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Background Monitoring seasonal influenza Vaccine Effectiveness (VE) is key to inform vaccination strategies and sustain uptake. Pooling data across multiple seasons increases precision and allows for subgroup analyses, providing more conclusive evidence. Our aim was to assess VE against hospitalization with laboratory-confirmed influenza in Greece over six seasons, from 2013 to 2014 to 2018–2019, using routinely collected surveillance data. Methods Swab samples from hospitalized patients across the country were tested for influenza by RT-PCR. We used the test-negative design, with patients testing positive for influenza serving as cases and those testing negative serving as controls. VE was calculated as one minus the Odds Ratio (OR) for influenza vaccination, estimated by mixed-effects logistic regression and adjusted for age, sex, hospitalization type (being in intensive care or not), time from symptom onset to swabbing, and calendar time. Stratified estimates by age and hospitalization type were obtained, and also subgroup estimates by influenza type/subtype and season. Antigenic and genetic characterization of a subset of circulating influenza strains was performed. Results A total of 3,882 test-positive cases and 5,895 test-negative controls were analyzed. Across all seasons, adjusted VE was 45.5% (95% CI: 31.6–56.6) against all influenza, 62.8% against A(H1N1)pdm09 (95% CI: 40.7–76.7), 28.2% against A(H3N2) (95% CI: 12.0–41.3) and 45.5% against influenza B (95% CI: 29.1–58.1). VE was slightly lower for patients aged 60 years and over, and similar between patients hospitalized inside or outside intensive care. Circulating A(H1N1)pdm09 and B strains were antigenically similar to the vaccine strains, whereas A(H3N2) were not. Conclusion Our results confirm the public health benefits from seasonal influenza vaccination, despite the suboptimal effectiveness against A(H3N2) strains. Continued monitoring of VE is essential, and routinely collected surveillance data can be valuable in this regard.

BackgroundThe available evidence on whether neuraminidase inhibitors reduce mortality in patients with influenza is inconclusive and focuses solely on influenza A/H1N1pdm09. We assessed whether early oseltamivir treatment (≤48 hours from symptom onset) decreases mortality compared to late treatment in a large cohort of critically ill patients with influenza of all types.MethodsThe study included all adults with laboratory-confirmed influenza hospitalized in intensive care units (ICUs) in Greece over 8 seasons (2010–2011 to 2017–2018) and treated with oseltamivir. The association of early oseltamivir with mortality was assessed with log-binomial models and a competing risks analysis estimating cause-specific and subdistribution hazards for death and discharge. Effect estimates were stratified by influenza type and adjusted for multiple covariates.ResultsA total of 1330 patients were studied, of whom 622 (46.8%) died in the ICU. Among patients with influenza A/H3N2, early treatment was associated with significantly lower mortality (relative risk, 0.69 [95% credible interval {CrI}, .49–.94]; subdistribution hazard ratio, 0.58 [95% CrI, .37–.88]). This effect was purely due to an increased cause-specific hazard for discharge, whereas the cause-specific hazard for death was not increased. Among survivors, the median length of ICU stay was shorter with early treatment by 1.8 days (95% CrI, .5–3.5 days). No effect on mortality was observed for A/H1N1 and influenza B patients.ConclusionsSeverely ill patients with suspected influenza should be promptly treated with oseltamivir, particularly when A/H3N2 is circulating. The efficacy of oseltamivir should not be assumed to be equal against all types of influenza.

Objectives Excess population mortality during winter is most often associated with influenza A(H3N2), though susceptibility differs by age. We examined differences between influenza types/subtypes in their association with severe laboratory-confirmed cases, overall and by age group, to determine which type is the most virulent. Methods We used nine seasons of comprehensive nationwide surveillance data from Greece (2010–2011 to 2018–2019) to examine the association, separately for influenza A(H1N1)pdm09, A(H3N2) and B, between the number of laboratory-confirmed severe cases (intensive care hospitalizations or deaths) per type/subtype and the overall type-specific circulation during the season (expressed as a cumulative incidence proxy). Quasi-Poisson models with identity link were used, and multiple imputation to handle missing influenza A subtype. Results For the same level of viral circulation and across all ages, influenza A(H1N1)pdm09 was associated with twice as many intensive care hospitalizations as A(H3N2) (rate ratio (RR) 1.89, 95% CI 1.38–2.74) and three times more than influenza B (RR 3.27, 95%CI 2.54–4.20). Similar associations were observed for laboratory-confirmed deaths. A(H1N1)pdm09 affected adults over 40 years at similar rates, whereas A(H3N2) affected elderly people at a much higher rate than younger persons (≥65 vs. 40–64 years, RR for intensive care 5.42, 95% CI 3.45–8.65, and RR for death 6.19, 95%CI 4.05–9.38). Within the 40–64 years age group, A(H1N1)pdm09 was associated with an approximately five times higher rate of severe disease than both A(H3N2) and B. Discussion Influenza A(H1N1)pdm09 is associated with many more severe laboratory-confirmed cases, likely due to a more typical clinical presentation and younger patient age, leading to more testing. A(H3N2) affects older people more, with cases less often recognized and confirmed.

The 2014-2015 influenza season was marked by circulation of antigenically drifted A/H3N2 strains, raising the possibility of low seasonal influenza Vaccine Effectiveness (VE). We assessed VE against hospitalization with laboratory-confirmed influenza for the 2014-2015 season, using routine surveillance data. Non-sentinel swab samples from Greek hospital inpatients were tested for influenza by RT-PCR in three laboratories, covering the entire country. We estimated VE using a test-negative design. Out of 883 patients with known vaccination status, 161 (18.2%) were vaccinated, and 392/883 patients (44.4%) tested positive for influenza, of whom 162 (41.3%) had type B and 151 (38.5%) had A/H3N2. Adjusted VE was 31.6% (95%CI: 2.9-51.8%) against any influenza, 46.8%, 95%CI: 12.5-67.6%) against type B and -1.9%, 95%CI: -69.5 to 38.7%) against A/H3N2. VE against non-ICU hospitalization appeared to be higher, but the difference did not reach statistical significance. Circulating A/H3N2 viruses showed substantial antigenic drift, while about half of the type B strains were similar to the vaccine strain. Despite the antigenic drift of the A/H3N2 strains, the vaccine still offered substantial protection against hospitalization with laboratory-confirmed influenza, mostly due to a surge in type B influenza late in the season. Vaccine coverage was low, even among groups targeted for vaccination, and considerable effort should be made to improve it. J. Med. Virol. 88:1896-1904, 2016. © 2016 Wiley Periodicals, Inc.

Background The clinico-epidemiological characteristics of children with severe influenza-related intensive care unit (ICU) admissions in Greece during 2010–2019 are described. Methods All laboratory-confirmed influenza cases (real-time PCR), in children 0–16 years old, admitted to Pediatric ICUs throughout the country, are reported using a mandatory notification system to the National Public Health Organization of Greece. Case fatality rates (CFR) were analyzed according to age and presence of comorbidities. Results From October 2010 to April 2019, 131 influenza cases [7.2/100,000 children, 65 (49.6%) girls] with PICUs admissions were recorded. The majority of cases (n = 78; 60%) occurred in the age group 0–4 years-old [31 (24%) children were < 12 months-old]. Sixty-five (49.6%) children had underlying comorbidities (22 neurological disease, 12 congenital syndromes, 7 cancer, 5 chronic respiratory, 19 other). The most common diagnosis was febrile ARDS and 67 (51.14%) had severe pneumonia (40% viral, 7% bacterial). Seventy-five (57.2%) children required invasive ventilation. Influenza A accounted for 102 (77.86%) of cases; out of 86 (84.31%) subtyped, 68 (79%) were AH1N1pdm09, and 18 (21%) were AH3N2. Influenza B accounted for 29 (22.13%) of cases. All children received oseltamivir. Median length of stay was 10 days (range 1–90). A total of 32 deaths was recorded (CFR 24.4%, total rate: 1.76/100,000 children); 13 (40.1%) deaths occurred in children with no known co-morbidity. Mortality rates were higher in children aged > 4 years (18/53, 33.9% vs. 14/78, 17.9%, P = 0.04) while there was a trend for children with comorbidities (19/65, 29.2% vs. 13/66, 19.69%, P = 0.1). Only 4% of children were previously immunized against influenza. Conclusion AH1N1pdm09 accounted for the vast majority of severe cases and influenza associated deaths in children in Greece over the last 10 years. Severe disease occurred also in children with no comorbitidies. Longitudinal clinico-epidemiological data should be considered in shaping the national immunization program. Disclosures All authors: No reported disclosures.

Background Excess population mortality during winter is most often associated with influenza A(H3N2), particularly “pneumonia and influenza” deaths. We examined differences between influenza types in their association with severe laboratory-confirmed cases, to determine which is the most virulent. Methods We used nine seasons of comprehensive nationwide surveillance data from Greece (from 2010/11 to 2018/19) to examine the association, separately for influenza A(H1N1)pdm09, A(H3N2) and B, between the number of laboratory-confirmed severe cases (intensive care hospitalizations or deaths) and the overall type-specific circulation during the season (expressed as a cumulated incidence proxy—ILI rate times percent positive, summed over the season), using additive Poisson regression. Results During the study period, and for the same level of circulation during a season, influenza A(H1N1)pdm09 was associated with 3.7 times (95% CI 2.7–5.0) more laboratory-confirmed deaths compared with influenza B, and 2.2 times (95% CI 1.6–3.1) more compared with A(H3N2) (Figure 1). Similar differences were observed for intensive care hospitalizations. Laboratory-confirmed A(H1N1)pdm09 severe cases were more often younger (median age 56 years) compared with influenza B or A(H3N2) (median age 64 and 72 years respectively, both P < 0.001) (Figure 2). Conclusion Influenza A(H1N1)pdm09 is associated with many more severe laboratory-confirmed cases; this is likely due to a more typical clinical presentation and younger patient age, leading to more laboratory testing. In contrast A(H3N2) affects older people and presents more atypically, which is less likely to lead to laboratory testing and confirmation. Focusing on laboratory-confirmed cases, although useful in itself, may provide severely biased estimates of the burden of influenza mortality and morbidity. Disclosures All authors: No reported disclosures.

Background In 2016 and 2017, 535,000 refugees/migrants crossed the Mediterranean Sea to reach Europe, with 203,000 arriving in Greece. To address enhanced epidemiological surveillance needs, in May 2016 Greece established an ad hoc surveillance system in points of care for refugees/migrants in hosting centers, complementary to routine surveillance. Methods Data on number of cases per age group for 14 syndromes of public health (PH) interest were collected daily from primary healthcare units of refugee/migrant hosting centers in the country, along with the number of consultations from any cause. Additional information enabling case-finding was collected for syndromes representing diseases that require PH measures at an individual level. Observed daily proportional morbidity (PM) was compared with expected PM using a quasi-Poisson regression model. PM ≥2 standard deviations from expected was defined as a “warning signal.” “Warning signals” appearing for ≥2 consecutive days were considered “alert signals.” Signals were evaluated daily and public health measures were implemented as necessary. Results The number of centers participating in the system ranged between 27 and 51. Mean weekly reporting rate reached 96%. From 16 May 2016 to 31 December 2017, 500,166 consultations from any cause were reported, with 28,300 cases of the syndromes under surveillance (5.6%). Syndromes with the higher PM were respiratory infections with fever (3.3%), gastroenteritis (1.3%), suspected scabies (0.6%), and rash with fever (0.3%, of whom 95.1% were varicella cases, with no measles or rubella identified). Two hundred fifteen cases of suspected tuberculosis were referred to hospitals for further diagnostic testing and treatment. Of 92 cases of jaundice with acute onset, 85% were verified as hepatitis A, triggering interventions such as vaccination. None of the produced signals corresponded to a major PH incident, all being of low severity and duration. Conclusion Infections represented a small proportion of refugees’ health problems. Syndromic surveillance in hosting centers guided PH action and confirmed no major PH event. Disclosures All authors: No reported disclosures.

Background We examined risk factors for influenza related death in all severe cases in Greece during the 2014-15 influenza season. Methods A national severe influenza surveillance network includes reporting to the Hellenic Ctr for Disease Control & Prevention (HCDCP) of all laboratory-confirmed influenza cases admitted to ICU &/or in-hospital deaths of influenza patients. Each case is followed up daily, with a structured questionnaire until discharged. We evaluated risk factors for death using univariate & multivariate analyses. Results 248 cases were recorded (median age 67 yrs, 54.7% male, 87.1% high risk pts with comorbidities). Influenza A was noted in 56.5%. 111 deaths were recorded (median age 57 yrs, 55% male). In 64 (57.7%) deaths, influenza A was diagnosed [A(H1N1): 36%, A(H3N2): 64%]. 99/111 (89.2%) deaths occurred in pts with immunization indications; 15 were immunized. ARDS (OR 3.43 (95%CI 1.27 9.3) p=0.006), renal insufficiency (OR 3.9; 95% CI 1.4-11.3, p = 0.01), occurrence of secondary bacterial infection & septic shock (OR 4.4; 95% CI 1.2-16.4, p=0.015) were risk factors for death. Influenza A cases did not differ from B regarding age, comorbidities, rates of intubation or death. Within 31 vaccinated cases influenza A was more prevalent to B (77.4% vs. 22.6%, p=0.06). Conclusion ARDS, renal insufficiency & the presence of secondary infections or septic shock were risk factors for death in a mixed A & B season. Influenza B did not differ from A in the risk for complications & death. Vaccine failures were noted especially among serious influenza A cases, consistent with the reported drift of A(H3N2). Sotirios Tsiodras, MD, DSc University of Athens Med. Sch. Athens, Greece 1 Rimini Street 12462 Athens, Greece Tel: 0030 210 58 31 641 Tel (2nd): 0030 693 26 65 820 FAX: 0030 210 53 26 446 e-mail: tsiodras@med.uoa.gr

In this manuscript, we summarise the experience of Greece during the post-pandemic influenza season 2010/11 from 04 October 2010 to 22 May 2011. The spread of the disease and its impact were monitored using multiple surveillance systems, such as sentinel surveillance, virological surveillance and all-cause mortality surveillance. We also focus on the characteristics of laboratory-confirmed severe influenza cases who required admission to an intensive care unit (ICU) (n=368), and/or with a fatal outcome (n=180). The influenza-like illness rate reported from sentinel surveillance started rising in early January 2011 and peaked between 31 January and 6 February 2011. The total number of ICU admissions was higher in the post-pandemic influenza season than during the pandemic period causing a lot of pressure on ICUs. The overall population mortality rate due to influenza A(H1N1)2009 was higher than during the pandemic period (15.9 vs 13.2 fatal cases per million, p=0.087). Our data suggest that the severity of clinical illness in the first post-pandemic influenza season was comparable or even higher than during the pandemic.