Respiratory illness virus infections with special emphasis on Covid-19 (preprint)

Viruses that emerge pose challenges for treatment options as their uniqueness would not know completely. In spite of large diversity, viruses share common characteristics for infection. There are at least 12 different respiratory borne viruses that belong to different virus taxonomic families. Many of these viruses multiply and cause damage to the upper and lower respiratory tracts. The description about these viruses in comparison to each other with reference to their epidemiology, molecular characteristics, disease manifestations, diagnosis and treatment is lacking. Such information helps to diagnose, differentiate and for formulating the control measures at faster pace. The leading cause of acute illness worldwide are the acute respiratory infections (ARIs) and are being responsible for nearly 4 million deaths every year which are mostly in young children and infants. Among the above ARIs, influenza, respiratory syncytial virus (RSV), parainfluenza virus type 3 (PIV-3), Streptococcus pneumoniae, Haemophilus influenzae and corona viruses are the main infectious agents. WHO recognized respiratory syncytial virus, parainfluenza viruses, coronavirus, rhinovirus, and human metapneumovirus [non-influenza RNA respiratory viruses (NIRVs)], as considerable global health burden. Lower respiratory tract infections are the fourth most common cause of death globally, after the non-infectious chronic conditions. This review aimed at presenting the characteristics of different viruses causing the respiratory infections highlighting the uniqueness of Covid-19. We expect that this review would help in understanding the similarities and differences among the closely related viruses causing respiratory infections and hence to formulate the specific preventive or control measures.

Paridiprubart inhibits TLR4-dependant NF-κB activation by multiple pathogens (preprint)

Respiratory pathogens such as SARS-CoV-2 and influenza can activate an exaggerated inflammatory response (cytokine storm) in the lungs that may result in acute respiratory distress syndrome (ARDS), hospitalization, and death. Therapies that target a specific pathogen (i.e. anti-virals) must, by nature, be selected after a specific diagnosis and may become ineffective due to pathogen evolution. An alternate strategy is to counter the exaggerated innate immune response present in ARDS patients using host-directed drug therapies that are agnostic to the infectious agent to overcome both of these challenges. Originally described as the innate immune receptor for lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4) is now understood to be an important mediator of inflammation caused by a variety of pathogen-associated molecular patterns (PAMPs) and host-derived damage-associated molecular patterns (DAMPs). Here we show that paridiprubart, a monoclonal antibody that prevents TLR4 dimer formation, inhibits the response to TLR4 agonists including LPS, the SARS-CoV-2 spike protein, the DAMP high mobility group box 1 (HMGB1), as well as the NF-{kappa}B response to infection by both viral and bacterial pathogens. Notable in this regard, we demonstrate that SARS-CoV-2 increases HMGB1 levels, and that paridiprubart inhibits both the SARS-CoV-2 and HMGB1-triggered NF-{kappa}B response, illustrating its potential to suppress this self-amplifying inflammatory signal. We also observed that the inhibitory effect of paridiprubart is apparent when cells are exposed to the SARS-CoV-2 spike protein, which is itself a direct TLR4 agonist. In the context of active infection, paridiprubart suppressed the NF-{kappa}B-dependent response elicited by infection with SARS-CoV-2, the seasonal coronavirus 229E, influenza A virus or Haemophilus influenzae, a gram-negative bacterial pathogen. Combined, these findings reinforce the central role played by TLR4 in the inflammatory response to infection by diverse pathogens, and demonstrates the protective potential of paridiprubart-dependent inhibition of pathogenic TLR4 responses.

The Rapid Rebound of Invasive Meningococcal Disease in France at the End of 2022 (preprint)

Background: Invasive meningococcal disease (IMD) cases declined upon the implementation of non-pharmaceutical measures to control the COVID-19 pandemic. A rebound in IMD cases was feared upon easing these measures.Methods: We conducted a retrospective cohort study using the French National Reference Centre Database for meningococci between 2015-2022. We scored serogroups, sex, age groups, and clonal complexes of the corresponding isolates.Findings: Our data clearly show a decline in the number of IMD cases for all serogroups and age groups until 2021. This decline was mainly due to a decrease in IMD cases provoked by the hyperinvasive ST-11 clonal complex. However, since the fall of 2021, there has been an increase in IMD cases, which accelerated in the second half of 2022. This rebound concerned all age groups, in particular 16-24 years. The increase in cases due to serogroups B, W, and Y were mainly due to the expansion of isolates of the ST-7460, the clonal complex ST-9316 strains and the clonal complex ST-23, respectively.Interpretation: IMD epidemiology remains unpredictable and with profound epidemiological changes have been observed. The surveillance of IMD needs to be enhanced using molecular tools. Additionally, vaccination strategies need to be updated to acknowledge recent epidemiological changes.Funding: Institut Pasteur and Santé Publique France.Declaration of Interest: MKT performs contract works for the Institut Pasteur funded by GSK, Sanofi and Pfizer outside the submitted manuscript, and MKT and AED have a patent with GSK, 630133. ST was a recipient of a fellowship from Pfizer that had no role in the data collection, interpretation, or writing of the manuscript. The other authors declare no conflicts of interest.Ethical Approval: These data were collected anonymously as part of the mission of the National Reference Centre for meningococci and Haemophilus influenzae (NRCMHi) for routine surveillance of IMD and isolate identification and typing. The procedure for collecting samples and information was submitted and approved by the CNIL N°1475242/2011 (Commission Nationale de l'Informatique et des Libertés) and the requirement for consent was waived.

Effects of contagious respiratory infections on breath biomarkers (preprint)

Background Due to their immediate exhalation after generation at the cellular/microbiome levels, exhaled volatile organic compounds (VOCs) may provide real-time information on pathophysiological mechanisms and host response to infections. In recent years, metabolic profiling of most frequent respiratory infection gained interest as it holds potential for early non-invasive detection of pathogens and monitoring of disease progression and response to therapy.Methods In contrast to previous studies with pre-selected patient groups, we conducted a real-time mass-spectrometry based breath profiling in hundreds of consecutive subjects under an actual respiratory infection screening scenario. Recruited subjects were grouped for further comparisons, based on multiplex-PCR confirmed infection (infected by common respiratory pathogen(s) and healthy) and presence or absence of flu like symptoms.Results Amongst recruitments, we obtained 256 healthy cases and 223 infected/coinfected (171 mono-infections, 52 coinfections) with Haemophilus influenza, Streptococcus pneumoniae and Rhinovirus. We observed multiple effects of these mono-infections and co-infections onto the exhaled VOC profiles and variations, especially on endogenous ketone, short-chain fatty acid, organosulfur, aldehyde and terpene concentrations. Based on VOCs origins, we encountered changes in patient’s energy metabolism, systemic microbial immune homeostasis, inflammation, oxidative stress and antioxidative defense. Presence of bacterial pathogens depicted more complex metabolic effects and cross-talk – most likely due to their own metabolism.Conclusion Alike our recent reports on COVID-19 and in line with other recent multi-omics and clinical microbiological reports, these results offered unique insight into common respiratory infections, pathogenesis, ‘host-microbiome-pathogen’ interactions. Breathomics depicted the non-invasive potential for ‘monitoring’ respiratory mono-infections and coinfections.

Low-Dose Interferon I and III-Based Nasal Sprays: A Good-Looking COVID-19 Vaccine Candidate and a Therapy of the Future? (preprint)

The SARS–CoV-2 infection has caused both acute and chronic COVID–19 disease during the recent pandemic with emerging more transmissible SARS–CoV–2 Omicron variants (BQ1 and XBB1) that have increased demands for more effective immunogens and therapeutic approaches to protect the lives of numerous SARS–CoV-2 affected individuals and reduce overall disease burden that could be affected by concurrent other pathogens causing diseases. Following a worldwide campaign of mass vaccination, there is still a significant demand to quell the harmful effects of novel SARS–CoV–2 infections due to higher mutation rates within specific areas of the SARS–CoV-2 domain, leading to enhanced viral entry, especially within individuals with one or more significant comorbidities, and there is still a dilemma of how prevention of future pandemics will occur as within host animal mutations and cross species transfer naturally occurs. Concerns intersect at a specific point; a gained evolutionary ability of several viruses over the previous centuries to remain undetected during the first stages of infection by means of capping the 5' end of their DNA and RNA genes respectively. This may occur by reducing the rate of host Type I and Type III Interferons (IFN) cellular synthesis, that would usually occur and affect both apoptotic pathways, that facilitate viral replication and clearance, as well as immune cells, that process and present pathogenic antigen epitopes. Furthermore, although methods of vaccination exist, other methods in clinical development remain that could evoke an immune response in different cellular, serum or mucosal compartments being cellular, serum and mucosal that evoke differential antibody responses. Antibodies are classed as natural and synthetic. Natural antibodies are further classified into neutralizing and non-neutralizing, whilst synthetic antibodies are also further classified into monoclonal and polyclonal. As a result of single cell study transcriptome research, viruses do utilize an array of protein receptors for receptor-mediated cellular entry. This, therefore suggests that potential differential production of antibody immunoglobulins (Ig) within serum and mucosal areas remains affected by cytokines, adhesion molecules and chemokines that can be upregulated or downregulated upon host viral infection. Serum plasma antibodies can be multimeric that may not efficiently cross the nasal epithelium cell layer, therefore offering less protection against mucosal inflammation due to mucin proteins. On the other hand, antibodies produced by mucosal plasma cells at epithelial surfaces are known to provide effective immune responses in some viral infections. The existence of developments that stimulate mucosal immune responses has so far only been seen with influenza nasal immunogens. Nevertheless, scientists developed ways of immunization and early treatment worldwide that generally showed good success rates and fewer risks of adverse events, and the still early present stages of COVID-19 research should also be taken into consideration. For example, the administration of human interferons I and III into the nasal mucosa cellular layer, as key mediators of anti–viral activity, can stimulate cellular activity to train the innate and adaptive immune system cells to develop and appropriately stimulate an adequate immune response through B and T cells. Recently, it was discovered that specific plants secrete proteins that also stimulate the production of Type I Interferons. It might be that focusing on directly offering the immune system the information about the genetics and protein structure of the pathogen, rather than training its first-line mechanisms to develop faster, excessively increases its specificity, making it reach a level that brings the virus the opportunity to evolve and escape previously-developed host immune mechanisms. Naturally-selected polymorphic viruses through genetic recombination pose challenges to traditional concepts of cellular and molecular immune system neutralization of these viruses during the first stages of cellular infection. It is until the scientific community realizes this potentially crucial aspect that we will probably continue to face serious epidemics and pandemics of respiratory diseases over the coming several decades, evidenced with dengue fever and more recently monkeypox. Type I IFNs tend to be produced faster than Type III IFNs, and the first induce slightly more abundant pro-inflammatory signals than the latter, meaning that type III IFNs, if produced early, may further decrease the extent of excessive proinflammatory signals. Hence, we believe that nasal sprays containing a low dosage of Type I and Type III IFNs not only represent a relevant COVID-19 therapeutic, but also a potential unknown modulatory therapy of the future. Of note, it has been indicated that IFN I and / or III display significant immunizing and early therapeutic effects for other viral evoked diseases like Influenza (Influenza (A)H1N1), rabies (Rabies lyssavirus), measles (Measles virus), rubella (Rubivirus rubellae), Hepatitis B, HIV-induced AIDS, Ebola, Marburg, as well as bacterial diseases, such as lower respiratory tract infectious diseases induced by Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus, and a number of oncological diseases, like hepatic melanoma.

Prevalence of respiratory pathogens in COVID patients (preprint)

Background: Management of a novel respiratory virus causing severe pneumonitis included the use of antibiotics to prevent bacterial co-infections and secondary infections. However, the impact of this antibiotic use on the selection of resistant bacterial isolates needs to be evaluated. Methods: We conducted a single-center retrospective study from November 14, 2020 to December 31, 2021 to assess the prevalence of several members of the nasopharyngeal microbiota from PCR-positive SARS-CoV-2 subjects. The study population corresponded to 1030 nasopharyngeal swabs positive for SARS-CoV-2 at the university hospital of Rouen site in symptomatic patients aged 16 years and older. Real-time PCR was used to detect the presence of Haemophilus influenzae, Streptococcus pneumonia, Neisseria meningitidis and influenza A virus. An analysis of the ftsI gene was further used to analyze beta-lactam resistance in H. influenzae. Results: The results reveled less than expected carriage rate with 5% for H. influenzae, 1.2% for N. meningitidisand 3.7% for S. pneumoniae and an absence of influenza A. On the other hand, there was a significant difference (p<0.01) between the "carriage" and "no carriage" groups on age, sex, oxygen therapy and orotracheal intubation, implying a more severe evolution of the COVID-19 in carriers. Analysis of the ftsI gene reveals 26% of predicted resistance to amoxicillin without resistance to third generation cephalosporins. Conclusions: COVID-19 pandemic has disrupted bacterial and viral epidemiology, leading to lower circulation of several respiratory pathogens.

Sustained reductions in life-threatening invasive bacterial diseases during the first two years of the COVID-19 pandemic: analyses of prospective surveillance data from 30 countries participating in the IRIS Consortium (preprint)

Background The Invasive Respiratory Infection Surveillance (IRIS) Consortium was established to assess the impact of the COVID-19 pandemic on invasive diseases caused by Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis and Streptococcus agalactiae. Here we analyse the incidence and distribution of disease during the first two years of the pandemic. Methods Laboratories in 30 countries/territories representing five continents submitted case data from 2018-2021 to private projects within databases in PubMLST. The impact of COVID-19 containment measures on the overall number of cases was analysed, and changes in disease distributions by patient age and serotype/group were examined. Interrupted time series analyses quantified the impact of pandemic response measures and their relaxation on disease rates, and autoregressive integrated moving average models estimated effect sizes and forecasted counterfactual trends by hemisphere. Findings Overall, 116,841 cases were analysed: 76,481 (2018-2019, pre-pandemic) plus 40,360 (2020-2021, pandemic). During the pandemic there was a significant reduction in the risk of disease caused by S pneumoniae (risk ratio: 0.47; 95% confidence interval: 0.40-0.55), H influenzae (0.51; 0.40-0.66) and N meningitidis (0.26; 0.21-0.31), whereas no significant changes were observed for the non-respiratory-transmitted pathogen S agalactiae (1.02; 0.75-1.40). No major changes in the distribution of cases were observed when stratified by patient age or serotype/group. An estimated 36,289 (17,145-55,434) cases of invasive bacterial disease were averted during the first two years of the pandemic among IRIS participating countries/territories. Interpretation COVID-19 containment measures were associated with a sustained decrease in the incidence of invasive disease caused by S pneumoniae, H influenzae and N meningitidis during the first two years of the pandemic, but cases began to increase in some countries as pandemic restrictions were lifted.

Pathogens in PICU before and during the SARS-CoV-2 Pandemic in China: A Multicenter Retrospective Study (preprint)

Background Nonpharmacological interventions for COVID-19 could reduce the incidence of children hospitalized in pediatric intensive care units (PICU) and the incidence of children with bacterial infections. This study aimed to evaluate changes in the bacterial profile of children in PICU before and during the COVID-19 pandemics. Methods The present study is a retrospective, involving clinical data of children with positive bacterial cultures admitted to the PICU respectively in 2019 and 2021. Results In total 652 children were included in this study. The total number of hospitalized patients and the incidence of bacteria-positive children in 2021 were lower than those in 2019. There were no significant differences in the ratio of Gram-positive bacterial infection, Gram-negative bacteria infection or fungi infection between the two years. The rate of Streptococcus pneumoniae in 2021 was higher than that in 2019(p = 0.127). The incidence of Haemophilus influenzae in hospitalized patients decreased with a downward trend(p = 0.002).The distribution of previous underlying diseases in children admitted to PICU with different outcomes of bacterial infection between the two years were homogeneous (P > 0.05). Conclusion After the implementation of COVID-19 isolation, prevention and control measures, the number of hospitalizations and bacterial infections in PICU decreased, which may be due to changes in population's behavior patterns. Meanwhile, the incidence of Haemophilus influenzae in hospitalized patients decreased with a downward trend. Trial Registration http://www.chictr.org.cn/index.aspx (ChiCTR2200057182). The date of registration is March 02, 2022.

Estimating the global and regional burden of meningitis in children caused by Haemophilus influenzae type b: A systematic review and meta-analysis.

Background: Haemophilus influenzae Type B (Hib) meningitis caused significant public health concern for children. Recent assessment in 2015 suggests vaccination has virtually eliminated invasive Hib diseases. However, many countries launched their programs after 2010, and few are yet to establish routine Hib immunisations. We therefore aimed to update the most recent global burden of Hib meningitis before the impact of COVID-19 pandemic, from 2010 to 2020, in order to aid future public health policies on disease management and prevention. Methods: Epidemiological data regarding Hib meningitis in children <5 years old were systematically searched and evaluated from PubMed and Scopus in August, 2020. We included studies published between 2010 and 2019 that reported incidence, prevalence, mortality, or case-fatality-ratio (CFR), and confirmation of meningitis by cerebrospinal fluid culture, with a minimum one year study period and ten cases. Each data was stratified by one study-year. Median study-year was used if information was not available. Quality of all studies were assessed using our adapted assessment criteria from Grading of Recommendations Assessment, Development and Evaluation (GRADE) and Study Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies from National Heart, Lung and Blood Institute (NHLBI). We constructed and visually inspected a funnel plot of standard error by the incidence rate and performed an Egger's regression test to statistically assess publication bias. To ascertain incidence and CFR, we performed generalised linear mixed models on crude individual study estimates. Heterogeneity was assessed using I-squared statistics whilst further exploring heterogeneity by performing subgroup analysis. Results: 33 studies were identified. Pooled incidence of global Hib meningitis in children was 1.13 per 100 000-child-years (95% confidence interval (CI) = 0.80-1.59). Southeast Asian Region (SEAR) of World Health Organisation (WHO) region reported the highest incidence, and European Region (EUR) the lowest. Considering regions with three or more data, Western Pacific Region (WPR) had the highest incidence rate of 5.22 (95% CI = 3.12-8.72). Post-vaccination incidence (0.67 cases per 100 000-child-years, 95% CI = 0.48-0.94) was dramatically lower than Pre-vaccination incidence (4.84 cases per 100 000-child-years, 95% CI = 2.95-7.96). Pooled CFR in our meta-analysis was 11.21% (95% CI = 7.01-17.45). Eastern Mediterranean Region (EMR) had the highest CFR (26.92, 95% CI = 13.41-46.71) while EUR had the lowest (4.13, 95% CI = 1.73-9.54). However, considering regions with three or more data, African Region (AFR) had the highest CFR at 21.79% (95% CI = 13.65-32.92). Before the coronavirus disease 2019 (COVID-19) impact, the estimation for global Hib meningitis cases in 2020 is 7645 and 857 deaths. Conclusions: Global burden of Hib meningitis has markedly decreased, and most regions have implemented vaccination programs. Extrapolating population-at-risk from studies has possibly led to an underestimation. Continuous surveillance is necessary to monitor vaccination impact, resurgence, vaccine failures, strain variance, COVID-19 impact, and to track improvement of regional and global Hib meningitis mortality.

Oral and gut microbiome biomarkers of susceptibility to respiratory tract infection in adults: a longitudinal cohort feasibility study (preprint)

Background and aim Respiratory tract infections (RTIs) are common in the community. There is some evidence that microbial biomarkers can be used to identify individuals most susceptible to RTI acquisition. We investigated the feasibility of recruiting healthy adults to collect at-home self-reported socio-demographic data and biological samples, saliva (oral) and stool (gut) at three time points (TPs): baseline/start of the study (TP-A), during an RTI (TP-B) and end of study (TP-C). Methods Healthy adults were recruited from two urban Bristol GP practices. To identify respiratory pathogens in all saliva samples and RTI-S stool samples reverse transcriptase PCR (RT-PCR) was applied. We compared oral and gut samples from participants who developed RTI symptoms (RTI-S) and those who remained healthy (no-RTI) using 16S rRNA profiling microbiome analysis to identify the core microbiome, alpha and beta diversity, and biomarkers for susceptibility to RTIs from baseline samples (TP-A) when all participants were healthy. Results We recruited 56 participants but due to the UK COVID-19 pandemic disruption we did not receive samples from 16 participants leaving 19 RTI-S and 21 no-RTI participants with socio-demographic and microbiome data. RT-PCR revealed coagulase-negative Staphylococcus carriage was significantly higher in RTI-S participants compared to those who remained healthy and RTI symptoms may have been due to viral influenzae and bacterial co-infection with Haemophilus influenzae . Core microbiomes of no-RTI participants contained a greater number of taxa compared to RTI-S participants. Microbial biomarkers of RTI susceptibility in the oral cavity were an increased abundance of the pathobiont Streptococcus sobrinus and decreased probiotic bacterium Lactobacillus salivarius whereas in the gut there was an increased abundance of the genus Veillonella and decreased abundance of Coprobacillus . Conclusion In our feasibility study we found oral and gut microbial biomarkers for susceptibility to RTI acquisition. Strategies to identify those most vulnerable to RTI in the community could lead to novel interventions to decrease respiratory infection and associated health services burden.

The Changing Pattern of Bacterial and Fungal Respiratory Isolates in Patients with COVID-19 Admitted to Intensive Care Unit (preprint)

Objectives: Severe acute respiratory syndrome 2 (SARS-CoV-2) pandemic has had a heavy impact on national health system, especially in the first wave. That impact hit principally the Intensive Care Units (ICUs). The large number of patients requiring hospitalization in ICUs lead to a complete upheaval of intensive wards. The increase in bed, the fewer number of nurses per patient, the constant use of personal protective equipment, the new antimicrobial surveillance protocols could have had deeply effects on microbiological flora of these wards. Moreover, the overconsumption of antimicrobial therapy in COVID-19 patients, like several studies report, could have impact of this aspect. Aim of this study is to evaluate the changing pattern of microbiological epidemiology during and before COVID-19 pandemic in a tertirary hospital ICUs. Methods: A retrospective, observational study was conducted in ICUs of “ASST Papa Giovanni XXIII”, a large tertiary referral hospital in Northern Italy. We have retrospectively collected the microbiological data from BAL and TA of patients hospitalized in ICUs from 22 nd February 2020 to 31 st May 2020 (Period 1) and from 22 nd February 2019 to 31 st May 2019 (Period 2). We compared the prevalence and the antibiotic profile of bacterial and fungal species in the two time periods. Results: The prevalence of Pseudomonas spp. shows a statistically significant increase from period 2 to period 1, as well as the prevalence of Enterococcus spp. On the contrary, the prevalence of Gram negative non fermenting bacteria (GN-NFB), Haemophilus influenzae and Streptococcus pneumoniae showed a significant reduction between two periods. Therewas a statistically significant increase in resistance of Pseudomonas spp. to carbapenems and piperacillin/tazobactam and Enterobacterales spp. for piperacillin/tazobactam, in period 1 compared to period 2, respectively. Conclusions: A changing pattern in prevalence and resistance profiles of bacterial and fungal species was observed during COVID-19 pandemic.

Reducing Childhood Immunization to Scale Up COVID-19 Immunization in Low- and Lower Middle-Income Countries: Impact on Under-Five Mortality (preprint)

Background: Since the onset of COVID-19 pandemic, many of the routine childhood immunization campaigns have been postponed or cancelled in many low and lower-middle income countries (LLMICs). In this study, we evaluated the impact of reduction in routine childhood immunization coverage in 75 LLIMCs on the under-five mortality.Method: We estimated the impact on under-five mortality of a 10%-point reduction in the childhood immunization coverage. The analysis was done based on the reported child mortality due to diphtheria, tetanus, pertussis, Haemophilus influenzae type b, Streptococcus pneumoniae , rotavirus, measles and tuberculosis, the baseline coverage of each vaccine in each country and the efficacy of each vaccine.Findings: We estimated a total of 188 078 under-five deaths per 10%-point reduction in childhood immunization coverage in LLMICs. Approximately 61% of the deaths would occur in Sub-Saharan Africa. More than half of the deaths would be due to whooping cough and diarrheal diseases. Furthermore, 31 of 41 Sub-Saharan African countries would have more than 50 extra deaths per 100 000. The most affected countries would be Chad, Niger, and the Central African Republic with 150 or more extra deaths per 100 000. Among the Asian LLMICs, Myanmar and Tajikistan would have the highest number of deaths.Interpretation: Shifting resources from routine childhood immunization to COVID-19 vaccine programs would increase under-five mortality from vaccine preventable diseases. Therefore, maintaining childhood immunization coverage is crucial along with the measures to control COVID-19 pandemic.Funding: This study has been funded by NORAD and Trond Mohn Foundation.Declaration of Interest: None to declare.

Indirect Effects of the COVID-19 Pandemic on Childhood Infection in England: A Population Based Observational Study (preprint)

Background: Children are largely unaffected following Sars-CoV-2 infection with low rates of significant disease and the inflammatory syndrome MIS-C. However, the lives of children have been substantially disrupted by the pandemic through physical distancing measures and the impact on health systems and economies. In this study, the impact of the COVID-19 pandemic on hospital admissions for childhood respiratory infections, severe invasive infections, and vaccine preventable disease in England was assessed along with associated mortality outcomes.Methods: In this population-based observational study, we examined hospital admission data from every National Health Service hospital from Mar 1 2017 to Feb 28 2021. We report monthly and annual numbers of individuals hospitalised with 19 common childhood respiratory, severe invasive, and vaccine preventable infections. We compare the frequency of admissions for these conditions before and after the onset of the pandemic in England and calculate percentage changes since Mar 1 2020 for each infection overall and by demographic characteristics including age, region, deprivation, and comorbidity, and quantify mortality outcomes.Findings: In the 12 months from Mar 1 2020, there were significant reductions compared with the preceding 36 months in the numbers of children admitted for every infection studied except pyelonephritis. These reductions were seen in all geographic regions, Index of Multiple Deprivation categories, ethnic groups and in those with underlying comorbidities. Among the respiratory infections, the greatest percentage reductions were for influenza where the number of individuals admitted decreased by 94% (95% CI 88, 97) from 5,061 (annual mean from Mar 1 2017 - Feb 29 2020) to 290 in the 12 months after Mar 1 2020, and for bronchiolitis where the number of individuals admitted decreased by over 80% (95% CI 78, 83) from 41,777 (annual mean 2017–2020) to 7,883 in 2020-21. Among the severe invasive infections, percentage decreases ranged from 20% (95% CI 13, 26) for osteomyelitis to 54% (95% CI 51, 56) for meningitis. Among the vaccine preventable infections, the greatest reduction was for measles, where the number of individuals admitted in the 12 months after Mar 1 2020 (n=12) was 92% lower (95% CI 84, 96) than the average number admitted in the previous three years (n=143). Admissions for Neisseria meningitidis decreased by 70% (95% CI 55, 80), and admissions for Streptococcus pneumoniae, Haemophilus influenzae and mumps more than halved. Alongside the decreases in admissions, there were also decreases in the absolute numbers of 60-day fatalities after admission for sepsis, meningitis, bronchiolitis, pneumonia, viral wheeze and upper respiratory tract infection (RTI). For pneumonia, although the absolute number of 60-day fatalities decreased (from a 3-year average of 159 to 115 after Mar 1 2020), the proportion of individuals admitted who died within 60 days increased (age-sex adjusted odds ratio 1.73, 95% CI 1.42, 2.11).Interpretation: During the COVID-19 pandemic, a range of behavioural changes (adoption of non-pharmacological interventions (NPIs)) and societal strategies (school closures, lockdowns and restricted travel) were used to reduce transmission of SARS CoV2 which have also significantly reduced transmission of common and severe childhood infections. NPIs could be used in the future to better protect healthcare systems and the most vulnerable children in society.Funding Information: Public Health England, Health Data Research UK, and the National Institute for Health Research Oxford Biomedical Research Centre.Declaration of Interests: None to declare. Ethics Approval Statement: Ethical approval to study the record-linked datasets was obtained from the Central and South Bristol Multi-Centre Research Ethics Committee (04/Q2006/176). All patient records were pseudonymized by the data providers through encryption of personal identifiers.

Inequities in childhood immunisation coverage associated with socioeconomic, geographic, maternal, child, and place of birth characteristics in Kenya (preprint)

Background The global Immunisation Agenda 2030 highlights coverage and equity as a strategic priority goal to reach high equitable immunisation coverage at national levels and in all districts. We estimated inequities in full immunisation coverage associated with socioeconomic, geographic, maternal, child, and place of birth characteristics among children aged 12-23 months in Kenya. Methods We analysed full immunisation coverage (1-dose BCG, 3-dose DTP-HepB-Hib (diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type B), 3-dose polio, 1-dose measles, and 3-dose pneumococcal vaccines) of 3,943 children aged 12–23 months from the 2014 Kenya Demographic and Health Survey. We disaggregated mean coverage by socioeconomic (household wealth, religion, ethnicity), geographic (place of residence, province), maternal (maternal age at birth, maternal education, maternal marital status, maternal household head status), child (sex of child, birth order), and place of birth characteristics, and estimated inequities in full immunisation coverage using bivariate and multivariate logistic regression. Results Immunisation coverage ranged from 82% [81–84] for the third dose of polio to 97.4% [96.7–98.2] for the first dose of DTP-HepB-Hib, while full immunisation coverage was 68% [66–71] in 2014. After controlling for other background characteristics through multivariate logistic regression, children of mothers with primary school education or higher have at least 54% higher odds of being fully immunised compared to children of mothers with no education. Children born in clinical settings had 41% higher odds of being fully immunised compared to children born in home settings. Children in the Coast, Western, Central, and Eastern regions had at least 74% higher odds of being fully immunised compared to children in the North Eastern region, while children in urban areas had 26% lower odds of full immunisation compared to children in rural areas. Children in the middle and richer wealth quintile households were 43–57% more likely to have full immunisation coverage compared to children in the poorest wealth quintile households. Children who were sixth born or higher had 37% lower odds of full immunisation compared to first-born children. Conclusions Children of mothers with no education, born in home settings, in regions with limited health infrastructure, living in poorer households, and of higher birth order are associated with lower rates of full immunisation. Targeted programmes to reach under-immunised children in these subpopulations will lower the inequities in childhood immunisation coverage in Kenya.

The Invasive Respiratory Infection Surveillance (IRIS) Initiative reveals significant reductions in invasive bacterial infections during the COVID-19 pandemic (preprint)

BackgroundStreptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis are leading causes of invasive diseases including bacteraemic pneumonia and meningitis, and of secondary infections post-viral respiratory disease. They are typically transmitted via respiratory droplets. We investigated rates of invasive disease due to these pathogens during the early phase of the COVID-19 pandemic. MethodsLaboratories in 26 countries across six continents submitted data on cases of invasive disease due to S pneumoniae, H influenzae and N meningitidis from 1 January 2018 to 31 May 2020. Weekly cases in 2020 vs 2018-2019 were compared. Streptococcus agalactiae data were collected from nine laboratories for comparison to a non-respiratory pathogen. The stringency of COVID-19 containment measures was quantified by the Oxford COVID-19 Government Response Tracker. Changes in population movements were assessed by Google COVID-19 Community Mobility Reports. Interrupted time series modelling quantified changes in rates of invasive disease in 2020 relative to when containment measures were imposed. FindingsAll countries experienced a significant, sustained reduction in invasive diseases due to S pneumoniae, H influenzae and N meningitidis, but not S agalactiae, in early 2020, which coincided with the introduction of COVID-19 containment measures in each country. Similar impacts were observed across most countries despite differing stringency in COVID-19 control policies. There was no evidence of a specific effect due to enforced school closures. InterpretationThe introduction of COVID-19 containment policies and public information campaigns likely reduced transmission of these bacterial respiratory pathogens, leading to a significant reduction in life-threatening invasive diseases in many countries worldwide.

Why Infants Rarely Die of COVID-19 and Morbidity and Mortality Rates Vary by Location: Pneumococcal and Hib Vaccinations as Possible Means to Mitigate Future Pandemics (preprint)

Two conundrums have puzzled COVID-19 investigators: 1) morbidity and mortality is rare among Infants and young children and 2) rates of morbidity and mortality exhibit very large variances across nations, locals and even within cities. These differences correlate with rates of Haemophilus influenzae type B (Hib) and pneumococcal vaccination, which are almost universal among infants and vary widely by geography among adults and the elderly. The higher the rate of vaccination, the lower the COVID-19 morbidity and mortality. Vaccination rates with other vaccines, including BCG and poliovirus, do not correlate with COVID-19 risks. Notably, both Hib and pneumoccoci are common co-infections with influenza and coronaviruses and are associated with more severe disease and risk of death. Whether the vaccines simply protect against COVID-19 complications, directly protect against COVID-19 infection by inducing cross-reactive immunity, or are markers for some other types of protection such as availability of better healthcare, is not yet known. What is known is that improving coverage rates of Hib and pneumococcal vaccination has significantly lowered severe morbidity and mortality in influenza epidemics and might have similar efficacy for mitigating coronavirus outbreaks. If infants and children are valid indicators, the beneficial effects might be very significant. The possibility that anti-viral proteins in milk (e.g., lactoferrin) protect against COVID-19 is also explored.