Burden of primary influenza and respiratory syncytial virus pneumonia in hospitalised adults: insights from a 2-year multi-centre cohort study (2017-2018).

BACKGROUND: Viral community-acquired pneumonia (CAP) is a potentially serious illness, particularly in adult patients with underlying chronic conditions. In addition to the most recent SARS-CoV-2, influenza, and respiratory syncytial virus (RSV) are considered the most relevant causes of viral CAP. AIMS: To describe the clinical features of hospitalised adults admitted for influenza-A/B and RSV pneumonia and analyse, according to aetiology, factors associated with non-invasive ventilation (NIV) failure and in-hospital death (IHD). METHODS: This was a retrospective and multi-centre study of all adults who were admitted for laboratory-confirmed influenza-A/B or RSV pneumonia, during two consecutive winter seasons (October-April 2017-2018 and 2018-2019) in three tertiary hospitals in Portugal, Italy and Cyprus. RESULTS: A total of 356 adults were included in the study. Influenza-A, influenza-B and RSV were deemed to cause pneumonia in 197 (55.3%), 85 (23.9%) and 74 (20.8%) patients, respectively. Patients with both obstructive sleep apnoea or obesity hypoventilation syndrome and influenza-A virus pneumonia showed a higher risk for NIV failure (odds ratio (OR) 4.66; 95% confidence interval (CI) 1.42-15.30). Patients submitted to NIV showed a higher risk for IHD, regardless of comorbidities (influenza-A OR 3.00; 95% CI 1.35-6.65, influenza-B OR 4.52; 95% CI 1.13-18.01, RSV OR 5.61; 95% CI 1.26-24.93). CONCLUSION: The increased knowledge of influenza-A/B and RSV pneumonia burden may contribute to a better management of patients with viral CAP.

Correlation of Lymphocyte Subpopulations, Clinical Features and Inflammatory Markers during Severe COVID-19 Onset.

BACKGROUND: Dysregulation of the immune response in the course of COVID-19 has been implicated in critical outcomes. Lymphopenia is evident in severe cases and has been associated with worse outcomes since the early phases of the pandemic. In addition, cytokine storm has been associated with excessive lung injury and concomitant respiratory failure. However, it has also been hypothesized that specific lymphocyte subpopulations (CD4 and CD8 T cells, B cells, and NK cells) may serve as prognostic markers for disease severity. The aim of this study was to investigate possible associations of lymphocyte subpopulations alterations with markers of disease severity and outcomes in patients hospitalized with COVID-19. MATERIALS/METHODS: A total of 42 adult hospitalized patients were included in this study, from June to July 2021. Flow-cytometry was used to calculate specific lymphocyte subpopulations on day 1 (admission) and on day 5 of hospitalization (CD45, CD3, CD3CD8, CD3CD4, CD3CD4CD8, CD19, CD16CD56, CD34RA, CD45RO). Markers of disease severity and outcomes included: burden of disease on CT (% of affected lung parenchyma injury), C-reactive protein and interleukin-6 levels. PO2/FiO2 ratio and differences in lymphocytes subsets between two timepoints were also calculated. Logistic and linear regressions were used for the analyses. All analyses were performed using Stata (version 13.1; Stata Corp, College Station, TX, USA). RESULTS: Higher levels of CD16CD56 cells (Natural Killer cells) were associated with higher risk of lung injury (>50% of lung parenchyma). An increase in CD3CD4 and CD4RO cell count difference between day 5 and day 1 resulted in a decrease of CRP difference between these timepoints. On the other hand, CD45RARO difference was associated with an increase in the difference of CRP levels between the two timepoints. No other significant differences were found in the rest of the lymphocyte subpopulations. CONCLUSIONS: Despite a low patient number, this study showed that alterations in lymphocyte subpopulations are associated with COVID-19 severity markers. It was observed that an increase in lymphocytes (CD4 and transiently CD45RARO) resulted in lower CRP levels, perhaps leading to COVID-19 recovery and immune response homeostasis. However, these findings need further evaluation in larger scale trials.

Multicentre Surveillance of Candida Species from Blood Cultures during the SARS-CoV-2 Pandemic in Southern Europe (CANCoVEU Project).

Introduction: Surveillance of Candida species isolates from blood cultures (BCs) in Europe is considered fragmented, unable to allow the definition of targets of antifungal stewardship recommendations especially during the SARS-CoV-2 pandemic. Methods: We performed a multicentric retrospective study including all consecutive BC Candida isolates from six Southern European tertiary hospitals (1st January 2020 to 31st December 2021). Etiology, antifungal susceptibility patterns, and clinical setting were analyzed and compared. Results: C. albicans was the dominant species (45.1%), while C. auris was undetected. Candida species positive BC events increased significantly in COVID-19 ICUs in 2021 but decreased in other ICUs. Resistance to azole increased significantly and remained very high in C. albicans (fluconazole from 0.7% to 4.5%, p = 0.03) and C. parapsilosis complex (fluconazole up to 24.5% and voriconazole up to 8.9%), respectively. Resistance to caspofungin was remarkable in C. tropicalis (10%) and C. krusei (20%), while resistance to at least one echinocandin increased in 2021, especially in C. parapsilosis complex (from 0.8% to 5.1%, p = 0.05). Although no significant differences were observed over the study period, fluconazole and echinocandin resistance increased in COVID-19 ICUs by up to 14% and 5.8%, respectively, but remained undetected in non-intensive COVID-19 wards. Conclusions: Antifungal stewardship activities aimed at monitoring resistance to echinocandin in C. tropicalis and C. krusei, and against the spread of fluconazole resistant C. parapsilosis complex isolates are highly desirable. In COVID-19 patients, antifungal resistance was mostly present when the illness had a critical course.

Efficacy and safety of early soluble urokinase plasminogen receptor plasma-guided anakinra treatment of COVID-19 pneumonia: A subgroup analysis of the SAVE-MORE randomised trial.

Background: The SAVE-MORE trial demonstrated that anakinra treatment in COVID-19 pneumonia with plasma soluble urokinase plasminogen activator (suPAR) levels of 6 ng/mL or more was associated with 0.36 odds for a worse outcome compared to placebo when expressed by the WHO-Clinical Progression Scale (CPS) at day 28. Herein, we report the results of subgroup analyses and long-term outcomes. Methods: This prospective, double-blind, randomised clinical trial, recruited patients with a confirmed SARS-CoV-2 infection, in need of hospitalisation, lower respiratory tract infection and plasma suPAR ≥6 ng/mL from 37 academic and community hospitals in Greece and Italy. Patients were 1:2 randomised to subcutaneous treatment with placebo or anakinra (100 mg) once daily for 10 days. Pre-defined subgroups of Charlson's comorbidity index (CCI), sex, age, level of suPAR, and time from symptom onset were analysed for the primary endpoint (overall comparison of distribution of frequencies of the scores from the WHO-CPS between treatments on day 28), by multivariable ordinal regression analysis in the intention to treat (ITT) population. This trial is registered with the EU Clinical Trials Register (2020-005828-11) and ClinicalTrials.gov (NCT04680949). Findings: Patients were enrolled between 23 December 2020 and 31 March 2021; 189 patients in the placebo arm and 405 patients in the anakinra arm were the ITT population. Multivariable analysis showed that anakinra treatment was accompanied by significantly lower odds for worse outcome compared to placebo at day 28 for all studied subgroups (CCI ≥ 2, OR: 0.34, 95% confidence intervals [CI] 0.22-0.50; CCI < 2, OR: 0.38, 95% CI 0.21-0.68; suPAR > 9 ng/mL, OR: 0.35, 95% CI 0.19-0.66; suPAR 6-9 ng/mL, OR: 0.35, 95% CI 0.24-0.52; patients ≥65 years, OR: 0.41, 95% CI 0.25-0.66; and patients <65 years, OR: 0.29, 95% CI 0.19-0.45). The benefit was uniform, irrespective of the time from start of symptoms until the start of the study drug. At days 60 and 90, anakinra treatment had odds of 0.40 (95% CI 0.28-0.57) and 0.46 (95% CI 0.32-0.67) respectively, for a worse outcome compared to placebo. The costs of general ward stay, ICU stay, and drugs were lower with anakinra treatment. Interpretation: Anakinra represents an important therapeutic tool in the management of COVID-19 that may be administered in all subgroups of patients; benefits are maintained until day 90. Funding: Hellenic Institute for the Study of Sepsis; Swedish Orphan Biovitrum AB.

Effect of Vaccination against SARS-CoV-2 on Long COVID-19: A Narrative Review.

Vaccines against SARS-CoV-2 have saved millions of lives and played an important role in containing the COVID-19 pandemic. Vaccination against SARS-CoV-2 is also associated with reduced disease severity and, perhaps, with COVID-19 symptom burden. In this narrative review, we present, in a clinically relevant question-and-answer manner, the evidence regarding the association between vaccination against SARS-CoV-2 and long COVID-19. We discuss how the mechanism of action of vaccines could interplay with the pathophysiology of post-COVID-19 condition. Furthermore, we describe how specific factors, such as the number of vaccine doses and the type of SARS-CoV-2 variants, may affect post-COVID-19 condition. We also discuss the role of timing for vaccination in relation to the onset of long COVID-19 symptoms, as it seems to affect the frequency and severity of the condition. Additionally, we describe the potential modifying effect of age, as well as the association of type and level of immune response with long COVID-19. We also describe how system-specific long COVID-19 sequelae, namely neurocognitive-psychologic symptoms and cardiovascular pathology, could be altered by vaccination. Last, we address the question of whether seasonal influenza vaccination has a meaningful impact on the frequency of long COVID-19.

Medical students' attitudes and perceptions of influenza and SARS-CoV-2 vaccination in Cyprus.

Introduction: Infectious diseases constitute a significant problem globally and healthcare professionals (HCP) show suboptimal vaccination rates. We aimed to evaluate the determinants affecting vaccination against influenza and SARS-CoV-2 among medical students in Cyprus. Methods: We conducted a cross-sectional study based on a self-reported, anonymous questionnaire that was sent to all medical students of two Medical Schools in the Republic of Cyprus. Results: Among 266 respondents, 50.8% had been vaccinated against influenza in the past and 20.1% in 2020-21. The majority believed that influenza and SARS-CoV-2 vaccines are safe and effective. Regarding vaccination in Cyprus, 41.3% did not know the current recommendations and a higher proportion of preclinical students replied incorrectly, compared to clinical students. Slightly over half (56.4%) considered themselves adequately informed about influenza vaccination, with more clinical students appearing confident (p=0.068). An overwhelming 71.2% were concerned about contracting SARS-CoV-2, compared to 25.4% with regards to influenza. Up to 76.8% considered themselves adequately informed about SARS-CoV-2 vaccination, with significantly more clinical students being confident (p<0.001). Although more preclinical students appeared hesitant, most students had either been vaccinated against SARS-CoV-2 (49.4%) or would be as soon as possible (32.1%). Vaccination refusal was 2.3%, a group comprised entirely of preclinical students. Conclusions: Our study provides relevant and actionable information about differences in attitudes and perceptions between clinical and preclinical medical students regarding vaccination against influenza and SARS-CoV-2 and highlights the importance of organized, systemic efforts to increase vaccination coverage.

Pityriasis Rosea Induced by COVID-19 Vaccination.

It is increasingly recognized that SARS-CoV-2 infection and COVID-19 vaccines have been associated with skin disorders, including pityriasis rosea. It has been reported that pityriasis rosea has been triggered by several vaccines, as a rare side-effect. We present two cases of COVID-19 vaccine-induced pityriasis rosea. Skin lesions appeared in a 49-year-old female 8 days after the first dose of the BNT162b2 mRNA vaccine and in a 53-year-old male 7 days after the second dose of the same vaccine. The exanthem was self-limited in both patients over a period of a month. LEARNING POINTS: Physicians should be aware that pityriasis rosea is a rare side-effect of COVID-19 vaccination.Pityriasis rosea is self-limiting and no medical treatment is usually required.

Circulating IgG Levels in SARS-CoV-2 Convalescent Individuals in Cyprus.

Long-term persistence and the heterogeneity of humoral response to SARS-CoV-2 have not yet been thoroughly investigated. The aim of this work is to study the production of circulating immunoglobulin class G (IgG) antibodies against SARS-CoV-2 in individuals with past infection in Cyprus. Individuals of the general population, with or without previous SARS-CoV-2 infection, were invited to visit the Biobank at the Center of Excellence in Biobanking and Biomedical Research of the University of Cyprus. Serum IgG antibodies were measured using the SARS-CoV-2 IgG and the SARS-CoV-2 IgG II Quant assays of Abbott Laboratories. Antibody responses to SARS-CoV-2 were also evaluated against participants' demographic and clinical data. All statistical analyses were conducted in Stata 16. The median levels of receptor binding domain (RBD)-specific IgG in 969 unvaccinated individuals, who were reportedly infected between November 2020 and September 2021, were 432.1 arbitrary units (AI)/mL (interquartile range-IQR: 182.4-1147.3). Higher antibody levels were observed in older participants, males, and those who reportedly developed symptoms or were hospitalized. The RBD-specific IgG levels peaked at three months post symptom onset and subsequently decreased up to month six, with a slower decay thereafter. IgG response to the RBD of SARS-CoV-2 is bi-phasic with considerable titer variability. Levels of IgG are significantly associated with several parameters, including age, gender, and severity of symptoms.

Gaps in Knowledge About SARS-CoV-2 & COVID-19 Among University Students Are Associated With Negative Attitudes Toward People With COVID-19: A Cross-Sectional Study in Cyprus.

University students represent a highly active group in terms of their social activity in the community and in the propagation of information on social media. We aimed to map the knowledge, attitudes, and perceptions of University students in Cyprus about severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and Coronavirus disease 2019 (COVID-19) to guide targeted future measures and information campaigns. We used a cross-sectional online survey targeting all students in conventional, not distance-learning, programs in five major universities in the Republic of Cyprus. Students were invited to participate through the respective Studies and Student Welfare Office of each institution. The survey was made available in English and Greek on REDCap. Participation was voluntary and anonymous. The questionnaire was developed based on a consensus to cover the main factual information directed by official channels toward the general public in Cyprus at the time of the survey. In addition to sociodemographic information (N = 8), the self-administered questionnaire consisted of 19 questions, assessing the knowledge regarding the characteristics of SARS-CoV-2 and COVID-19, infection prevention and control measures (N = 10), perceptions related to COVID-19, for instance, whether strict travel measures are necessary (N = 4), and attitudes toward a hypothetical person infected (N = 2). Furthermore, participants were asked to provide their own assessment of their knowledge about COVID-19 and specifically with regard to the main symptoms and ways of transmission (N = 3). The number of students who completed the survey was 3,641 (41% studying Health/Life Sciences). Amongst them, 68.8% responded correctly to at least 60% of knowledge-related questions. Misconceptions were identified in 30%. Only 29.1% expressed a positive attitude toward a hypothetical person with COVID-19 without projecting judgment (9.2%) or blame (38%). Odds of expressing a positive attitude increased by 18% (95% CI 13-24%; p < 0.001) per unit increase in knowledge. Postgraduate level education was predictive of better knowledge (odds ratio (OR) 1.81; 95% CI 1.34-2.46; p < 0.001 among doctoral students] and positive attitude [OR 1.35; 95% CI 1.01-1.80; p = 0.04). In this study, we show that specific knowledge gaps and misconceptions exist among University students about SARS-CoV-2 and COVID-19 and their prevalence is associated with negative attitudes toward people with COVID-19. Our findings highlight the integrated nature of knowledge and attitude and suggest that improvements to the former could contribute to improvements in the latter.

Effect of public health interventions during the first epidemic wave of COVID-19 in Cyprus: a modelling study.

BACKGROUND: Cyprus addressed the first wave of SARS CoV-2 (COVID-19) by implementing non-pharmaceutical interventions (NPIs). The aims of this study were: a) to estimate epidemiological parameters of this wave including infection attack ratio, infection fatality ratio, and case ascertainment ratio, b) to assess the impact of public health interventions and examine what would have happened if those interventions had not been implemented. METHODS: A dynamic, stochastic, individual-based Susceptible-Exposed-Infected-Recovered (SEIR) model was developed to simulate COVID-19 transmission and progression in the population of the Republic of Cyprus. The model was fitted to the observed trends in COVID-19 deaths and intensive care unit (ICU) bed use. RESULTS: By May 8th, 2020, the infection attack ratio was 0.31% (95% Credible Interval [CrI]: 0.15, 0.54%), the infection fatality ratio was 0.71% (95% CrI: 0.44, 1.61%), and the case ascertainment ratio was 33.2% (95% CrI: 19.7, 68.7%). If Cyprus had not implemented any public health measure, the healthcare system would have been overwhelmed by April 14th. The interventions averted 715 (95% CrI: 339, 1235) deaths. If Cyprus had only increased ICU beds, without any social distancing measure, the healthcare system would have been overwhelmed by April 19th. CONCLUSIONS: The decision of the Cypriot authorities to launch early NPIs limited the burden of the first wave of COVID-19. The findings of these analyses could help address the next waves of COVID-19 in Cyprus and other similar settings.

Extensive Testing and Public Health Interventions for the Control of COVID-19 in the Republic of Cyprus between March and May 2020.

Coronavirus disease 2019 (COVID-19) has significantly affected the well-being of individuals worldwide. We herein describe the epidemiology of COVID-19 in the Republic of Cyprus during the first epidemic wave (9 March-3 May 2020). We analyzed surveillance data from laboratory-confirmed cases, including targeted testing and population screening. Statistical analyses included logistic regression. During the surveillance period, 64,136 tests (7322.3 per 100,000) were performed, 873 COVID-19 cases were diagnosed, and 20 deaths were reported (2.3%). Health-care workers (HCWs) represented 21.4% of cases. Overall, 19.1% of cases received hospital care and 3.7% required admission to Intensive Care Units. Male sex (adjusted Odds Ratio (aOR): 3.04; 95% Confidence Interval (CI): 1.97-4.69), increasing age (aOR: 1.56; 95%CI: 1.36-1.79), symptoms at diagnosis (aOR: 6.05; 95%CI: 3.18-11.50), and underlying health conditions (aOR: 2.08; 95%CI: 1.31-3.31) were associated with hospitalization. For recovered cases, the median time from first to last second negative test was 21 days. Overall, 119 primary cases reported 616 close contacts, yielding a pooled secondary attack rate of 12% (95%CI: 9.6-14.8%). Three population-based screening projects, and two projects targeting employees and HCWs, involving 25,496 people, revealed 60 positive individuals (0.2%). Early implementation of interventions with targeted and expanded testing facilitated prompt outbreak control on the island.

Influenza and respiratory syncytial virus infections in the oldest-old continent.

SARS-CoV-2 dramatically revealed the sudden impact of respiratory viruses in our lives. Influenza and respiratory syncytial virus (RSV) infections are associated with high rates of morbidity, mortality, and an important burden on healthcare systems worldwide, especially in elderly patients. The aim of this study was to identify severity predictors in the oldest-old admitted with influenza and/or RSV infections. This is a multicenter, retrospective study of all oldest-old patients (≥ 85 years old) admitted for laboratory-confirmed influenza and/or RSV infection in three tertiary hospitals in Portugal, Italy, and Cyprus over two consecutive winter seasons. The outcomes included the following: pneumonia on infection presentation, use of non-invasive ventilation (NIV), and in-hospital death (IHD). The association with possible predictors, including clinical features and type of virus infection, was assessed using uni- and multivariable analyses. A total of 251 oldest-old patients were included in the study. Pneumonia was evident in 32.3% (n = 81). NIV was implemented in 8.8% (n = 22), and IHD occurred in 13.9% (n = 35). Multivariable analyses revealed that chronic obstructive pulmonary disease (COPD) or asthma was associated with pneumonia (OR 1.86; 95% CI 1.02-3.43; p = 0.045). COPD or asthma (OR 4.4; 95% CI 1.67-11.6; p = 0.003), RSV (OR 3.12; 95% CI 1.09-8.92; p = 0.023), and influenza B infections (OR 3.77; 95% CI 1.06-13.5; p = 0.041) were associated with NIV use, respectively, while chronic kidney disease was associated with IHD (OR 2.50; 95% CI 1.14-5.51; p = 0.023). Among the oldest-old, chronic organ failure, such as COPD or asthma, and CKD predicted pneumonia and IHD, respectively, beyond the importance of viral virulence itself. These findings could impact on public health policies, such as fostering influenza immunization campaigns, home-based care programs, and end-of-life care. Filling knowledge gaps is crucial to set priorities and advise on transition model of care that best fits the oldest-old.