
0.1%
 
India
482
5.4%
11
0.9%
 
Mexico
301
3.4%
49
4.0%
 
South Africa
899
10.1%
5
0.4%
 
Vaccinated, n (%)
In 2015–2016
718
8.0%
949
78.0%
< 0.0001
In 2014–2015
589
6.6%
818
67.2%
< 0.0001

IVE estimates for included patients

In the selected sites for IVE estimates, vaccination coverage was 11.7% among the influenza positives and 22.2% among the influenza negatives. The overall IVE was 27.24% (95% CI 15.62 to 37.27%) in targeted groups for vaccination. Table 7 shows IVE for different strains, Fig. 10 by study country.
Table 7
IVE for all cases and for targeted groups only by age and strain
   
Influenza-positive
Influenza-negative
Adjusted IVE(*)
Population
Strain
Age
Total
Vaccinated
Total
Vaccinated
Percent
(95% CI)
P-value
Overall
Any
Any
2895
279
7245
938
27 (15, 38)
 
 
<65 y
2013
84
5558
265
27 (−1, 48)
0.804
 
≥65 y
882
195
1687
673
25 (3, 43)
 
A (H1N1) pdm09
Any
76
7
7245
938
39 (−68, 78)
 
 
<65 y
66
6
5558
265
2 (−138, 60)
0.346
 
≥65 y
10
1
1687
673
99 (1, 100)
 
A (H3N2)
Any
1840
221
7245
938
25 (13, 35)
 
 
<65 y
1124
46
5558
265
31 (1, 51)
0.703
 
≥65 y
716
175
1687
673
19 (−10, 40)
 
B/Yamagata
Any
108
9
7245
938
41 (−110, 84)
 
 
<65 y
73
3
5558
265
7 (−178, 69)
0.203
 
≥65 y
35
6
1687
673
73 (−38, 95)
 
B/Victoria
Any
618
25
7245
938
43 (−15, 71)
 
 
<65 y
596
24
5558
265
27 (−14, 54)
0.191
 
≥65 y
22
1
1687
673
89 (40, 98)
 
Targeted groups only
Any
Any
2314
256
4723
869
27 (16, 37)
 
 
<65 y
1432
61
3036
196
37 (0, 47)
0.657
 
≥65 y
882
195
1687
673
25 (3, 43)
 
A (H1N1) pdm09
Any
54
7
4723
869
18 (−142, 72)
 
 
<65 y
44
6
3036
196
−62 (−303, 35)
0.423
 
≥65 y
10
1
1687
673
99 (1, 100)
 
A (H3N2)
Any
1572
214
4723
869
23 (9, 34)
 
 
<65 y
856
39
3036
196
27 (−7, 50)
0.485
 
≥65 y
716
175
1687
673
19 (−10, 40)
 
B/Yamagata
Any
63
7
4723
869
72 (8, 92)
 
 
<65 y
28
1
3036
196
65 (−35, 91)
0.037
 
≥65 y
35
6
1687
673
73 (−38, 95)
 
B/Victoria
Any
449
14
4723
869
66 (3, 80)
 
 
<65 y
427
13
3036
196
41 (10, 62)
0.262
 
≥65 y
22
1
1687
673
89 (40, 98)
 
(*) .IVE was obtained in each case using the same model (described in the ‘Methods’ section) but restricting it by strain, age or targeted groups.. P-value obtained comparing patients <65 y and ≥ 65 y
IVE was statistically significant for all strains except for A(H1N1)pdm09 due to the limited sample size, and the point estimate was higher for both influenza B lineages, even using the trivalent vaccine (Fig. 11). Heterogeneity among influenza types/subtypes was relevant (I2 = 57.4%).
This season IVE estimate was higher in patients 85 years old or older (51.17% [95% CI: 35.13 to 63.24]). IVE was also high and statistically significant for patients 2 to 4 years old (49.37% [95% CI: 21.60 to 67.30]) (Fig. 12). Heterogeneity among the different age groups was relevant (I2 = 69%).

Discussion

The GIHSN included sites from the two hemispheres in the 2016/17 season. However, Ivory Coast and Peru were not included in the epidemiology study or in the IVE study due to the low influenza cases detected. This season was characterized by a predominance in the circulation of A(H3N2) virus, and a second wave of B/Victoria. However, A(H1N1)pdm09 was predominant in Mexico. B/Yamagata-strain, which was not included in the vaccine, also circulated in some areas.
Influenza A(H1N1)pdm09 was mainly found in Mexico. A low vaccination coverage was seen in most of the GIHSN sites.
The GIHSN represents an opportunity to analyse the epidemiology of hospitalized influenza cases, and an assessment of the vaccine effectiveness worldwide. However, there are some limitations that should be mentioned:
  • Although the same protocol was developed, the adaptation to different countries or sites produced some heterogeneity in the results, as previously reported in the network [3].
  • In general vaccination coverage was low in most sites, even among high risk groups.
  • Other factors as number of cases per site, and variability in the vaccination coverage, increased the heterogeneity in the reporting and analysis.
All of these limitations contributed to the complexity of the interpretation of the results.
In the northern hemisphere, the season differed by latitude [14], and this may have implications in the calendar of the vaccination campaigns.
Patients tested for influenza 8 to 9 days after symptoms onset had a higher proportion of samples negative for influenza than patients tested within the first 7 days after symptoms onset, as that viral load decreases with increasing time since infection, [15]. However, there were a few cases in our study as we collected all cases whose admission was in the 7 days after ILI symptoms started, and any delay in approaching the patient could result in a late swabbing.
Among inpatients with COPD, there was not a higher risk of testing for influenza. As all the cases were hospitalized, this result cannot be interpreted as COPD not being a risk factor for influenza hospitalization, as any other respiratory infection may decompensate the respiratory condition and force an admission. Besides vaccination coverage is higher in subjects with chronic conditions [16] and therefore, protection from the vaccine may also impact on our finding.
The risk of testing positive for influenza in diabetic patients was slightly higher than non-diabetic patients, as it also happened in previous seasons [3, 4]. Pregnancy also increased the probability of having influenza in women, particularly if they had at least one comorbidity in the first trimester.
Despite differences in the characteristics of the included patients relative to the age or pregnancy status, heterogeneity in the IVE analysis among the 6 sites with the highest numbers of vaccinated patients was low. Point estimates of the overall IVE from a two-step pooling was 27.2% (95% CI: 15.62 to 37.27) in hospitalized, which is higher than that reported in Europe for hospitalised patients [17], that ranged from 2.4 to 7.9%, depending on the age group, and lower to that estimated by the US CDC, which was 40% (95% CI: 32 to 46) [18].
Pooled Influenza vaccine effectiveness showed protection against all influenza virus that circulated, although for A(H1N1)pdm09 did not reach statistical significance, as the circulation of the virus was low except in Mexico. There was a significant effectiveness against both B lineages, even though most of the vaccines used were trivalent, i.e. only contained the B/Victoria linage, following recommendations of the World Health Organisation (WHO) for trivalent vaccines in the Northern Hemisphere [19]. Although antigenically different, there has been shown some degree of cross-protection among both B lineages.

Conclusion

The GIHSN provides an opportunity to analyse influenza epidemiology and vaccine effectiveness worldwide. In the 2016/17 season, A(H3N2) was the predominant influenza strain this season (first wave), followed by B/Victoria (second wave). Influenza A(H1N1)pdm09 was mainly found in Mexico. A low vaccination coverage was seen in most of the GIHSN sites.
Differences in the distribution of influenza cases among the age groups were mainly due to the characteristics of the participating hospitals. Pregnant women had higher risk of testing positive for influenza, as occurred with diabetics, however this difference was not seen in COPD subjects.
Overall IVE was low to moderate 27.24 (95% CI 15.62 to 37.27) in this season. A moderate to high effectiveness was seen for both influenza B lineages, and a non-significant low effectiveness for Influenza A(H1N1)pdm09.

Acknowledgements

The authors would like to acknowledge the Foundation for Influenza Epidemiology for the financial support and all members of the GIHSN, which are listed below (sites are firstly ordered by contribution to this manuscript and secondly by alphabetical order):
Valencia: B Escribano-López, S García Esteban, B Guglieri-López, M Martín-Navarro, A Mira-Iglesias and M J Sánchez-Catalán from FISABIO-Salud Pública, Valencia, Spain, and X López-Labrador from FISABIO-Salud Pública, Valencia, Spain and the Consorcio de Investigación Biomédica de Epidemiología y Salud Pública, Spain, Instituto Carlos III, Madrid, Spain; E Adriana-Magos and M Carballido-Fernández from the Hospital General de Castellón, Castellón, Spain; J Mollar Maseres and M Roldán-Aguado from the Hospital Universitario y Politécnico La Fe, Valencia, Spain; J Fernández-Dopazo and M Tortajada-Girbés from the Hospital Doctor Peset, Valencia, Spain, and P Llorente-Nieto and G Schwarz-Chavarri from the Hospital General de Alicante, Alicante, Spain.
Moscow: E Garina, L Kisteneva, L Kolobukhina, K Krasnoslobotsev, I Kruzhkova, L Merkulova and E Mukasheva from the D.I. Ivanovsky Institute of Virology FSBI “N.F. Gamaleya FRCEM” Ministry of Health, Moscow, Russian Federation.
Canada: A Ambrose, M Andrew, M ElSherif, D MacKinnon-Cameron, M Nichols-Evans and P Ye from the Canadian Center for Vaccinology, IWK Health Centre and Nova Scotia Health Authority, Halifax, Canada.
St. Petersburg: O Afanasieva, A Afanasieva, S Demina, E Dondurei, M Eropkin, A Fadeev, L Generalova, A Go, E Golovacheva, V Gonchar, A Komissarov, N Konovalova, S Kuvarzina, T Levanyuk, T Lobova, L Osidak, M Pisareva, E Rozhkova, K Sintsova, Z Sirotkina, E Smorodintseva, K Stolyarov, V Sukhovetskaya, M Tamila, L Voloshuk, M Yanina and P Zarishnyuk from the Research Institute of Influenza, St. Petersburg, Russian Federation.
South Africa: S. A. Madhi from the Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, University of the Witwatersrand, Johannesburg, South Africa.
Romania: V Aramă, D.Florea, M Luminos, D Otelea, O Sandulescu and O Vlaicu, from the National Institute of Infectious Diseases “Prof. Dr.MateiBals”, Bucharest (INBIMB), Romania, and D Pitigoi from the National Institute of Infectious Diseases “Prof. Dr.MateiBals”, Bucharest (INBIMB) and the University of Medicine and Pharmacy “Carol Davila” Bucharest, Romania.
Turkey: K Aykac, T Bagcı Bosi, E Bilgin, M Durusu, A Kara, L Ozisik and S Tanir Basaranoglu from the Hacettepe University Faculty of Medicine, Ankara, Turkey; T Bedir Demirdag, O Guzel Tunccan, O Ozgen and H Tezer from the Gazi University Faculty of Medicine, Ankara, Turkey; B Gulhan and A Ozkaya-Parlakay from the Ankara Hematology Oncology Children’s Training and Research Hospital, Ankara, Turkey; M Ozsoy and N Tulek from the Ankara Research and Training Hospital, Ankara, Turkey, and M Akcay Ciblak, from Sanofi Pasteur, Turkey.
Mexico: A Galindo Fraga, M L Guerrero Almeida and G M Ruiz-Palacios from the National Institute of Medical Sciences and Nutrition Salvador Zubirán (INCMNSZ), Mexico; A de Colsa Ranero and W Dolores Domínguez-Viveros from the Instituto Nacional de Pediatría, Mexico; I Jiménez-Escobar, J P Ramírez-Hinojosa and R P Vidal-Vázquez from the Hospital General Dr. Manuel Gea González, Mexico; D de la Rosa-Zamboni, A E Gamiño-Arroyo and S Moreno-Espinosa from the Hospital Infantil de México, Mexico, and A Hernández from the Instituto Nacional de Enfermedades Infecciosas Ismael Cosio Villegas, Mexico.
India: S Ali, M Khan, H Mir, Soumya and R Yusuf from the Sher-i-Kashmir Institute of Medical Sciences (SKIMS), India, and N Bali from the Department of Clinical Microbiology, Government Medical College, Srinagar, India.
Czech Republic: M Havlickova, H Jirincova, R Kralova, Z Mandakova, J Prochazkova, H Sebestova from the National Institute of Public Health, Prague, Czech Republic, and D Dvorska, K Herrmanova, H Rohacova, T Rudova and I Standerova from the Hospital Na Bulovce, Prague, Czech Republic
Suzhou/Shanghai: K Chen, W Shan, F Zhang, G Zhao from the Fudan University, Shanghai, China; Y Yan from the Soochow University Affiliated Children Hospital, Suzhou, China; J Zheng from the Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing 102206, China, and J Pan from the State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
Kazakhstan: N Gaukhar from the Center for Sanitary-Epidemiological Expertise and Monitoring, Almaty, Kazakhstan.
Tunisia: S Amine from the Hôpital Charles-Nicolle, Tunis, Tunisia; J Ben Khelil from the Medical Intensive Care Unit, Abderrahmen Mami Hospital, Ariana, Tunisia; M Ben Jeema and M Koubâa from the Hedi Chaker Hospital, Sfax, Tunisia; K Menif from the Children’s Hospital of Tunis, Tunis, Tunisia; A Boukthir, S Chlif, M K Dellagi, A Gharbi, H Louzir, R Yazidi and W Zid from the Pasteur Institute of Tunis, Tunisia.
Peru: A Laguna, from the Instituto de Medicina Tropical Daniel Alcides Carrión, UNMSM, Lima, Peru; J Pérez-Bao, from the United States Naval Medical Research Center Detachment, Iquitos and Lima, Peru, and N Reyes from the Universidad Nacional Mayor de San Marcos, Lima, Peru.
Ivory Coast: D Coulibaly, from the Pasteur Institute of Côte d’Ivoire, Abidjan, Côte d’Ivoire.

Funding

The study was funded by FISABIO-Public Health and the participating institutions of the manuscript (listed in the affiliations in the author list), and Sanofi Pasteur, who had no role in the analysis or discussion of the results. All participating institutions contributed to the data collection of the corresponding site, as well as the datasets transfer to FISABIO and the interpretation of GIHSN results. FISABIO-Public Health contributed to the design of the study, the recruitment and data collection of patients from Valencia Region and all participant sites, and the data analysis and interpretation of GIHSN results.

Availability of data and materials

Datasets were collected by each participating site and gathered on a pooled database by FISABIO. An authorisation is needed to any participating site in order to require sites databases. Data cannot be publicly shared due to confidentiality reasons, as some confidential patient data should not be shared, and in order to accomplish privacy laws from the participating sites. The corresponding author must be contacted with in order to ask for information about databases.
This study has been approved by the Ethics Committees of the participating sites, who have approved their participation in the GIHSN network. Each adult patient tested for influenza had signed an informed consent in order to be included in the study. In case the patient did not reach the legal age or is impaired, parents or legal guardians signed the informed consent. The Ethics Committees of the participating sites are listed below:
  • St. Petersburg: Local Ethical Committee under the FGBU “Research Institute of Influenza” of the Ministry of Health of the Russian Federation
  • Moscow: The local Ethic Committee of Hospital #1 for Infectious Diseases of Moscow Health Department
  • Kazakhstan: The study was carried in Almaty, Kazakhstan as part of the implementation of the national Severe Acute Respiratory Infections (SARI) surveillance program in Kazakhstan for purposes of communicable disease control. Ethical approval was not required but informed consent was obtained before inclusion. Informed consent provided in accordance with the Constitution of the Republic of Kazakhstan (section II article 29)
  • Czech Republic: Ethics Committee of the Hospital Na Bulovce
  • Canada: The Nova Scotia Health Authority Research Ethics Board and the IWK Research Ethics Board (IWK: Isaak Walton Killam)
  • Romania: Bioethics Committee of the National Institute for Infectious Diseases “Prof. Dr. Matei Bals” Bucharest, Romania
  • Turkey: Hacettepe University Non-interventional Clinical Research Ethics Board
  • Valencia: Comité Ético de Investigación Clínica Dirección General de Salud Pública-Centro Superior de Investigación en Salud Pública (CEIC-DGSP-CSISP)
  • Tunisia: The ethics committee of Abderrahmane Mami hospital, Ariana, Tunisia
  • Suzhou/Shanghai: Fudan University School of Public Health Institutional Review Board
  • India: Institutional Ethics Committee of the Sher-i-Kashmir Institute of Medical Sciences, Srinagar
  • Mexico: Research Ethics Committee of the National Institute of Medical Science and Nutrition Salvador Zubiran & Research Committee of the National Institute of Medical Science and Nutrition Salvador Zubiran
  • South Africa: The Human Research Ethics Committee of the University of the Witwatersrand
All of these Ethics Committees approved the participation of the site in the study and the data transfer to FISABIO, who led the implementation and data collection in the 2016–2017 season.
Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Metadaten
Titel
Influenza epidemiology and influenza vaccine effectiveness during the 2016–2017 season in the Global Influenza Hospital Surveillance Network (GIHSN)
verfasst von
Víctor Baselga-Moreno
Svetlana Trushakova
Shelly McNeil
Anna Sominina
Marta C. Nunes
Anca Draganescu
Serhat Unal
Parvaiz Koul
Jan Kyncl
Tao Zhang
Ainagul Kuatbayeva
Afif Ben-Salah
Elena Burtseva
Joan Puig-Barberà
Javier Díez-Domingo
for the Global Influenza Hospital Surveillance Network (GIHSN)
Publikationsdatum
01.12.2019
Verlag
BioMed Central
Erschienen in
BMC Public Health / Ausgabe 1/2019
Elektronische ISSN: 1471-2458
DOI
https://doi.org/10.1186/s12889-019-6713-5

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