Aging shapes infection profiles of influenza A virus and SARS-CoV-2 in human lung slices (preprint)

The recent coronavirus disease 2019 (COVID-19) outbreak revealed the susceptibility of elderly patients to respiratory virus infections, showing cell senescence or subclinical persistent inflammatory profiles and favouring the development of severe pneumonia. In our study, we evaluated the potential influence of lung aging on the efficiency of replication of influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2), as well as determined the pro-inflammatory and antiviral responses of the distal lung tissue. Using precision-cut lung slices (PCLS) from donors of different ages, we found that pandemic H1N1 and avian H5N1 IAV replicated in the lung parenchyma with high efficacy. In contrast to these IAV strains, SARS-CoV-2 early isolate and Delta variant of concern (VOC) replicated less efficiently in PCLS. Interestingly, both viruses showed reduced replication in PCLS from older compared to younger donors, suggesting that aged lung tissue represents a sub optimal environment for viral replication. Regardless of the age-dependent viral loads, PCLS responded to infection with both viruses by an induction of IL-6 and IP-10/CXCL10 mRNAs, being highest for H5N1. Finally, while SARS-CoV-2 infection was not causing detectable cell death, IAV infection caused significant cytotoxicity and induced significant early interferon responses. In summary, our findings suggest that aged lung tissue might not favour viral dissemination, pointing to a determinant role of dysregulated immune mechanisms in the development of severe disease.

Respiratory viral infection promotes the awakening and outgrowth of dormant metastatic breast cancer cells in lungs (preprint)

Breast cancer is the second most common cancer globally. Most deaths from breast cancer are due to metastatic disease which often follows long periods of clinical dormancy1. Understanding the mechanisms that disrupt the quiescence of dormant disseminated cancer cells (DCC) is crucial for addressing metastatic progression. Infection with respiratory viruses (e.g. influenza or SARS-CoV-2) is common and triggers an inflammatory response locally and systemically2,3. Here we show that influenza virus infection leads to loss of the pro-dormancy mesenchymal phenotype in breast DCC in the lung, causing DCC proliferation within days of infection, and a greater than 100-fold expansion of carcinoma cells into metastatic lesions within two weeks. Such DCC phenotypic change and expansion is interleukin-6 (IL-6)-dependent. We further show that CD4 T cells are required for the maintenance of pulmonary metastatic burden post-influenza virus infection, in part through attenuation of CD8 cell responses in the lungs. Single-cell RNA-seq analyses reveal DCC-dependent impairment of T-cell activation in the lungs of infected mice. SARS-CoV-2 infected mice also showed increased breast DCC expansion in lungs post-infection. Expanding our findings to human observational data, we observed that cancer survivors contracting a SARS-CoV-2 infection have substantially increased risks of lung metastatic progression and cancer-related death compared to cancer survivors who did not. These discoveries underscore the significant impact of respiratory viral infections on the resurgence of metastatic cancer, offering novel insights into the interconnection between infectious diseases and cancer metastasis.

Human long noncoding RNA,VILMIR, is induced by major respiratory viral infections and modulates the host interferon response (preprint)

Long noncoding RNAs (lncRNAs) are a newer class of noncoding transcripts identified as key regulators of biological processes. Here we aimed to identify novel lncRNA targets that play critical roles in major human respiratory viral infections by systematically mining large-scale transcriptomic datasets. Using bulk RNA-sequencing (RNA-seq) analysis, we identified a previously uncharacterized lncRNA, named virus inducible lncRNA modulator of interferon response ( VILMIR ), that was consistently upregulated after in vitro influenza infection across multiple human epithelial cell lines and influenza A virus subtypes. VILMIR was also upregulated after SARS-CoV-2 and RSV infections in vitro . We experimentally confirmed the response of VILMIR to influenza infection and interferon-beta (IFN-β) treatment in the A549 human epithelial cell line and found the expression of VILMIR was robustly induced by IFN-β treatment in a dose and time-specific manner. Single cell RNA-seq analysis of bronchoalveolar lavage fluid (BALF) samples from COVID-19 patients uncovered that VILMIR was upregulated across various cell types including at least five immune cells. The upregulation of VILMIR in immune cells was further confirmed in the human T cell and monocyte cell lines, SUP-T1 and THP-1, after IFN-β treatment. Finally, we found that knockdown of VILMIR expression reduced the magnitude of host transcriptional responses to IFN-β treatment in A549 cells. Together, our results show that VILMIR is a novel interferon-stimulated gene (ISG) that regulates the host interferon response and may be a potential therapeutic target for human respiratory viral infections upon further mechanistic investigation.

Immune imprinting revealed by SARS-CoV-2 Omicron infection prior to vaccination (preprint)

Immune imprinting or original antigenic sin (OAS) originally referred to a phenomenon of suboptimal immune response to a repeat exposure to a virus that was antigenically distinct from the original virus infection. OAS has been implicated in higher mortality in young people during the 2009-10 H1N1 pandemic where the elderly (H1N1 exposure in childhood) appeared relatively well protected compared to younger individuals whose first influenza infection was not H1N1. Immune imprinting is part of a rapid recall system and is highly effective against a slowly evolving virus (drifting) but not antigenically shifting viruses such as influenza and SARS CoV-2. As predicted by OAS, suboptimal neutralization responses to the highly divergent SARS-COV-2 lineage Omicron have been observed in animal models and individuals previously vaccinated with primary course of ancestral (Wu-1) vaccine. Due to the rapid scale up of vaccine before emergence of the antigenically distinct Omicron variant, it is unknown whether immunological imprinting for occurs in the context of SARS-COV-2 infection itself. We longitudinally assessed humoral responses to primary two dose Ad26.COV2.S Wu-hu-1 based vaccination in a Nigerian population following the global emergence of Omicron. At study entry in Jan 2023, we found 93% and 58% of pre-vaccination participants previously exposed to ancestral Wu-1 and Omicron virus respectively by anti-N IgG and anti-receptor binding domain (RBD) IgG Wu-1 and Omicron -specific antibodies. In participants with no evidence of prior exposure to Omicron, neutralisation against Wu-1 was significantly higher than Omicron variants as expected. However, serum neutralisation titres in participants who were anti-RBD Omicron IgG positive were paradoxically 2-fold lower for Omicron BA.1 as compared to Wu-1. This is clear evidence for imprinted immunity from the ancestral pre-omicron lineage viruses, and remarkably these old responses to Wu-1 were able to dominate over more recent, likely multiple, Omicron lineage infections. Furthermore, in these participants with prior exposure to Omicron and evidence of imprinting, we observed that further Omicron infection and Wu-1 based vaccine was associated with boosting of responses across variants with equalisation of neutralisation titres for Wu-1 and Omicron variants. However, omicron responses did not surpass ancestral responses, suggesting persistence of imprinting and only partial mitigation. Although neutralization responses at high titres were observed post dose 1 vaccination against ancestral and Omicron variants BA.1, BA.2, BA.4 in nearly all participants, neutralisation against the highly immune evasive XBB recombinant variant remained substantially lower, with a second vaccine dose providing very modest boosting. These data highlight immune imprinting against SARS-CoV-2 prior to vaccination and its persistence thereafter. In present day unvaccinated populations where serum neutralisation responses to pre-Omicron variants dominate, use of an omicron variant based vaccine should be used in preference to Wu-1 based vaccine to override imprinting and provide broader protection for vulnerable populations such as the elderly or those with compromised immunity.

Mutability and hypermutation antagonize immunoglobulin codon optimality (preprint)

The efficacy of polyclonal antibody responses is inherently linked to paratope diversity, as generated through V(D)J recombination and somatic hypermutation (SHM). These processes arose in early jawed vertebrates; however, little is known about how immunoglobulin diversity, mutability, and hypermutation have evolved in tandem with another more ubiquitous feature of protein-coding DNA - codon optimality. Here, we explore these relationships through analysis of germline IG genes, natural V(D)J repertoires, serum VH usage, and monoclonal antibody (mAb) expression, each through the lens of multiple optimality metrics. Strikingly, proteomic serum IgG sequencing showed that germline IGHV codon optimality positively correlated with VH representation after influenza vaccination, and in vitro, codon deoptimization of mAbs with synonymous amino acid sequences caused consistent expression loss. Germline V genes exhibit a range of codon optimality that is maintained by functionality, and inversely related to mutability. SHM caused a load-dependent deoptimization of IGH VDJ repertoires within human tonsils, bone marrow, and lymph nodes (including SARS-CoV-2-specific clones from mRNA vaccinees), influenza-infected mice, and zebrafish. Comparison of natural mutation profiles to true random suggests the presence of selective pressures that constrain deoptimization. These findings shed light on immunoglobulin evolution, providing unanticipated insights into the antagonistic relationship between variable region diversification, codon optimality, and antibody secretion; ultimately, the need for diversity takes precedence over that for the most efficient expression of the antibody repertoire.

Rhinovirus infection of airway epithelial cells uncovers the non-ciliated subset as a likely driver of genetic susceptibility to childhood-onset asthma (preprint)

Asthma is a complex disease caused by genetic and environmental factors. Epidemiological studies have shown that in children, wheezing during rhinovirus infection (a cause of the common cold) is associated with asthma development during childhood. This has led scientists to hypothesize there could be a causal relationship between rhinovirus infection and asthma or that RV-induced wheezing identifies individuals at increased risk for asthma development. However, not all children who wheeze when they have a cold develop asthma. Genome-wide association studies (GWAS) have identified hundreds of genetic variants contributing to asthma susceptibility, with the vast majority of likely causal variants being non-coding. Integrative analyses with transcriptomic and epigenomic datasets have indicated that T cells drive asthma risk, which has been supported by mouse studies. However, the datasets ascertained in these integrative analyses lack airway epithelial cells. Furthermore, large-scale transcriptomic T cell studies have not identified the regulatory effects of most non-coding risk variants in asthma GWAS, indicating there could be additional cell types harboring these 'missing regulatory effects'. Given that airway epithelial cells are the first line of defense against rhinovirus, we hypothesized they could be mediators of genetic susceptibility to asthma. Here we integrate GWAS data with transcriptomic datasets of airway epithelial cells subject to stimuli that could induce activation states relevant to asthma. We demonstrate that epithelial cultures infected with rhinovirus significantly upregulate childhood-onset asthma-associated genes. We show that this upregulation occurs specifically in non-ciliated epithelial cells. This enrichment for genes in asthma risk loci, or 'asthma heritability enrichment' is also significant for epithelial genes upregulated with influenza infection, but not with SARS-CoV-2 infection or cytokine activation. Additionally, cells from patients with asthma showed a stronger heritability enrichment compared to cells from healthy individuals. Overall, our results suggest that rhinovirus infection is an environmental factor that interacts with genetic risk factors through non-ciliated airway epithelial cells to drive childhood-onset asthma.

Examination of Influenza A Infection Rate, Its Determinants, and Seasonal Influenza Vaccine Effectiveness in the Post-COVID-19 Pandemic Era (preprint)

BackgroundIn the context of the COVID-19 pandemic, a pronounced wave of Influenza A occurred in the 2022/23 winter season under generally relaxed post-pandemic non-pharmaceutical preventive measures. AimThis study aimed to investigate the Influenza A infection rate, factors influencing its occurrence and seasonal Influenza vaccine effectiveness on seroconversion in the post-COVID-19 pandemic era. MethodsThe seroconversion of Anti-Influenza-A-Nucleoprotein/Matrix IgG was investigated in 402 healthcare workers (HCWs) during the winter season of 2022/2023 (23 May 2022 to 11 May 2023). The participants provided a serum sample and completed a study questionnaire both before and after the seasonal Influenza A wave (24 October 2022 to 8 January 2023). The levels of a vaccine-independent Anti-Influenza-A-Nucleoprotein/Matrix IgG were measured using the SERION ELISA classic Influenza A IgG assay, with a 2-fold increase as indicative of seroconversion after asymptomatic or symptomatic influenza infection. ResultsAmong the participants, 20.6% (95% CI 17.0-24.9%; 83/402) showed seroconversion. The multivariate logistic regression analysis revealed that the age category of [≥] 45 years (p=0.03) and regular patient contact (p=0.02) significantly influenced seroconversion. However, the factors male gender, BMI, smoking, household size, seasonal Influenza vaccination, and SARS-CoV-2 infection during the Influenza A season were not significantly associated with seroconversion. The effectiveness of the 2022/23 seasonal Influenza vaccine on seroconversion induced by Influenza infection was 22.6% (95% CI -17.1-50.6%). ConclusionDuring the initial Influenza A season following the COVID-19 pandemic, approximately 20% of HCWs contracted an Influenza A infection. This highlights a potential risk and a significant asymptomatic or symptomatic infection rate posing a theoretical risk for intrahospital transmission chains and nosocomial infections.

Influenza vaccination in older adults during the COVID-19 pandemic: a population-based study in 133 Brazilian cities. / Vacinação para influenza em idosos na pandemia COVID-19: estudo de base populacional em 133 cidades brasileiras.

Routine immunization during pandemics can be harmed. This study estimated the influenza vaccination coverage in older adults during the COVID-19 through the EPICOVID-19, a population-based study conducted in 133 cities from the 26 Brazilian states and Federal District. We selected 25 census tracts per city, with probability proportional to the tract's size, ten households by census tract, and one random individual interviewed. A total of 8,265 older adults (≥60 years old) were interviewed and asked whether they had been vaccinated against flu in 2020. Vaccination coverage was 82.3% (95% CI: 80.1-84.2) with no difference by gender, age, and region; higher vaccination coverage was observed among the wealthiest (84.7% versus 80.1% in the poorest) and among the more educated (87.3% versus 83.2% less educated); lower coverage among indigenous (56.9% versus > 80% among other ethnic groups). A positive association was identified with the number of comorbidities among men but not among women. Most of the population was vaccinated (97.5%) in the public health system. The private network was chosen mainly in the South by the wealthiest and more educated. Vaccination coverage was seven percentage points lower than the government target (90%), and inequalities should be reversed in future campaigns.

Imunizações de rotina durante pandemias podem ser prejudicadas. Este estudo estimou a cobertura vacinal para influenza em idosos durante a COVID-19 através do EPICOVID-19, inquérito populacional realizado em 133 cidades sentinelas dos 26 estados brasileiros e Distrito Federal. Selecionou-se 25 setores censitários por cidade, amostragem proporcional ao tamanho, dez domicílios por setor e uma pessoa por domicílio, aleatoriamente. O quantitativo de 8.265 idosos (≥ 60 anos) foram entrevistados e responderam se haviam sido vacinados contra gripe em 2020. A cobertura foi 82,3% (IC95% 80,1; 84,2), sem diferenças por sexo, idade ou região. Maiores coberturas ocorreram nos mais ricos (84,7% versus 80,1% nos mais pobres) e nos mais escolarizados (87,3% versus 83,2% nos menos escolarizados). Menor cobertura nos indígenas (56,9% versus coberturas superiores a 80% nos demais grupos étnicos). Houve associação positiva com número de comorbidades entre homens, mas não entre mulheres. A maioria vacinou-se na rede pública (97,5%), sendo a rede privada mais utilizada na região Sul, pelos mais escolarizados e mais ricos. Conclui-se que a cobertura vacinal ficou sete pontos percentuais abaixo da meta governamental (90%), e que desigualdades devem ser revertidas em futuras campanhas.

[Connotation of Xiao Chaihu Decoction combined with Maxing Shigan Decoction based on severe cases and modern pathophysiological mechanism and application for severe pulmonary infection and acute exacerbation of chronic obstructive pulmonary disease in critical care medicine].

Xiao Chaihu Decoction combined with Maxing Shigan Decoction is a classic herbal formula. All of them are derived from Treatise on Cold Damage(Shang Han Lun) by ZHANG Zhong-jing. This combination has the effects of harmonizing lesser yang, relieving exterior syndrome, clearing lung heat, and relieving panting. It is mainly used for treating the disease involving the triple-Yang combination of diseases and accumulation of pathogenic heat in the lung. Xiao Chaihu Decoction combined with Maxing Shigan Decoction is a classic combination for the treatment of exogenous diseases involving the triple-Yang combination. They are commonly used in exogenous diseases, especially in the north of China. This combination is also the main treatment strategy for coronavirus disease 2019(COVID-19) accompanied by fever and cough. Maxing Shigan Decoction is a classical herbal formula for treating the syndrome of phlegm-heat obstructing the lung. "Dyspnea after sweating" suggests the accumulation of pathogenic heat in the lung. Patients with mild symptoms may develop cough and asthma along with forehead sweating, and those in critical severe may develop whole-body sweating, especially the front chest. Modern medicine believes that the above situation is related to lung infection. "Mild fever" refers to syndromes rather than pathogenesis. It does not mean that the heat syndrome is not heavy, instead, it suggests that severe heat and inflammation have occurred. The indications of Xiao Chaihu Decoction combined with Maxing Shigan Decoction are as follows.(1) In terms of diseases, it is suitable for the treatment of viral pneumonia, bronchopneumonia, lobar pneumonia, mycoplasma pneumonia, COVID-19 infection, measles with pneumonia, severe acute respiratory syndrome(SARS), avian influenza, H1N1 influenza, chronic obstructive pulmonary disease with acute exacerbation, pertussis, and other influenza and pneumonia.(2) In terms of syndromes, it can be used for the syndromes of bitter mouth, dry pharynx, vertigo, loss of appetite, vexation, vomiting, and fullness and discomfort in the chest and hypochondrium. It can also be used to treat alternate attacks of chill and fever and different degrees of fever, as well as chest tightness, cough, asthma, expectoration, dry mouth, wanting cold drinks, feeling agitated, sweating, yellow urine, dry stool, red tongue, yellow or white fur, and floating, smooth, and powerful pulse, especially the right wrist pulse.

Implementation of the preventive vaccination program in the time of the COVID-19 pandemic - single center study.

INTRODUCTION: In addition to many diagnostic and therapeutic procedures, the COVID-19 pandemic also limited prophylaxis, including the implementation of the vaccination program among children. OBJECTIVE: The aim of the study was to assess the implementation of the vaccination program in the area covered by the care of patients of a selected Primary Health Care clinic in the city of Krakow in the field of selected vaccinations during the COVID-19 pandemic. MATERIAL AND METHODS: A retrospective study based on secondary data was conducted in a selected clinic (Kraków, Poland) that cares for 1,982 children aged 0-19 years. An analysis of the vaccination coverage in selected groups of children in 2019, 2020 and 2021 was carried out based on annual reports (MZ-54). Vaccination coverage against: diphtheria, tetanus, whooping cough, measles, mumps, rubella, influenza and pneumococcal infection was analyzed. The collected data were analyzed using descriptive statistics, Chi2 test and Fisher's exact test. RESULTS: In the general vaccination status of two-year-olds, no significant differences were observed in the period 2019-2021 (p=0.156). The percentage of fully vaccinated increased from 77.6% in 2019, to 81.5% in 2020 and to 85.2% in 2021. However, a high rate of vaccination refusals was observed in 2021 (4.1%) in this group. The percentage of 2-year-olds vaccinated against pneumococci (PCV) and 3-year-olds against diphtheria, tetanus, pertussis (DTP), and measles, mumps, rubella (MMR) in the years 2019-2021 was increasing. For DTP and MMR, this increase was significant (p<0.05). In the group of older children, in 2020 the percentage of 7- and 15-year-olds vaccinated decreased compared to 2019 and 2021, but the difference was insignificant (p>0.05). A significant difference in vaccination coverage was observed in the group of 19-year-olds, in which in 2020 the percentage of vaccinated was 58% (in 2019 - 74.6%, in 2021 - 81%). The largest number of children under the age of 5 were vaccinated against influenza in 2021, but it was only less than 2% of this group. CONCLUSIONS: Sanitary restrictions introduced during the COVID-19 pandemic did not significantly affect the vaccination status of children in selected age groups against the analyzed vaccine-preventable diseases. The exception is the group of 19-year-olds, whose vaccination coverage in 2020 was much lower than in 2019 and 2021. In addition, an increase in refusals of vaccination was observed, reaching 4.1% in 2021 in the group of the youngest patients.

Seesaw Effect Between COVID-19 and Influenza From 2020 to 2023 in World Health Organization Regions: Correlation Analysis.

BACKGROUND: Seasonal influenza activity showed a sharp decline in activity at the beginning of the emergence of COVID-19. Whether there is an epidemiological correlation between the dynamic of these 2 respiratory infectious diseases and their future trends needs to be explored. OBJECTIVE: We aimed to assess the correlation between COVID-19 and influenza activity and estimate later epidemiological trends. METHODS: We retrospectively described the dynamics of COVID-19 and influenza in 6 World Health Organization (WHO) regions from January 2020 to March 2023 and used the long short-term memory machine learning model to learn potential patterns in previously observed activity and predict trends for the following 16 weeks. Finally, we used Spearman correlation coefficients to assess the past and future epidemiological correlation between these 2 respiratory infectious diseases. RESULTS: With the emergence of the original strain of SARS-CoV-2 and other variants, influenza activity stayed below 10% for more than 1 year in the 6 WHO regions. Subsequently, it gradually rose as Delta activity dropped, but still peaked below Delta. During the Omicron pandemic and the following period, the activity of each disease increased as the other decreased, alternating in dominance more than once, with each alternation lasting for 3 to 4 months. Correlation analysis showed that COVID-19 and influenza activity presented a predominantly negative correlation, with coefficients above -0.3 in WHO regions, especially during the Omicron pandemic and the following estimated period. The diseases had a transient positive correlation in the European region of the WHO and the Western Pacific region of the WHO when multiple dominant strains created a mixed pandemic. CONCLUSIONS: Influenza activity and past seasonal epidemiological patterns were shaken by the COVID-19 pandemic. The activity of these diseases was moderately or greater than moderately inversely correlated, and they suppressed and competed with each other, showing a seesaw effect. In the postpandemic era, this seesaw trend may be more prominent, suggesting the possibility of using one disease as an early warning signal for the other when making future estimates and conducting optimized annual vaccine campaigns.

Comprehensive surveillance of acute respiratory infections during the COVID-19 pandemic: a methodological approach using sentinel networks, Castilla y León, Spain, January 2020 to May 2022.

BackgroundSince 1996, epidemiological surveillance of acute respiratory infections (ARI) in Spain has been limited to seasonal influenza, respiratory syncytial virus (RSV) and potential pandemic viruses. The COVID-19 pandemic provides opportunities to adapt existing systems for extended surveillance to capture a broader range of ARI.AimTo describe how the Influenza Sentinel Surveillance System of Castilla y León, Spain was rapidly adapted in 2020 to comprehensive sentinel surveillance for ARI, including influenza and COVID-19.MethodsUsing principles and methods of the health sentinel network, we integrated electronic medical record data from 68 basic surveillance units, covering 2.6% of the regional population between January 2020 to May 2022. We tested sentinel and non-sentinel samples sent weekly to the laboratory network for SARS-CoV-2, influenza viruses and other respiratory pathogens. The moving epidemic method (MEM) was used to calculate epidemic thresholds.ResultsARI incidence was estimated at 18,942 cases per 100,000 in 2020/21 and 45,223 in 2021/22, with similar seasonal fold increases by type of respiratory disease. Incidence of influenza-like illness was negligible in 2020/21 but a 5-week epidemic was detected by MEM in 2021/22. Epidemic thresholds for ARI and COVID-19 were estimated at 459.4 and 191.3 cases per 100,000 population, respectively. More than 5,000 samples were tested against a panel of respiratory viruses in 2021/22.ConclusionExtracting data from electronic medical records reported by trained professionals, combined with a standardised microbiological information system, is a feasible and useful method to adapt influenza sentinel reports to comprehensive ARI surveillance in the post-COVID-19 era.

Spreading processes with mutations over multilayer networks.

A key scientific challenge during the outbreak of novel infectious diseases is to predict how the course of the epidemic changes under countermeasures that limit interaction in the population. Most epidemiological models do not consider the role of mutations and heterogeneity in the type of contact events. However, pathogens have the capacity to mutate in response to changing environments, especially caused by the increase in population immunity to existing strains, and the emergence of new pathogen strains poses a continued threat to public health. Further, in the light of differing transmission risks in different congregate settings (e.g., schools and offices), different mitigation strategies may need to be adopted to control the spread of infection. We analyze a multilayer multistrain model by simultaneously accounting for i) pathways for mutations in the pathogen leading to the emergence of new pathogen strains, and ii) differing transmission risks in different settings, modeled as network layers. Assuming complete cross-immunity among strains, namely, recovery from any infection prevents infection with any other (an assumption that will need to be relaxed to deal with COVID-19 or influenza), we derive the key epidemiological parameters for the multilayer multistrain framework. We demonstrate that reductions to existing models that discount heterogeneity in either the strain or the network layers may lead to incorrect predictions. Our results highlight that the impact of imposing/lifting mitigation measures concerning different contact network layers (e.g., school closures or work-from-home policies) should be evaluated in connection with their effect on the likelihood of the emergence of new strains.

[Clinic and functional features of chronic obstructive pulmonary disease after virus-induced acute exacerbations.]

AIM: To establish symptoms, lung function and to evaluate subsequent exacerbations of chronic obstructive pulmonary disease (COPD) during a year after virus-induced COPD exacerbations. MATERIALS AND METHODS: Patients hospitalized with viral (n=60), bacterial (n=60) and viral-bacterial (n=60) COPD exacerbations were enrolled to single-center prospective observational study. COPD was diagnosed according spirography criteria. Viral infection was established in bronchoalveolar lavage fluid or sputum by real-time reverse transcription-polymerase chain reaction for RNA of influenza A and B virus, rhinovirus, respiratory syncytial virus and SARS-CoV-2. Symptoms, lung function, COPD exacerbations were assessed. Patients were investigated at the hospitalization onset and then 4 and 52 weeks following the discharge from the hospital. RESULTS: After 52 weeks in viral and viral-bacterial COPD exacerbations groups the rate of forced expiratory volume in one second (FEV1) decline were maximal - 71 (68; 73) ml/year and 69 (67; 72) ml/year versus 59 (55; 62) ml/year after bacterial exacerbations. Low levels of diffusion lung capacity for carbon monoxide (DLco/Va) - 52.5% (45.1%; 55.8%), 50.2% (44.9%; 56.0%) and 75.3% (72.2%; 80.1%) respectively, of 6-minute walk distance; p<0.001 in relation to bacterial exacerbations. In Cox proportional hazards regression analyses viral and viral-bacterial exacerbations were associated with increased risk of subsequent COPD exacerbations by 2.4 times independent of exacerbations rate before index event and FEV1. In linear regression models the relationships between airflow limitation and respiratory syncytial virus, rhinovirus and influenza virus infection, between low DLco/Va and rhinovirus, influenza virus and SARS-CoV-2 infection. CONCLUSION: COPD after virus-induced exacerbations were characterized by progression of airflow limitation, low DLco/Va, low 6-minute walking test distance, subsequent COPD exacerbations risk.

Prevalence of respiratory pathogens and risk of developing pneumonia under non-pharmaceutical interventions in Suzhou, China.

This study aims to evaluate the impact of non-pharmaceutical interventions (NPIs) on the prevalence of respiratory pathogens among hospitalised children with acute respiratory infections (ARIs) in Suzhou. Children with ARIs admitted to the Children's Hospital of Soochow University between 1 September 2021 and 31 December 2022 and subjected to 13 respiratory pathogen multiplex PCR assays were included in the study. We retrospectively collected demographic details, results of respiratory pathogen panel tests, and discharge diagnostic information of the participants, and described the age and seasonal distribution of respiratory pathogens and risk factors for developing pneumonia. A total of 10,396 children <16 years of age, including 5,905 males and 4,491 females, were part of the study. The positive rates of the 11 respiratory pathogen assays were 23.3% (human rhinovirus (HRV)), 15.9% (human respiratory syncytial virus (HRSV)), 10.5% (human metapneumovirus (HMPV)), 10.3% (human parainfluenza virus (HPIV)), 8.6% (mycoplasma pneumoniae (MP)), 5.8% (Boca), 3.5% (influenza A (InfA)), 2.9% (influenza B (InfB)), 2.7% (human coronavirus (HCOV)), 2.0% (adenovirus (ADV)), and 0.5% (Ch), respectively. Bocavirus and HPIV detection peaked during the period from September to November (autumn), and MP and HMPV peaked in the months of November and December. The peak of InfA detection was found to be in summer (July and August), whereas the InfB peak was observed to be in winter (December, January, and February). HRSV and HRV predominated in the <3 years age group. HRV and HMPV were common in the 3-6 years group, whereas MP was predominant in the ≥6 years group. MP (odds ratio (OR): 70.068, 95%CI: 32.665-150.298, P < 0.01), HMPV (OR: 6.493, 95%CI: 4.802-8.780, P < 0.01), Boca (OR: 3.300, 95%CI: 2.186-4.980, P < 0.01), and HRSV (OR: 2.649, 95%CI: 2.089-3.358, P < 0.01) infections were more likely to develop into pneumonia than the other pathogens. With the use of NPIs, HRV was the most common pathogen in children with ARIs, and MP was more likely to progress to pneumonia than other pathogens.

Antiviral Activity of Pyrimidine Containing Compounds: Patent Review.

Viruses are still the most prevalent infectious pathogens on a worldwide scale, with many of them causing life-threatening illnesses in humans. Influenza viruses, because of their significant morbidity and mortality, continue to pose a major threat to human health. According to WHO statistics, seasonal influenza virus epidemics are predicted to cause over 2 million severe illness cases with high death rates yearly. The whole world has been suffering from the COVID-19 epidemic for two years and is still suffering so far, and the deaths from this virus have exceeded three million cases. Because the great majority of viral infections do not have a specific medication or vaccination, discovering novel medicines remains a vital task. This review covers reports in the patent literature from 1980 to the end of 2021 on the antiviral activities of pyrimidine moieties. The patent database, SciFinder, was used to locate patent applications. A large variety of pyrimidine molecules have been produced and tested for antiviral activity over the last decade. These molecules were reported to inhibit a wide range of viruses, including influenza virus, respiratory syncytial virus, rhinovirus, dengue virus, herpes virus, hepatitis B and C, and human immunodeficiency virus. The cytotoxicity of the developed pyrimidine derivatives was tested in almost all reported studies and the selectivity index was calculated to show the selectivity and safety of such molecules. From the remarkable activity of pyrimidine compounds as antivirals for several dangerous viruses, we expect that these derivatives will be used as potent drugs in the very near future.

Epidemiology of Respiratory Infections during the COVID-19 Pandemic.

To face the COVID-19 outbreak, a wide range of non-pharmaceutical interventions (NPIs) aimed at limiting the spread of the virus in communities, such as mask-wearing, hand hygiene, social distancing, travel restrictions, and school closures, were introduced in most countries. Thereafter, a significant reduction of new asymptomatic and symptomatic COVID-19 cases occurred, although there were differences between countries according to the type and duration of the NPIs. In addition, the COVID-19 pandemic has been accompanied by significant variations in the global incidence of diseases due to the most common non-SARS-CoV-2 respiratory viruses and some bacteria. In this narrative review, the epidemiology of the most common non-SARS-CoV-2 respiratory infections during the COVID-19 pandemic is detailed. Moreover, factors that could have had a role in modifying the traditional circulation of respiratory pathogens are discussed. A literature analysis shows that NPIs were the most important cause of the general reduction in the incidence of influenza and respiratory syncytial virus infection in the first year of the pandemic, although the different sensitivity of each virus to NPIs, the type and duration of measures used, as well as the interference among viruses may have played a role in modulating viral circulation. Reasons for the increase in the incidences of Streptococcus pneumoniae and group A Streptococcus infections seem strictly linked to immunity debt and the role played by NPIs in reducing viral infections and limiting bacterial superimposed infections. These results highlight the importance of NPIs during pandemics, the need to monitor the circulation of infectious agents that cause diseases similar to those caused by pandemic agents, and the need to make efforts to improve coverage with available vaccines.

Productivity costs associated with reactive school closures related to influenza or influenza-like illness in the United States from 2011 to 2019.

INTRODUCTION: Schools close in reaction to seasonal influenza outbreaks and, on occasion, pandemic influenza. The unintended costs of reactive school closures associated with influenza or influenza-like illness (ILI) has not been studied previously. We estimated the costs of ILI-related reactive school closures in the United States over eight academic years. METHODS: We used prospectively collected data on ILI-related reactive school closures from August 1, 2011 to June 30, 2019 to estimate the costs of the closures, which included productivity costs for parents, teachers, and non-teaching school staff. Productivity cost estimates were evaluated by multiplying the number of days for each closure by the state- and year-specific average hourly or daily wage rates for parents, teachers, and school staff. We subdivided total cost and cost per student estimates by school year, state, and urbanicity of school location. RESULTS: The estimated productivity cost of the closures was $476 million in total during the eight years, with most (90%) of the costs occurring between 2016-2017 and 2018-2019, and in Tennessee (55%) and Kentucky (21%). Among all U.S. public schools, the annual cost per student was much higher in Tennessee ($33) and Kentucky ($19) than any other state ($2.4 in the third highest state) or the national average ($1.2). The cost per student was higher in rural areas ($2.9) or towns ($2.5) than cities ($0.6) or suburbs ($0.5). Locations with higher costs tended to have both more closures and closures with longer durations. CONCLUSIONS: In recent years, we found significant heterogeneity in year-to-year costs of ILI-associated reactive school closures. These costs have been greatest in Tennessee and Kentucky and been elevated in rural or town areas relative to cities or suburbs. Our findings might provide evidence to support efforts to reduce the burden of seasonal influenza in these disproportionately impacted states or communities.

Vaccination in pregnancy.

The evidence indicates that pregnancy is associated with increased severity of some infectious diseases. Given the high maternal morbidity associated with influenza in pregnancy and the high neonatal morbidity and mortality associated with pertussis, the traditionally two recommended vaccines during pregnancy were those against influenza and Tdap (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis) vaccines. The recent COVID-19 pandemic introduced a third vaccine that after much debate is now recommended for all pregnant women. Other vaccines can be offered based for high-risk pregnant women, and only when the benefits of receiving them outweigh the risks. The soon expected vaccines against group B streptococcus infection and respiratory syncytial virus infection will be a breakthrough in reducing perinatal mortality. In this paper, the recommendations for administration of each vaccine during pregnancy are discussed.