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Interactions between influenza and bacterial respiratory pathogens: implications for pandemic preparedness
Abstract
It is commonly believed that the clinical and epidemiological characteristics of the next influenza pandemic will mimic those of the 1918 pandemic. Determinative beliefs regarding the 1918 pandemic include that infections were expressed as primary viral pneumonias and/or acute respiratory distress syndrome, that pandemic-related deaths were the end states of the natural progression of disease caused by the pandemic strain, and that bacterial superinfections caused relatively fewer deaths in 1918 than in subsequent pandemics. In turn, response plans are focused on developing and/or increasing inventories of a strain-specific vaccine, antivirals, intensive care beds, mechanical ventilators, and so on. Yet, there is strong and consistent evidence of epidemiologically and clinically important interactions between influenza and secondary bacterial respiratory pathogens, including during the 1918 pandemic. Countermeasures (eg, vaccination against pneumococcal and meningococcal disease before a pandemic; mass uses of antibiotic(s) with broad spectrums of activity against common bacterial respiratory pathogens during local epidemics) designed to prevent or mitigate the effects of influenza-bacterial interactions should be major focuses of pandemic-related research, prevention, and response planning.
... In the fight against COVID-19, it is critical to know what other diseases are competing with the coronavirus to better manage resources in our health care facilities. Synergies between virus and bacteria have, in fact, already been observed with influenza A, since during the influenza pandemic of 1918-1919, a large number of cases of meningococcal meningitis were described following the initial viral infection [9]. Studies have shown the presence of an association between meningitis and influenza that measures the impact on airborne agents reduces both influenza and meningitis transmissions and thus reduces the incidence of invasive meningococcal disease (IMD) [9]. ...
... Synergies between virus and bacteria have, in fact, already been observed with influenza A, since during the influenza pandemic of 1918-1919, a large number of cases of meningococcal meningitis were described following the initial viral infection [9]. Studies have shown the presence of an association between meningitis and influenza that measures the impact on airborne agents reduces both influenza and meningitis transmissions and thus reduces the incidence of invasive meningococcal disease (IMD) [9]. This result was observed a century ago when the 3-foot bed distance in military barracks reduced the risk of infectious meningitis (IM) epidemics in recruits [10]. ...
... Thus, COVID 19 could have varieties of presentations that may include meningitis-like disease [38]. The association between secondary viral and bacterial infection was proven during the 1918 influenza A epidemic, including IMD [9,39]. ...
Bacterial meningitis is a diagnostic, therapeutic, and prophylactic emergency, particularly for children. In Morocco, meningitis remains a major public health challenge with lethality between 10% and 12% of cases. Our objective is to determine the impact of COVID-19 pandemic on the incidence of pediatric meningitis in central Morocco. A retrospective epidemiological study was carried out in the Department of Pediatric Emergencies of the Mother and Child Hospital of Marrakech in Morocco. Data were collected from patient files of Meningitis cases reported during the confinement period in March, April, and May of 2019 and 2020 respectively. Then, data were analyzed using SPSS software. The results showed a notification of 72 cases of suspected meningitis between March 2019 and March 2020 with dominance of boys (up to 70%) and age range of 1 month to 2 years (up to 34%). We noted a decrease in the number of patients hospitalized for suspected meningitis during COVID-19 pandemic. The final diagnosis of suspected meningitis was confirmed for 20% of the cases during the containment period against only 2.38% before the pandemic. This difference was statistically significant (P<0.05). Our investigations confirm the effect of the COVID-19 pandemic on the incidence of bacterial meningitis of children in the study area, more investigations are needed to generalize and explain these results in Morocco.
... Secondary bacterial infections play a crucial role in mortality and morbidity associated with several respiratory viral infections. 31,32 Bacterial superinfections often occur during outbreaks of viral infections and often leads to poor outcomes and fatal clinical complications. 28 [31][32][33] Over the past 2 decades, viral respiratory tract infections have contributed significantly to mortality in both developed and developing countries, and in most cases, deaths do not result from direct viral damage alone but instead most cases of deaths are associated with secondary bacterial infections. ...
... 31,32 Bacterial superinfections often occur during outbreaks of viral infections and often leads to poor outcomes and fatal clinical complications. 28 [31][32][33] Over the past 2 decades, viral respiratory tract infections have contributed significantly to mortality in both developed and developing countries, and in most cases, deaths do not result from direct viral damage alone but instead most cases of deaths are associated with secondary bacterial infections. 34 Table 1 shows common respiratory viral-bacterial coinfections. ...
... Despite the importance of these superinfections in large outbreaks of respiratory viral infections, they are often understated and understudied. 31 During the influenza pandemic in 1918, there was an estimated death toll of 40 to 50 million, many of which were as a result of pneumonia caused by Streptococcus pneumonia. 31 This implies that secondary bacterial super-infections were highly associated with severe disease. ...
As the world continues to respond to the coronavirus pandemic (COVID-19), there is a larger hidden threat of antimicrobial resistance (AMR) lurking behind. AMR remains worrisome in that the pathogens causing resistant infections to thrive in hospitals and medical facilities, putting all patients at risk, irrespective of the severity of their medical conditions, further compounding the management of COVID-19. This study aims to provide overview of early findings on COVID-19 and AMR as well as to provide recommendations and lesson learned toward improving antimicrobial stewardship. We conducted a rapid narrative review of published articles by searching PubMed and Google Scholar on COVID-19 and Antimicrobial Resistance with predetermined keywords. Secondary bacterial infections play crucial roles in mortality and morbidity associated with COVID-19. Research has shown that a minority of COVID-19 patients need antibiotics to treat secondary bacterial infections. Current evidence reiterates the need not to give antibiotic therapy or prophylaxis to patients with mild COVID-19 or to patients with suspected or confirmed moderate COVID-19 illness unless it is indicated. The pandemic has also brought to the fore the deficiencies in health systems around the world. This comes with a lot of lessons, one of which is that despite the advances in medicine; we remain incredibly vulnerable to infections with limited or no standard therapies. This is worth thinking in the context of AMR, as the resistant pathogens are evolving and leading us to the era of untreatable infections. There is a necessity for continuous research into understanding and controlling infectious agents, as well as the development of newer functional antimicrobials and the need to strengthen the antimicrobial stewardship programs.
... These approaches, in addition to be very informative about the dynamic interplay between the virus and the host and hence the pathogenesis mechanisms, could also constitute a powerful tool to identify new therapeutic targets and/or propose novel antiviral strategies. In the case of HRSV, few studies have investigated the transcriptomic host response using clinical specimens, and an even more limited number have exploited respiratory tract samples [16][17][18]. ...
... Moreover, given the fact that the main purpose of patient sampling is usually clinical analysis rather than research, the low quantity and quality of exploitable material is far from being optimal. In this study, we showed that these hurdles for the exploitation of highly Initial signature analysis enabled the identification of well known markers of HRSV infection, namely the upheaval of the immune cascade [15][16][17], notably highlighting the strong overturning of CXCL10/IP-10 gene expression. We then advantageously used a biologically relevant reconstituted human airway epithelia (HAE) model to reproduce and validate these results by NanoString nCounter assay. ...
... In intensive care units, COVID-19 patients are at high risk of developing secondary infections, including fungal 65 infections e .g. invasive pulmonary aspergillosis [16]. Indeed, a recent study on the French COVID-19 cohort reported that 33% of critically ill COVID-19 patients also showed invasive aspergillosis[17]. However, while the reasons for increased vulnerability to As pe rgillus in COVID-19 patients remain undetermined, the putative contribution of As pe rgillus to SARS- ...
Les infections respiratoires aigües (IRAs) sont causées par de nombreux pathogènes et parmi eux, les virus respiratoires tiennent une place très privilégiée. Les études épidémiologiques mettent en lumière de nombreux cas d’infections causées par des rhinovirus, des adénovirus, des pneumovirus (Virus Respiratoire Syncytial et Métapneumovirus humain) ou encore des coronavirus, mais également des virus influenza et parainfluenza. Les jeunes enfants et les personnes immunodéprimées ou âgées sont considérés comme des populations à risque, mais aucune tranche d’âge n’est épargnée par ces infections virales respiratoires. Celles-ci constituent de ce fait une cause majeure de consultations, d’hospitalisations et de décès dans les pays en développement, mais aussi industrialisés. Elles sont la première cause de mortalité chez les jeunes enfants (plus de 2 millions de morts par an) et leur coût direct annuel pour nos sociétés est estimé à 2.5 milliards d'euros. Malgré cela, l’arsenal thérapeutique et / ou prophylactique est très peu fourni ou inexistant, excepté en ce qui concerne les virus influenza, dont les solutions restent malgré tout, limitées. L’émergence de souches influenza résistantes aux quelques antiviraux sur le marché est en effet une source de préoccupation importante, au même titre que la protection conférée par les vaccins annuels qui est parfois sous-optimale, du fait de la grande variabilité des souches virales saisonnières. Dans ce contexte de besoins médicaux non pourvus et d’enjeux sanitaires et économiques majeurs, mon travail de thèse s’est inscrit dans un programme de recherche (RESPIROMIX) visant à proposer une stratégie innovante de développement d’antiviraux, basée sur le repositionnement de médicaments déjà sur le marché pour de nouvelles indications thérapeutiques anti-infectieuses. Mon travail s’est focalisé sur la caractérisation et l’exploitation de signatures transcriptomiques d’infections in vivo (banque d'échantillons biologiques de patients infectés) et in vitro (modèle d’épithéliums respiratoires humains cultivés en interface air/liquide), obtenues par hybridation sur puces Affymetrix et par séquençage à haut débit (NGS), respectivement. Nos choix éclairés d’outils et la mise en place d’un pipeline adapté et optimisé ont permis l’analyse différentielle et fonctionnelle de ces signatures virogénomiques, ainsi que leur comparaison avec un ensemble de signatures chemogénomiques, issues de la base de données Connectivity Map (CMap). Cette base de données est une collection de données d’expression issues de cellules humaines en culture, traitées ou non avec de petites molécules bioactives (plus de 7 000 profils d'expression génique correspondant à 1 309 composés). Mes résultats ont notamment contribué (i) à l’identification et au repositionnement comme inhibiteur des virus influenza du diltiazem, un médicament usuellement utilisé comme antihypertenseur, et (ii) à la caractérisation en modèles in vitro et murin de son mode d’action (MoA), qui se traduit par l’activation endogène des gènes codant pour les interférons de type III et des voies de biosynthèse métabolique. Ces résultats ont ainsi permis la mise en place d’un essai clinique multicentrique de phase II (FLUNEXT TRIAL PHRC n°15-0442), visant à évaluer le Diltiazem dans la prise en charge de patients admis en réanimation pour des grippes sévères. Dans la même dynamique, la méthodologie et le pipeline développés au cours de mon travail doctoral ont également conduit, sur la base de signatures de patients infectés, à la sélection de plusieurs autres médicaments pour leur repositionnement thérapeutique contre les infections à pneumovirus (HRSV et HMPV). Certains de ces candidats, sont actuellement en cours de validation dans nos modèles in vitro et murin d’infections
... SPN has been the most common bacteria found to be associated with SBIs (Morens et al. 2008) and historically it has been linked to exacerbation of disease during influenza epidemics and pandemics, including the 1918 Spanish flu (Brundage 2006, Joseph et al. 2013. The mechanisms by which the host is rendered more susceptible to SBIs postinfluenza has been the subject of numerous studies. ...
... One suggested mode has been via epithelial cell damage as a result of cytolytic viral infection or via host-induced inflammation, which can result in upregulation of the host receptor molecules that SPN utilise for attachment and colonisation (Håkansson et al. 1994, Peltola andMcCullers 2004). Influenza virus infection has also been associated with suppressed function of airway macrophages, neutrophils, and dendritic cells (DC; Williams et al. 2004, Brundage 2006, Shahangian et al. 2009) by virus-induced reduction in TLR-activation (Williams et al. 2004), thereby promoting propagation and entry of SPN into sterile sites of the body. Moreover, influenza virus-induced immune cell suppression has been shown to last for prolonged periods of time (Williams et al. 2004, Didierlaurent et al. 2008. ...
It is well established that influenza virus infections predispose individuals to secondary bacterial infections (SBIs), which may result in a range of clinical outcomes from relatively mild (e.g. sinusitis, otitis media) to severe (e.g. pneumonia and septicaemia). The most common bacterial pathogen associated with SBI following influenza virus infections is Streptococcus pneumoniae. Of circulating human seasonal influenza viruses, influenza A viruses (IAV) of both the A(H1N1)pdm09 and A(H3N2) subtypes are associated with severe disease but have differing hospitalisation and complication rates. To study the interplay of these two IAV subtypes with SBI, we used a ferret model of influenza infection followed by secondary challenge with a clinical strain of Streptococcus pneumoniae (SPN) to determine the severity and the period of susceptibility for SBI. Ferrets challenged with SPN 5 days after infection with A(H3N2) or A(H1N1)pdm09 viruses developed severe disease that required euthanasia. When the time between viral infection and bacterial challenge was extended, A/H1N1pdm09-infected animals remained susceptible to SBI- for up to 10 days after the viral infection. For A(H3N2)- but not A(H1N1)pdm09-infected ferrets, susceptibility to SBI-associated disease could be extended out to 16 days post viral infection. While caution should be taken when extrapolating animal models to human infections, the differences between A(H3N2) and A(H1N1)pdm09 strains in duration of susceptibility to SBI observed in the ferret model, may provide some insight regarding the higher rates of SBI-associated disease associated with some strains of A(H3N2) viruses in humans.
... S. pneumoniae was isolated in almost 50% of the cases of hospital-acquired pneumonia 4 . It is the most common bacteria found in viral secondary bacterial infections and is mostly associated with high mortality and morbidity during influenza epidemics and pandemics 5 . A recent investigation demonstrated that poor oral hygiene was linked to an increase in the number of obligate anaerobes located in the pneumonia-affected lungs of the studied patient population 6 . ...
Herbal medicine combined with nanoparticles has caught much interest in clinical dental practice, yet the incorporation of chitosan with Salvadora persica (S. persica) extract as an oral care product has not been explored. The aim of this study was to evaluate the combined effectiveness of Salvadora persica(S. persica) and Chitosan nanoparticles (ChNPs) against oropharyngeal microorganisms. Agar well diffusion, minimum inhibitory concentration, and minimal lethal concentration assays were used to assess the antimicrobial activity of different concentrations of ethanolic extracts of S. persica and ChNPs against selected fungal strains, Gram-positive, and Gram-negative bacteria. A mixture of 10% S. persica and 0.5% ChNPs was prepared (SChNPs) and its synergistic effect against the tested microbes was evaluated. Furthermore, the strain that was considered most sensitive was subjected to a 24-h treatment with SChNPs mixture; and examined using SEM, FT-IR and GC–MS analysis. S. persica extract and ChNPs exhibited concentration-dependent antimicrobial activities against all tested strains. S. persica extract and ChNPs at 10% were most effective against S. pneumoni, K. pneumoni, and C. albicans. SEM images confirmed the synergistic effect of the SChNPs mixture, revealing S. pneumonia cells with increased irregularity and higher cell lysis compared to the individual solutions. GC–MS and FT-IR analysis of SChNPs showed many active antimicrobial phytocompounds and some additional peaks, respectively. The synergy of the mixture of SChNPs in the form of mouth-rinsing solutions can be a promising approach for the control of oropharyngeal microbes that are implicated in viral secondary bacterial infections.
... Influenza is a seasonal, acute, communicable, epidemic respiratory illness caused by influenza viruses (1)(2)(3). It has been estimated that influenza leads to up to 500,000 deaths per year worldwide (4). ...
The gut-lung axis is critical during viral respiratory infections such as influenza. Gut dysbiosis during infection translates into a massive drop of microbially produced short-chain fatty acids (SCFAs). Among them, butyrate is important during influenza suggesting that microbiome-based therapeutics targeting butyrate might hold promises. The butyrate-producing bacterium Faecalibacterium duncaniae (formerly referred to as F. prausnitzii) is an emerging probiotic with several health-promoting characteristics. To investigate the potential effects of F. duncaniae on influenza outcomes, mice were gavaged with live F. duncaniae (A2-165 or I-4574 strains) five days before infection. Supplementation of F. duncaniae was associated with less severe disease, a lower pulmonary viral load, and lower levels of lung inflammation. F. duncaniae supplementation impacted on gut dysbiosis induced by infection, as assessed by 16S rRNA sequencing. Interestingly, F. duncaniae administration was associated with a recovery in levels of SCFAs (including butyrate) in infected animals. The live form of F. duncaniae was more potent that the pasteurized form in improving influenza outcomes. Lastly, F. duncaniae partially protected against secondary (systemic) bacterial infection. We conclude that F. duncaniae might serve as a novel next generation probiotic against acute viral respiratory diseases.
... In a gene expression study of individuals with acute respiratory distress syndrome (ARDS), the PI3 gene was downregulated in the blood of patients with an acute stage of ARDS [83]. Hypoxia or low oxygen availability in cells is a severe, life-threatening manifestation of ARDS caused by severe acute respiratory syndrome coronaviruses [85]. SARS-CoV-2 virus, the causative agent for Coronavirus Disease 2019 (COVID-19), can infect erythroid precursors and progenitors with the consequence of hypoxia to cells and tissues [42]. ...
The human placenta is a multifunctional, disc-shaped temporary fetal organ that develops in the uterus during pregnancy, connecting the mother and the fetus. The availability of large-scale datasets on the gene expression of placental cell types and scholarly articles documenting adverse pregnancy outcomes from maternal infection warrants the use of computational resources to aid in knowledge generation from disparate data sources. Using maternal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection as a case study in microbial infection, we constructed integrated datasets and implemented visual analytics resources to facilitate robust investigations of placental gene expression data in the dimensions of flow, curation, and analytics. The visual analytics resources and associated datasets can support a greater understanding of SARS-CoV-2-induced changes to the human placental expression levels of 18,882 protein-coding genes and at least 1233 human gene groups/families. We focus this report on the human aquaporin gene family that encodes small integral membrane proteins initially studied for their roles in water transport across cell membranes. Aquaporin-9 (AQP9) was the only aquaporin downregulated in term placental villi from SARS-CoV-2-positive mothers. Previous studies have found that (1) oxygen signaling modulates placental development; (2) oxygen tension could modulate AQP9 expression in the human placenta; and (3) SARS-CoV-2 can disrupt the formation of oxygen-carrying red blood cells in the placenta. Thus, future research could be performed on microbial infection-induced changes to (1) the placental hematopoietic stem and progenitor cells; and (2) placental expression of human aquaporin genes, especially AQP9.
... Additionally, infection rate increases for other respiratory pathogens may directly potentiate IMD increases. For example, historical evidence on individual and population levels link IMD with prior influenza infection [51]. ...
The global invasive meningococcal disease (IMD) landscape changed considerably during the COVID-19 pandemic, as evidenced by decreased incidence rates due to COVID-19 mitigation measures, such as limited social contact, physical distancing, mask wearing, and hand washing. Vaccination rates were also lower during the pandemic relative to pre-pandemic levels. Although policymakers may have shifted their focus away from IMD vaccination programs to COVID-19 vaccination programs, strong arguments support implementation and prioritization of IMD vaccination programs; IMD cases have increased in some countries and IMD rates may even have exceeded pre-pandemic levels. Additional concerns include increased susceptibility due to vaccination coverage gaps, increased incidence of other respiratory pathogens, immunity debt from lockdown restrictions, and increased IMD epidemiologic variability. The full range of benefits of widely available and effective meningococcal vaccines needs to be considered, especially in health technology assessments, where the broad benefits of these vaccines are neither accurately quantified nor captured in implementation policy decisions. Importantly, implementation of meningococcal vaccination programs in the current IMD climate also appeals to broader healthcare principles, including preparedness rather than reactive approaches, generally accepted benefit–risk approaches to vaccination, historical precedent, and the World Health Organization's goal of defeating meningitis by 2030. Countries should therefore act swiftly to bolster existing meningococcal vaccination strategies to provide broad coverage across age groups and serogroups given the recent increases in IMD incidence.
... Nanotechnology, also known as nanoparticle technology, is a field of study concerned with the possibility of processing matter on an atomic scale [1], with the goal of developing new methods and means whose dimensions are measured in nanometers, which is a thousandth of a micrometer, which is equivalent to a fraction of a millionth of a millimeter, and this technology is not limited to the field of biology [2][3]. Nanoscience or nanotechnology is one of the fields of materials science that directly relates to mechanical engineering, physics, chemical engineering, as it forms a group of branches and disciplines that investigate the properties of materials at a small level [4][5][6][7]. ...
In this study, lithium oxide nanoparticles were successfully prepared using a plant extract, which was diagnosed using XRD which was determined to comply with the international standard. It was also proven that the particles have very small dimensions that make them suitable for biological and medical uses. The most important results obtained is the effect of these particles in inhibiting bacteria with different extents and may reach 33 mm.
... Appreciation of the critical role that secondary bacterial infection plays in disease severity following influenza infection has led to studies to understand how viral infections and host immune responses may potentiate and exacerbate secondary bacterial infections. Numerous mechanisms have been proposed including bacterial production of proteases augmenting influenza infectivity by facilitating HA cleavage (54), enhanced bacterial colonization and adherence to host cells from viral damage (55,56), inhibition of respiratory cell repair (57), viral induced immunosuppression reducing the host's ability to fight bacteria (58)(59)(60), viral induced host inflammatory responses upregulating expression of host receptors available to bacteria (59,61), and other viral alterations of the immune response affecting bacterial pathogenesis (62,63). ...
The 1918 Spanish influenza pandemic was one of the deadliest infectious disease events in recorded history, resulting in approximately 50–100 million deaths worldwide. The origins of the 1918 virus and the molecular basis for its exceptional virulence remained a mystery for much of the 20th century because the pandemic predated virologic techniques to isolate, passage, and store influenza viruses. In the late 1990s, overlapping fragments of influenza viral RNA preserved in the tissues of several 1918 victims were amplified and sequenced. The use of influenza reverse genetics then permitted scientists to reconstruct the 1918 virus entirely from cloned complementary DNA, leading to new insights into the origin of the virus and its pathogenicity. Here, we discuss some of the advances made by resurrection of the 1918 virus, including the rise of innovative molecular research, which is a topic in the dual use debate.
... Pulmonary viral infections have been shown to both increase the likelihood and exacerbate the severity of secondary bacterial infections in the lung (1)(2)(3)(4)(5)(6)(7). The underlying immunological mechanisms are diverse and range from lung epithelial barrier breakdown and augmented adhesion of pathogens to the subversion of both adaptive and innate immunity from protective anti-bacterial pathways towards detrimental anti-viral inflammatory pathways like type-I interferon (IFN-I) (5,8). ...
Viral co-infections have been implicated in worsening tuberculosis (TB) and during the COVID-19 pandemic, the global rate of TB-related deaths has increased for the first time in over a decade. We and others have previously shown that a resolved prior or concurrent influenza A virus infection in Mycobacterium tuberculosis (Mtb)-infected mice resulted in increased pulmonary bacterial burden, partly through type I interferon (IFN-I)-dependent mechanisms. Here we investigated whether SARS-CoV-2 (SCV2) co-infection could also negatively affect bacterial control of Mtb. Importantly, we found that K18-hACE2 transgenic mice infected with SCV2 one month before, or months after aerosol Mtb exposure did not display exacerbated Mtb infection-associated pathology, weight loss, nor did they have increased pulmonary bacterial loads. However, pre-existing Mtb infection at the time of exposure to the ancestral SCV2 strain in infected K18-hACE2 transgenic mice or the beta variant (B.1.351) in WT C57Bl/6 mice significantly limited early SCV2 replication in the lung. Mtb-driven protection against SCV2 increased with higher bacterial doses and did not require IFN-I, TLR2 or TLR9 signaling. These data suggest that SCV2 co-infection does not exacerbate Mtb infection in mice, but rather the inflammatory response generated by Mtb infection in the lungs at the time of SCV2 exposure restricts viral replication.
... For most of those patients, SARS-CoV-2 infection was detected before or concurrent with IPD. This finding is similar to what has been observed for other viral infections, such as influenza viruses, rhinoviruses, and adenoviruses (19)(20)(21)(22). The mechanism through which SARS-CoV-2 ...
Streptococcus pneumoniae can co-infect persons who have viral respiratory tract infections. However, research on S. pneumoniae infections that are temporally associated with SARS-CoV-2 infections is limited. We described the epidemiology and clinical course of patients who had invasive pneumococcal disease (IPD) and temporally associated SARS-CoV-2 infections in Alaska, USA, during January 1, 2020-December 23, 2021. Of 271 patients who had laboratory-confirmed IPD, 55 (20%) had a positive SARS-CoV-2 test result. We observed no major differences in age, race, sex, or underlying medical conditions among IPD patients with and without SARS-CoV-2. However, a larger proportion of IPD patients with SARS-CoV-2 died (16%, n = 9) than for those with IPD alone (4%, n = 9) (p<0.01). IPD patients with SARS-CoV-2 were also more likely to be experiencing homelessness (adjusted OR 3.5; 95% CI 1.7-7.5). Our study highlights the risk for dual infection and ongoing benefits of pneumococcal and COVID-19 vaccination, especially among vulnerable populations.
... Therefore, endosomal TLR signaling may play an important role in activating antimicrobial responses at local infection sites and prevent systemic disease (Hafner et al., 2019). Several studies have reported a synergistic interaction for infection between S. pyogenes and pathogenic viruses of the respiratory tract (Brundage, 2006;Herrera et al., 2016), a fact made evident during the 1918 influenza pandemic (Morens and Fauci, 2007), the 2009 H1N1 influenza pandemic (Jean et al., 2010), and more recently, the 2019 SARS-CoV-2 pandemic (Khaddour et al., 2020). However, data on S. pyogenes superinfections are scarce and interactions with additional infective agents warrant further resource allocation and research (Turner, 2022). ...
Sepsis is a life-threatening condition and a significant cause of preventable morbidity and mortality globally. Among the leading causative agents of sepsis are bacterial pathogens Escherichia coli , Klebsiella pneumoniae , Staphylococcus aureus , Pseudomonas aeruginosa , and Streptococcus pyogenes , along with fungal pathogens of the Candida species. Here, we focus on evidence from human studies but also include in vitro and in vivo cellular and molecular evidence, exploring how bacterial and fungal pathogens are associated with bloodstream infection and sepsis. This review presents a narrative update on pathogen epidemiology, virulence factors, host factors of susceptibility, mechanisms of immunomodulation, current therapies, antibiotic resistance, and opportunities for diagnosis, prognosis, and therapeutics, through the perspective of bloodstream infection and sepsis. A list of curated novel host and pathogen factors, diagnostic and prognostic markers, and potential therapeutical targets to tackle sepsis from the research laboratory is presented. Further, we discuss the complex nature of sepsis depending on the sepsis-inducing pathogen and host susceptibility, the more common strains associated with severe pathology and how these aspects may impact in the management of the clinical presentation of sepsis.
... We could find no reports of pneumococcal SCJ arthritis that developed after influenza virus infection. Several mechanisms have been suggested for the association of S. pneumoniae infection with influenza virus infection, such as virus-induced conditions that promote bacterial growth, epithelial cell damage by influenza viruses, and enhancement of the inflammatory response [1,10]. Our patient had no typical symptoms or underlying conditions that could lead to the development of pneumococcal infection. ...
A 24-year-old female patient who had a type A influenza virus infection prior to admission visited our hospital complaining of a fever and right sternoclavicular pain. Blood culture was positive for penicillin-sensitive Streptococcus pneumoniae (pneumococcus). Magnetic resonance imaging of the right sternoclavicular joint (SCJ) showed a high signal intensity area on the diffusion-weighted images. Consequently, the patient was diagnosed with septic arthritis due to invasive pneumococcus. When a patient complains of gradually increasing chest pain after an influenza virus infection, SCJ septic arthritis should be considered in the differential diagnosis.
... For example, Clark et al. [43] reported that in England during the period following the relaxation of COVID-19 lockdown measures, MenB IMD cases in adolescents and young adults not only returned to pre-pandemic levels but rapidly exceeded them. An alternative hypothesis that may contribute to the explanation of low IMD incidence during the COVID-19 pandemic includes the suppression of seasonal respiratory viruses, such as influenza, which are associated with increased carriage and IMD [37,38,44]. Similar increases in childhood invasive pneumococcal disease (IPD) have been observed in the UK following the COVID-19 pandemic, despite modelling predictions that there would be a long-term reduced incidence [45]. ...
A combined Haemophilus influenzae type b (Hib)/meningococcal serogroup C (MenC) vaccine will soon be unavailable in the UK immunisation schedule due to discontinuation by the manufacturer. An interim statement by the Joint Committee on Vaccination and Immunisation (JCVI) advises stopping MenC immunisation at 12 months of age when this occurs. We undertook an analysis of the public health impact of various potential meningococcal vaccination strategies in the UK in the absence of the Hib/MenC vaccine. A static population-cohort model was developed evaluating the burden of IMD (using 2005–2015 epidemiological data) and related health outcomes (e.g., cases, cases with long-term sequelae, deaths), which allows for the comparison of any two meningococcal immunisation strategies. We compared potential strategies that included different combinations of infant and/or toddler MenACWY immunisations with the anticipated future situation in which a 12-month MenC vaccine is not used, but the MenACWY vaccine is routinely given in adolescents. The most effective strategy is combining MenACWY immunisation at 2, 4, and 12 months of age with the incumbent adolescent MenACWY immunisation programme, resulting in the prevention of an additional 269 IMD cases and 13 fatalities over the modelling period; of these cases, 87 would be associated with long-term sequelae. Among the different vaccination strategies, it was observed that those with multiple doses and earlier doses provided the greatest protection. Our study provides evidence suggesting that the removal of the MenC toddler immunisation from the UK schedule would potentially increase the risk of unnecessary IMD cases and have a detrimental public health impact if not replaced by an alternate infant and/or toddler programme. This analysis supports that infant and toddler MenACWY immunisation can provide maximal protection while complementing both infant/toddler MenB and adolescent MenACWY immunisation programmes in the UK.
... Zinc homeostasis genes were still upregulated (;3-to 4-fold) in the DyesMN strain under TPEN, suggesting that other factors also contribute to the increase in expression of these genes under reduced YesMN is required for robust colonization during concurrent influenza A infection. Epidemiological data show that bacterial-influenza A virus (IAV) coinfections occur in more than 30% of all IAV cases, predominantly with pneumococcus (33,34). These coinfections are associated with increased morbidity and mortality (35,36). ...
The ability to sense and respond rapidly to the dynamic environment of the upper respiratory tract (URT) makes Streptococcus pneumoniae (Spn) a highly successful human pathogen. Two-component systems (TCSs) of Spn sense and respond to multiple signals it encounters allowing Spn to adapt and thrive in various host sites. Spn TCS have been implicated in their ability to promote pneumococcal colonization of the URT and virulence. As the disease state can be a dead-end for a pathogen, we considered whether TCS would contribute to pneumococcal transmission. Herein, we determined the role of YesMN, an understudied TCS of Spn, and observe that YesMN contributes toward pneumococcal shedding and transmission but is not essential for colonization. The YesMN regulon includes genes involved in zinc homeostasis and glycan metabolism, which are upregulated during reduced zinc availability in a YesMN-dependent fashion. Thus, we identified the YesMN regulon and a potential molecular signal it senses that lead to the activation of genes involved in zinc homeostasis and glycan metabolism. Furthermore, in contrast to Spn monoinfection, we demonstrate that YesMN is critical for high pneumococcal density in the URT during influenza A virus (IAV) coinfection. We attribute reduced colonization of the yesMN mutant possibly due to increased association with and clearance by the mucus covering the URT epithelial surface. Thus, our results highlight the dynamic interactions that occur between Spn and IAV in the URT, and the role that TCSs play in modulation of these interactions.
... The extraordinary ability of this bacterium to become resistant to nearly all antibiotics via selected chromosomal genetic mutation and the spread of acquired resistance complicates the treatment of infected individuals (9). Gram-positive bacteria, such as Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae are known to cause post-influenza pneumonia (10), but Gram-negative bacteria, such as P. aeruginosa, are the more prominent pathogens that cause secondary bacterial pneumonia, according to recent clinical observations (2,4). A previous study showed that coinfection with influenza virus and P. aeruginosa occurred in 8% of patients at ICU admission (11). ...
Secondary bacterial infection greatly increased the morbidity and mortality of influenza virus infection. To investigate the underlying mechanism by which influenza impairs the pulmonary defense against secondary Pseudomonas aeruginosa ( P. aeruginosa ) infection, we established a lethal mouse model in which to study secondary P. aeruginosa infection after influenza virus infection. We found a significant increase in host susceptibility to a secondary infection with P. aeruginosa in mice after an influenza virus infection, and this was accompanied by severe immunopathology and pulmonary inflammation. Importantly, we demonstrated that neutrophils were essential for P. aeruginosa clearance in secondarily infected mice. Further, we revealed that influenza impaired the phagocytosis and digestion functions of pulmonary neutrophils for P. aeruginosa clearance. We identified that the activity of reactive oxygen species (ROS) and the myeloperoxidase (MPO) activity of neutrophils in the lungs played an important role in antibacterial host defense in influenza-infected lungs. Hereby, influenza virus infection causes deficient MPO activity in neutrophils, and this contributes to the increased susceptibility to secondary P. aeruginosa infection. Treatment with Bacillus Calmette-Guerin polysaccharide nucleic acid (BCG-PSN) prior to secondary P. aeruginosa infection may improve the function of neutrophils, resulting in significantly reduced lethality during secondary P. aeruginosa infection. We also demonstrated that treatment with anti-influenza immune serum during the early stage of an influenza virus infection could decrease the disease severity of secondary P. aeruginosa infection. Our findings suggest that improving the MPO activity of neutrophils may provide a therapeutic strategy for viral-bacterial coinfection.
IMPORTANCE A secondary bacterial infection, such as that of P. aeruginosa , often occurs after a pulmonary virus infection and contributes to severe disease. However, the underlying mechanisms responsible for viral-bacterial synergy in the lung remain largely unknown. In this study, we reported that influenza virus infection increases a host’s susceptibility to secondary infection by P. aeruginosa by reducing the MPO activity of neutrophils. We also demonstrated that treatment with BCG-PSN or anti-influenza immune serum prior to secondary P. aeruginosa infection can reduce the disease severity. Our findings suggest that improving the MPO activity of neutrophils may provide a therapeutic strategy for viral-bacterial coinfection.
... Dentre os mais graves e duradouros períodos pandêmicos já enfrentados pela humanidade, percebe-se um predomínio de infecções do trato respiratório dentre as doenças com potencial pandêmico. (Brundage, 2006) Em dezembro de 2019, na província de Wuhan (China) foi identificado o primeiro caso de COVID-19, pneumonia causada pelo SARS-CoV-2. Em março de 2020, considerando as proporções globais da infecção, foi declarada a pandemia da COVID-19 pelo diretor-geral da Organização Mundial da Saúde. ...
Além dos sinais e sintomas clássicos, uma variedade de manifestações em diferentes sistemas orgânicos já foi relatada durante a infecção pelo SARS-CoV-2. Números crescentes de estudos sobre manifestações dermatológicas são encontrados na literatura científica mundial. Em contrapartida, as alterações ungueais ainda são uma lacuna no conhecimento acerca da COVID-19 porque foram recentemente reconhecidas. Considerando o aumento da conscientização acerca das manifestações cutâneas dessa infecção, torna-se vital a investigação das alterações ungueais associadas para favorecer o diagnóstico precoce, intervenções mais precisas e melhores prognósticos nos pacientes com COVID-19. O objetivo é a realização de uma revisão de escopo para expandir o conhecimento sobreas alterações ungueais atribuídas à COVID-19 e o provável processo fisiopatológico que determina seu desenvolvimento. A presente revisão de escopo foi conduzida de acordo com a extensão da estratégia PRISMA-ScR, considerou apenas artigos em inglês publicados entre os anos de 2020 e 2022 no banco de dados PubMed. A estratégia de busca eletrônica usada foi ["nails" AND "COVID-19"]. Foram resgatados 52 estudos e 18 foram incluídas para compor a literatura de base para a revisão. Várias alterações ungueais já foram atribuídas à COVID-19, especificamente lúnulas vermelhas, linhas de Beau, leuconiquia, onicomadese, lesões transversais alaranjadas, COVID-toes, retroníquia múltipla, shorelinenails, unhas de Lindsay e unhas de Terry. É evidente que mais estudos precisam ser feitos para investigar de modo mais detalhado as alterações ungueais por COVID-19 para uma melhor compreensão e para que o manejo delas seja aprimorado.
... Las infecciones bacterianas secundarias juegan un papel importante en la morbilidad, y mortalidad en infecciones virales, sin embargo, a menudo se subestiman y son poco estudiadas; a pesar de que se tiene informes de este problema en pandemias anteriores. En 1918, durante la pandemia por influenza se reportaron aproximadamente de 40 a 50 millones de muertes por neumonía asociada a Streptococcus pneumoniae (Brundage, 2006;Gautret et al., 2020). ...
Algo que se ha pasado por alto durante la pandemia, es la relación del virus SARS-CoV2 con las bacterias resistentes. Un gran número de pacientes con COVID-19 han tenido infecciones secundarias, por bacterias resistentes o multirresistentes, adquiridas en
el hospital o asociadas a los respiradores, complicando la salud de los pacientes. Se estima que hasta el 50% de las defunciones por COVID-19 ha sido debido a infecciones bacterianas y no por el virus
... Studies have shown that pulmonary infections caused by respiratory viral infections such as influenza and respiratory syncytial virus can alter the gut microbiome (Wang et al., 2014;Yildiz et al., 2018). Viral infections easily cause secondary bacterial infections in patients, which often have a more severe clinical course (Brundage, 2006;Hanada et al., 2018). Recently, studies have provided direct evidence that altered fecal microbiota is associated with fecal SARS-CoV-2 levels and COVID-19 severity, and that the gut microbiota might be associated with COVID-19 severity by modulating host immune responses; strategies to alter the gut microbiota might reduce disease severity (Zuo et al., 2020;Yeoh et al., 2021). ...
Current studies have shown that gut microbiota may be closely related to the severity of coronavirus disease 2019 (COVID-19) by regulating the host immune response. Qing-Fei-Pai-Du decoction (QFPDD) is the recommended drug for clinical treatment of patients with COVID-19 in China, but whether it exerts a therapeutic effect by modulating the immune response through gut microbiota remains unclear. In this study, we evaluated the therapeutic effects of QFPDD in pneumonia model mice and performed 16S rRNA sequencing and serum and lung tissue metabolomic analysis to explore the underlying mechanisms during the treatment. Then, Spearman correlation analysis was performed on gut microbiome, serum metabolome, and immune-inflammation-related indicators. Our results suggest that QFPDD can restore the richness and diversity of gut microbiota, and multiple gut microbiota (including Alistipes, Odoribacter, Staphylococcus, Lachnospiraceae_NK4A136_group Enterorhabdus, and unclassified_f_Lachnospiraceae) are significantly associated with immune-inflammation-related indicators. In addition, various types of lipid metabolism changes were observed in serum and lung tissue metabolome, especially glycerophospholipids and fatty acids. A total of 27 differential metabolites (DMs) were significantly correlated with immune-inflammation-related indicators, including 9 glycerophospholipids, 7 fatty acids, 3 linoleic acid, 2 eicosanoids, 2 amino acids, 2 bile acids, and 2 others. Interestingly, these DMs showed a good correlation with the gut microbiota affected by QFPDD. The above results suggest that QFPDD can improve the immune function and reduce inflammation in pneumonia model mice by remodeling gut microbiota and host metabolism.
... Influenza is considered as a known potential risk factor for Staphylococcal diseases (3). There are strong and consistent pieces of evidence of epidemiologically and clinically important interactions between the influenza virus and secondary bacterial respiratory pathogens (4). A study in the United States (5) showed that S. aureus was the most common bacterial pathogen (44%) among the 36 children who died of bacterial co-infection reported during the 2004-2007 influenza season, while MRSA accounted for 60%. ...
With the rapid increase in the number of infections, children with Staphylococcus aureus ( S. aureus ) infection secondary to Influenza A virus (IAV), appear to have a great possibility of causing severe complications and illness. Despite some cases and research findings regarding the death of children with IAV and S. aureus , coinfection included, there were few details about successful treatment of pleural empyema and necrotizing pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) infection following IAV. In this case report, we describe the clinical symptoms and treatment of a teenager with pleural empyema and necrotizing pneumonia related to S. aureus secondary infection who was initially infected by IAV. This case highlights the importance of early recognition and application of thoracoscopy for this potentially fatal pleural empyema caused by MRSA and IAV coinfection. We conclude that this is a significant case that contributes to raising awareness regarding rarely occurring severe respiratory infections by MRSA in a child with normal immune function after IAV. In addition, further studies are needed to explore risk factors for IAV coinfection with S. aureus .
... The bacteria which are commonly associated with respiratory tract infections are Streptococcus pneumonia, Staphylococcus aureus and Haemophilus influenza and other associated bacteria include Streptococcus pyogenes, Pseudomonas aeruginosa and Moraxella catarrhalis 7,29 . From the last 20 years, S. pneumonia has shown to develop greater resistance to antibiotics like penicillin, doxycycline and secondgeneration and third-generation antibiotics 13,15 . ...
Respiratory tract infection (RTI) is among one of the common infections in human beings with life-threatening complications. Respiratory tract infection causes approximately 50 million deaths globally. The present study aimed to analyze two essential oils' anti-proliferative and antimicrobial activities against some common respiratory tract infection-causing microbes. The antibacterial activity of two essential oils including thyme and cinnamon oil, against the six RTI bacterial species, namely, Streptococcus pneumonia, Streptococcus pyogenes, Pseudomonas aeruginosa, Haemophilus influenza, Moraxella catarrhalis and Staphylococcus aureus, was assessed by cut well diffusion method. Cytotoxicity/anti-proliferative activity of essential oil (thyme and cinnamon) was investigated by using the SW480 cell line. The antibacterial activity of the oils was calculated by measuring the inhibitory zone and the maximum zone of 40.33 mm of cinnamon oil against H. influenza followed by a 40 mm zone of thyme oil against S. aureus and a minimum zone of 16.33 mm of cinnamon was observed against the S. pneumonia. The MIC value of the oils ranges from 0.10-0.60 mg/ml. The SW480 epithelial cells treated with the oils show an increase in cytotoxicity in a concentration-dependent manner. The in vitro cytotoxicity and antimicrobial activity results show that both the essential oils possess antimicrobial activity. The evidence shows that thyme oil has shown a little higher activity against respiratory tract infection. So, it can be used as an alternative to treat upper and lower respiratory infection-causing bacteria.
... In general, viral-bacterial coinfections are not uncommon, where S. aureus and pneumococcus are widely documented as complicating pathogens during infection with other viruses, most notably influenza A virus (IAV) [Reviewed in (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)]. During influenza pandemics, 45-95% of the mortality has been attributed to bacterial coinfections (47)(48)(49)(50). ...
Secondary bacterial infections can exacerbate SARS-CoV-2 infection, but their prevalence and impact remain poorly understood. Here, we established that a mild to moderate infection with the SARS-CoV-2 USA-WA1/2020 strain increased the risk of pneumococcal (type 2 strain D39) coinfection in a time-dependent, but sex-independent, manner in the transgenic K18-hACE2 mouse model of COVID-19. Bacterial coinfection increased lethality when the bacteria was initiated at 5 or 7 d post-virus infection (pvi) but not at 3 d pvi. Bacterial outgrowth was accompanied by neutrophilia in the groups coinfected at 7 d pvi and reductions in B cells, T cells, IL-6, IL-15, IL-18, and LIF were present in groups coinfected at 5 d pvi. However, viral burden, lung pathology, cytokines, chemokines, and immune cell activation were largely unchanged after bacterial coinfection. Examining surviving animals more than a week after infection resolution suggested that immune cell activation remained high and was exacerbated in the lungs of coinfected animals compared with SARS-CoV-2 infection alone. These data suggest that SARS-CoV-2 increases susceptibility and pathogenicity to bacterial coinfection, and further studies are needed to understand and combat disease associated with bacterial pneumonia in COVID-19 patients.
... Such discrepancies may be due to Nme strain variation in H 2 O 2 sensitivity, variable amount of H 2 O 2 expressed by the Streptococcal isolates, or the fact that the study by Pericone et al. (2000) was performed in rich media co-culture, in the absence of host cells and mucus. Infection with respiratory viruses, including respiratory syncytial virus (RSV) and Influenza virus A has also been correlated with increased risk of IMD (Cartwright et al., 1991;Brundage, 2006;Jacobs et al., 2014;Salomon et al., 2020). Infection modelling suggests that the neuraminidase of Influenza virus A can degrade the bacterial sialic acid capsule and therefore enhance the adhesion of Nme to the host epithelium (Rameix-Welti et al., 2009). ...
Neisseria meningitidis is a gram-negative diplococcus and a transient commensal of the human nasopharynx. It shares and competes for this niche with a number of other Neisseria species including N. lactamica, N. cinerea and N. mucosa. Unlike these other members of the genus, N. meningitidis may become invasive, crossing the epithelium of the nasopharynx and entering the bloodstream, where it rapidly proliferates causing a syndrome known as Invasive Meningococcal Disease (IMD). IMD progresses rapidly to cause septic shock and meningitis and is often fatal despite aggressive antibiotic therapy. While many of the ways in which meningococci survive in the host environment have been well studied, recent insights into the interactions between N. meningitidis and the epithelial, serum, and endothelial environments have expanded our understanding of how IMD develops. This review seeks to incorporate recent work into the established model of pathogenesis. In particular, we focus on the competition that N. meningitidis faces in the nasopharynx from other Neisseria species, and how the genetic diversity of the meningococcus contributes to the wide range of inflammatory and pathogenic potentials observed among different lineages.
... The most notorious flu pandemic, the Spanish flu, resulted in ~20-50 million deaths worldwide [29] more than a century ago, being the last great global pandemic before the ongoing pandemic caused by the SARS-CoV-2 virus. Interestingly, autopsy analysis of deceased patients from 1918 revealed a high frequency of secondary superinfection caused by URT bacteria [30], which could have contributed to this extremely high death rate. Indeed, IFV infections have been shown to disturb the microbial composition in the URT [31], affecting the relative abundances of bacteria from the genera Staphylococcus, Fusobacterium, Bacteroides, and others [32]. ...
On March 11, 2020, the World Health Organization declared a pandemic of coronavirus
infectious disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) and imposed the biggest public health challenge for our civilization, with unforeseen
impacts in the subsequent years. Similar to other respiratory infections, COVID-19 is associated with
significant changes in the composition of the upper respiratory tract microbiome. Studies have pointed to a
significant reduction of diversity and richness of the respiratory microbiota in COVID-19 patients.
Furthermore, it has been suggested that Prevotella, Staphylococcus, and Streptococcus are associated with
severe COVID-19 cases, while Dolosigranulum and Corynebacterium are significantly more abundant in
asymptomatic subjects or with mild disease. These results have stimulated the search for new
microorganisms from the respiratory microbiota with probiotic properties that could alleviate symptoms
and even help in the fight against COVID-19. To date, the potential positive effects of probiotics in the
context of SARS-CoV-2 infection and COVID-19 pandemics have been extrapolated from studies carried
out with other viral pathogens, such as influenza virus and respiratory syncytial virus. However, scientific
evidence has started to emerge demonstrating the capacity of immunomodulatory bacteria to beneficially
influence the resistance against SARS-CoV-2 infection. Here we review the scientific knowledge regarding
the role of the respiratory microbiota in viral infections in general and in the infection caused by
SARS-CoV-2 in particular. In addition, the scientific work that supports the use of immunomodulatory
probiotic microorganisms as beneficial tools to reduce the severity of respiratory viral infections is also
reviewed. In particular, our recent studies that evaluated the role of immunomodulatory Dolosigranulum
pigrum strains in the context of SARS-CoV-2 infection are highlighted.
... The exceptional lethality of the Spanish flu compared with subsequent influenza epidemics might also find an explanation that many if not most the fatal cases are believed to have occurred because of secondary complications caused by bacterial pathogens/infections (Taubenberger et al., 1997;Morens and Fauci, 2007). Bacterial superinfections were also found in fatal influenza infections during later influenza epidemics (Brundage, 2006), but did not cause this rampant mortality. ...
The COVID‐19 pandemic goes into its third year and the world population is longing for an end to the pandemic. Computer simulations of the future development of the pandemic have wide error margins and predictions on the evolution of new viral variants of SARS‐CoV‐2 are uncertain. It is thus tempting to look into the development of historical viral respiratory pandemics for insight into the dynamic of pandemics. The Spanish flu pandemic of 1918 caused by the influenza virus H1N1 can here serve as a potential model case. Epidemiological observations on the shift of influenza mortality from very young and old subjects to high mortality in young adults delimitate the pandemic phase of the Spanish flu from 1918 to 1920. The identification and sequencing of the Spanish flu agent allowed following the H1N1 influenza virus after the acute pandemic phase. During the 1920s H1N1 influenza virus epidemics with substantial mortality were still observed. As late as 1951, H1N1 strains of high virulence evolved but remained geographically limited. Until 1957, the H1N1 virus evolved by accumulation of mutations (‘antigenic drift’) and some intratypic reassortment. H1N1 viruses were then replaced by the pandemic H2N2 influenza virus from 1957, which was in 1968 replaced by the pandemic H3N2 influenza virus; both viruses were descendants from the Spanish flu agent but showed the exchange of entire gene segments (‘antigenic shift’). In 1977, H1N1 reappeared from an unknown source but caused only mild disease. However, H1N1 achieved again circulation in the human population and is now together with the H3N2 influenza virus an agent of seasonal influenza winter epidemics.
... Thus, viral and bacterial co-infection is related to increased mortality compared to single infections (Palacios et al., 2009;Hammerschmidt, 2016;Cawcutt and Kalil, 2017). Recently, it has been shown that co-infection occurs in seasonal and pandemic IAV infection in more than 30% of all cases (Brundage, 2006;Morens et al., 2008). The Gram-positive bacterium S. pneumoniae is mainly associated as secondary infection in IAV infected patients (Palacios et al., 2009). ...
Epithelial cells are an important line of defense within the lung. Disruption of the epithelial barrier by pathogens enables the systemic dissemination of bacteria or viruses within the host leading to severe diseases with fatal outcomes. Thus, the lung epithelium can be damaged by seasonal and pandemic influenza A viruses. Influenza A virus infection induced dysregulation of the immune system is beneficial for the dissemination of bacteria to the lower respiratory tract, causing bacterial and viral co-infection. Host cells regulate protein homeostasis and the response to different perturbances, for instance provoked by infections, by post translational modification of proteins. Aside from protein phosphorylation, ubiquitination of proteins is an essential regulatory tool in virtually every cellular process such as protein homeostasis, host immune response, cell morphology, and in clearing of cytosolic pathogens. Here, we analyzed the proteome and ubiquitinome of A549 alveolar lung epithelial cells in response to infection by either Streptococcus pneumoniae D39Δcps or influenza A virus H1N1 as well as bacterial and viral co-infection. Pneumococcal infection induced alterations in the ubiquitination of proteins involved in the organization of the actin cytoskeleton and Rho GTPases, but had minor effects on the abundance of host proteins. H1N1 infection results in an anti-viral state of A549 cells. Finally, co-infection resembled the imprints of both infecting pathogens with a minor increase in the observed alterations in protein and ubiquitination abundance.
... O vírus infetava as células do epitélio respiratório causando uma traqueobronquite aguda que se podia estender para o parênquima pulmonar e causar pneumonite viral (Taubenberger e Morens, 2008;Morens et al., 2008). A destruição do epitélio respiratório permitia a entrada de bactérias que colonizavam outras partes da árvore respiratória para dar início a pneumonia bacteriana (Brundage, 2006, Rosner, 2010Fornasin et al., 2018;Ferrari, 2020). A maioria das mortes ocorria 7 dias após o início da doença e foram o resultado de pneumonia bacteriana secundária causada por agentes bacterianos comuns no trato respiratório, como Haemophilus influenzae, Streptococcus pneumoniae, S. pyogenes ou Staphylococcus aureus (Shanks & Brundage, 2012;Opie et al., 1921). ...
A Gripe Espanhola, também chamada Pneumónica, foi uma pandemia causada pelo subtipo H1N1 de influenza, que surgiu em 1918, no último ano da I Guerra Mundial. O vírus afetava os pulmões e as vias respiratórias, provocava hemorragia pulmonar e infeção bacteriana secundária. Não se sabe a origem, mas ficou conhecida como Gripe Espanhola, já que os jornais espanhóis reportaram amplamente os efeitos do vírus no país, pois Espanha assumiu uma posição neutra na guerra, não sendo praticada a censura na imprensa. A pandemia disseminou-se por várias partes do mundo e teve três ondas, sendo que a segunda, no outono de 1918, foi responsável por elevadas taxas de morbilidade e mortalidade. No geral resultou em cerca de 500 milhões de infetados por todo o mundo e, em mais de 50 milhões de mortes. Distinguiu-se pela elevada mortalidade em jovens adultos. Portugal foi um país muito afetado. A Gripe Espanhola chegou ao país através do Alentejo, durante os meses de junho e julho de 1918.
Pretendemos, com o presente artigo, refletir sobre como a partir da pandemia de 1918-1919 desenvolveu-se o conhecimento científico na área da saúde pública e como os avanços científicos subsequentes facilitaram o desenvolvimento de medidas preventivas, incluindo vacinas e antivirais. Muitas lições da pandemia de Gripe Espanhola foram aprendidas e contribuíram para a história da ciência na prevenção de outras potenciais pandemias e epidemias que decorreram ou foram prevenidas no século XX e início do século XXI incluindo a pandemia da Covid-19.
... The mechanisms involved in such interactions include breakdown of physical barriers to tissue invasion; decreased mucociliary clearance activity; destruction, depression, and dysregulation of immune system components; increased aerosolization and dispersion of coinfecting agents; production of antibodies that block immune responses to other agents and up-regulation of expressions of genes that code for toxins. [27] In our patient, we could not isolate the organism; however presence of papilledema along with CSF picture and improvement with Meropenem points towards probable etiology of partially treated bacterial/viral infection. ...
Background and objective:
SARS-CoV-2 infections present with predominant respiratory symptoms. Only a few anecdotal reports of neurological involvement have come out from India so far. Adverse neurological events following immunization (AEFI) were also reported. We present the neurological symptoms seen either in association with vaccination or COVID-19 infection during the second wave.
Methods:
This was a retrospective study that included consecutive COVID-19 patients' admissions during the second wave of COVID-19 pandemic in two tertiary health care centres in Kerala. Neurological symptoms two weeks prior or thirty days after a positive status of antigen or RTPCR was termed as COVID-19-Associated Neurological Disorders (CAND) and those with neurological symptoms within one month of COVID-19 vaccination was termed as Post-Vaccinal Neurological Disorders (PVND).
Results:
During the study period, 1270 COVID-19 admissions were reported. We identified neurological symptoms in 42 patients (3.3%), of which 35 were CAND and 7 were PVND. Stroke was the most common (50%), followed by seizures and peripheral nervous system disorders (14.2% each). Encephalitis/demyelination (11.9%) and COVID-19-associated infections (9.5%) were also seen.
Conclusion:
During the SARS-CoV-2 pandemic, CAND and PVND have been emerging. Association of some of these may be fortuitous; however it is worth mentioning as pathogenic mechanisms of COVID-19 affecting various organ systems still remain unclear. Moreover, this may be helpful in future studies designing management options.
... Several factors have been implicated in secondary bacterial infection post-EIV infection, including viral denudation of the airway epithelium and surface receptor changes that may increase bacterial colonization [112,113]. Furthermore, in mice models, altered neutrophil functions and excessive production of immunosuppressive IL-10 have also been implicated [114][115][116][117]. Additionally, alveolar macrophages (AMs) have the ability to control bacterial infections by coordinating the innate immune response via the production of pro-inflammatory cytokines, and by recruiting and scavenging apoptotic polymorphonuclear cells [118,119]. ...
Influenza A viruses (IAVs) are important respiratory pathogens of horses and humans. Infected individuals develop typical respiratory disorders associated with the death of airway epithelial cells (AECs) in infected areas. Virulence and risk of secondary bacterial infections vary among IAV strains. The IAV non-structural proteins, NS1, PB1-F2, and PA-X are important virulence factors controlling AEC death and host immune responses to viral and bacterial infection. Polymorphism in these proteins impacts their function. Evidence from human and mouse studies indicates that upon IAV infection, the manner of AEC death impacts disease severity. Indeed, while apoptosis is considered anti-inflammatory, necrosis is thought to cause pulmonary damage with the release of damage-associated molecular patterns (DAMPs), such as interleukin-33 (IL-33). IL-33 is a potent inflammatory mediator released by necrotic cells, playing a crucial role in anti-viral and anti-bacterial immunity. Here, we discuss studies in human and murine models which investigate how viral determinants and host immune responses control AEC death and subsequent lung IL-33 release, impacting IAV disease severity. Confirming such data in horses and improving our understanding of early immunologic responses initiated by AEC death during IAV infection will better inform the development of novel therapeutic or vaccine strategies designed to protect life-long lung health in horses and humans, following a One Health approach.
... The interaction between viruses and bacteria is not a new phenomenon [72]: The associations between HIV and TB have been well documented, and CMV-associated symptoms, such as retinitis, constitute AIDS-defining illnesses [1, 73,74]. Severe bacterial pneumonia is common following influenza in human populations [75], and, experimentally, it has been found that mycobacterial growth is enhanced, and survival is decreased, when mice are exposed to influenza A virus prior to Mtb, in a type I IFNdependent pathway [76]. ...
Over 1 million children develop tuberculosis (TB) each year, with a quarter dying. Multiple factors impact the risk of a child being exposed to Mycobacterium tuberculosis ( Mtb ), the risk of progressing to TB disease, and the risk of dying. However, an emerging body of evidence suggests that coinfection with cytomegalovirus (CMV), a ubiquitous herpes virus, impacts the host response to Mtb , potentially influencing the probability of disease progression, type of TB disease, performance of TB diagnostics, and disease outcome. It is also likely that infection with Mtb impacts CMV pathogenesis. Our current understanding of the burden of these 2 diseases in children, their immunological interactions, and the clinical consequence of coinfection is incomplete. It is also unclear how potential interventions might affect disease progression and outcome for TB or CMV. This article reviews the epidemiological, clinical, and immunological literature on CMV and TB in children and explores how the 2 pathogens interact, while also considering the impact of HIV on this relationship. It outlines areas of research uncertainty and makes practical suggestions as to potential studies that might address these gaps. Current research is hampered by inconsistent definitions, study designs, and laboratory practices, and more consistency and collaboration between researchers would lead to greater clarity. The ambitious targets outlined in the World Health Organization End TB Strategy will only be met through a better understanding of all aspects of child TB, including the substantial impact of coinfections.
... Even with the global widespread use of the PCVs, S. pneumoniae remains a major bacterial cause of community-acquired pneumonia [70] and one of the main bacterial agents associated with viral co-infections. Since the first great influenza pandemic in 1918 [71], followed almost a century later in 2009 by H1N1 [72] and currently the worldwide COVID-19 pandemic [73] highlights continued surveillance and monitoring of S. pneumoniae as a priority. This study provides detailed genomic data of invasive pneumococcal isolates from national surveillance in Brazil, generating a baseline that can help for the creation of long-term surveillance to monitor the vaccine impact and public health strategies. ...
In 2010, Brazil introduced the 10-valent pneumococcal conjugate vaccine (PCV10) into the national children’s immunization programme. This study describes the genetic characteristics of invasive Streptococcus pneumoniae isolates before and after PCV10 introduction. A subset of 466 [pre-PCV10 (2008–2009): n =232, post-PCV10 (2012–2013): n =234;<5 years old: n =310, ≥5 years old: n =156] pneumococcal isolates, collected through national laboratory surveillance, were whole-genome sequenced (WGS) to determine serotype, pilus locus, antimicrobial resistance and genetic lineages. Following PCV10 introduction, in the <5 years age group, non-vaccine serotypes (NVT) serotype 3 and serotype 19A were the most frequent, and serotypes 12F, 8 and 9 N in the ≥5 years old group. The study identified 65 Global Pneumococcal Sequence Clusters (GPSCs): 49 (88 %) were GPSCs previously described and 16 (12 %) were Brazilian clusters. In total, 36 GPSCs (55 %) were NVT lineages, 18 (28 %) vaccine serotypes (VT) and 11 (17 %) were both VT and NVT lineages. In both sampling periods, the most frequent lineage was GPSC6 (CC156, serotypes 14/9V). In the <5 years old group, a decrease in penicillin ( P =0.0123) and cotrimoxazole ( P <0.0001) resistance and an increase in tetracycline ( P =0.019) were observed. Penicillin nonsusceptibility was predicted in 40 % of the isolates; 127 PBP combinations were identified (51 predicted MIC≥0.125 mg l ⁻¹ ); cotrimoxazole ( fol A and/or fol P alterations), macrolide ( mef and/or ermB ) and tetracycline ( tet M, tet O or tet S / M) resistance were predicted in 63, 13 and 21.6 % of pneumococci studied, respectively. The main lineages associated with multidrug resistance in the post-PCV10 period were composed of NVT, GPSC1 (CC320, serotype 19A), and GPSC47 (ST386, serotype 6C). The study provides a baseline for future comparisons and identified important NVT lineages in the post-PCV10 period in Brazil.
... Secondary infection, also known as co-infection, belongs to one of the leading causes of virus-related mortalities, especially the respiratory infections such as viral pneumonia (14,15). Generally, there are many opportunistic pathogens existing in human body, such as Mycoplasma pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pneumoniae and other resistant Enterobacteriaceae (16)(17)(18), with the changes of the immune system and micro-environment when fighting against the viral infection, these opportunists look to expand rapidly and cause severe secondary infection post-SARS-CoV-2-infection (19,20). ...
Emerging evidence has unveiled the secondary infection as one of the mortal causes of post-SARS-CoV-2 infection, but the factors related to secondary bacterial or fungi infection remains largely unexplored. We here systematically investigated the factors that might contribute to secondary infection. By clinical examination index analysis of patients, combined with the integrative analysis with RNA-seq analysis in the peripheral blood mononuclear cell isolated shortly from initial infection, this study showed that the antibiotic catabolic process and myeloid cell homeostasis were activated while the T-cell response were relatively repressed in those with the risk of secondary infection. Further monitoring analysis of immune cell and liver injury analysis showed that the risk of secondary infection was accompanied by severe lymphocytopenia at the intermediate and late stages and liver injury at the early stages of SARS-CoV-2. Moreover, the metagenomics analysis of bronchoalveolar lavage fluid and the microbial culture analysis, to some extent, showed that the severe pneumonia-related bacteria have already existed in the initial infection.
... Many cases of primary viral infection result in bacterial trafficking to the lower respiratory tract leading to bacterial and viral coinfections [1,4], which are characterized by an increased severity of the disease [2,5]. Recent studies have shown that seasonal influenza infections and influenza A virus (IAV) related pandemics like the "Spanish Flu" and others constitute of bacterial and viral co-infections in more than 30% of cases [6][7][8][9][10][11]. Bacterial pathogens, which are known to cause co-infections, are typical colonizers of the upper respiratory tract and include, amongst others, Streptococcus pneumoniae, Streptococcus pyogenes (group A streptococcus; GAS), and Staphylococcus aureus [12][13][14]. ...
Viral infections facilitate bacterial trafficking to the lower respiratory tract resulting in bacterial-viral co-infections. Bacterial dissemination to the lower respiratory tract is enhanced by influenza A virus induced epithelial cell damage and dysregulation of immune responses. Epithelial cells act as the first line of defense and detect pathogens by a high variety of pattern recognition receptors. The post-translational modification ubiquitin is involved in almost every cellular process. Moreover, ubiquitination contributes to the regulation of host immune responses, influenza A virus uncoating and transport within host cells. We applied proteomics with a special focus on ubiquitination to assess the impact of single bacterial and viral as well as bacterial-viral co-infections on bronchial epithelial cells. We used Tandem Ubiquitin Binding Entities to enrich polyubiquitinated proteins and assess changes in the ubiquitinome. Infecting 16HBE cells with Streptococcus pyogenes led to an increased abundance of proteins related to mitochondrial translation and energy metabolism in proteome and ubiquitinome. In contrast, influenza A virus infection mainly altered the ubiquitinome. Co-infections had no additional impact on protein abundances or affected pathways. Changes in protein abundance and enriched pathways were assigned to imprints of both infecting pathogens.
Significance
Viral and bacterial co-infections of the lower respiratory tract are a burden for health systems worldwide. Therefore, it is necessary to elucidate the complex interplay between the host and the infecting pathogens. Thus, we analyzed the proteome and the ubiquitinome of co-infected bronchial epithelial cells to elaborate a potential synergism of the two infecting organisms. The results presented in this work can be used as a starting point for further analyses.
... Although no antibiotics, antivirals or modern vaccines were available, passive immunisation with immunoglobulins was implemented (Luke et al., 2006). Mortality later in the pandemic is believed to be the result of secondary bacterial infections (Brundage, 2006, Morens et al., 2010. ...
Pandemic dynamics and health care responses are markedly different during the COVID-19 pandemic than in earlier outbreaks. Compared with established infectious disease such as influenza, we currently know relatively little about the origin, reservoir, cross-species transmission and evolution of SARS-CoV-2. Health care services, drug availability, laboratory testing, research capacity and global governance are more advanced than during 20th century pandemics, although COVID-19 has highlighted significant gaps. The risk of zoonotic transmission and an associated new pandemic is rising substantially. COVID-19 vaccine development has been done at unprecedented speed, with the usual sequential steps done in parallel. The pandemic has illustrated the feasibility of this approach and the benefits of a globally coordinated response and infrastructure. Some of the COVID-19 vaccines recently developed or currently in development might offer flexibility or sufficiently broad protection to swiftly respond to antigenic drift or emergence of new coronaviruses. Yet many challenges remain, including the large-scale production of sufficient quantity of vaccines, delivery of vaccines to all countries and ensuring vaccination of relevant age groups. This wide vaccine technology approach will be best employed in tandem with active surveillance for emerging variants or new pathogens using antigen mapping, metagenomics and next generation sequencing.
... 8 Thus, their pandemic potential is perceived to be less than influenza A. 7 However, influenza B viruses have the potential to predominate seasonal circulation as demonstrated during the 2019-2020 season 2 and have been shown to be associated with severe disease, in both pediatric and young adult populations. 5,9,10 The presence of comorbidities, including cardiovascular diseases and chronic lung diseases, represent known risk factors for severe influenza complications, 2 but these risk factors have primarily been derived from studies of patients with influenza A. 7,[11][12][13] In addition, the presence of coinfections with bacterial and/or viral pathogens has been found to be associated with increased disease severity, from studies of individuals with influenza A. [14][15][16] Systematic epidemiologic analyses regarding the association of comorbidity and coinfections in those infected influenza B have been relatively limited. 5,7,17 In this investigation, we retrospectively evaluated a large biorepository of nasopharyngeal specimens (NPs) taken from ED For all subjects who tested positive for influenza, a structured data collection form was completed by trained research coordinators using information from the electronic health records (EHR). ...
Background
Influenza B accounts for approximately one fourth of the seasonal influenza burden. However, research on the importance of influenza B has received less attention compared to influenza A. We sought to describe the association of both coinfections and comorbidities with disease severity among adults presenting to emergency departments (ED) with influenza B.
Methods
Nasopharyngeal samples from patients found to be influenza B positive in four US and three Taiwanese ED over four consecutive influenza seasons (2014–2018) were tested for coinfections with the ePlex RP RUO panel. Multivariable logistic regressions were fitted to model adjusted odds ratios (aOR) for two severity outcomes separately: hospitalization and pneumonia diagnosis. Adjusting for demographic factors, underlying health conditions, and the National Early Warning Score (NEWS), we estimated the association of upper respiratory coinfections and comorbidity with disease severity (including hospitalization or pneumonia).
Results
Amongst all influenza B positive individuals (n = 446), presence of another upper respiratory pathogen was associated with an increased likelihood of hospitalization (aOR = 2.99 [95% confidence interval (95% CI): 1.14–7.85, p = 0.026]) and pneumonia (aOR = 2.27 [95% CI: 1.25–4.09, p = 0.007]). Chronic lung diseases (CLD) were the strongest predictor for hospitalization (aOR = 3.43 [95% CI: 2.98–3.95, p < 0.001]), but not for pneumonia (aOR = 1.73 [95% CI: 0.80–3.78, p = 0.166]).
Conclusion
Amongst ED patients infected with influenza B, the presence of other upper respiratory pathogens was independently associated with both hospitalization and pneumonia; presence of CLD was also associated with hospitalization. These findings may be informative for ED clinician's in managing patients infected with influenza B.
Green nanoparticle production has received a lot of attention due to its medical and biological applications. In this study, lithium oxide Nano-particles (Li2O2 NP) were synthesized using aqueous extract from Hibiscus sabdariffa plants, and the results were examined using an ultraviolet-visible Spector-photometer, X-ray diffraction, Fourier transform infrared, and transmission electron microscopy, as well as antibacterial activity against a variety of microorganisms.
Background
The trends in clinical practice patterns and health resource use, as well as risk factors for severe conditions among children hospitalized with coronavirus disease-2019 (COVID-19), remain unclear.
Materials and Methods
We conducted a retrospective observational study consisting of 9876 children hospitalized with COVID-19 during 2020–2022 using the Medical Data Vision database in Japan. We investigated trends in patient characteristics, health resource use, treatment patterns and laboratory data. Additionally, log-binomial regression models were used to investigate the risk factors associated with severe COVID-19 among pediatric inpatients with COVID-19.
Results
We observed decreasing trends in the lengths of hospital stays, healthcare costs, computed tomography use, and antibiotic use, and increasing trends in treatment with intravenous hydration and use of antipyretics, antiepileptics, antiemetics and antivirals from the first wave to the seventh wave of COVID-19 pandemic. During the 3-year period, the risk of severe COVID-19 was almost stable at 3%. Risk factors associated with severe COVID-19 were children aged 0 years [risk ratio (RR): 1.69; 95% confidence interval (CI): 1.02–2.78], the number of complex chronic diseases (RR for 1 disease: 4.49; 95% CI: 2.76–7.32; RR for 2 or more diseases: 10.2; 95% CI: 5.19–20.3) and asthma (RR: 1.84; 95% CI: 1.06–3.20).
Conclusions
Our study observed the changes in practice patterns and health resource use for children hospitalized with COVID-19 and identified risk factors associated with severe COVID-19. These findings indicate the importance of vigilant monitoring and tailored treatment strategies in children with these risk factors.
The pathobiont, Nontypeable Haemophilus influenzae (NTHi), colonises the airway of individuals with chronic respiratory disease and is particularly associated with severe, neutrophilic, steroid-resistant asthma. Although NTHi has been implicated in asthma, respiratory tract viral infections remain the main aetiological agent of asthma exacerbations. However, it is now becoming clear that the presence of potentially pathogenic bacteria, such as NTHi, are present in the airway prior to respiratory tract viral infections. The macrophage is the predominant immune cell in the airway, yet accumulating evidence suggests NTHi is able to infect and persist within macrophages, which are also a target of the influenza A virus (IAV). It is unclear whether NTHi infection and persistence modulates macrophage responses to respiratory tract viral infections.
The aim of this thesis was to investigate modulation of macrophage gene expression during intracellular NTHi infection and how this interaction impacts on the response of these cells to subsequent infection with IAV. In addition, this thesis aimed to investigate transcriptomic alterations of NTHi during intracellular infection of macrophages, in order to identify mechanisms of persistence.
To achieve these aims, dual RNASeq analysis of an NTHi-monocyte-derived macrophage (MDM) infection model was performed. Transcriptomic analysis of NTHi-infected MDM identified enrichment of macrophage intracellular immune response pathways. Use of WGCNA identified CASP4, PNRC1 and SGPP2 to be the central MDM genes in the gene module most significantly associated with NTHi infection. Despite activation of MDM innate immune responses, NTHi was still able to persist within these cells. NTHi adaptation to persistence was associated with modulation of bacterial pathways involved in metabolic and stress responses, and downregulation of NTHi ribosomal protein genes. However, validation of the top NTHi differentially expressed genes bioC, mepM and dps, found strain-dependent expression of NTHi genes. Validation of select macrophage intracellular immune response genes demonstrated conservation of the MDM transcriptomic response when challenged with additional clinical strains of NTHi. Furthermore, NTHi presence was detected by FISH in 56% of severe asthma bronchoalveolar lavage (BAL) samples, which was associated with increased neutrophil inflammation (p=0.0462) and asthma duration (p=0.0436). Elevated IL1B (p=0.0041), GBP1 (p=0.0477) and SGPP2 (p=0.0221) gene expression was detected in samples determined as NTHi positive compared to NTHi negative, indicating modulation of airway inflammation by NTHi. Adaptation of the MDM model to incorporate the IAV following NTHi infection resulted in further modulation of the infection process; IAV replication levels decreased (p=0.0049), whereas NTHi load increased (p=0.0313). Decreased IAV levels was suggested to be due to NTHi-mediated upregulation of macrophage anti-viral immunity, specifically the type I IFN pathway, prior to IAV infection. Increased NTHi presence was associated with transcriptomic changes in NTHi genes previously identified to be involved in NTHi adaptation to intracellular persistence, bioC and mepM. Consequently, NTHi-infected macrophages exhibited a sustained inflammatory response, compared to MDM infected with IAV-alone.
The data in this thesis indicate the ability of NTHi to adapt in order to persist within macrophages, despite activation of macrophage intracellular immune response pathways. The subsequent modulation of IAV infection and NTHi colonisation during co-infection resulted in sustained macrophage inflammation that was not sufficient to completely clear either pathogen. Modulation of macrophage responses prior to and during bacterial-viral co-infection could have important implications for designing future studies to better our understanding of multiple host-pathogen interactions in the lung.
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.
Purposes
This study investigated the prevalence and clinical outcomes of pulmonary bacterial co-infections and secondary bacterial infections in patients with severe influenza pneumonitis.
Methods
We retrospectively analyzed the data of adult patients with severe influenza pneumonitis admitted to medical ICUs. Bacterial co-infections and secondary bacterial infections were identified. The risk factors of bacterial infection were evaluated. The outcomes of patients regarding co-infection or secondary bacterial infection were analyzed.
Results
We identified 117 critically ill patients with laboratory-confirmed influenza pneumonitis admitted to the medical ICUs. Klebsiella pneumoniae (31.4%) and Staphylococcus aureus (22.8%) were the most identified bacteria in patients with bacterial co-infection. A high proportion of methicillin-resistant Staphylococcus aureus (17.1%) was noted. Liver cirrhosis and diabetes mellitus were the independent risk factors for bacterial co-infection. Acinetobacter baumannii (30.7%) and S. aureus (23.1%) were the most often identified bacteria in patients with secondary bacterial pneumonia. Patients with secondary bacterial infections had a longer duration of mechanical ventilation, and longer ICU and hospital stay.
Conclusions
High rates of drug-resistant bacterial co-infections and secondary bacterial infections were identified in patients with severe influenza pneumonitis requiring ICU care and were associated with more morbidity in these patients.
Influenza virus and bacterial infection contributed to massive morbidity and mortality. However, the underlying mechanisms were poorly understood. A coinfected model was generating by using sublethal doses of influenza A virus H1N1 A/FM/1/47(H1N1) and methicillin-resistant Staphylococcus aureus (MRSA). Further, the model was optimized to achieve the highest peak of mortality initiated by intranasal infection with 0.2LD50 H1N1 and 0.16LD50 MRSA at 3 days interval. Excessive neutrophil recruitment, accompanied by high levels of inflammatory cytokines and chemokines, and increased bacterial and viral load were observed in coinfected mice. Under the inflammatory environments triggered by H1N1 and MRSA, the excessive neutrophil recruitment led to the formation of neutrophil extracellular traps (NETs), associated with severe inflammation and vascular endothelial injury. Importantly, the severity of lung injury could be alleviated by treatment with DNase I or a selective neutrophil elastase inhibitor (NEi). Therefore, our data suggested that excessive neutrophil recruitment and NETs formation contributed to severe inflammation and acute lung injury in coinfected animals.
Secondary bacterial infections can exacerbate SARS-CoV-2 infection, but their prevalence and impact remain poorly understood. Here, we established that a mild to moderate SARS-CoV-2 infection increased the risk of pneumococcal coinfection in a time-dependent, but sex-independent, manner in the transgenic K18-hACE mouse model of COVID-19. Bacterial coinfection was not established at 3 d post-virus, but increased lethality was observed when the bacteria was initiated at 5 or 7 d post-virus infection (pvi). Bacterial outgrowth was accompanied by neutrophilia in the groups coinfected at 7 d pvi and reductions in B cells, T cells, IL-6, IL-15, IL-18, and LIF were present in groups coinfected at 5 d pvi. However, viral burden, lung pathology, cytokines, chemokines, and immune cell activation were largely unchanged after bacterial coinfection. Examining surviving animals more than a week after infection resolution suggested that immune cell activation remained high and was exacerbated in the lungs of coinfected animals compared with SARS-CoV-2 infection alone. These data suggest that SARS-CoV-2 increases susceptibility and pathogenicity to bacterial coinfection, and further studies are needed to understand and combat disease associated with bacterial pneumonia in COVID-19 patients.
Objective:
Influenza co-infection with fungal infection increases the risk of death. Our study was to estimate risk factors associated with invasive pulmonary mycosis (IPM) among severe influenza patients at a single center in Beijing, China.
Methods:
A retrospective chart review was carried out of all patients with severe influenza admitted to respiratory the department including the respiratory intensive care unit (RICU) during the 2014 to 2019 influenza seasons in Beijing Chao-yang hospital, China. We compared the differences of characteristics and examination outcomes between IPM patients and non-IPM patients, and explored the predictors of IPM by a multivariate logistic regression.
Results:
Influenza associated IPM was found in 65 of 131 (49.62%) patients. The average age of IPM patients was 57.28±14.56 years and 70.77% were male. The mortality rate was much higher in the IPM group than the non-IPM group (34.85% versus 18.46%, P=0.026). Older age, hypoimmunity, liver disease, hypertension, positive serum GM test, steroids using, gasping, gastrointestinal symptoms, high APECHEII, low oxygenation index, other viruses co-infection, bacterial co-infection, low lymphocyte counts, low CD4+ T-cell counts, low CD8+ T-cell counts, low RBC, low hemoglobin, low platelets, high N%, low total protein, high CRP, low albumin, low fibrinogen, high BUN, positive serum GM test, more mechanical ventilation requirement, and more renal replacement requirement were risk factors of influenza IPM co-infection.
Conclusion:
IPM is a severe complication of influenza hospitalizations. It is associated with increasing mortality, longer hospital stays, and higher hospital charges compared with non-IPM patients. Clinicians caring for patients with severe influenza should consider IPM.
In the winter of 1998-1999 an outbreak of pneumococcal pneumonia occurred among Ranger students undergoing high-intensity training. Thirty pneumonia cases (attack rate = 12.6%) were identified among a group of 239 students. Eighteen students were hospitalized; Streptococcus pneumoniae-positive cultures were detected in 11 (61.1%) of these 18 hospitalized cases. Pneumococci were also identified in throat swabs of 30 (13.6%) of 221 nonhospitalized students surveyed. Serum antipneumolysin seroconversions were detected in 30 (18.3%) of 164 students tested. An association between development of serum antipneumolysin antibody and pneumococcal pharyngeal carriage/colonization was found. Of 30 seroconverters, eight (26.7%) had S. pneumoniae-positive cultures compared with only 17 (12.7%) of 134 nonseroconverters (relative risks = 2.02, 95% confidence interval = 1.02-4.02, p = 0.05). The outbreak was controlled by administrating low-dose, oral azithromycin prophylaxis (250 mg weekly for 2 weeks) and was associated with a 69% reduction in pneumococcal carriage and a 94% reduction in pneumonia rates.
An outbreak of highly pathogenic avian influenza A
(H5N1) has recently spread to poultry in 9 Asian countries.
H5N1 infections have caused >52 human deaths in
Vietnam, Thailand, and Cambodia from January 2004 to
April 2005. Genomic analyses of H5N1 isolates from birds
and humans showed 2 distinct clades with a nonoverlapping
geographic distribution. All the viral genes were of avian
influenza origin, which indicates absence of reassortment
with human influenza viruses. All human H5N1 isolates tested
belonged to a single clade and were resistant to the
adamantane drugs but sensitive to neuraminidase
inhibitors. Most H5N1 isolates from humans were antigenically
homogeneous and distinct from avian viruses circulating
before the end of 2003. Some 2005 isolates showed
evidence of antigenic drift. An updated nonpathogenic H5N1
reference virus, lacking the polybasic cleavage site in the
hemagglutinin gene, was produced by reverse genetics in
anticipation of the possible need to vaccinate humans.
The temporal and spatial association of meningococcal disease and influenza-like syndrome (ILS) was assessed from surveillance
data on these diseases in France for a 6-year period (19851990). Using time series methods to account for the usual seasonal
pattern of meningococcal disease, the incidence of meningococcal disease in a given week was found to be linked to incidence
of ILS in the 5 previous weeks but not to that in subsequent weeks. Geographic spread of meningococcal disease correlated
with spread of ILS. This study also suggests that meningococcal disease is more severe for a 2-month period during and after
an ILS epidemic: The proportion of cases with purpura fulminans increased by 24% and those resulting in death by 26% during
this period. No shift in the age distribution was observed. When an ILS epidemic is identified, medical practitioners should
be informed of the likelihood of an increased incidence and severity of meningococcal disease.
The influenza epidemic of 1918 killed more people in one year than the Great War killed in four, sickening at least one quarter of the world's population. In Fever of War, Carol R. Byerly uncovers the startling impact of the 1918 influenza epidemic on the American army, its medical officers, and their profession, a story which has long been silenced. Through medical officers' memoirs and diaries, official reports, scientific articles, and other original sources, Byerly tells a grave tale about the limits of modern medicine and warfare. The tragedy begins with overly confident medical officers who, armed with new knowledge and technologies of modern medicine, had an inflated sense of their ability to control disease. The conditions of trench warfare on the Western Front soon outflanked medical knowledge by creating an environment where the influenza virus could mutate to a lethal strain. This new flu virus soon left medical officers' confidence in tatters as thousands of soldiers and trainees died under their care. They also were unable to convince the War Department to reduce the crowding of troops aboard ships and in barracks which were providing ideal environments for the epidemic to thrive. After the war, and given their helplessness to control influenza, many medical officers and military leaders began to downplay the epidemic as a significant event for the U. S. army, in effect erasing this dramatic story from the American historical memory.
During the late fall and early winter of 1940-1941 an epidemic of influenza involved most sections of the United States, as well as the Hawaiian Islands, Puerto Rico and probably many other areas.¹ Virus isolations during the acute phase and immunologic studies of acute and convalescent phase serums on patients from widely scattered localities indicated that the virus of influenza A was by far the predominant, if not the only, one of the known viruses implicated in the epidemic.² If one judges from the available reports, the disease generally was mild and pulmonary complications were neither frequent nor severe.
The epidemic reached Boston late in December and persisted throughout January; most cases of the disease occurred during the first two weeks of the latter month. The clinical features of some of the uncomplicated cases, along with the results of virus isolations and immunologic studies, have been reported
It is common knowledge that neonatal staphylococcal disease has troubled hospitals ever since nurseries were first established as convenient places to house large numbers of newborn infants.1 In recent years, the increased frequency of occurrence of this disease throughout the world has focused additional attention on this problem, since nursery-acquired staphylococcal infection represents a substantial cause of death among infants during the first several months of life. In addition, this condition is a constant source of annoyance to patients as well as physicians because of such manifestations as pyoderma, conjunctivitis, and mastitis, occurring not only in the infants themselves but also among their family contacts and the medical personnel attending them.2
The introduction of phage typing methods3 has contributed a refinement to epidemiologic methods which make it possible to map out the routes by which a Staphylococcus aureus may spread through a hospital. Unfortunately, the very complexity
TOXIC shock syndrome is a potentially fatal multisystem illness associated with Staphylococcus aureus infection and production of toxins. Although this syndrome usually occurs in menstruating women, we saw a case of fatal toxic shock syndrome in a young man who developed S aureus pneumonia during an influenza outbreak.Report of a Case
A previously healthy 18-year-old male college student presented to a local hospital during an influenza outbreak with three days of fever, sore throat, myalgias, and diarrhea and one day of productive cough and dyspnea. His blood pressure was 80/60 mm Hg and his temperature was 39.4°C. He was admitted. Congested lung fields were noted. The leukocyte count was 3700/mm3 (3.7×109/L), with 18% (0.18) polymorphonuclear cells, 65% (0.65) band forms, 3% (0.3) lymphocytes, 1% (0.1) mononuclear cells, and 13% (0.13) metamyelocytes. The platelet count was 104000/mm3 (104×109/L) and the prothrombin and partial thromboplastin
Background : Nasal carriage of Staphylococcus aureus is common among health care workers, but outbreaks caused by such carriers are relatively uncommon. We previously reported outbreaks of S. aureus skin infections that affected newborn infants and were attributed to an S. aureus nasal carrier who had had an associated upper respiratory tract infection (URI) during the outbreak period. Objective : To investigate the contribution of a nasal methicillin-resistant S. aureus (MRSA) carrier (physician 4) who contracted a URI to an outbreak of MRSA infections that involved 8 of 43 patients in a surgical intensive care unit during a 3-week period. Design : An epidemiologic study of an outbreak of MRSA infections and a quantitative investigation of airborne dispersal of S. aureus associated with an experimentally induced rhinoviral infection. Setting : A university hospital. Participants : 43 patients in a surgical intensive care unit and 1 physician. Measurements : Molecular typing was done, and risk factors for MRSA colonization were analyzed. Agar settle plates and volumetric air cultures were used to evaluate the airborne dispersal of S. aureus by physician 4 before and after a rhinoviral infection and with or without a surgical mask. Results : A search for nasal carriers of MRSA identified a single physician (physician 4) ; molecular typing showed that the MRSA strain from physician 4 and those from the patients were identical. Multivariate logistic regression analysis identified exposure to physician 4 and duration of ventilation as independent risk factors for colonization with MRSA (P < 0.008). Air cultures showed that physician 4 dispersed little S. aureus in the absence of a URI. After experimental induction of a rhinovirus URI, physician 4's airborne dispersal of S. aureus without a surgical mask increased 40-fold ; dispersal was significantly reduced when physician 4 wore a mask (P < 0.015). Conclusions : Physician 4 became a cloud adult, analogous to the cloud babies described by Eichenwald and coworkers who shed S. aureus into the air in association with viral URIs. Airborne dispersal of S. aureus in association with a URI may be an important mechanism of transmission of S. aureus.
Asian influenza was first noted in New Haven late in September, 1957, and during the ensuing month a large number of patients with influenza was seen at the New Haven Hospital. In most the illness was benign; however, 91 were hospitalized during a six-week period in October and early November for a complication of influenza, usually pneumonia. Eleven of these patients died. It is the purpose of this report to summarize the experience with the complications of influenza, with particular emphasis on fatal cases of pneumonia.
Epidemiology
The arrival of the epidemic in New Haven was heralded by a sudden sharp increment in the number of adult medical patients seen in the emergency clinic. Usually medical house officers see from 120 to 150 patients per week, of whom only 10% have complaints referable to the respiratory system. This relationship is depicted in Figure 1 (Weeks 1-4). On Oct. 3, 1957
An outbreak of meningococcal disease among children on a school bus offered the opportunity to study a proposed association between this infection and preceding influenza infection. Five students who rode the bus became ill with invasive group C meningococcus. Transmission was limited to the bus; there was no evidence for school transmission. All five students reported influenzalike symptoms within several weeks before the development of meningococcal disease. School absenteeism, principally due to upper respiratory tract illness, was higher during the 3 weeks before the outbreak of meningococcal disease than during any period in the preceding 3 1/2 years, suggesting an unusually severe outbreak of respiratory illness. A case-control study comparing students with and without influenza symptoms revealed that the outbreak of respiratory disease was due to B/Ann Arbor/1/86 influenza (geometric mean titers, 86 for 80 patients and 33 for 47 controls [P=.0007]). These data add to the evidence suggesting that influenza respiratory infection predisposes to meningococcal disease.
(Arch Intern Med. 1991;151:1005-1009)
If an influenza pandemic struck today, borders would close, the global economy would shut down, international vaccine supplies and health-care systems would be overwhelmed, and panic would reign. To Emit the fallout, the industrialized world must create a detailed response strategy involving the public and private sectors.
Camp Devens had been somewhat forewarned of the impending epidemic of influenza through rumors of its existence in the naval district about Boston, so that on September 7 the admission from one company of fourteen men with ill-defined fever aroused immediate suspicion. These patients were at once isolated, and an intensive study was started on them. Blood and urine cultures were consistently negative; those from the nasopharynx were also unsatisfactory, owing to the fact that the technic employed at that time was in some respects inadequate. None of these first patients had deep enough pulmonary involvement to yield satisfactory sputum, so that it was impossible to utilize that method of diagnosis.A detailed account of the epidemic is not within the scope of this paper. It is quite sufficient to state that the disease spread like wildfire, and that in the course of four or five days the hospital was
In the standard textbooks the staphylococcus is usually noted among other micro-organisms as a possible etiologic agent in the production of bronchopneumonia. A detailed description of the clinical picture of the disease associated with the presence of this organism in the lung has thus far failed to come to our attention. This is no doubt due in part to the relative rarity of this infection as encountered in civil practice, and possibly to the lack of careful study of the bacteriology of acute respiratory affections until but recently. How rarely Staphylococcus aureus infection of the lung occurs and how grave the prognosis is may best be stated by noting that in a series of about 800 cases of pneumonia, drawn from all classes of the population of New York City, only thirteen cases were treated at the hospital of the Rockefeller Institute under the direction of Dr. Rufus Cole, in
The expected storm of the prevailing pandemic infection broke suddenly on the Eighth Division, U. S. Army, Camp Fremont, Calif., Oct. 8, 1918, and during the next six weeks, 2,418 patients suffering from respiratory diseases were admitted to the base hospital. In addition, many soldiers having more or less mild infections were cared for in the various camp infirmaries in order to avoid overcrowding in the base hospital. Altogether there were, at a conservative estimate, 3,000 cases.Pneumonia was diagnosed in 408 cases, an incidence of nearly 14 per cent. We know now, however, that there were many cases of pneumonia that were diagnosed as bronchitis, and that the true incidence of pneumonia was greater than that indicated.Of the 408 patients with pneumonia diagnosed, 147 died, a mortality of 36 per cent. for the pneumonia series and about 5 per cent. for the epidemic. No deaths occurred without a
Primary staphylococcic pneumonia has been adequately described as a clinical entity. Chickering and Park1 reported 155 cases of Staphylococcus aureus pneumonia occurring during the influenza epidemic of 1918. At this time there were 8,100 patients with influenza at Camp Jackson, S. C., approximately 1,400 of whom later developed inflammatory changes in the lungs. The picture, as described, was one of over-whelming sepsis, the temperatures ranging from 104 to 106 F. with frequent remissions. A peculiar "cherry red indigo blue cyanosis" was a regular accompaniment of the picture. Physical signs were diffuse and surprisingly sparse in view of the extensive consolidation on roentgenographic examination. The sputum was described as being friable, purulent and of a dirty salmon pink color resembling anchovy sauce or the "contents of an overripe furuncle"; on culture this yielded Staphylococcus aureus as the predominating organism. Because of technical difficulties, few blood cultures were taken, and two
The existence of an epidemic of influenza at Camp Pike was recognized when 214 cases of influenza were admitted to the base hospital, September 23. The epidemic was foreshadowed by a steady increase in the number of admissions to the base hospital diagnosed as acute bronchitis. This increase began about September 1, and on September 18 there were fifty admissions with this diagnosis.Beginning September 23, the number of cases showed a sudden and alarming increase. September 27, there were 1,037 new cases, and the number continued in the neighborhood of 1,000 a day until October 3, when the final decline began. During the period from September 20 to October 19, there were 11,899 cases of influenza. Table 1 gives the number of cases of influenza by days from September 1 to October 31, including those cases diagnosed as acute bronchitis during the first part of September, and also the
Influenza first made its appearance in epidemic form at the U. S. Naval Hospital, League Island, Pa., Sept. 12, 1918, on which day sixty-six patients were admitted from the receiving ship extension barracks. The epidemic continued in unabated form until September 17, when the crisis was reached.Our clinical observations were made on 600 cases of influenza of which 168 patients developed pneumonia; of the latter, forty-eight died. The disease spread more rapidly among men in barracks than among those living in tents.In general, the prognosis in uncomplicated cases of influenza is good as to life. Several instances of acute pulmonary tuberculosis have been observed following an attack of influenza, and it is very probable that latent tuberculosis lesions are converted into active foci by the influenza infection. Influenza occurring in patients with chronic diseases, such as nephritis, is a very serious matter.TREATMENT
No specific treatment has been
During an epidemic, in November and December 1968, the influenza A Hong Kong/68 virus was isolated from 127 adult patients. The procedures for isolation and identification of this virus are described. The clinical manifestations were similar to those of Asian influenza in 1957. Pneumonia was a complication in 20 cases. Based on roentgenograms, these cases were separated into the following two distinct syndromes: localized pneumonia (ten cases), either bacterial or viral, with low mortality (two deaths); and bilateral or diffuse pneumonia (ten cases), a primary influenza virus pneumonia, with high mortality (six deaths). Staphylococcus aureus or Pseudomonas aeruginosa infection was present in six of the eight fatal cases. Patients who were elderly, had associated chronic disease, or were hospitalized with other illnesses were most prone to develop pneumonia. Current methods of influenza control are discussed.
This investigation of pneumonia made at the base hospital at Fort Riley includes all cases of pneumonia that have occurred between July 23 and Aug. 31, 1918, at Camp Funston, including Detention Camp No. 1 for white troops and Detention Camp No. 2 for colored troops, in the 311th Cavalry stationed at Fort Riley, at the base hospital, and at the Medical Officers' Training Camp.During the period of the investigation there has been no large outbreak of pneumonia at Camp Funston. The average number of cases has been two a day, the total number studied being 62. The number of troops in the camp has been approximately 42,000, so that for the month of August the pneumonia rate has not exceeded 1.5 per thousand.Pneumonia has been of mild type; there have been only three deaths, and empyema has occurred in one instance. The clinical diagnosis has been lobar
These experiments were performed to ascertain whether patients who had recovered from the bronchopneumonia accompanying influenza had developed antibodies that could be demonstrated by the complement fixation test, Bacillus influenzae being used as antigen.During the recent epidemic in the First Naval District, attempts were made in this laboratory to demonstrate agglutinins, precipitins or opsonins in the blood of the patients who had the disease. The results so far have been negative with B. influenzae. This, indeed, was disappointing, as it was hoped that individuals who had recovered might show some demonstrable changes in the blood which would indicate the part the immune processes might have played in their recovery.This expectation was especially strengthened in view of the highly suggestive results obtained by Drs. McGuire and Redden1 in their treatment of patients in the active stage of influenzal pneumonia with serum from patients who had recovered from the
Sept. 21, 1918, an epidemic disease characterized by a sore or dry throat, cough, fever, general prostration, and in a certain number of patients by a rapidly progressing pneumonia, broke out at Camp Grant. While the date September 21 is given as the day of onset during which fifty-six patients were admitted to the base hospital, there had been about fifteen or twenty patients admitted during the three or four days immediately preceding with symptoms identical, and had been considered to have "influenza."The rapidity with which the disease spread can be appreciated best by reviewing the number of hospital admissions on the days succeeding the onset of the epidemic, indicated in Chart 1. The first death occurred on the third day, and the postmortem examination confirmed the clinical diagnosis of bronchopneumonia. The number of deaths on the subsequent days of the epidemic are indicated in Chart 2. Practically all
Bacteriological, serological, and clinical findings in 128 patients with pneumonia admitted to the medical service of Grady Memorial Hospital, Atlanta, during the 1968-1969 Hong Kong influenza epidemic were compared with the findings in patients with pneumonia admitted during a one-year period beginning July 1, 1967. During the influenza epidemic a threefold increase in the incidence of staphylococcal pneumonia occurred, which accounted for 25.9% of the bacteriologically proved cases. A high correlation between pneumonia, especially staphylococcal pneumonia, and influenza infection was documented. Comparison of preexisting disease in patients with pneumonia during the two time periods failed to reveal any major differences, which suggests similar host susceptibility during epidemic and nonepidemic periods. With no change in the case fatality rate, the excess influenza and pneumonia mortality during the Hong Kong epidemic was primarily due to the increased incidence of bacterial pneumonia.
From a knowledge of what other camps were experiencing with the epidemic of so-called "influenza," and in anticipation of an outbreak of a similar infection in this camp, certain preliminary bacteriologic work was attempted. Several days before any cases of influenza were reported at Camp Custer, a study was begun to determine the prevalent mouth flora of healthy individuals. For this purpose cultures were made from the throats of enlisted men of the Fourteenth Sanitary Train. Smears and cultures on plain blood agar plates were made from the nose and nasopharynx; in all, 357 cultures were taken. The usual mouth organisms were recovered. In addition, 75 per cent. of the cultures showed a hemolyzing streptococcus. In only five cases, or in a little more than 1 per cent., was the influenza bacillus identified. Before these studies could be extended, the epidemic broke. However, this much was apparent: A high percentage
The history of influenza so far as it is known, that is, for several centuries, comprises a series of long cycles in which great pandemics alternate with periods of relative quiescence, the length of cycles as measured by the intervals between pandemics being usually a matter of decades. The special characteristics of influenza pandemics are their wide and rapid extension, their high attack rates, and great effect on general mortality rates. Since these cycles are undoubtedly of fundamental significance in the natural history of influenza any proper discussion of the epidemiology of the disease should cover at least one full cycle, preferably the last, from 1889 to the present. The material for such a discussion must, however, be collected from many and diverse sources and laboriously fitted together, since there is no concrete specific and continuous record of the prevalence or mortality of influenza during such a period of years.
To present a paper on this subject at a time when the periodicals are filled with articles of similar title, and to an audience, almost every member of which has had an all too large personal experience with the subject, requires a word of explanation, if not of apology. To be accurate, the title should read "The Symptomatology and Complications of Influenza as Seen in the Army in This Country." No attempt is made to record the manifestations of this disease as they appear in children, in women, or in persons of advanced years; nor as observed in our own, or in other, armies in Europe. Moreover, the statements to be made relate solely to the great epidemic which swept over the country in the autumn of last year. It is interesting to note, however, that in the late winter and the spring of 1918, epidemics of what was regarded
At the time of the epidemic of influenza1 and influenzal pneumonia, the military population of the United States Reservation at Fort Riley was 63,374, distributed as in Table 1.The total number of cases of influenza were divided as shown in Table 2. The influenza incidence for the population of the military reservation was 23.9 per cent.As will be observed in Table 3, 2,624 instances of pneumonia occurred during the epidemic, of which 2,496 were definitely traceable to influenza. The largest number of influenza and pneumonia patients admitted to the base hospital was on September 30, when 785 were received. The largest total number of patients in the hospital was 5,666, October 8, of whom 2,951 had influenza and 719 influenzal pneumonia. The largest number of pneumonia patients at one time under treatment in the base hospital was 1,338, October 15, as shown in the accompanying chart. The incidence
During the period from Sept. 13 to Oct. 8, 1918, inclusive, there were admitted to the base hospital 2,487 cases of influenza, and 416 cases of pneumonia developed, practically all from the influenza cases. The pneumonia has differed in character so widely from the types reported elsewhere that a record seems to be advisable.Clinically, the disease was lobar pneumonia in all but fifty cases. Generally on the second to the fourth day of the influenza the temperature rose, usually, to about 104, occasionally with a distinct chill. Flatness over one lower lobe, often over both, was found at the first examination. In about half the cases suppressed respiration was noted, but crepitant râles could be elicited in nearly all cases and sharp bronchophony in a considerable number, even from the time of the first examination. Of the whole number of cases, in only four did the disease begin in
The influenza epidemic began at Camp Dix, [ill] 15, and ended, October 6. The number of daily admissions increased rapidly and reached the maximum, September 26, on which day 806 patients were received, making a total of 4,025 in the hospital on that date. The number then decreased daily, reaching the normal average of eighty admissions, October 7. During the twenty-two days of the epidemic, 6,500 patients were cared for. Approximately 6,000 of these men had influenza. There have been 800 deaths due to the epidemic. Four of our nurses and one dietitian died during the epidemic, contracting the disease while on duty. One medical officer was taken ill while on leave and died from bronchopneumonia a few days later at the Massachusetts General Hospital.When the epidemic began to subside and the hospital discharges to increase, wards were consolidated as rapidly as possible. The emptied wards were renovated and disinfected
Following the reports of a rapidly spreading and highly fatal pandemic of influenza and pneumonia in the Eastern States, and while the epidemic of influenza was raging at the Great Lakes Naval Training Station, a severe outbreak of this disease appeared among the civil population of Chicago. During the past five weeks, from September 23 to October 29, more than 2,000 patients were admitted to the wards of Cook County Hospital. Of these, 642 died, a mortality of 31 per cent. In the accompanying chart, of the first 500 deaths, it will be noted that the age period of highest mortality falls between 25 and 30 years.
Among the total number of admissions during this period there were 122 soldiers, and thus far twenty-one cases have terminated fatally—a mortality of 16 per cent. So far as the admissions to a large charity institution, such as the Cook County Hospital, may
Factors that affect the spread of Streptococcus pneumoniae and the antibody responses associated with colonization were studied in 64 families for periods of eight to 52 weeks. Surveillance
included daily recording of respiratory symptoms and bimonthly pharyngeal cultures for identification of the pneumococcal
currier state. Rhinovirus cultures were included for a portion of the study period. Intrafamilial carriage of a single type
of S. pneumoniae and simultaneous spread to more than one family member were common. Spread often occurred in association with an upper respiratory
tract infection; simultaneous transmission of S. pneumoniae and a rhinovirus was documented. Preexisting, type-specific serum antibody did not prevent acquisition of homotypic S. pneumoniae but did appear to shorten the duration of pharyngeal carriage. Sera of all 11 adults had > 150 ng of antibody nitrogen/ml
of homotypic serum antibody (measured by a radioimmunoassay) before colonization. In contrast, only one of 13 preschool children
had homotypic antibody concentrations of this magnitude before colonization. A threefold or greater rise in the concentration
of homotypic antibody occurred in 13 of 24 children (54%) after acquisition of S. pneumoniae ; the increase in antibody concentration was associated with illness in six of the children. On the other hand, acquisition
of S. pneumoniae in adults was not associated with an increase in concentration of homotypic serum antibody.
During an outbreak of meningococcal disease in a rural community in southwest Alabama in 1975-76, we undertook an aggressive campaign of house-to-house, community-wide chemoprophylaxis distribution. Over a three-day period 1,045 households were visited and 4,454 persons received medication. The 1970 census lists 967 households with 4,067 persons residing in the community. To evaluate compliance we cultured for meningococcal carriers before and after the chemoprophylaxis campaign. All of the previously discovered carriers were negative three weeks after the drug distribution. The cost of the campaign ($26,520) was very small compared to the possible benefit achieved. The methods of planning and executing this campaign are described in detail.
In experimental animals, influenza prediposes the lung to superinfection by reducing the antibacterial efficiency of the alveolar macrophage system. Because such defects may represent abnormalities in ingestion or inactivation of inhaled bacteria, these subcomponents of phagocytosis were tested in mice infected 5 days previously with influenza A virus (NWS or WSN). The mice were exposed to aerosols of Staphylococcus epidermidis and then the rates of bacterial inactivation and percentages of intracellularly located staphylococci were measured. Rates of bacterial inactivation were determined for the left lung by pour-plate enumeration methods. The percentage of ingested bacteria was determined in the in situ perfused right lung by histologically determining the intra- or extracellular location of 100 or more staphylococci. Rates of inactivation of S. epidermidis at 4 hours after bacterial challenge were: control, 90.1 per cent; WSN, 73.0 per cent; NWS, 68.6 per cent, P less than 0.01. The percentage of intracellular staphylococci at 4 hours were: control, 90.9 per cent; WSN, 69.9 per cent; and NWS, 73.8 per cent, P less than 0.01. Microcolonies of proliferating staphylococci were also observed within macrophages of mice infected with each strain of influenza. These experiments demonstrated that in this experimental model, influenzal infection impairs the inactivation of inhaled bacteria by retarding the ingestion of bacteria and by allowing bacteria to proliferate within macrophages.
The potential role of IgA antibody to Neisseria meningitidis, which blocks bacteriolysis by IgG and IgM, in producing the susceptible state in military recruits, a population at greater
than expected risk, was investigated in 28 patients with meningococcal disease. IgA was removed from acute-phase sera by immunoadsorption;
IgG was separated by ion-exchange, and IgM by gel-filtration chromatography. The bactericidal activity of acute-phase sera,
before and after removal of IgA, and of IgG and IgM fractions from the sera, was tested against each of the homologous infecting
strains. Bactericidal activity, the correlate of protective immunity, was deficient in 24 of 28 unabsorbed sera, but uniformly
present after the removal of IgA in a median titer of 1:16. IgM accounted for all or nearly all of the bactericidal activity.
IgG was largely inactive. Susceptibility to meningococcal disease may be affected by the blocking of bactericidal IgM by circulating
IgA.
An outbreak of meningococcal disease in a family of six resulted in four simultaneous cases of meningococcemia without meningitis. Although no definite explanation for this unusual collection of meningococcemia cases could be identified, a preceding influenza-like illness in the family may have increased their susceptibility to meningococcemia.
After an outbreak of acute rheumatic fever at a US Army training installation, a benzathine penicillin G prophylaxis program
was instituted. Surveillance data were analyzed to measure rates of febrile, acute respiratory disease (ARD)among trainees
before and after prophylaxis was begun. Annual admissions for ARD decreased from 1927 to 690 (−64.2%) after benzathine penicillin
G prophylaxis was begun. Admissions with throat cultures positive for Streptococcus pyogenes fell from 595 to 63 (−89.4%), a reduction that accounted only for a minority (43%) of the total 1237 "prevented" admissions.
Temporal changes in disease rates at other installations where drug was not administered were also analyzed. Only a small
decrease in the number of annual ARD admissions (−6.3%) was observed at other training installations. These findings support
a hypothesis that benzathine penicillin G has a broad effect in the prevention of ARD that extends beyond the simple elimination
of group A streptococcal infection.
There are several anecdotal accounts of the association between outbreaks of influenza and meningococcal disease. The exceptional increase in the number of cases of meningococcal infection 2 weeks after an influenza A outbreak in England and Wales during November and December, 1989, provided an opportunity to investigate the relation between the two events. Patients with meningococcal disease in December, 1989, were more likely than age-matched controls to show serological evidence of recent influenza A infection (odds ratio 3.9, 95% Cl 1.2-13.9). The most likely explanation for the association is immune suppression induced by influenza A, though a lowering of mucosal resistance to meningococcal invasion may also be a factor. Public health authorities should be aware of the association and should be prepared to alert medical practitioners and the public to the increased risk of meningococcal disease when influenza A outbreaks occur.
Chemoprophylaxis with antibiotics is both feasible and desirable for prevention of a potentially serious disease when specific
groups at risk can be defined and when a safe, effective, and affordable prophylactic agent is available. Although the Advisory
Committee on Immunization Practices recommends rifampin for prophylaxis of meningococcal disease, there are failures of treatment
and adverse reactions associated with the administration of this drug, and it cannot be used during pregnancy. In 1987, during
an outbreak of group A meningococcal disease in Saudi Arabia, the efficacy of a single intramuscular dose of ceftriaxone was
compared with the standard regimen of rifampin for eradication of pharyngeal carriage of Neisseria meningitidis among persons at risk. Follow-up cultures indicated successful eradication for 97% of those who received ceftriaxone and
75% of those who received rifampin. Thus, although ceftriaxone exceeds rifampin in fulfilling the criteria for an effective
prophylactic agent, recommendations regarding its use still must be made with caution because of limited clinical experience.
An outbreak of meningococcal disease among children on a school bus offered the opportunity to study a proposed association between this infection and preceding influenza infection. Five students who rode the bus became ill with invasive group C meningococcus. Transmission was limited to the bus; there was no evidence for school transmission. All five students reported influenza-like symptoms within several weeks before the development of meningococcal disease. School absenteeism, principally due to upper respiratory tract illness, was higher during the 3 weeks before the outbreak of meningococcal disease than during any period in the preceding 3 1/2 years, suggesting an unusually severe outbreak of respiratory illness. A case-control study comparing students with and without influenza symptoms revealed that the outbreak of respiratory disease was due to B/Ann Arbor/1/86 influenza (geometric mean titers, 86 for 80 patients and 33 for 47 controls [P = .0007]). These data add to the evidence suggesting that influenza respiratory infection predisposes to meningococcal disease.
Severe influenza virus infections with pneumonic involvement are known to predispose the lungs to bacterial superinfections due to dysfunctions in the alveolar macrophage (AM) phagocytic system. To determine whether milder forms of influenza without pneumonic involvement have a similar outcome, pulmonary antibacterial defenses and AM phagocytosis were compared in murine models of mild and severe influenza virus A/HK/68 infections. Bactericidal activity was quantitated by the intrapulmonary killing of Staphylococcus aureus following aerosol challenge, whereas the functional capacity of the AMs was determined by Fc-receptor-mediated phagocytosis. With the severe virus infection, maximal suppression of bactericidal activity occurred on day 8 of infection and correlated with impairment of AM phagocytosis. A lesser but significant degree of suppression of pulmonary antibacterial defenses and AM phagocytosis was observed on the third day of the mild virus infection. The data demonstrate that mild influenza virus infections that are limited to the upper respiratory tract also impair pulmonary antibacterial defenses and may predispose the lungs to bacterial superinfections.