RSV Severe Infection Risk Stratification in a French 5-Year Birth Cohort Using Machine-learning.

BACKGROUND: Respiratory syncytial virus (RSV) poses a substantial threat to infants, often leading to challenges in hospital capacity. With recent pharmaceutical developments to be used during the prenatal and perinatal periods aimed at decreasing the RSV burden, there is a pressing need to identify infants at risk of severe disease. We aimed to stratify the risk of developing a clinically severe RSV infection in infants under 1 year of age. METHODS: This retrospective observational study was conducted at the Hospices Civils de Lyon, France, involving infants born between 2014 and 2018. This study focused on infants hospitalized with severe and very severe acute lower respiratory tract infections associated with RSV (SARI-WI group). Data collection included perinatal information and clinical data, with machine-learning algorithms used to discriminate SARI-WI cases from nonhospitalized infants. RESULTS: Of 42,069 infants, 555 developed SARI-WI. Infants born in November were very likely (>80%) predicted SARI-WI. Infants born in October were very likely predicted SARI-WI except for births at term by vaginal delivery and without siblings. Infants were very unlikely (<10%) predicted SARI-WI when all the following conditions were met: born in other months, at term, by vaginal delivery and without siblings. Other infants were possibly (10-30%) or probably (30-80%) predicted SARI-WI. CONCLUSIONS: Although RSV preventive measures are vital for all infants, and specific recommendations exist for patients with high-risk comorbidities, in situations where prioritization becomes necessary, infants born just before or within the early weeks of the epidemic should be considered as a risk group.

Change in Age profile of Respiratory Syncytial Virus disease over the course of annual epidemics: a multi-national study.

OBJECTIVES: We aimed to study whether the percentwise age distribution of RSV cases changes over time during annual epidemics. METHODS: We used surveillance data (2008-2019) from the Netherlands, Lyon (France), Portugal, Singapore, Ecuador, South Africa, and New Zealand. In each country, every season was divided into "epidemic quarters", i.e. periods corresponding to each quartile of RSV cases. Multinomial logistic regression models were fitted to evaluate whether the likelihood of RSV cases being aged <1 or ≥5 years (vs. 1 to <5) changed over time within a season. RESULTS: In all countries, RSV cases were significantly more likely to be aged <1 year in the 4th vs. 1st epidemic quarter; the relative risk ratio [RRR] ranged between 1.35 and 2.56. Likewise, RSV cases were significantly more likely to be aged ≥5 years in the 4th vs. 1st epidemic quarter (except in Singapore); the RRR ranged from 1.75 to 6.70. The results did not change when stratifying by level of care or moving the lower cut-off to 6 months. CONCLUSIONS: The age profile of RSV cases shifts within a season, with infants and adolescents, adults, and the elderly constituting a higher proportion of cases in the later phases of annual epidemics. These findings may have implications for RSV prevention policies with newly approved vaccines.

Comparison of mortality and outcomes of four respiratory viruses in the intensive care unit: a multicenter retrospective study.

This retrospective study aimed to compare the mortality and burden of respiratory syncytial virus (RSV group), SARS-CoV-2 (COVID-19 group), non-H1N1 (Seasonal influenza group) and H1N1 influenza (H1N1 group) in adult patients admitted to intensive care unit (ICU) with respiratory failure. A total of 807 patients were included. Mortality was compared between the four following groups: RSV, COVID-19, seasonal influenza, and H1N1 groups. Patients in the RSV group had significantly more comorbidities than the other patients. At admission, patients in the COVID-19 group were significantly less severe than the others according to the simplified acute physiology score-2 (SAPS-II) and sepsis-related organ failure assessment (SOFA) scores. Using competing risk regression, COVID-19 (sHR = 1.61; 95% CI 1.10; 2.36) and H1N1 (sHR = 1.87; 95% CI 1.20; 2.93) were associated with a statistically significant higher mortality while seasonal influenza was not (sHR = 0.93; 95% CI 0.65; 1.31), when compared to RSV. Despite occurring in more severe patients, RSV and seasonal influenza group appear to be associated with a more favorable outcome than COVID-19 and H1N1 groups.

Impact of the H274Y Substitution on N1, N4, N5, and N8 Neuraminidase Enzymatic Properties and Expression in Reverse Genetic Influenza A Viruses.

The H274Y substitution (N2 numbering) in neuraminidase (NA) N1 confers oseltamivir resistance to A(H1N1) influenza viruses. This resistance has been associated with reduced N1 expression using transfected cells, but the effect of this substitution on the enzymatic properties and on the expression of other group-1-NA subtypes is unknown. The aim of the present study was to evaluate the antiviral resistance, enzymatic properties, and expression of wild-type (WT) and H274Y-substituted NA for each group-1-NA. To this end, viruses with WT or H274Y-substituted NA (N1pdm09 or avian N4, N5 or N8) were generated by reverse genetics, and for each reverse-genetic virus, antiviral susceptibility, NA affinity (Km), and maximum velocity (Vm) were measured. The enzymatic properties were coupled with NA quantification on concentrated reverse genetic viruses using mass spectrometry. The H274Y-NA substitution resulted in highly reduced inhibition by oseltamivir and normal inhibition by zanamivir and laninamivir. This resistance was associated with a reduced affinity for MUNANA substrate and a conserved Vm in all viruses. NA quantification was not significantly different between viruses carrying WT or H274Y-N1, N4 or N8, but was lower for viruses carrying H274Y-N5 compared to those carrying a WT-N5. In conclusion, the H274Y-NA substitution of different group-1-NAs systematically reduced their affinity for MUNANA substrate without a significant impact on NA Vm. The impact of the H274Y-NA substitution on viral NA expression was different according to the studied NA.

Contribution of Infant Rhinovirus Bronchiolitis to Hospital Bed and Ventilation Use.

This cohort study compares the use of hospital resources related to human rhinovirus and respiratory syncytial virus infections among infants during 3 consecutive seasons before nirsevimab implementation.

Determining the timing of respiratory syncytial virus (RSV) epidemics: a systematic review, 2016 to 2021; method categorisation and identification of influencing factors.

BackgroundThere is currently no standardised approach to estimate respiratory syncytial virus (RSV) epidemics' timing (or seasonality), a critical information for their effective prevention and control.AimWe aimed to provide an overview of methods to define RSV seasonality and identify factors supporting method choice or interpretation/comparison of seasonal estimates.MethodsWe systematically searched PubMed and Embase (2016-2021) for studies using quantitative approaches to determine the start and end of RSV epidemics. Studies' features (data-collection purpose, location, regional/(sub)national scope), methods, and assessment characteristics (case definitions, sampled population's age, in/outpatient status, setting, diagnostics) were extracted. Methods were categorised by their need of a denominator (i.e. numbers of specimens tested) and their retrospective vs real-time application. Factors worth considering when choosing methods and assessing seasonal estimates were sought by analysing studies.ResultsWe included 32 articles presenting 49 seasonality estimates (18 thereof through the 10% positivity threshold method). Methods were classified into eight categories, two requiring a denominator (1 retrospective; 1 real-time) and six not (3 retrospective; 3 real-time). A wide range of assessment characteristics was observed. Several studies showed that seasonality estimates varied when methods differed, or data with dissimilar assessment characteristics were employed. Five factors (comprising study purpose, application time, assessment characteristics, healthcare system and policies, and context) were identified that could support method choice and result interpretation.ConclusionMethods and assessment characteristics used to define RSV seasonality are heterogeneous. Our categorisation of methods and proposed framework of factors may assist in choosing RSV seasonality methods and interpretating results.

Year-Round Respiratory Syncytial Virus Transmission in The Netherlands Following the COVID-19 Pandemic: A Prospective Nationwide Observational and Modeling Study.

We initiated a nationwide prospective study to monitor respiratory syncytial virus (RSV)-related pediatric hospitalizations in 46 hospitals throughout the Netherlands between May 2021 and August 2022. We showed year-round RSV transmission in the Netherlands after an initial 2021 summer outbreak. The pattern was unprecedented and distinct from neighboring countries. We extended a dynamic simulation model to evaluate the impact of waning immunity on pediatric RSV hospitalizations in the Netherlands using 4 different scenarios. Our results suggest that the observed continuous RSV transmission pattern could be associated with waning immunity due to the period of very low RSV circulation during the COVID-19 pandemic.

The increasing age of respiratory syncytial virus-related hospitalisation during COVID-19 pandemic in Lyon was associated with reduced hospitalisation costs.

BACKGROUND: Preventive measures applied during the COVID-19 pandemic have modified the age distribution, the clinical severity and the incidence of Respiratory Syncytial Virus (RSV) hospitalisations during the 2020/21 RSV season. The aim of the present study was to estimate the impact of these aspects on RSV-associated hospitalisations (RSVH) costs stratified by age group between pre-COVID-19 seasons and 2020/21 RSV season. METHODS: We compared the incidence, the median costs, and total RSVH costs from the national health insurance perspective in children < 24 months of age during the COVID-19 period (2020/21 RSV season) with a pre-COVID-19 period (2014/17 RSV seasons). Children were born and hospitalised in the Lyon metropolitan area. RSVH costs were extracted from the French medical information system (Programme de Médicalisation des Systémes d'Information). RESULTS: The RSVH-incidence rate per 1000 infants aged < 3 months decreased significantly from 4.6 (95 % CI [4.1; 5.2]) to 3.1 (95 % CI [2.4; 4.0]), and increased in older infants and children up to 24 months of age during the 2020/21 RSV season. Overall, RSVH costs for RSVH cases aged below 2 years old decreased by €201,770 (31 %) during 2020/21 RSV season compared to the mean pre-COVID-19 costs. CONCLUSIONS: The sharp reduction in costs of RSVH in infants aged < 3 months outweighed the modest increase in costs observed in the 3-24 months age group. Therefore, conferring a temporal protection through passive immunisation to infants aged < 3 months should have a major impact on RSVH costs even if it results in an increase of RSVH in older children infected later in life. Nevertheless, stakeholders should be aware of this potential increase of RSVH in older age groups presenting with a wider range of disease to avoid any bias in estimating the cost-effectiveness of passive immunisation strategies.

The impact of the SARS-CoV-2 pandemic on global influenza surveillance: Insights from 18 National Influenza Centers based on a survey conducted between November 2021 and March 2022.

Background: National Influenza Centers (NICs) have played a crucial role in the surveillance of SARS-CoV-2. The FluCov project, covering 22 countries, was initiated to monitor the impact of the SARS-CoV-2 pandemic on influenza activity. Methods: This project consisted of an epidemiological bulletin and NIC survey. The survey, designed to assess the impact of the pandemic on the influenza surveillance system, was shared with 36 NICs located across 22 countries. NICs were invited to reply between November 2021 and March 2022. Results: We received 18 responses from NICs in 14 countries. Most NICs (76%) indicated that the number of samples tested for influenza decreased. Yet, many NICs (60%) were able to increase their laboratory testing capacity and the "robustness" (e.g., number of sentinel sites) (59%) of their surveillance systems. In addition, sample sources (e.g., hospital or outpatient setting) shifted. All NICs reported a higher burden of work following the onset of the pandemic, with some NICs hiring additional staff or partial outsourcing to other institutes or departments. Many NICs anticipate the future integration of SARS-CoV-2 surveillance into the existing respiratory surveillance system. Discussion: The survey shows the profound impact of SARS-CoV-2 on national influenza surveillance in the first 27 months of the pandemic. Surveillance activities were temporarily disrupted, whilst priority was given to SARS-CoV-2. However, most NICs have shown rapid adaptive capacity underlining the importance of strong national influenza surveillance systems. These developments have the potential to benefit global respiratory surveillance in the years to come; however, questions about sustainability remain.

Application of a forecasting model to mitigate the consequences of unexpected RSV surge: Experience from the post-COVID-19 2021/22 winter season in a major metropolitan centre, Lyon, France.

Background: The emergence of COVID-19 triggered the massive implementation of non-pharmaceutical interventions (NPI) which impacted the circulation of respiratory syncytial virus (RSV) during the 2020/2021 season. Methods: A time-series susceptible-infected-recovered (TSIR) model was used early September 2021 to forecast the implications of this disruption on the future 2021/2022 RSV epidemic in Lyon urban population. Results: When compared to observed hospital-confirmed cases, the model successfully captured the early start, peak timing, and end of the 2021/2022 RSV epidemic. These simulations, added to other streams of surveillance data, shared and discussed among the local field experts were of great value to mitigate the consequences of this atypical RSV outbreak on our hospital paediatric department. Conclusions: TSIR model, fitted to local hospital data covering large urban areas, can produce plausible post-COVID-19 RSV simulations. Collaborations between modellers and hospital management (who are both model users and data providers) should be encouraged in order to validate the use of dynamical models to timely allocate hospital resources to the future RSV epidemics.

Level of maternal antibodies against respiratory syncytial virus (RSV) nucleoprotein at birth and risk of RSV very severe lower respiratory tract infection.

BACKGROUND: The nucleoprotein (N protein) of respiratory syncytial virus (RSV) is a candidate antigen for new RSV vaccine development. The aim of the present study was to investigate the association between maternal antibody titers against the RSV N protein at birth and the newborns' risk of developing very severe lower respiratory tract infection (VS-LRTI). METHODS: In this single-center prospective cohort study, 578 infants born during the RSV epidemic season in France were included. Among these, 36 were hospitalized for RSV VS-LRTI. A generalized linear model was used to test the occurrence of a VS-LRTI in function of sex, mode of delivery, parity of the mother, type of pregnancy, date of birth in relation to the peak of the epidemic, and antibody titer against N protein. RESULTS: All cord blood samples had detectable antibodies against N protein. The mean titers were significantly lower in newborns with risk factors for RSV severe LRTI (preterm infants, birth before the peak epidemic, multiparous mother). There was no association between antibody titer against the N protein and a protection against VS-LRTI. CONCLUSIONS: Further studies are needed to support the hypothesis that transfer of maternal antibodies against the RSV N protein can provide a significant immune protection early in infancy and that N protein candidate vaccine may be a suitable target for maternal vaccine.

[RSV and associated diseases]. / Le VRS et les maladies associées.

Similarly to many respiratory viruses, respiratory syncytial virus (RSV) is surprising in its ability to reinfect children and adults who have already been immunized. It is not so much in the evolution of its genome that we must look for the cause, but more probably in the structure/function of its viral proteins, which are capable of interfering with the immune response and memory. After an incubation of three to eight days, RSV infection most often results in nasopharyngitis with little or no fever. RSV infection of the respiratory epithelium is characterized by marked mucus production, desquamation of infected respiratory cells and persistent impairment of mucociliary transport. The extension of the infection to the lower respiratory tract therefore contributes to the formation of mucous plugs obstructing the lumen of the bronchioles. This is the cause of the clinical most commonly associated with RSV infection: bronchiolitis in newborns and infants which is a frequent reason for hospitalization due to secondary respiratory and digestive complications. The recent data from the literature, however, indicate that by far the most frequent complication is a community infection: acute otitis media. RSV infections are therefore a very common reason for the prescription of antibiotics.

Comme de nombreux virus respiratoires, le virus respiratoire syncytial (VRS) nous étonne par sa capacité à réinfecter les enfants et adultes déjà immunisés. Ce n'est pas tant du côté de l'évolution de son génome qu'il faut en chercher la cause, mais plus probablement dans la structure/ fonction de ses protéines virales capables d'interférer avec la réponse et la mémoire immunitaire. Après une incubation de trois à huit jours, l'infection à VRS se traduit le plus souvent par une rhinopharyngite peu ou pas fébrile. L'infection de l'épithélium respiratoire par le VRS se caractérise par une production marquée de mucus, une desquamation des cellules respiratoires infectées et une altération persistante du transport mucociliaire. L'extension de l'infection vers l'appareil respiratoire bas contribue ainsi à la formation de bouchons muqueux obstruant la lumière des bronchioles. Elle est à l'origine du tableau clinique le plus communément associé à l'infection à VRS : la bronchiolite des nouveau-nés et des nourrissons qui est un motif fréquent d'hospitalisation du fait des complications respiratoires et digestives secondaires. Pourtant les données récentes de la littérature indiquent que la complication de loin la plus fréquente est une infection communautaire : l'otite moyenne aiguë. Les infections à VRS sont donc une cause très fréquente de prescription d'antibiotiques.

Risk Factors of Very Severe RSV Infections in a Multicenter Cohort of Very Preterm and Extreme Preterm Babies Receiving or Not Palivizumab.

Introduction: Preterm infants are at risk of lower respiratory tract infections (LRTI), including Respiratory Syncytial Virus (RSV) associated bronchiolitis, for which palivizumab prophylaxis can be proposed. Our aim was to determine risk factors of very severe RSV disease in children born before 34 weeks of gestation. Methods: Among 2,101 infants born before 34 weeks of gestation in 3 maternity wards between 2012 and 2017, the laboratory confirmed RSV-infected patients requiring hospitalization before 12 months of corrected age were retrospectively included. We collected data about the neonatal period, the palivizumab prophylaxis and the hospitalization for a RSV-related LRTI. LRTI was considered as very severe (VS-LRTI) when patients required invasive or non-invasive positive pressure ventilation. Results: Among 86 included patients, 31 met the criteria of VS-LRTI. The VS-LRTI patients had a higher birth gestational age and weight but less heart disease and bronchopulmonary dysplasia. They received palivizumab prophylaxis less frequently than the other patients but the difference was not significant. At the onset of infection, VS-LRTI patients had a younger corrected age for prematurity and presented more frequently with apnea, bradycardia, life-threatening event, hemodynamic failure, hypercapnia. Using logistic regression, the main factor associated with VS-LRTI was a younger corrected age for prematurity at the onset of infection [Odd ratio for each month of corrected age = 0.77 (0.62; 0.93), p = 0.012]. Conclusion: Infants at the highest risk of VS-LRTI were infants with a younger corrected age for prematurity. Therefore, a better targeting of infants requiring palivizumab prophylaxis and early interventions at hospital discharge could limit VS-LRTI in these infants.

Identifying the Target Population for Primary Respiratory Syncytial Virus Two-Step Prevention in Infants: Normative Outcome of Hospitalisation Assessment for Newborns (NOHAN).

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of acute respiratory infection- related hospitalisations in infants (RSVh). Most of these infants are younger than 6 months old with no known risk factors. An efficient RSVh prevention program should address both mothers and infants, relying on Non-Pharmaceutical (NPI) and Pharmaceutical Interventions (PI). This study aimed at identifying the target population for these two interventions. METHODS: Laboratory-confirmed RSV-infected infants hospitalised during the first 6 months of life were enrolled from the Hospices Civils de Lyon birth cohort (2014 to 2018). Clinical variables related to pregnancy and birth (sex, month of birth, birth weight, gestational age, parity) were used for descriptive epidemiology, multivariate logistic regression, and predictive score development. RESULTS: Overall, 616 cases of RSVh in 45,648 infants were identified. Being born before the epidemic season, prematurity, and multiparity were independent predictors of RSVh. Infants born in January or June to August with prematurity and multiparity, and those born in September or December with only one other risk factor (prematurity or multiparity) were identified as moderate-risk, identifying the mothers as candidates for a first-level NPI prevention program. Infants born in September or December with prematurity and multiparity, and those born in October or November were identified as high-risk, identifying the mothers and infants as candidates for a second-level (NPI and PI) intervention. CONCLUSIONS: It is possible to determine predictors of RSVh at birth, allowing early enrollment of the target population in a two-level RSV prevention intervention.

Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. METHODS: In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0-60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400). FINDINGS: In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4-44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9-4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100-49 100), and 101 400 RSV-attributable overall deaths (84 500-125 200) in children aged 0-60 months. In infants aged 0-6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6-9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0-2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800-28 100), and 45 700 RSV-attributable overall deaths (38 400-55 900). 2·0% of deaths in children aged 0-60 months (UR 1·6-2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0-4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs). INTERPRETATION: RSV contributes substantially to morbidity and mortality burden globally in children aged 0-60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0-60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).

T cell response against SARS-CoV-2 persists after one year in patients surviving severe COVID-19.

BACKGROUND: In critically ill COVID-19 patients, the initial response to SARS-CoV-2 infection is characterized by major immune dysfunctions. The capacity of these severe patients to mount a robust and persistent SARS-CoV-2 specific T cell response despite the presence of severe immune alterations during the ICU stay is unknown. METHODS: Critically ill COVID-19 patients were sampled five times during the ICU stay and 9 and 13 months afterwards. Immune monitoring included counts of lymphocyte subpopulations, HLA-DR expression on monocytes, plasma IL-6 and IL-10 concentrations, anti-SARS-CoV-2 IgG levels and T cell proliferation in response to three SARS-CoV-2 antigens. FINDINGS: Despite the presence of major lymphopenia and decreased monocyte HLA-DR expression during the ICU stay, convalescent critically ill COVID-19 patients consistently generated adaptive and humoral immune responses against SARS-CoV-2 maintained for more than one year after hospital discharge. Patients with long hospital stays presented with stronger anti-SARS-CoV-2 specific T cell response but no difference in anti-SARS-CoV2 IgG levels. INTERPRETATION: Convalescent critically ill COVID-19 patients consistently generated a memory immune response against SARS-CoV-2 maintained for more than one year after hospital discharge. In recovered individuals, the intensity of SARS-CoV-2 specific T cell response was dependent on length of hospital stay. FUNDING: This observational study was supported by funds from the Hospices Civils de Lyon, Fondation HCL, Claude Bernard Lyon 1 University and Région Auvergne Rhône-Alpes and by partial funding by REACTing (Research and ACTion targeting emerging infectious diseases) INSERM, France and a donation from Fondation AnBer (http://fondationanber.fr/).

A retrospective comparison of COVID-19 and seasonal influenza mortality and outcomes in the ICUs of a French university hospital.

BACKGROUND: SARS-Cov-2 (COVID-19) has become a major worldwide health concern since its appearance in China at the end of 2019. OBJECTIVE: To evaluate the intrinsic mortality and burden of COVID-19 and seasonal influenza pneumonia in ICUs in the city of Lyon, France. DESIGN: A retrospective study. SETTING: Six ICUs in a single institution in Lyon, France. PATIENTS: Consecutive patients admitted to an ICU with SARS-CoV-2 pneumonia from 27 February to 4 April 2020 (COVID-19 group) and seasonal influenza pneumonia from 1 November 2015 to 30 April 2019 (influenza group). A total of 350 patients were included in the COVID-19 group (18 refused to consent) and 325 in the influenza group (one refused to consent). Diagnosis was confirmed by RT-PCR. Follow-up was completed on 1 April 2021. MAIN OUTCOMES AND MEASURES: Differences in 90-day adjusted-mortality between the COVID-19 and influenza groups were evaluated using a multivariable Cox proportional hazards model. RESULTS: COVID-19 patients were younger, mostly men and had a higher median BMI, and comorbidities, including immunosuppressive condition or respiratory history were less frequent. In univariate analysis, no significant differences were observed between the two groups regarding in-ICU mortality, 30, 60 and 90-day mortality. After Cox modelling adjusted on age, sex, BMI, cancer, sepsis-related organ failure assessment (SOFA) score, simplified acute physiology score SAPS II score, chronic obstructive pulmonary disease and myocardial infarction, the probability of death associated with COVID-19 was significantly higher in comparison to seasonal influenza [hazard ratio 1.57, 95% CI (1.14 to 2.17); P = 0.006]. The clinical course and morbidity profile of both groups was markedly different; COVID-19 patients had less severe illness at admission (SAPS II score, 37 [28 to 48] vs. 48 [39 to 61], P < 0.001 and SOFA score, 4 [2 to 8] vs. 8 [5 to 11], P < 0.001), but the disease was more severe considering ICU length of stay, duration of mechanical ventilation, PEEP level and prone positioning requirement. CONCLUSION: After ICU admission, COVID-19 was associated with an increased risk of death compared with seasonal influenza. Patient characteristics, clinical course and morbidity profile of these diseases is markedly different.

The pitfalls of inferring virus-virus interactions from co-detection prevalence data: application to influenza and SARS-CoV-2.

There is growing experimental evidence that many respiratory viruses-including influenza and SARS-CoV-2-can interact, such that their epidemiological dynamics may not be independent. To assess these interactions, standard statistical tests of independence suggest that the prevalence ratio-defined as the ratio of co-infection prevalence to the product of single-infection prevalences-should equal unity for non-interacting pathogens. As a result, earlier epidemiological studies aimed to estimate the prevalence ratio from co-detection prevalence data, under the assumption that deviations from unity implied interaction. To examine the validity of this assumption, we designed a simulation study that built on a broadly applicable epidemiological model of co-circulation of two emerging or seasonal respiratory viruses. By focusing on the pair influenza-SARS-CoV-2, we first demonstrate that the prevalence ratio systematically underestimates the strength of interaction, and can even misclassify antagonistic or synergistic interactions that persist after clearance of infection. In a global sensitivity analysis, we further identify properties of viral infection-such as a high reproduction number or a short infectious period-that blur the interaction inferred from the prevalence ratio. Altogether, our results suggest that ecological or epidemiological studies based on co-detection prevalence data provide a poor guide to assess interactions among respiratory viruses.

Estimating the impact of influenza on the epidemiological dynamics of SARS-CoV-2.

As in past pandemics, co-circulating pathogens may play a role in the epidemiology of coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In particular, experimental evidence indicates that influenza infection can up-regulate the expression of ACE2-the receptor of SARS-CoV-2 in human cells-and facilitate SARS-CoV-2 infection. Here we hypothesized that influenza impacted the epidemiology of SARS-CoV-2 during the early 2020 epidemic of COVID-19 in Europe. To test this hypothesis, we developed a population-based model of SARS-CoV-2 transmission and of COVID-19 mortality, which simultaneously incorporated the impact of non-pharmaceutical control measures and of influenza on the epidemiological dynamics of SARS-CoV-2. Using statistical inference methods based on iterated filtering, we confronted this model with mortality incidence data in four European countries (Belgium, Italy, Norway, and Spain) to systematically test a range of assumptions about the impact of influenza. We found consistent evidence for a 1.8-3.4-fold (uncertainty range across countries: 1.1 to 5.0) average population-level increase in SARS-CoV-2 transmission associated with influenza during the period of co-circulation. These estimates remained robust to a variety of alternative assumptions regarding the epidemiological traits of SARS-CoV-2 and the modeled impact of control measures. Although further confirmatory evidence is required, our results suggest that influenza could facilitate the spread and hamper effective control of SARS-CoV-2. More generally, they highlight the possible role of co-circulating pathogens in the epidemiology of COVID-19.