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How do viral infections predispose patients to bacterial infections? Curr Opin Infect Dis
Abstract
Bacterial sepsis is a leading cause of death in the United States, accounting for over 200,000 fatalities annually. Approximately half of bacterial sepsis cases occur following acute respiratory infections, and the lungs are the most common organs to fail. Notably, outbreaks of respiratory viral infections are associated with an increased incidence or severity of bacterial co-infections, with normally innocuous infections often becoming fatal. Understanding the 'lethal synergism' associated with concomitant infections may point the way toward improved anti-sepsis treatments.
Murine models of viral and bacterial co-infection mimic the lethal synergism observed in humans and reveal at least two mechanisms of interaction. First, bacterial infiltration is heightened during acute viral infection. Secondly, the nature of responding cell populations is dramatically altered during concomitant infections. Although natural killer cells and macrophages are predominant cell populations responding to bacterial infection in a naïve host, there is also a large T cell component that is activated upon viral infection. Inflammatory cytokines produced by these cells contribute to lethal immunopathology, and therapeutic strategies need to target the initial causative microbes as well as subsequent inflammatory responses. Current therapies directed only at the host immune response have not been overly successful, owing largely to difficulties in reversing the severe immunopathology associated with sepsis.
Respiratory viral infections may facilitate secondary bacterial infections and increase host immunopathology through the overproduction of inflammatory cytokines. Preventive measures, including vaccination and aggressive antimicrobial therapy early in the course of infection, may significantly reduce the morbidity and mortality of sepsis.
... Despite the proven importance of secondary bacterial infections (SBIs) affecting the severity of viral respiratory diseases, they are still understudied during large outbreaks of viral respiratory infections. 3,4 There remains a knowledge gap in the nature, frequency, and antimicrobial profiles of secondary bacterial pathogens in the current COVID-19 pandemic. 5,6 Due to this knowledge gap and paucity of literature, the majority of patients tend to receive unnecessary empirical antibiotics, with no adherence to the antimicrobial stewardship guidelines. ...
... Acinetobacter species was the commonest organism (51, 35.6%) (49 Acinetobacter baumannii and 2 Acinetobacter nosocomialis), followed by Klebsiella pneumoniae (26,18.1%), Pseudomonas species (16,11%) (Pseudomonas aeruginosa [13], Pseudomonas stutzeri [3]), Escherichia coli (9%) and Burkholderia species (4.2%) (Burkholderia cepacia [3], Burkholderia cenocepacia (2), Burkholderia multivorans [1]). Most of the Acinetobacter species (74.5%) were found in ICU patients (Table 4). ...
... Acinetobacter species was the commonest organism (51, 35.6%) (49 Acinetobacter baumannii and 2 Acinetobacter nosocomialis), followed by Klebsiella pneumoniae (26,18.1%), Pseudomonas species (16,11%) (Pseudomonas aeruginosa [13], Pseudomonas stutzeri [3]), Escherichia coli (9%) and Burkholderia species (4.2%) (Burkholderia cepacia [3], Burkholderia cenocepacia (2), Burkholderia multivorans [1]). Most of the Acinetobacter species (74.5%) were found in ICU patients (Table 4). ...
Objective:
Bacterial co-pathogens are common in various viral respiratory tract infections, leading to increased disease severity and mortality. Still, they are understudied during large outbreaks and pandemics. This study was conducted to highlight the overall burden of these infections in COVID-19 patients admitted to our tertiary care hospital, along with their antibiotic susceptibility patterns.
Material and methods:
During the six-month study period, clinical samples (blood samples, respiratory samples, and sterile body fluids, including cerebrospinal fluid [CSF]) of COVID-19 patients with suspected bacterial coinfections (at presentation) or secondary infections (after 48 hours of hospitalization) were received and processed for the same.
Results:
Clinical samples of 814 COVID-19 patients were received for bacterial culture and susceptibility. Out of the total patient sample, 75% had already received empirical antibiotics before the samples were sent for analysis. Overall, 17.9% of cultures were positive for bacterial infections. Out of the total patients with bacterial infection, 74% (108/146) of patients had secondary bacterial infections (after 48 hours of hospitalization) and 26% (38/146) had bacterial coinfections (at the time of admission). Out of the 143 total isolates obtained, the majority (86%) were gram-negative organisms, of which Acinetobacter species was the commonest organism (35.6%), followed by Klebsiella pneumoniae (18.1%). The majority (50.7%) of the pathogenic organisms reported were multidrug resistant.
Conclusion:
The overall rate of secondary bacterial infections (SBIs) in our study was lower (7.9%) than reported by other studies. A rational approach would be to adhere to the practice of initiating culture-based guidance for antibiotics and to restrict unnecessary empirical antimicrobial therapy.
... . A partir de estudos clínicos, laboratoriais e epidemiológicos, conclui-se que o aumento significativo da taxa de mortalidade em relação aos pacientes infectados por agentes virais, se deve às infecções bacterianas secundárias(BEADLING;SLIFKA, 2004). Esses dados corroboram com epidemias passadas, como o surto da influenza em vários países, mostrando a influência das infecções bacterianas secundárias na taxa de mortalidade de indivíduos infectados pelo vírus influenza tipo A(JIA et al., 2017).Estudos realizados no "Hospital IRCCS San Raffaele" em Milão (Itália) relataram a incidência de infecções bacterianas secundárias em relação aos pacientes positivados com SARS-CoV-2 internados precocemente em UTIs, sendo 9,3% de um total de 731 indivíduos. ...
... . A partir de estudos clínicos, laboratoriais e epidemiológicos, conclui-se que o aumento significativo da taxa de mortalidade em relação aos pacientes infectados por agentes virais, se deve às infecções bacterianas secundárias(BEADLING;SLIFKA, 2004). Esses dados corroboram com epidemias passadas, como o surto da influenza em vários países, mostrando a influência das infecções bacterianas secundárias na taxa de mortalidade de indivíduos infectados pelo vírus influenza tipo A(JIA et al., 2017).Estudos realizados no "Hospital IRCCS San Raffaele" em Milão (Itália) relataram a incidência de infecções bacterianas secundárias em relação aos pacientes positivados com SARS-CoV-2 internados precocemente em UTIs, sendo 9,3% de um total de 731 indivíduos. ...
O novo Coronavírus atinge as células do trato respiratório inferior, iniciando um processo inflamatório. Diante dessa infecção, compete ao sistema imune a eliminação de agentes, a homeostasia celular, reparação tecidual e geração de imunidade de memória. Quando há uma falha nessa via, esse sistema encontra uma série de dificuldades para a retomada do equilíbrio, além de infecções secundárias, levando a complicações clínicas adicionais. Assim, este estudo buscou abordar a resposta imunológica frente ao Sars-CoV-2, e as principais infecções secundárias pós-Covid (bacterianas e fúngicas) e a resistência antimicrobiana nesse contexto. Trata-se de uma revisão de literatura realizada a partir da análise de periódicos provenientes das seguintes plataformas acadêmicas: Google Acadêmico, Center for Biotechnology Information (PubMed), Science Direct, Biblioteca eletrônica Scientific Eletronic Library Online (SciELO) e Scopus. A pesquisa foi delimitada em um intervalo de 2003 a 2021, usando como ferramenta de busca palavras-chaves COVID-19; Resposta imunológica; Infecções bacterianas; Infecções fúngicas; Resistência. Os resultados obtidos nos estudos demonstram o impacto das infecções secundárias na mortalidade, com isso, dentre as principais infecções, se destacam as bacterianas (84%), incluindo principalmente os agentes: Staphylococcus aureus, Streptococcus pneumoniae, Clostridioides difficile e Mycoplasma pneumoniae. Quanto às infecções secundárias fúngicas, as espécies Aspergillus sp. e Candida acometeram principalmente pacientes em estado grave. Com base nos dados, uma problemática evidente foi à dificuldade de identificação do agente causador da infecção secundária, acarretando em cenário de intensa utilização de antibióticos de amplo espectro, contribuindo para a seleção de patógenos resistentes e, de maneira controversa, a piora no prognóstico do paciente.
... Bacterial co-infection is known to be associated with higher mortality in the setting of viral and parasitic diseases. This is due to severe inhibition of the host's immune system as well as an increased resistance to the antibacterial therapy [1][2][3]. The devastating effects of a bacterial pneumonia in determining serious and fatal outcomes are not a novelty, as have been previously described in detail in association to other pandemic and non-pandemic viruses [4][5][6][7][8][9]. ...
... Notably, in 2004, Beadling and colleagues clarified that bacterial co-or super-infection of viral acute infections affects the outcome negatively through a severe alteration of the immune response; these include impaired natural killer cells and macrophage functions, co-activation of T cells, and lastly, hypersecretion of inflammatory cytokines. All of the previously depicted contribute to a lethal immunopathology [3]. Interestingly, similar cellular pathways have been reported in the pathogenesis of some central nervous system infections in which S. pneumoniae u-Ag has been thought as a potentially effective tool to detect an underlying pneumococcal infection in COVID-19 patients [36][37][38][39][40][41][42][43][44][45][46]. ...
Background and objectives:
Streptococcus pneumoniae urinary antigen (u-Ag) testing has recently gained attention in the early diagnosis of severe and critical acute respiratory syndrome coronavirus-2/pneumococcal co-infection. The aim of this study is to assess the effectiveness of Streptococcus pneumoniae u-Ag testing in coronavirus disease 2019 (COVID-19) patients, in order to assess whether pneumococcal co-infection is associated with different mortality rate and hospital stay in these patients.
Materials and methods:
Charts, protocols, mortality, and hospitalization data of a consecutive series of COVID-19 patients admitted to a tertiary hospital in northern Italy during COVID-19 outbreak were retrospectively reviewed. All patients underwent Streptococcus pneumoniae u-Ag testing to detect an underlying pneumococcal co-infection. Covid19+/u-Ag+ and Covid19+/u-Ag- patients were compared in terms of overall survival and length of hospital stay using chi-square test and survival analysis.
Results:
Out of 575 patients with documented pneumonia, 13% screened positive for the u-Ag test. All u-Ag+ patients underwent treatment with Ceftriaxone and Azithromycin or Levofloxacin. Lopinavir/Ritonavir or Darunavir/Cobicistat were added in 44 patients, and hydroxychloroquine and low-molecular-weight heparin (LMWH) in 47 and 33 patients, respectively. All u-Ag+ patients were hospitalized. Mortality was 15.4% and 25.9% in u-Ag+ and u-Ag- patients, respectively (p = 0.09). Survival analysis showed a better prognosis, albeit not significant, in u-Ag+ patients. Median hospital stay did not differ among groups (10 vs. 9 days, p = 0.71).
Conclusions:
The routine use of Streptococcus pneumoniae u-Ag testing helped to better target antibiotic therapy with a final trend of reduction in mortality of u-Ag+ COVID-19 patients having a concomitant pneumococcal infection. Randomized trials on larger cohorts are necessary in order to draw definitive conclusion.
... Viral respiratory infections have been shown to predispose patients to secondary bacterial infections and alter host immunopathology, leading to increased morbidity and mortality. 16,17 Identifying pathogens coinfecting with SARS-CoV-2 is critical in developing clinical and public health measures to improve patient outcomes. Identifying pathogens co-infecting with SARS-CoV-2 is critical in developing clinical and public health measures that can improve patient outcomes. ...
Background
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has been the most significant public health challenge in over a century. SARS‐CoV‐2 has infected over 765 million people worldwide, resulting in over 6.9 million deaths. This study aimed to detect community transmission of SARS‐CoV‐2 and monitor the co‐circulation of SARS‐CoV‐2 with other acute respiratory pathogens in Rift Valley, Kenya.
Methods
We conducted a cross‐sectional active sentinel surveillance for the SARS‐CoV‐2 virus among patients with acute respiratory infections at four sites in Rift Valley from January 2022 to December 2022. One thousand two hundred seventy‐one patients aged between 3 years and 98 years presenting with influenza‐like illness (ILI) were recruited into the study. Nasopharyngeal swab specimens from all study participants were screened using a reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR) for SARS‐CoV‐2, influenza A, influenza B and respiratory syncytial virus (RSV).
Results
The samples that tested positive for influenza A ( n = 73) and RSV ( n = 12) were subtyped, while SARS‐CoV‐2 ( n = 177) positive samples were further screened for 12 viral and seven bacterial respiratory pathogens. We had a prevalence of 13.9% for SARS‐CoV‐2, 5.7% for influenza A, 2% for influenza B and 1% for RSV. Influenza A‐H1pdm09 and RSV B were the most dominant circulating subtypes of influenza A and RSV, respectively. The most common co‐infecting pathogens were Streptococcus pneumoniae ( n = 29) and Haemophilus influenzae ( n = 19), accounting for 16.4% and 10.7% of all the SARS‐CoV‐2 positive samples.
Conclusions
Augmenting syndromic testing in acute respiratory infections (ARIs) surveillance is crucial to inform evidence‐based clinical and public health interventions.
... The current COVID-19 pandemic has entered a stable period under the effective control of government departments and has gradually become a "normal" existence similar to influenza . It has been reported that coinfection caused by opportunistic pathogens in the host may significantly inhibit the immune system and adversely affect the prognosis (Li and Zhou, 2013), which may increase the mortality rate of patients infected with the virus (Beadling and Slifka, 2004;Metzger and Sun, 2013). In addition to coronaviruses, infections caused by opportunistic pathogens can also increase the burden on the host (Bengoechea and Bamford, 2020). ...
Background
The impact of COVID-19 on the world is still ongoing, and it is currently under regular management. Although most infected people have flu-like symptoms and can cure themselves, coexisting pathogens in COVID-19 patients should not be taken lightly. The present study sought to investigate the coexisting pathogens in SARS-CoV-2 infected patients and identify the variety and abundance of dangerous microbes to guide treatment strategies with a better understanding of the untested factors.
Methods
We extracted total DNA and RNA in COVID-19 patient specimens from nasopharyngeal swabs to construct a metagenomic library and utilize Next Generation Sequencing (NGS) to discover chief bacteria, fungi, and viruses in the body of patients. High-throughput sequencing data from Illumina Hiseq 4000 were analyzed using Krona taxonomic methodology for species diversity.
Results
We studied 56 samples to detect SARS-CoV-2 and other pathogens and analyzed the species diversity and community composition of these samples after sequencing. Our results showed some threatening pathogens such as Mycoplasma pneumoniae, Klebsiella pneumoniae, Streptococcus pneumoniae, and some previously reported pathogens. SARS-CoV-2 combined with bacterial infection is more common. The results of heat map analysis showed that the abundance of bacteria was mostly more than 1000 and that of viruses was generally less than 500. The pathogens most likely to cause SARS-CoV-2 coinfection or superinfection include Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Klebsiella pneumoniae, and Human gammaherpesvirus 4.
Conclusions
The current coinfection and superinfection status is not optimistic. Bacteria are the major threat group that increases the risk of complications and death in COVID-19 patients and attention should be paid to the use and control of antibiotics. Our study investigated the main types of respiratory pathogens prone to coexisting or superinfection in COVID-19 patients, which is valuable for identifying and treating SARS-CoV-2.
... It is important to also note that the case:carrier ratio for invasive meningococcal disease could change in the future, perhaps for example if SARS-CoV-2 continues to circulate widely. It is unclear if there is any association between SARS-CoV-2 and IMD [26,27] but an increased risk of invasive bacterial disease has been observed following other viral infections [28,29]. ...
Country-wide social distancing and suspension of non-emergency medical care due to the COVID-19 pandemic will undoubtedly have affected public health in multiple ways. While non-pharmaceutical interventions are expected to reduce the transmission of several infectious diseases, severe disruptions to healthcare systems have hampered diagnosis, treatment, and routine vaccination. We examined the effect of this disruption on meningococcal disease and vaccination in the UK. By adapting an existing mathematical model for meningococcal carriage, we addressed the following questions: What is the predicted impact of the existing MenACWY adolescent vaccination programme? What effect might social distancing and reduced vaccine uptake both have on future epidemiology? Will catch-up vaccination campaigns be necessary? Our model indicated that the MenACWY vaccine programme was generating substantial indirect protection and suppressing transmission by 2020. COVID-19 social distancing is expected to have accelerated this decline, causing significant long-lasting reductions in both carriage prevalence of meningococcal A/C/W/Y strains and incidence of invasive meningococcal disease. In all scenarios modelled, pandemic social mixing effects outweighed potential reductions in vaccine uptake, causing an overall decline in carriage prevalence from 2020 for at least 5 years. Model outputs show strong consistency with recently published case data for England.
... Whether the failure of the patient's monocytes to respond to viral signals induces, contributes to, or amplifies the hyperinflammatory bacterial response remains to be determined. 48 Future studies testing differential transcriptional and secretomic responses to bacterial and viral stimuli may reveal patient-specific innate immunodeficiencies that predispose some children to FIRES in the context of prodromal bacterial infection, while other children are susceptible to FIRES as the result of a preceding viral infection. Such studies may also provide critical insights into the pathogenesis and pathophysiology of FIRES that may result in novel and individualized therapeutic approaches. ...
Objective:
Therapeutic strategies for patients with febrile infection-related epilepsy syndrome (FIRES) are limited, ad hoc, and frequently ineffective. Based on evidence that inflammation drives pathogenesis in FIRES, we used ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) to characterize the monocytic response profile before and after therapy in a child successfully treated with dexamethasone delivered intrathecally six times between hospital Day 23 and 40 at 0.25 mg/kg/dose.
Methods:
PBMCs were isolated from serial blood draws acquired during refractory status epilepticus (RSE) and following resolution associated with intrathecal dexamethasone therapy in a previously healthy 9-year-old male that presented with seizures following Streptococcal pharyngitis. Cells were stimulated with bacterial or viral ligands and cytokine release was measured and compared to responses in age-matched healthy control PBMCs. Levels of inflammatory factors in the blood and CSF were also measured and compared to pediatric healthy control ranges.
Results:
During RSE, serum levels of IL6, CXCL8, HMGB1, S100A8/A9, and CRP were significantly elevated. IL6 was elevated in CSF. Ex vivo stimulation of PBMCs collected during RSE revealed hyperinflammatory release of IL6 and CXCL8 in response to bacterial stimulation. Following intrathecal dexamethasone, RSE resolved, inflammatory levels normalized in serum and CSF, and the PBMC hyperinflammatory response renormalized.
Significance:
FIRES may be associated with a hyperinflammatory monocytic response to normally banal bacterial pathogens. This hyperinflammatory response may induce a profound neutrophil burden and the consequent release of factors that further exacerbate inflammation and drive neuroinflammation. Intrathecal dexamethasone may resolve RSE by resetting this inflammatory feedback loop.
... On other hand, co-exposure can substantially alter infection dynamics through several mechanisms such as synergistic effects or disease-related mortality (Cattadori et al., 2008;Risco et al., 2014;Barasona et al., 2016). As exampled, influenza viruses have the capability of suppress the immune response to bacterial infections, which can lead to increased bacterial load and decreased survival (Beadling and Slifka, 2004). However, information on the mortality caused by these pathogens in the Park's ungulate community is only available for the MTC, which represented 42% of the total deaths in the case of wild boar and was being to be relevant in deer species (Barasona et al., 2016; The authors, data not published). ...
Multiple infections or co-exposure to pathogens should be considered systematically in wildlife to better understand the ecology and evolution of host-pathogen relationships, so as to better determine the potential use of multiple pathogens as indicators to guide health management. We describe the pattern of co-exposure to several pathogens (i.e. simultaneous positive diagnosis to pathogens in an individual considering Mycobacterium tuberculosis complex lesions, and the presence of antibodies against Toxoplasma gondii, bluetongue virus, and hepatitis E virus) and assessed their main drivers in the wild ungulate community from Doñana National Park (red deer, fallow deer, and wild boar) for a 13-years longitudinal study. The lower-than-expected frequency of co-exposure registered in all species was consistent with non-mutually exclusive hypotheses (e.g. antagonism or disease-related mortality), which requires further investigation. The habitat generalist species (red deer and wild boar) were exposed to a greater diversity of pathogens (frequency of co-exposure around 50%) and/or risk factors than fallow deer (25.0% ± CI95% 4.9). Positive relationships between pathogens were evidenced, which may be explained by common risk factors favouring exposure. The specific combination of pathogens in individuals was mainly driven by different groups of factors (individual, environmental, stochastic, and populational), as well as its interaction, defining a complex eco-epidemiological landscape. To deepen into the main determinants and consequences of co-infections in a complex assemblage of wild hosts, and at the interface with humans and livestock, there also is needed to expand the range of pathogens and compare diverse assemblages of hosts under different environmental and management circumstances.
... Co-infections and/or superinfections are common in respiratory viral infections 37,42 . It has previously been documented that the mortality rate associated with respiratory viral infections can be influenced by different factors, such as bacterial co-infection 4,26,28,38,46 . ...
... Therefore, understanding the epidemiological patterns of COVID-19 with coinfection and secondary infection is crucial for clinical treatment and to help ensure rational use of antibiotics. Coinfections and super-infections are common in respiratory viral infections (McArdle et al., 2018;Paget and Trottein, 2019).According to the laboratory, clinical, and epidemiological studies, secondary or bacterial co-infections with other viruses can significantly increase the mortality rate in patients infected with viral infections (Beadling and Slifka, 2004;Metzger and Sun, 2013). It has previously documented that the mortality rate of viral infections can be influenced by different factors, such as bacterial co-infection (Jia L. et al., 2017;Katsurada et al., 2017;Quah et al., 2018). ...
This study is conducted on patients infected with COVID19 Those who are hospitalized in intensive care units in to AL-Shifa Center at AL-Zahraa Teaching Hospital for the period from December 2021 to March 2021, for age groups (41-80 years) and of both sexes. As 50 swabs samples are collected two swabs for each patient one for culture and other for PCR after direct extraction for DNA, in order to investigate S. pyogen and K. pneumoniae infections associated with the emerging corona virus. During the laboratory diagnosis, culturing was obtained 21 (42%) positive samples for S. pyogen and 5 (10%) for K. pneumoniae. The extent of resistance of some commonly used antibiotics against S. pyogen and K. pneumoniae was 8 antibiotic disk for each all.PCR detection for 50 patients after extraction for swab gave positive result for S. pyogen 5 (10%) and K. pnemonaie 7(14%). Compared to those without additional pathogens, patients with co-infections and/or secondary infections were more likely to receive antibiotics.
... Indeed, VRE bacteremia occurred after a few days from clinical worsening and the patient suffered from ventilator-associated pneumonia. It is wellestablished that seasonal viral respiratory infection is linked to increased risk of bacterial infection [17]. This is also possible in patients with COVID-19 [18]. ...
A 65-year-old male patient with an end-stage renal disease was diagnosed with coronavirus disease 2019 (COVID-19) by reverse transcription polymerase chain reaction. The patient complained of cough, sputum, and respiratory distress that worsened three days ago. The patient required mechanical ventilation and extracorporeal mentrane oxygenation. On day 9, convalescent plasma collected from a 34-year old man who recovered from COVID-19 45 days ago was administered. The patient showed immediate clinical improvement. However, on day 14, the patient's clinical course worsened again. On day 19 and day 24, vancomycin-resistant Enterococcus faecium bacteremia and methicillin-resistant Staphylococcus aureus pneumonia were found. After long-term supportive care, he slowly recovered. He was discharged on day 91 without any oxygen requirement. This case report suggests that convalescent plasma therapy might just provide a short-term relief and that persistent effort for critical care is necessary to save patients from severe COVID-19.
... These include an increased pathogen load (Mohindra et al. 2021), active social behavior that creates many secondary contacts (Al-Tawfiq and Rodriguez-Morales 2020, Beldomenico 2020, Mohindra et al. 2021), patient transfer within or between hospitals (Mc-Donald et al. 2004, Wang Sh et al. 2006, Cho et al. 2016, Lee et al. 2017, prolonged asymptomatic carrier state (Marineli et al. 2013, Cave 2020, immune suppression (Al-Tawfiq and Rodriguez-Morales 2020, Zenk et al. 2020), and coinfection with several pathogens (Lass et al. 2013). The ability of bacterial and viral infections to complicate each other and lead to more severe outcomes in the same host has been recognized for a long time, and the mechanisms involved have been extensively studied (Degré 1986, Babiuk et al. 1988, Beadling and Slifka 2004, Bellinghausen et al. 2016, Almand et al. 2017, Bakaletz 2017, Jia et al. 2017. However, the ability of bacteria and viruses to enhance each other's dispersion has been less well-understood (Wherry and Butterfield 1920, Glover 1941, Laennec 1923, Shope 1931). ...
The transmission of infectious diseases is characterized by heterogeneities that are shaped by the host, the pathogen, and the environment. Extreme forms of these heterogeneities are called super-spreading events. Transmission heterogeneities are usually identified retrospectively, but their contribution to the dynamics of outbreaks makes the ability to predict them valuable for science, medicine, and public health. Previous studies identified several factors that facilitate super-spreading; one of them is the interaction between bacteria and viruses within a host. The heightened dispersal of bacteria colonizing the nasal cavity during an upper respiratory viral infection, and the increased shedding of HIV-1 from the urogenital tract during a sexually transmitted bacterial infection, are among the most extensively studied examples of transmission heterogeneities that result from bacterial-viral interactions. Interrogating these transmission heterogeneities, and elucidating the underlying cellular and molecular mechanisms, are part of much-needed efforts to guide public health interventions, in areas that range from predicting or controlling the population transmission of respiratory pathogens, to limiting the spread of sexually transmitted infections, and tailoring vaccination initiatives with live attenuated vaccines.
... Pathways by which RSV infection contributes to common, nonsevere illnesses that account for the majority of antimicrobial prescribing merit further investigation. While some antimicrobial treatment may occur for LRTI episodes directly attributable to RSV, a substantial proportion may also occur for bacterial infections precipitated by prior and possibly, mild or asymptomatic RSV infection in the respiratory tract (37)(38)(39). It remains to be determined to what extent the observed efficacy of the RSV F vaccine against RSV-associated LRTI in this trial resulted from prevention of acquisition of RSV or protection against progression to medically significant illness and how these modes of protection may impact risk of diseases that result in antimicrobial prescriptions. ...
Significance
Strategies to reduce consumption of antimicrobial drugs are needed to contain the growing burden of antimicrobial resistance. Respiratory syncytial virus (RSV) is a prominent cause of upper and lower respiratory tract infections, as a single agent and in conjunction with bacterial pathogens, and may thus contribute to the burden of both inappropriately treated viral infections and appropriately treated polymicrobial infections involving bacteria. In a double-blind, randomized, placebo-controlled trial, administering an RSV vaccine to pregnant mothers reduced antimicrobial prescribing among their infants by 12.9% over the first 3 mo of life. Our findings implicate RSV as an important contributor to antimicrobial exposure among infants and demonstrate that this exposure is preventable by use of effective maternal vaccines against RSV.
... A major concern is their mortality rate which is increasingly ranging from 1 to > 5% [1]. There are various forms of respiratory syndromes such as MERS and SARS, caused by the family of coronavirus [2]. ...
The recent pandemic due to the COVID-19 virus has caused a global catastrophe. ACE2 and TMPRSS2 are recognized as key targets for viral entry into the host cells. The pandemic has led to the utilization of many synthetic drugs; however, due to various side effects, there is still no effective drug available against the virus. Several natural approaches have been devised, including herbal and ayurvedic medicines, that have proven to be effective against the COVID-19 virus. In the present study, the effect of phytocompounds of Piper longum and Ocimum sanctum on ACE2 and TRMPSS2 proteins has been studied. The in silico study is done using computational tools of networks of protein-protein interaction , molecular docking, and drug assessment in terms of physicochemical properties, drug-likeness, lipophilicity, water solubility, and pharmacokinetics. Out of selected phy-toconstituents, vicenin 2, rosmarinic acid, and orientin were found to have the highest efficacy in terms of molecular interaction and drug-likeness properties against ACE2 and TMPRSS2 host receptor proteins. Our in silico study proposes the therapeutic potential of phytocompounds from Piper longum and Ocimum sanctum in modulating ACE2 and TMPRSS2 expression. Targeting ACE2 and TMPRSS2 against the SARS-CoV2 by phyto-molecules can serve as a rational approach for designing future anti-COVID drugs.
... The question whether bacterial infections can predispose to viral in-fections may initially strike one as odd. After all, it is generally accepted that viral infections precede and promote bacterial colonization [32,33]. While a considerable amount of literature exists on the predisposing influence of viral infections on the occurrence of bacterial superinfections, substantially less literature is available on the reverse phenomenon [34]. ...
Respiratory disease in horses is caused by a multifactorial complex of infectious agents and environmental factors. An important pathogen in horses is equine herpesvirus type 1 (EHV-1). During co-evolution with this ancient alphaherpesvirus, the horse’s respiratory tract has developed multiple antiviral barriers. However, these barriers can become compromised by environmental threats. Pollens and mycotoxins enhance mucosal susceptibility to EHV-1 by interrupting cell junctions, allowing the virus to reach its basolateral receptor. Whether bacterial toxins also play a role in this impairment has not been studied yet. Here, we evaluated the role of α-hemolysin (Hla) and adenylate cyclase (ACT), toxins derived from the facultative pathogenic bacterium Staphylococcus aureus (S. aureus) and the primary pathogen Bordetella bronchiseptica (B. bronchiseptica), respectively. Equine respiratory mucosal explants were cultured at an air–liquid interface and pretreated with these toxins, prior to EHV-1 inoculation. Morphological analysis of hematoxylin–eosin (HE)-stained sections of the explants revealed a decreased epithelial thickness upon treatment with both toxins. Additionally, the Hla toxin induced detachment of epithelial cells and a partial loss of cilia. These morphological changes were correlated with increased EHV-1 replication in the epithelium, as assessed by immunofluorescent stainings and confocal microscopy. In view of these results, we argue that the ACT and Hla toxins increase the susceptibility of the epithelium to EHV-1 by disrupting the epithelial barrier function. In conclusion, this study is the first to report that bacterial exotoxins increase the horse’s sensitivity to EHV-1 infection. Therefore, we propose that horses suffering from infection by S. aureus or B. bronchiseptica may be more susceptible to EHV-1 infection.
... spleen tissues by short or long-term incubation with IL-4 (Mulder et al., 2017;Banete et al., 2021). Genetic approaches have been used to investigate Mϕ activation (Biswas and Mantovani, 2010;Smale, 2010;Lawrence and Natoli, 2011), but little is known about dysregulated Mϕ functions during viral infection (Beadling and Slifka, 2004;Trivedi et al., 2018). ...
Macrophages (Mφ) are innate immune cells with a variety of functional phenotypes depending on the cytokine microenvironment they reside in. Mφ exhibit distinct activation patterns that are found within a wide array of activation states ranging from the originally discovered classical pro-inflammatory (M1) to the anti-inflammatory (M2) with their multi-facades. M1 cells are induced by IFNγ + LPS, while M2 are further subdivided into M2a (IL-4), M2b (Immune Complex) and M2c (IL-10) based on their inducing stimuli. Not surprisingly, Mφ activation influences the outcome of viral infections as they produce cytokines that in turn activate cells of the adaptive immune system. Generally, activated M1 cells tend to restrict viral replication, however, influenza and HIV exploit inflammation to support their replication. Moreover, M2a polarization inhibits HIV replication at the post-integration level, while HCMV encoded hrIL-10 suppresses inflammatory reactions by facilitating M2c formation. Additionally, viruses such as LCMV and Lassa Virus directly suppress Mφ activation leading to viral chronicity. Here we review how Mφ activation affects viral infection and the strategies by which viruses manipulate Mφ polarization to benefit their own fitness. An understanding of these mechanisms is important for the development of novel immunotherapies that can sway Mφ phenotype to inhibit viral replication.
... COVID-19 patients are prone to bacterial co-infection and superinfection, which are related to a poor prognosis and a fatal outcome, similar to other respiratory viruses such as influenza [5][6][7]. According to previous studies, the overall proportion of secondary bacterial infections in COVID-19 patients was actually low [8], however they were more common in critically ill patients [9]. ...
Background:
Co-infection with bacteria and severe acute respiratory syndrome coronavirus 2 may result in greater use of healthcare resources and a poor prognosis. Therefore, early selection and use of optimal antibiotics are essential. The direct rapid antibiotic susceptibility test (dRAST) can detect antibiotic resistance within 6 h of a Gram smear result. This study aimed to assess the effectiveness of dRAST for improving early selection of appropriate antibiotics for coronavirus disease 2019 (COVID-19) patients with bacteremia.
Materials and methods:
This retrospective study included 96 blood culture-positive COVID-19 patients. Bacterial isolates and antimicrobial resistance profiles of each case were evaluated. Cases were divided into two groups based on whether they underwent conventional antibiotic susceptibility test (AST) or dRAST. The time to optimal targeted treatment for the two groups was investigated and compared. In addition, we examined the proportion of cases for which appropriate antibiotics were selected and broad spectrum antibiotics were administered at 72 h from blood sample collection.
Results:
The mean time to optimal targeted antibiotic treatment was shorter for the dRAST group [55.7; standard deviation (SD), 28.7 vs. 92.3; SD, 51.1 h; P = 0.041]. The proportion of cases receiving optimal targeted antibiotics 72 h after blood collection for culture was higher [6/10 (60.0%) vs. 10/25 (40.0%)] and the percentage receiving broad spectrum antibiotics at 72 h was lower [6/10 (60.0%) vs. 19/25 (76.0%)] in the dRAST group than in the conventional AST group. In terms of microbiology profile, the contamination rate was high (35.5%) and multidrug-resistant strains were common (63.2%) in COVID-19 patients with bacteremia.
Conclusion:
Application of dRAST for selection of antibiotics to treat bacteremia in COVID-19 patients may enable earlier and optimal treatment. The high incidence of contamination and resistant organisms in blood cultures from COVID-19 patients suggest that dRAST may speed up appropriate targeted treatment.
... Viral infection has a dual effect on disease progression-first, there is direct damage to the airway epithelial layer and mucociliary escalator, thereby increasing susceptibility to secondary bacterial infection; secondly, the immunosuppressive nature of viral infection can lead to a decrease in the potency of immune responses, thereby potentially increasing opportunity for bacterial pathogens to be inhaled deeply into the lungs, causing lower respiratory tract (LRT) disease [21][22][23]. Consequently, immunity is further suppressed, potentially aiding invasion from opportunistic non-commensal bacteria [16,[24][25][26]. This results in bovine respiratory disease which presents as calf pneumonia. ...
Vaccination is widely regarded as a cornerstone in animal or herd health and infectious disease management. Nineteen vaccines against the major pathogens implicated in bovine respiratory disease are registered for use in the UK by the Veterinary Medicines Directorate (VMD). However, despite annual prophylactic vaccination, bovine respiratory disease is still conservatively estimated to cost the UK economy approximately £80 million per annum. This review examines the vaccine types available, discusses the surrounding literature and scientific rationale of the limitations and assesses the potential of novel vaccine technologies.
... 2. AMR in the backdrop of COVID-19: a clinical overview 2.1. Co-infections and secondary infections in healthcare during the COVID-19 pandemic Viral respiratory infections have been closely linked to increased chances of bacterial co-infections (Rawlinson et al., 2003;Beadling and Slifka, 2004). Although secondary infections caused by bacteria and fungal pathogens were reported frequently in severe cases of COVID-19 , this finding is not universal (Hughes et al., 2020;Rawson et al., 2020b;Garcia-Vidal et al., 2021). ...
The COVID-19 pandemic has shattered millions of lives globally and continues to be a challenge to public health due to the emergence of variants of concern. Fear of secondary infections following COVID-19 has led to an escalation in antimicrobial use during the pandemic, while some antimicrobials have been repurposed as treatments for SARS-CoV-2, further driving antimicrobial resistance. India is one of the largest producers and consumers of antimicrobials globally, hence the task of curbing antimicrobial resistance is a huge challenge. Practices like empirical antimicrobial prescription and repurposing of drugs in clinical settings, self-medication and excessive use of antimicrobial hygiene products may have deteriorated the prevalence of antimicrobial resistance in India. However, the expanded production of antimicrobials and disinfectants during the pandemic in response to increased demand may have had an even greater impact on the threat of antimicrobial resistance through major impacts on the environment. The review provides an outline of the impact COVID-19 can have on antimicrobial resistance in clinical settings and the possible outcomes of the same on environment. This review calls for the up gradation of existing antimicrobial policies and emphasizes the need for research studies to understand the impact of the pandemic on antimicrobial resistance in India.
... Previous studies have revealed that patients with viral respiratory infections may suffer an increased risk of secondary infections, including severe secondary infections with high mortality [4]. The possible underlying mechanisms for this phenomenon include direct damage of the upper airway and lungs due to viral-related inflammation, as well as virus-induced immunological impairment [5]. Therefore, it is plausible that COVID-19 can also alter people's susceptibility to other severe secondary infections. ...
Background
With the increasing number of people infected with and recovered from coronavirus disease 2019 (COVID-19), the extent of major health consequences of COVID-19 is unclear, including risks of severe secondary infections.
Methods
Based on 445,845 UK Biobank participants registered in England, we conducted a matched cohort study where 5151 individuals with a positive test result or hospitalized with a diagnosis of COVID-19 were included in the exposed group. We then randomly selected up to 10 matched individuals without COVID-19 diagnosis for each exposed individual ( n = 51,402). The life-threatening secondary infections were defined as diagnoses of severe secondary infections with high mortality rates (i.e., sepsis, endocarditis, and central nervous system infections) from the UK Biobank inpatient hospital data, or deaths from these infections from mortality data. The follow-up period was limited to 3 months after the initial COVID-19 diagnosis. Using a similar study design, we additionally constructed a matched cohort where exposed individuals were diagnosed with seasonal influenza from either inpatient hospital or primary care data between 2010 and 2019 (6169 exposed and 61,555 unexposed individuals). After controlling for multiple confounders, Cox models were used to estimate hazard ratios (HRs) of life-threatening secondary infections after COVID-19 or seasonal influenza.
Results
In the matched cohort for COVID-19, 50.22% of participants were male, and the median age at the index date was 66 years. During a median follow-up of 12.71 weeks, the incidence rate of life-threatening secondary infections was 2.23 (123/55.15) and 0.25 (151/600.55) per 1000 person-weeks for all patients with COVID-19 and their matched individuals, respectively, which corresponded to a fully adjusted HR of 8.19 (95% confidence interval [CI] 6.33–10.59). The corresponding HR of life-threatening secondary infections among all patients with seasonal influenza diagnosis was 4.50, 95% CI 3.34–6.08 ( p for difference < 0.01). Also, elevated HRs were observed among hospitalized individuals for life-threatening secondary infections following hospital discharge, both in the COVID-19 (HR = 6.28 [95% CI 4.05–9.75]) and seasonal influenza (6.01 [95% CI 3.53–10.26], p for difference = 0.902) cohorts.
Conclusion
COVID-19 patients have increased subsequent risks of life-threatening secondary infections, to an equal extent or beyond risk elevations observed for patients with seasonal influenza.
... Viruses play a significant role in HAI, as evidence shows that viral infections predispose patients to bacterial infections through the overproduction of inflammatory cytokines and dysbiosis of systemic microbiomes [16][17][18]. For instance, infection with Influenza A virus disrupts enteric microbiota, rendering the small intestine more vulnerable to Salmonella Typhimurium [18]. ...
Background: Firefighters spend about 64% of their time responding to medical emergencies and providing medical care without a patient history, which can render them vulnerable to healthcare-associated infections (HAI). Infection prevention, control, and surveillance systems have been instituted at hospitals. However, the prevalence of firefighters’ exposure to HAI is unknown. The objective of this study was to document evidence of HAI on surfaces in fire stations and engines to inform disinfection procedures and identify which pathogens might contribute to occupational exposures. (2) Methods: High-touch or high-use surfaces of two fire departments were sampled during five separate occasions. One fire station from one fire department was sampled over a 4-week period, whereas four fire stations were sampled from a different fire department only once. Sampled surfaces included: entryway floor, washing machine, medical bag, back seat of engine, keyboard of reporting computer, engine console, and uniform pants. (3) Results: Multiple statistical models determined that bacterial contamination was similar between the two fire departments and their stations. Keyboards were the most contaminated surface for all fire stations and departments, E. coli was the most common bacteria detected, and C. difficile was the least detected bacteria. Adjustments for rates of contamination found that contamination rates varied between fire stations. (4) Conclusions: Comprehensive environmental sampling and clinical studies are needed to better understand occupational exposures of firefighters to HAI.
... Respiratory infection is commonly associated with coinfections [4,5]. Generally, secondary bacterial co-infections with viral infections contributes to the reported increase in mortality of affected patients [6,7]. We therefore investigated the effect of adding antibiotics to the treatment regimen of COVID19 patients and compared the outcome to patients who did not take any antibiotics. ...
This is a single center, retrospective, observational study carried out in Ohud hospital, the main referral hospital for SARS-CoV-2 infections in the region of Madinah, Kingdom of Saudi Arabia. The study was carried on hospitalized patients with moderate to severe symptoms, including critically ill patients in the intensive care unit mostly of them requiring oxygen or mechanical ventilator support. Medical records from 432 cases were investigated showing that the majority of infected population were adults with an average age of 48 years, where 68.3% were males and the mortality rate was 5.6%. Duration of the disease was determined as the period between the first positive and the first negative PCR results. Patients who received antibiotics or Metoclopramide showed shorter duration of the disease time course while those who received Hydroxychloroquine, Omeprazole or Calcium exhibited longer durations before obtaining a negative PCR result. Regression analysis furtherly confirmed that antibiotics administration was associated with shorter course of disease while hydroxychloroquine or omeprazole were correlated with longer duration of the disease. Antiviral drugs, however, showed no correlations to the COVID-19 duration of stay in hospital. Finally, combining antibiotics and antiviral agents did not result in a better outcome, suggesting that the use of antibacterial agents helps in the recovery of SARS-CoV-2 patients.
... Critically ill patients showed greater percentage of coinfection compared with hospitalized patients [4]. Previous experience during other respiratory viral infections supported the use of antibiotics; so, at the onset of COVID-19 infection, early guidelines for COVID-19 treatment suggested the use of antibiotics in all the patients [5,6]. Identification of prevalence of bacterial coinfection is crucial for the initial empiric antibiotic treatment, in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients. ...
Background
The pandemic of SARS COV-2 raised the attention toward bacterial coinfection and their role in COVID-19 disease. This study aims to systematically review and identify the pooled prevalence of the bacterial coinfection in the related articles.
Methods
A comprehensive search was conducted in international databases, including Medline, Scopus, Web of Science, and Embase, to identify the articles on the prevalence of Bacterial coinfections in COIVD-19 patients from December 1, 2019, until December 30, 2020. All observational epidemiological studies that evaluated the prevalence of bacterial coinfections in COVID-19 patients included without any restriction.
Results
Forty two studies including total sample size of 54695 were included in the analysis. The pooled estimate for prevalence of bacterial coinfections was 20.97% (95% CI: 15.95 to 26.46) the pooled prevalence of bacterial coinfections was 5.20% (95% CI: 2.39 to 8.91) for Respiratory subtype and 4.79% (95% CI: 0.11 to 14.61) for Gastrointestinal subtype. The pooled prevalence for Eastern Mediterranean Regional Office (EMRO) and South-East Asia Regional Office (SEARO) was 100 % (95% CI: 82.35 to 100.00) and 2.61 % (95% CI: 1.74 to 3.62).
Conclusion
This rate of coinfection poses a great danger toward patients especially those in critical condition. Although there are multiple complication and adverse effect related to extensive use of antibiotics to treat COVID-19 patients but it seems there is no other option except the applying them and it needs to be done carefully.
... Variable incidence of concurrent bacterial infection in COVID-19 has been reported. [5][6][7][8][9] Identification of co-infections is very complicated. The organism itself might be carried by the patient before the viral infection, might be part of an underlying chronic infection, or might be picked up nosocomially increasing chances of hospital and ventilator acquired infections. ...
Background: The pandemic due to severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) has drawn worldwide worst effect with diagnostic challenge. Every investigation has its own importance for diagnosis, care, treatment and for management of corona virus disease-2019 (COVID-19) patients. Here this prospective study aimed to investigate the microbiological profile, prevalence of co-infection, and antibiotic susceptibility pattern of patients with confirmed SARS-CoV-2.Methods: A total of 336 samples were processed in COVID laboratory, Department of Microbiology. An array of serological investigations was done by rapid card screening test. C-Reactive protein (CRP) was analyzed by nephelometer. Blood culture was done by automated system and urine culture on Cystine-Lactose-Electrolyte-Deficient (CLED) Agar. Antibiotic susceptibility tests were done by Kirby Bauer disc diffusion method.Results: Out of 336 samples tested 76%were male and 24%were female. All samples tested were negative for HIV, HBsAg, HCV, syphilis, malarial parasite. CRP and Typhi -dot with IgM and IgG antibody were positive in 89.28% and 11.42% respectively. About 27% of COVID-19 patients showed bacterial and fungal co-infections. The most prevalent organisms were MR-CoNS (26%), K. pneumoniae (19%) and less prevalent were P. aeruginosa (6%) and A. baumannii (4%). C. albicans (11%) was the only isolated fungi. All gram positive isolates were 100% sensitive to Linezolid and vancomycin, among gram negative isolates, 100% were sensitive to colistin and polymyxin B.Conclusions: Microbiological investigation for presence of other co-infecting agents among patients with COVID-19 infection should be considered, and prompt treatment should be carried out accordingly.
... Secondary bacterial infections are taken as an important risk factor for higher mortality and severity of the infection in COVID-19 [158]. It is confirmed by epidemiological, laboratory and clinical studies that mortality rate due to any viral disease is increased if bacterial co-infection accompanies [159,160]. Influence of secondary bacterial infections on mortality rate due to viral infection is well previously documented [161][162][163][164]. The effects of bacterial co-infections during any epidemic or pandemic mainly in immunosuppressive diseases are irreversible [164] (Table 4). ...
Severe acute respiratory syndrome coronavirus (SARS-CoV-2), a novel corona virus, causing COVID-19 with Flu-like symptoms is the first alarming pandemic of the third millennium. SARS-CoV-2 belongs to beta coronavirus as Middle East respiratory syndrome coronavirus (MERS-CoV). Pandemic COVID-19 owes devastating mortality and destructively exceptional consequences on Socio-Economics life around the world. Therefore, the current review is redirected to the scientific community to owe comprehensive visualization about SARS-CoV-2 to tackle the current pandemic. As systematically shown through the current review, it indexes unmet medical problem of COVID-19 in view of public health and vaccination discovery for the infectious SARS-CoV-2; it is currently under-investigational therapeutic protocols, and next possible vaccines. Furthermore, the review extensively reports the precautionary measures to achieve" COVID-19/Flatten the curve". It is concluded that vaccines formulation within exceptional no time in this pandemic is highly recommended, via following the same protocols of previous pandemics; MERS-CoV and SARS-CoV, and excluding some initial steps of vaccination development process.
... The finding of a respiratory virus does not necessarily mean that the patient has only a viral infection. Occurrences of viral respiratory tract infections have been associated with increased risk of bacterial coinfections (11) . The rate of concurrent severe bacterial infections with viral illness in COVID-19 patients is appreciable. ...
... Thus, secondary bacterial infections occur following the elimination of the virus from the lungs of patients with COVID-19. According to laboratory, clinical, and epidemiological studies, secondary bacterial infections can significantly increase the mortality rate in patients with viral infections (40,41). In this study, none of the 4 patients in whom bacterial pathogens were isolated developed signs of secondary bacterial infections, such as fever or respiratory symptoms. ...
Objective To describe the clinical features and clinical course of individuals diagnosed with asymptomatic SARS-CoV-2 infection or mild COVID-19.
Patients The study participants consisted of 7 crewmembers of the passenger cruise-liner, Diamond Princess, who were admitted to our hospital after becoming infected with SARS-CoV-2 aboard the ship.
Methods The data on patient background and biochemical test results were obtained from the patients' medical records. All patients had a chest X-ray, and a throat swab and sputum samples were sent for culture on admission.
Results The median age of the 7 patients, of whom 4 were male and 3 were female, was 39 years (range: 23-47 years). On admission, none of them had fever, but 4 (57%) had a cough. None of them showed any signs of organ damage on laboratory testing. Chest X-ray showed pneumonia in one individual, which resolved spontaneously, while the other 6 had normal chest X-ray findings. Culture of throat swabs and sputum samples revealed that 4 patients (57%) had bacterial upper respiratory infections (Haemophilus influenzae, Klebsiella pneumoniae, and Staphylococcus aureus). The period from a positive PCR test to negative conversion ranged from 5 to 13 days, with a median of 8 days.
Conclusion Healthy young adults without risk factors who acquire SARS-CoV-2 infection may have an asymptomatic infection or may experience mild COVID-19. In addition to obesity, an older age, underlying illness, and being overweight can lead to a risk of exacerbation; thus, hospital management for such individuals may be desirable. Culturing respiratory samples may be useful for diagnosing secondary bacterial pneumonia.
... 4,5 According to the laboratory, clinical, and epidemiological studies, secondary or bacterial co-infections with other viruses can significantly increase the mortality rate in patients infected with viral infections. 6,7 It has previously documented that the mortality rate of viral infections can be influenced by different factors, such as bacterial co-infection. [8][9][10] For instance, influenza-related bacterial infections contribute to severe illness and mortality during the epidemic and seasonal influenza outbreaks. ...
The pandemic coronavirus disease 2019 (COVID‐19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2), has affected millions of people worldwide. To date, there are no proven effective therapies for this virus. Efforts made to develop antiviral strategies for the treatment of COVID‐19 are underway. Respiratory viral infections, such as influenza, predispose patients to co‐infections and these lead to increased disease severity and mortality. Numerous types of antibiotics such as azithromycin have been employed for the prevention and treatment of bacterial co‐infection and secondary bacterial infections in patients with a viral respiratory infection (e.g., SARS‐CoV‐2). Although antibiotics do not directly affect SARS‐CoV‐2, viral respiratory infections often result in bacterial pneumonia. It is possible that some patients die from bacterial co‐infection rather than virus itself. To date, a considerable number of bacterial strains have been resistant to various antibiotics such as azithromycin, and the overuse could render those or other antibiotics even less effective. Therefore, bacterial co‐infection and secondary bacterial infection are considered critical risk factors for the severity and mortality rates of COVID‐19. Also, the antibiotic‐resistant as a result of overusing must be considered. In this review, we will summarize the bacterial co‐infection and secondary bacterial infection in some featured respiratory viral infections, especially COVID‐19.
... The viruses, which cause illness in animals and human, coronavirus is the member of that family of viruses. In human, common cold, Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS) are the different types of respiratory infections which these viruses can cause (Beadling & Slifka, 2004;de Wit et al., 2016). COVID-19 is the most recently declared disease by WHO caused by a new member "novel coronavirus" of this virus family (https://www.who.int/, ...
The recent appearance of COVID-19 virus has created a global crisis due to unavailability of any vaccine or drug that can effectively and deterministically work against it. Naturally, different possibilities (including herbal medicines having known therapeutic significance) have been explored by the scientists. The systematic scientific study (beginning with in silico study) of herbal medicines in particular and any drug in general is now possible as the structural components (proteins) of COVID-19 are already characterized. The main protease of COVID-19 virus is Mpro or 3CLpro which is a key CoV enzyme and an attractive drug target as it plays a pivotal role in mediating viral replication and transcription. In the present study, 3CLpro is used to study drug:3CLpro interactions and thus to investigate whether all or any of the main chemical constituents of Tinospora cordifolia (e.g. berberine (C20H18NO4), β-sitosterol (C29H50O), coline (C5H14NO), tetrahydropalmatine (C21H25NO4) and octacosanol (C28H58O)) can be used as an anti-viral drug against SARS-CoV-2. The in silico study performed using tools of network pharmacology, molecular docking including molecular dynamics have revealed that among all considered phytochemicals in Tinospora cordifolia, berberine can regulate 3CLpro protein's function due to its easy inhibition and thus can control viral replication. The selection of Tinospora cordifolia was motivated by the fact that the main constituents of it are known to be responsible for various antiviral activities and the treatment of jaundice, rheumatism, diabetes, etc.
Communicated by Ramaswamy H. Sarma
... It is well established that seasonal viral respiratory tract infections have been linked to increased risk of bacterial co-infection [1] and current evidence suggests that the This article is protected by copyright. All rights reserved. ...
We would like to report our experience of 2 patients co‐infected with Streptococcus pneumoniae (S. pneumoniae) and coronavirus disease 2019 (Covid‐19) in the United Kingdom.
This article is protected by copyright. All rights reserved.
... The finding of a respiratory virus does not necessarily mean that the patient has only a viral infection, especially that occurrences of viral respiratory tract infections have been associated to increased risk of bacterial coinfections ( Beadling & Slifka, 2004;Rawlinson et al., 2003). ...
Viral respiratory infections are very common and they are frequently eliminated from the body without any detrimental consequences. Secondary serious bacterial infection has been an apprehension expressed by health care providers, and this fear has been exacerbated in the era of Covid-19. Several published studies have shown an association between Covid-19 illness and secondary bacterial infection. However, the proposed mechanism by which a virus can develop a secondary bacterial infection is not well delineated. The aim of this commentary is to update the current evidence of the risk of bacterial infection in patients with Covid-19. We present several clinical studies related to the topic as well as a brief review of the potential pathophysiology of secondary infections that could present with Covid-19.
... Novel strategies to prevent and/or reduce pneumococcal inflammatory responses are important in the context of secondary viral infections and disease (53). The effect of VitD 3 in co-infection models is unknown, and further research into the potential benefits are required (54,55). ...
Streptococcus pneumoniae (pneumococcus) and respiratory syncytial virus (RSV) are the leading causes of respiratory infections amongst children <5 years of age. Co-infection with these pathogens is common during early life and often associated with increased disease severity. Epidemiological studies have shown that low levels of Vitamin D3 (VitD3) are associated with increased susceptibility to respiratory pathogens. However, the role of VitD3 in the context of pneumococcal and RSV exposure are poorly understood. We found that VitD3 significantly reduced Th17 cell expression and IL-17A and IL-22 secretion in peripheral blood mononuclear cells (PBMCs) when stimulated with a pneumococcal whole cell antigen (WCA). Levels of IFN-γ were also decreased whilst IL-10 and IL-1β were increased. Effects of VitD3 on innate responses following RSV stimulation was limited, only reducing IL-6. VitD3 also reduced the number of TLR2+CD14+ monocytes, whilst increasing TLR7+CD14+ monocytes and TLR4+CD56+ NK cells. In WCA-stimulated PBMCs, VitD3 increased IL-1β levels but reduced TLR2+CD14+ monocytes. For pneumococcal WCA-RSV co-stimulation, VitD3 only had a limited effect, mainly through increased IL-1β and RANTES as well as TLR4+CD56+ NK cells. Our results suggest that VitD3 can modulate the inflammatory response to pneumococci but has limited effects during viral or bacterial-viral exposure. This is the first study to examine the effects of VitD3 in the context of pneumococcal-RSV co-stimulation, with important implications on the potential role of VitD3 in the control of excessive inflammatory responses during pneumococcal and RSV infections.
To investigate a comprehensive segmentation of chest X-ray (CXR) in promoting deep learning–based World Health Organization’s (WHO) radiologically confirmed pneumonia diagnosis in children.
A total of 4400 participants between January 2016 and June 2021were identified for a cross-sectional study and divided into primary endpoint pneumonia (PEP), other infiltrates, and normal groups according to WHO’s diagnostic criteria. The CXR was divided into six segments of left lung, right lung, mediastinum, diaphragm, ext-left lung, and ext-right lung by adopting the RA-UNet. To demonstrate the benefits of lung field segmentation in pneumonia diagnosis, the segmented images and images that were not segmented, which constituted seven segmentation combinations, were fed into the CBAM-ResNet under a three-category classification comparison. The interpretability of the CBAM-ResNet for pneumonia diagnosis was also performed by adopting a Grad-CAM module.
The RA-UNet achieved a high spatial overlap between manual and automatic segmentation (averaged DSC = 0.9639). The CBAM-ResNet when fed with the six segments achieved superior three-category diagnosis performance (accuracy = 0.8243) over other segmentation combinations and deep learning models under comparison, which was increased by around 6% in accuracy, precision, specificity, sensitivity, F1-score, and around 3% in AUC. The Grad-CAM could capture the pneumonia lesions more accurately, generating a more interpretable visualization and enhancing the superiority and reliability of our study in assisting pediatric pneumonia diagnosis.
The comprehensive segmentation of CXR could improve deep learning–based pneumonia diagnosis in childhood with a more reasonable WHO’s radiological standardized pneumonia classification instead of conventional dichotomous bacterial pneumonia and viral pneumonia.
The comprehensive segmentation of chest X-ray improves deep learning–based WHO confirmed pneumonia diagnosis in children, laying a strong foundation for the potential inclusion of computer-aided pediatric CXR readings in precise classification of pneumonia and PCV vaccine trials efficacy in children.
• The chest X-ray was comprehensively segmented into six anatomical structures of left lung, right lung, mediastinum, diaphragm, ext-left lung, and ext-right lung.
• The comprehensive segmentation improved the three-category classification of primary endpoint pneumonia, other infiltrates, and normal with an increase by around 6% in accuracy, precision, specificity, sensitivity, F1-score, and around 3% in AUC.
• The comprehensive segmentation gave rise to a more accurate and interpretable visualization results in capturing the pneumonia lesions.
Acute respiratory infections (ARI), especially lower respiratory infections (LRI), are a leading cause of childhood morbidity and mortality globally. Non-pharmaceutical interventions (NPI) employed during the COVID-19 pandemic have impacted on the epidemiology and burden of paediatric ARI, although accurately describing the full nature of the impact is challenging. For most ARI pathogens, a reduction was observed in the early phase of the pandemic, correlating with the most stringent NPI. In later phases of the pandemic resurgence of disease was observed as NPI eased. This pattern was most striking for seasonal viruses, such as influenza and respiratory syncytial virus. The impact on ARI-associated bacterial disease varied; marked reductions in invasive Streptococcus pneumoniae and Streptococcus pyogenes were observed, followed by a resurgence that correlated with increases in respiratory viral infections. For Corynebacterium diphtheriae,Bordetella pertussis, andMycoplasma pneumoniae, a sustained reduction of disease was observed well into 2022 in most regions. Proposedmechanisms for the varied epidemiological disruption amongst ARI pathogens includedifferential effects of NPI on specific pathogens, population-level immunological effects, and ecological and genetic pathogen adaptations. Additionally, important indirect effects of pandemic restrictions on paediatric respiratory infections have been identified. These occurred as a result of disruptions to routine health services, reductions in vaccination coverage, and disruptions to respiratory infection research and surveillance activities. Impacts have been disproportionately borne by those in low resource settings. We discuss opportunities to leverage pandemic learnings to support improved understanding of the epidemiology of paediatric respiratory infections to inform future prevention and health system strengthening. Educational Aims. The reader will gain an improved understanding of.
Mortality of any respiratory viral disease is usually attributed in part to other reasons than the damaging effect of the virus alone. One of these reasons is the bacterial super-infection. For this reason, this scoping review attampts to evaluate the significant contribution of bacterial super-infection on the mortality among hospitalized COVID-19 patients and determine the true prevalence of bacterial super-infections in that population. Accordingly, a systematic search was employed with precise criteria on the MEDLINE, SCOPUS, PUBMED, and GOOGLE SCHOLAR databases published in the English language three years from January 2020 to January 2023. The prevalence of bacterial super-infection (BSI) among COVID-19 patients constitutes a point of contention among publications. This heterogeneity among publications came from the semantic dilemma of co-infection and super-infection.Co-infection was determined to be found in a relatively narrow range (1.2-3.1%), while prevalence of bacterial super-infection among COVID-19 patients varied from 18.2 to 50%. The bacterial super-infection significantly increases COVID-19 mortality, with the Odd ratio ranging from 1.76 to 10.53 [CI 95%]. Bacterial super-infection among hospitalized COVID-19 patients represents a non-recognized threat, especially during the first wave of the pandemic. The Prevalence of bacterial super-infection is comparable with those observed in previous influenza and SARS epidemics. A significant contribution of bacterial super-infection, especially the pulmonary to mortality of COVID-19 patients, was observed clearly
Coinfection of Porcine circovirus type 2 (PCV2) and Glaesserella parasuis type 4 (GPS4) is widespread clinically, resulting in high morbidity and mortality, however, interactions between the two pathogens during coinfection and the coinfection pathogenesis are poorly understood. In this study, a piglet model coinfected with PCV2 and GPS4 was established; coinfection of the piglets' group showed more obvious symptoms, such as high fever and emaciation, and more severe histological lesions appeared in various organs. Importantly, piglets in the coinfection group produced lower levels of PCV2 and GPS4 antibodies, and showed high levels of inflammatory cytokines, TLR2, and TLR4, while the levels of CD4, CD8, MHC II, costimulatory molecules, and IL-12p40 were decreased. In addition, a model of macrophage 3D4/21 cells coinfection with PCV2 and GPS4 was established, coinfected cells exhibited increased expression of the cytokines IL-6, IL-8, TNF-α, IL-1β, and the receptors TLR2, TLR4, while decreased MHC II. We further demonstrate that cytokine production is associated with the activation of NF-κB and NLRP3 inflammasome signaling pathways, and TLR4 is also involved. Altogether, our findings suggest that coinfection with PCV2 and GPS4 exacerbates the inflammatory response, resulting in severe tissue damage, and probably impaired macrophage antigen presentation and T cell activation, resulting in immune dysregulation, aggravating host infection.
Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic of severe coronavirus disease 2019 (COVID-19). Staphylococcus aureus is one of the most common pathogenic bacteria in humans, rheumatoid arthritis (RA) is among the most prevalent autoimmune conditions. RA is a significant risk factor for SARS-CoV-2 and S. aureus infections, although the mechanism of RA and SARS-CoV-2 infection in conjunction with S. aureus infection has not been elucidated. The purpose of this study is to investigate the biomarkers and disease targets between RA and SARS-CoV-2 and S. aureus infections using bioinformatics analysis, to search for the molecular mechanisms of SARS-CoV-2 and S. aureus immune escape and potential drug targets in the RA population, and to provide new directions for further analysis and targeted development of clinical treatments.
Methods
The RA dataset (GSE93272) and the S. aureus bacteremia (SAB) dataset (GSE33341) were used to obtain differentially expressed gene sets, respectively, and the common differentially expressed genes (DEGs) were determined through the intersection. Functional enrichment analysis utilizing GO, KEGG, and ClueGO methods. The PPI network was created utilizing the STRING database, and the top 10 hub genes were identified and further examined for functional enrichment using Metascape and GeneMANIA. The top 10 hub genes were intersected with the SARS-CoV-2 gene pool to identify five hub genes shared by RA, COVID-19, and SAB, and functional enrichment analysis was conducted using Metascape and GeneMANIA. Using the NetworkAnalyst platform, TF-hub gene and miRNA-hub gene networks were built for these five hub genes. The hub gene was verified utilizing GSE17755, GSE55235, and GSE13670, and its effectiveness was assessed utilizing ROC curves. CIBERSORT was applied to examine immune cell infiltration and the link between the hub gene and immune cells.
Results
A total of 199 DEGs were extracted from the GSE93272 and GSE33341 datasets. KEGG analysis of enrichment pathways were NLR signaling pathway, cell membrane DNA sensing pathway, oxidative phosphorylation, and viral infection. Positive/negative regulation of the immune system, regulation of the interferon-I (IFN-I; IFN-α/β) pathway, and associated pathways of the immunological response to viruses were enriched in GO and ClueGO analyses. PPI network and Cytoscape platform identified the top 10 hub genes: RSAD2, IFIT3, GBP1, RTP4, IFI44, OAS1, IFI44L, ISG15, HERC5, and IFIT5. The pathways are mainly enriched in response to viral and bacterial infection, IFN signaling, and 1,25-dihydroxy vitamin D3. IFI44, OAS1, IFI44L, ISG15, and HERC5 are the five hub genes shared by RA, COVID-19, and SAB. The pathways are primarily enriched for response to viral and bacterial infections. The TF-hub gene network and miRNA-hub gene network identified YY1 as a key TF and hsa-mir-1-3p and hsa-mir-146a-5p as two important miRNAs related to IFI44. IFI44 was identified as a hub gene by validating GSE17755, GSE55235, and GSE13670. Immune cell infiltration analysis showed a strong positive correlation between activated dendritic cells and IFI44 expression.
Conclusions
IFI144 was discovered as a shared biomarker and disease target for RA, COVID-19, and SAB by this study. IFI44 negatively regulates the IFN signaling pathway to promote viral replication and bacterial proliferation and is an important molecular target for SARS-CoV-2 and S. aureus immune escape in RA. Dendritic cells play an important role in this process. 1,25-Dihydroxy vitamin D3 may be an important therapeutic agent in treating RA with SARS-CoV-2 and S. aureus infections.
Bacterial co-pathogens are commonly identified in viral respiratory infections and are important causes of morbid-mortality. The prevalence of Chlamydia (C.) pneumoniae infection in patients infected with SARS-CoV-2 has not been sufficiently studied. The objective of the present review was to describe the prevalence of C. pneumoniae in patients with coronavirus disease 2019 (COVID-19). A search in MEDLINE and Google Scholar databases for English language literature published between January 2020 to August 2021 was performed. Studies evaluating patients with confirmed COVID-19 and reporting the simultaneous detection of C. pneumoniae were included. Eleven articles were included in the systematic review (5 case cross-sectional studies and 6 retrospective studies). A total of 18450 patients were included in the eleven studies. The detection of laboratory-confirmed C. pneumoniae infection varied between 1.78-71.4% of the total number of co-infections. The median age of patients ranged from 35-71 years old and 65% were male. Most of the studies reported one or more pre-existing comorbidities and the majority of the patients presented with fever, cough and dyspnea. Lymphopenia and eosinopenia were described in COVID-19 co-infected patients. The main chest CT scan showed a ground glass density shadow, consolidation and bilateral pneumonia. Most patients received empirical antibiotics. Bacterial co-infection was not associated with increased ICU admission and mortality. Despite frequent prescription of broad-spectrum empirical antimicrobials in patients with coronavirus 2-associated respiratory infections, there is a paucity of data to support the association with respiratory bacterial co-infection. Prospective evidence generation to support the development of an antimicrobial policy and appropriate stewardship interventions specific for the COVID-19 pandemic are urgently required.
This observational retrospective study aimed to analyze whether/how the spectrum of bacterial pathogens and their resistance to antibiotics changed during the worst part of the COVID-19 pandemic (1 November 2020 to 30 April 2021) among intensive care patients in University Hospital Olomouc, Czech Republic, as compared with the pre-pandemic period (1 November 2018 to 30 April 2019). A total of 789 clinically important bacterial isolates from 189 patients were cultured during the pre-COVID-19 period. The most frequent etiologic agents causing nosocomial infections were strains of Klebsiella pneumoniae (17%), Pseudomonas aeruginosa (11%), Escherichia coli (10%), coagulase-negative staphylococci (9%), Burkholderia multivorans (8%), Enterococcus faecium (6%), Enterococcus faecalis (5%), Proteus mirabilis (5%) and Staphylococcus aureus (5%). Over the comparable COVID-19 period, a total of 1500 bacterial isolates from 372 SARS-CoV-2-positive patients were assessed. While the percentage of etiological agents causing nosocomial infections increased in Enterococcus faecium (from 6% to 19%, p < 0.0001), Klebsiella variicola (from 1% to 6%, p = 0.0004) and Serratia marcescens (from 1% to 8%, p < 0.0001), there were significant decreases in Escherichia coli (from 10% to 3%, p < 0.0001), Proteus mirabilis (from 5% to 2%, p = 0.004) and Staphylococcus aureus (from 5% to 2%, p = 0.004). The study demonstrated that the changes in bacterial resistance to antibiotics are ambiguous. An increase in the frequency of ESBL-positive strains of some species (Serratia marcescens and Enterobacter cloacae) was confirmed; on the other hand, resistance decreased (Escherichia coli, Acinetobacter baumannii) or the proportion of resistant strains remained unchanged over both periods (Klebsiella pneumoniae, Enterococcus faecium). Changes in pathogen distribution and resistance were caused partly due to antibiotic selection pressure (cefotaxime consumption increased significantly in the COVID-19 period), but mainly due to clonal spread of identical bacterial isolates from patient to patient, which was confirmed by the pulse field gel electrophoresis methodology. In addition to the above shown results, the importance of infection prevention and control in healthcare facilities is discussed, not only for dealing with SARS-CoV-2 but also for limiting the spread of bacteria.
As has been highlighted by the recent COVID-19 pandemic, eukaryotic viral infections impose a considerable public health and economic burden. Such viral infection occurs in the presence of other microorganisms like bacteria, and in many cases the composition and presence of these microorganisms has been found to influence numerous factors and outcomes associated with viral infection. Such interactions between eukaryotic viruses and bacteria will be surveyed in this chapter. Specifically, these interactions have potential to enhance or inhibit viral infection in numerous ways through both direct and indirect interactions. Such interactions also occur in numerous tissues throughout the host body, with special focus on the effect of the bacteria in the intestines and lungs. Finally, the chapter will conclude by presenting the latest set of work on the influence of host bacteria on SARS-CoV-2 infection, while identifying areas of needed future research.KeywordsVirus-bacteria interactionsRespiratory virusesEnteric virusesGut microbiotaLung microbiotaViral pathogenesis
Disease tolerance has emerged as an alternative way, in addition to host resistance, to survive viral-bacterial co-infections. Disease tolerance plays an important role not in reducing pathogen burden, but in maintaining tissue integrity and controlling organ damage. A common co-infection is the synergy observed between influenza virus and Streptococcus pneumoniae that results in superinfection and lethality. Several host cytokines and cells have shown promise in promoting tissue protection and damage control while others induce severe immunopathology leading to high levels of morbidity and mortality. The focus of this review is to describe the host cytokines and innate immune cells that mediate disease tolerance and lead to a return to host homeostasis and ultimately, survival during viral-bacterial co-infection.
Maoto, a traditional Japanese medicine (Kampo), is widely used to treat upper respiratory tract infections, including influenza virus infection. Although maoto is known to inhibit pro-inflammatory responses in a rodent model of acute inflammation, its underlying mechanism remains to be determined. In this study, we investigated the involvement of immune responses and noradrenergic function in the inhibitory action of maoto. In a mouse model of polyI:C-induced acute inflammation, maoto (2 g/kg) was administered orally in conjunction with intraperitoneal injection of PolyI:C (6 mg/kg), and blood was collected after 2 hours for measurement of plasma cytokines by ELISA. Maoto significantly decreased PolyI:C-induced TNF-α levels and increased IL-10 production. Neither pretreatment with IL-10 neutralizing antibodies nor T-cell deficiency using nude mice modified the inhibitory effect of maoto, indicating that the anti-inflammatory effects of maoto are independent of IL-10 and T cells. Furthermore, the inhibitory effects of maoto on PolyI:C-induced TNF-α production were not observed in ex vivo splenocytes, suggesting that maoto does not act directly on inflammatory cells. Lastly, pretreatment with a β-adrenergic receptor antagonist partially cancelled the anti-inflammatory effects of maoto. Collectively, these results suggest that maoto mediates its anti-inflammatory effects via β-adrenergic receptors in vivo.
Purpose
Lower respiratory infections remain the most lethal communicable disease worldwide. Viral and bacterial coinfections (VBC) are common complications in patients with seasonal influenza and are associated with around 25% of all influenza-related deaths. The burden of pneumonia in patients with VBC in Spain is poorly characterized. To address this question, we aimed to provide population data over a period of six consecutive influenza seasons, from 2009–10 to 2014–15.
Methods
We used the discharge report from the Minimum Basic Data Set (MBDS), published annually by the Spanish Ministry of Health, to retrospectively analyse hospital discharge data in individuals aged ≥60 years with a diagnosis of pneumonia and influenza, based on the International Classification of Diseases (ICD-9-CM codes 480–486 and 487–488, respectively), from 1 October 2009 to 30 September 2015.
Results
In total, 1933 patients ≥60 years old were hospitalized for pneumonia and influenza, of whom 55.2% were male. The median age was 74 years (interquartile range [IRQ] 15); half of the patients were ≥75 years old. Influenza was the main diagnosis in 64.4% of the patients, and all–cause pneumonia in 15.8%, half of whom were assigned a diagnostic code for pneumococcal pneumonia. The mean annual hospitalization rate was 2.99 per 100,000 population (95% CI 2.9–3.1) throughout the study period, while the highest rate, 5.6 per 100,000 population (95% CI 5.2–6.0), was observed in the 2013–14 season. The mean annual mortality rate was 0.5 deaths per 100,000 population (95% CI 0.4–0.6) and in-hospital case fatality rate was 16.1% (95% CI 14.5–17.8).
Conclusions
In Spain, community-acquired pneumonia and influenza continue to be an important cause of hospitalization and mortality in patients over 60 years of age. There is an urgent need to further develop prevention strategies such as joint vaccination for both pathologies.
In order to exploit the advantages to the full of multidrug salification strategy in amending the pharmaceutical properties of drugs both in vitro and in vivo, and further to open up a new way for its applications in bacteria-virus mixed cross-infection drugs, a novel dual-drug crystalline molecular salt hybridizing antibacterial drug sulfamethoxazole (SFM) with antiviral ingredient amantadine (ATE), namely SFM-ATE, is successfully designed and synthesized via multidrug salification strategy oriented by proton exchange reaction. The crystal structure of the firstly obtained molecular salt is precisely identified by employing single-crystal X-ray diffraction and multiple other techniques. The results show that, in the crystal lattice of molecular salt SFM-ATE, the classical hydrogen bonds together with charge-assisted hydrogen bonds contribute to two- dimensional networks, between which the hydrophobic interaction plays an important role. The relevant in vitro/vivo pharmaceutical properties of the dual-drug molecular salt are carried out through a comparative investigation of theoretical and experimental methods. It has been found that SFM displays concurrent improvements over the bulk drug in its permeability and dissolution after forming the molecular salt, which is supported by the molecular electrostatic potential calculation and Hirshfeld surface analysis. Encouragingly, the perfected in vitro biopharmaceutical properties can effectually turn into the in vivo pharmacokinetic preponderances with the expedited peak plasma concentration, lengthened half-life and enhanced bioavailability. Better yet, the antibacterial activities of SFM from the molecular salt get stronger with enlargement in inhibition areas and reduction in values of minimum inhibitory concentrations against the tested bacterial strains. Consequently, the present contribution not only supplies an opportunity for widening applications for classical sulfa drugs via dual-drug salification strategy, but also offers an alternative approach in dealing with viral-bacterial coinfection even other complex diseases by drugs’ hybridization at the molecular level.
Background. Acute respiratory viral infections (ARVI) and pneumococcal infections (PI) annually cause great damage to the health and working capacity of the population, and lead to economic losses for employers and the state. Aim. To study the impact of influenza and PI vaccination coverage on morbidity of ARVI and community-acquired pneumonia (CAP) of the morbidity of population in Central administrative district (CAD) of Moscow. Material and methods. The analysis of official data on monitoring of morbidity from ARVI and CAP was carried out, and information on vaccination of the population against influenza and PI for 2012–2018 was used. Results. In 2018 ARVI accounted for 95.2% of infectious morbidity and the incidence rate was 29853.5 per 100 ths population. Over the period from 2012–2018, the incidence of ARVI and influenza gradually decreased by 2016, but in 2017 the incidence of ARVI was increased to the level of 2012 (+25.3%) however influenza was decreased (-40.9%). In 2018, the incidence of ARVI in adults remained at the level of 2017, and in children there was a decrease (-16.9%). The incidence of influenza in 2018 decreased in both adults (-65.4%) and children (-63.9%). During 2012–2018 the incidence of CAP had a persistent tendency to increase. The coverage of influenza vaccination in CAD population of Moscow has increased annually since 2012 and in 2018 reached 85.5% of children 0–17 years old and 65.5% of adults 18 years and older, and against PI – 46.3% of children and 2.6% of adults. Conclusion. The epidemic circulation of ARVI and influenza had a significant impact on the morbidity of CAD population of Moscow in 2012–2018. Annual vaccination of the population lead to decreasing of influenza incidence but the incidence of pneumonia tended to increase and need to improve prevention.
Relevance. The COVID-19 pandemic has led to significant overloads in the work of health systems in many countries, a shortage
of beds and staff, which contributes to a decrease in adherence to measures to prevent and control nosocomial infections, which
can significantly worsen the course of viral pneumonia. Aim. To assess the possibility of the formation of hospital strains of multidrugresistant microorganisms in hospitals repurposed to provide medical care to patients with COVID-19. Materials and methods.
The study included patients with severe and moderate forms of COVID-19 (ICD codes U07.1, U07.2), who were admitted to two
large hospitals repurposed for the treatment of this infection. The data of microbiological studies of the biomaterial associated with
the respiratory tract (sputum, bronchoalveolar lavage, tracheal aspirates) obtained from 1101 patients from May to January 2021
were analyzed using a combination of molecular genetic methods (RAPD-PCR, detection of integrons and the carbapenemase gene
bla NDM.), and molecular typing of carbapenem-resistant strains of Klebsiella pneumoniae and Acinetobacter baumannii was
carried out. Results. It was found that carbapenem resistant gram-negative bacteria predominate in the structure of the nosocomial
microbiota of the respiratory tract of patients with COVID-19 in both hospitals. Based on molecular typing made the wide distribution
of several genetic lines of integron-positive carbapenem resistant Klebsiella pneumoniae and Acinetobacter baumannii was detected.
Conclusions. The COVID-19 pandemic has exacerbated the spread and circulation of bacteria with multiple antibiotic resistance
in hospitals. This study has demonstrated the possibility of the formation of hospital strains of nosocomial infections in COVID-19
hospitals, which justifies the need to improve infection control measures in the context of a new coronavirus infection pandemic
Objective:
This paper aims to compare the efficacy of antiviral drug alone and antiviral-antibiotic combination in prevention of complications associated with Influenza B hospitalized patients.
Method:
Laboratory confirmed Influenza B hospitalized patients who presented in emergency room after 48 hours of symptoms onset were identified and divided into two groups; Group-1 patients were initiated on Antiviral drug (oseltamivir) while Group-2 patients were initiated on Antiviral drug (oseltamivir) in combination with Antibiotic for at least 3 days. Patients were evaluated for different clinical outcomes among both treatment group patients.
Results:
A total of 153 and 131 patients were identified for Group-1 and Group-2 respectively. Clinical outcomes such as secondary bacterial infections (20.9%-vs-9.1%; P= 0.031), need of respiratory support (28.7%-vs-12.9%; P= 0.002), length of hospitalization stay (6.57-vs-4.95 days; P= <0.001), incidences of ICU admission (15.7%-vs-7.6%; P= 0.036), early clinical failure (32.6%-vs-16.1%; P= 0.01) and time to clinical stability (4.83-vs-4.1 days;P= 0.001) were found to be statistically less significant (P-value <0.05) for Group-2 patients.
Conclusion:
Early initiation of antibiotic therapy in combination with oseltamivir was found to be more efficacious than oseltamivir alone in prevention of Influenza B associated complications especially in high risk patients.
The introduction of new classes of antibiotics, and the high use of antimicrobials in healthcare, agriculture, and the food industry, have all contributed to accelerate the development of antimicrobial resistance (AMR) in bacterial species and dissemination of antibiotic resistant bacterial strains worldwide. At present, the dramatic rise in AMR among important human bacterial pathogens is reaching a state of global crisis threatening a return to the pre-antibiotic era. AMR, already a significant burden on public health and economies, is anticipated to grow even more severe in the coming decades.
The first molecular salt concurrently combining antibacterial drug sulfathiazole (SFZ) and antiviral constituent amantadine (ATD) is designed and successfully synthesized via salification strategy. The precise structure of the newly obtained dual-drug molecular salt SFZ-ATD has been perfectly solved by single-crystal X-ray diffraction and other techniques. The single-crystal diffraction analysis confirms that the occurrence of a proton transference from SFZ to ATD molecules gives rise to the composition for the molecular salt with an equimolar ratio of SFZ and ATD, where the supramolecular network in the crystal is mainly dominated by charge-assisted one-dimensional hydrogen-bonding chains and two-dimensional hydrophobic layer. The relevant properties of the molecular salt are subjected to theoretical and experimental studies. The experimental results highlight that both the permeability and dissolubility of SFZ in the molecular salt display enhancements comparing with pure SFZ, which is further supported by the theoretical calculation of molecular electrostatic potential. More importantly, the advantages of ameliorated physicochemical profiles for the dual-drug salt lead to the intensified antibacterial activities of SFZ against the tested bacterial strains. Thus, this work not only provides a regeneration opportunity for classical sulfa drugs, but also offers some new idea for the therapeutic hybridization associated with virus and bacterial using multidrug combination via salification strategy.
Respiratory infections are the third leading cause of death worldwide. Illness is caused by pathogen replication and disruption of airway homeostasis by excessive expansion of cell numbers. One strategy to prevent lung immune-mediated damage involves reducing the cellular burden. To date, antiinflammatory strategies have affected both antigen-specific and naive immune repertoires. Here we report a novel form of immune intervention that specifically targets recently activated T cells alone. OX40 (CD134) is absent on naive T cells but up-regulated 1-2 d after antigen activation. OX40-immunoglobulin fusion proteins block the interaction of OX40 with its ligand on antigen-presenting cells and eliminate weight loss and cachexia without preventing virus clearance. Reduced proliferation and enhanced apoptosis of lung cells accompanied the improved clinical phenotype. Manipulation of this late costimulatory pathway has clear therapeutic potential for the treatment of dysregulated lung immune responses.
The interplay between viral infection and lipopolysaccharide (LPS) was studied. Infection with a noncytopathogenic virus,
lymphocytic choriomeningitis virus (LCMV), was found to sensitize mice to low doses of LPS. In vivo, this hypersensitivity
correlated with hyperproduction of tumor necrosis factor-α (TNF-α), and in vitro, LPS-stimulated splenic adherent cells produced
increased amounts of TNF-α. Hyperproduction of TNF-α was temporally correlated with virus-induced production of interferon-γ
(IFN-γ); only marginally increased IFN-γ and TNF-α production was observed in LCMV-infected, T cell-deficient mice and in
mice infected with vesicular stomatitis virus, a virus that induces much less T cell activation than does LCMV. Finally, LCMV
infection was much less efficient in priming IFN-γ knockout mice for hyperproduction of TNF-α. These findings indicate that
clinically silent viral infections may induce hypersensitivity to LPS through T cell activation and subsequent production
of IFN-γ; this sensitizes monocytes/macrophages for hyperproduction of TNF-α.
Viral infections in humans or mice can result in increased sensitivity to challenges with bacteria, bacterial products, or cytokine administration. During lymphocytic choriomeningitis virus infections, mice are more sensitive to the lethal effects of bacterial endotoxin LPS, and in the experiments reported here, were observed at up to 10-fold lower doses in infected than in uninfected mice. The mechanisms responsible for heightened susceptibility under these conditions were evaluated. Kinetic studies demonstrated that virus-infected mice had 3- to 50-fold increases over uninfected mice in peak serum TNF, IL-12, and IFN-gamma levels after LPS administration. All three cytokines contributed to lethality during dual challenge, because neutralization of any one of the factors protected from death. Production of TNF was not dependent on either NK or T cells. In contrast, these populations were the predominant sources of IFN-gamma, as determined by lack of detectable IFN-gamma production in NK and T cell-deficient mice and by intracellular cytokine expression in the cell subsets. Concordant with the demonstrations that both cell populations produced IFN-gamma and that this factor was critical for lethality, removal of either subset alone was not sufficient to protect mice from death resulting from dual challenges. Increased resistance required absence of both cell subsets. Taken together, the data show that during viral infections, the normally protective immune responses can profoundly modify reactions to secondary heterologous challenges, to result in dysregulated cytokine expression and consequent heightened detrimental effects.
LPS is the major active agent in the pathogenesis of Gram-negative septic shock. In this report we have studied the influence of concurrent viral infection on the outcome of LPS-induced shock. We find that infection with vesicular stomatitis virus sensitizes mice to LPS at an early time point following infection. Treatment of mice with the chemical IFN inducer, polyinosinic:polycytidylic acid, has a similar effect. This hypersensitivity to LPS correlated with hyperproduction of TNF-alpha in vivo. The cellular and molecular mechanisms underlying this phenomenon were investigated using Ab-depleted and gene-targeted mice. Our results revealed that while NK cell depletion and elimination of IFN-gamma partially protected against the sensitizing effects of vesicular stomatitis virus and polyinosinic:polycytidylic acid, the most striking effect was observed in IFN-alphabetaR-deficient mice. Thus hyperproduction of TNF-alpha was completely abrogated in IFN-alphabetaR-deficient mice, indicating that the principal mechanism underlying rapid virus-induced sensitization to LPS is an IFN-alphabeta-mediated priming of mice for an augmented production of TNF-alpha in response to LPS. This conclusion was further supported by the finding that pretreatment of mice with rIFN-alphabeta mimicked the effect of viral infection. In conclusion, our results reveal a previously unrecognized proinflammatory effect of IFN-alphabeta and point to a new pathway through which viral infection may influence the outcome of concurrent bacterial infection.
Underlying viral infections can heighten sensitivity and worsen cytokine-mediated disease following secondary inflammatory challenges. Mechanisms for this are poorly understood. The impact of the innate response to lymphocytic choriomeningitis virus (LCMV) infection on sensitivity to endotoxin (LPS) was investigated. Compared with uninfected mice, infection with LCMV for 2-days-sensitized mice to LPS by approximately 2-fold for lethality and by 2- to 6-fold for serum TNF-alpha levels. Priming for LPS-induced TNF-alpha was also seen with splenic and peritoneal leukocytes isolated from infected mice and challenged with LPS ex vivo. The effect on TNF-alpha production was present in the absence of IFN-gamma, its major producers NK and T cells, and the major pathways for its induction through IL-12 and the signal transducer and activator of transcription 4 (STAT4), and therefore was IFN-gamma independent. Early LCMV infection induces high concentrations of the type 1 IFNs, IFN-alphabeta. Administration of recombinant IFN-alpha alone heightened the TNF-alpha response to LPS. Innate IFN-alphabeta and IFN-gamma responses to LCMV exist in a delicate balance. To reduce priming for LPS-induced TNF-alpha during LCMV, deficiencies in both the IFN-alphabeta and IFN-gamma receptors or STAT1, a transcription factor downstream to both IFNs, were required. These data demonstrate that early viral infection can enhance sensitivity to bacterial products, and that this sensitization can occur in part as a result of endogenously expressed IFN-alphabeta. This work also raises issues about potential complications associated with IFN-alphabeta therapies.
This study developed methods and determined the impact of influenza vaccination on elderly persons in 3 large health plans:
Kaiser Permanente Northwest, HealthPartners, and Oxford Health Plans. Data for the 1996–1997 and 1997–1998 seasons were extracted
from administrative databases. Subjects were health plan members ⩾65 years old. Comorbid conditions collected from the preceding
year were used for risk adjustment with logistic regression. The virus-vaccine match was excellent for year 1 and fair for
year 2. Both years, during peak and total periods, vaccination reduced all causes of death and hospitalization for pneumonia
and influenza: hospitalizations were reduced by 19%–20% and 18%–24% for years 1 and 2, respectively, and deaths were reduced
by 60%–61% and 35%–39% for the same periods. These results show that all elderly persons should be immunized annually for
influenza. The methods used in this study are an efficient cost-effective way to study vaccine impact and similar questions
This serial cohort study assessed the risk of hospitalization or death associated with influenza and the effectiveness of
influenza vaccination among subgroups of elderly members of 3 managed-care organizations in the United States. Data on baseline
characteristics and outcomes were obtained from computerized databases. A total of 122,974 (1996–1997 season) and 158,454
(1997–1998 season) persons were included in the cohorts. Among unvaccinated persons, hospitalizations for pneumonia/influenza
or death occurred in 8.2 of 1000 healthy and 38.4 of 1000 high-risk persons in year 1, and in 8.2 of 1000 healthy and 29.3
of 1000 high-risk persons in year 2. After adjustments, vaccination was associated with a 48% reduction in the incidence of
hospitalization or death (95% confidence interval [CI], 42–52) in year 1 and 31% (95% CI, 26–37) in year 2. Effectiveness
estimates were statistically significant and generally consistent across the healthy and high-risk subgroups. The absolute
risk reduction, however, was 2.4- to 4.7-fold higher among high-risk than among healthy elderly persons. All elderly individuals
may substantially benefit from vaccination. However, the impact of influenza is greater in persons with high-risk medical
conditions
Septic shock may be associated with relative adrenal insufficiency. Thus, a replacement therapy of low doses of corticosteroids has been proposed to treat septic shock.
To assess whether low doses of corticosteroids improve 28-day survival in patients with septic shock and relative adrenal insufficiency.
Placebo-controlled, randomized, double-blind, parallel-group trial performed in 19 intensive care units in France from October 9, 1995, to February 23, 1999.
Three hundred adult patients who fulfilled usual criteria for septic shock were enrolled after undergoing a short corticotropin test.
Patients were randomly assigned to receive either hydrocortisone (50-mg intravenous bolus every 6 hours) and fludrocortisone (50- micro g tablet once daily) (n = 151) or matching placebos (n = 149) for 7 days.
Twenty-eight-day survival distribution in patients with relative adrenal insufficiency (nonresponders to the corticotropin test).
One patient from the corticosteroid group was excluded from analyses because of consent withdrawal. There were 229 nonresponders to the corticotropin test (placebo, 115; corticosteroids, 114) and 70 responders to the corticotropin test (placebo, 34; corticosteroids, 36). In nonresponders, there were 73 deaths (63%) in the placebo group and 60 deaths (53%) in the corticosteroid group (hazard ratio, 0.67; 95% confidence interval, 0.47-0.95; P =.02). Vasopressor therapy was withdrawn within 28 days in 46 patients (40%) in the placebo group and in 65 patients (57%) in the corticosteroid group (hazard ratio, 1.91; 95% confidence interval, 1.29-2.84; P =.001). There was no significant difference between groups in responders. Adverse events rates were similar in the 2 groups.
In our trial, a 7-day treatment with low doses of hydrocortisone and fludrocortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse events.
In this issue of THE JOURNAL, the article by Thompson and colleagues1 estimates the burden of annual influenza mortality
and provides much new and challenging information. The basic mortality question
under consideration is what causes excess deaths during annual winter influenza
"seasons"? Such mortality excesses can be estimated reasonably well from available
data, but it is another problem entirely to determine what proportion is actually
due to influenza. Traffic deaths, fire deaths, and other death categories
can also increase during the same months.
Influenza and respiratory syncytial virus (RSV) cause substantial morbidity and mortality. Statistical methods used to estimate deaths in the United States attributable to influenza have not accounted for RSV circulation.
To develop a statistical model using national mortality and viral surveillance data to estimate annual influenza- and RSV-associated deaths in the United States, by age group, virus, and influenza type and subtype.
Age-specific Poisson regression models using national viral surveillance data for the 1976-1977 through 1998-1999 seasons were used to estimate influenza-associated deaths. Influenza- and RSV-associated deaths were simultaneously estimated for the 1990-1991 through 1998-1999 seasons.
Attributable deaths for 3 categories: underlying pneumonia and influenza, underlying respiratory and circulatory, and all causes.
Annual estimates of influenza-associated deaths increased significantly between the 1976-1977 and 1998-1999 seasons for all 3 death categories (P<.001 for each category). For the 1990-1991 through 1998-1999 seasons, the greatest mean numbers of deaths were associated with influenza A(H3N2) viruses, followed by RSV, influenza B, and influenza A(H1N1). Influenza viruses and RSV, respectively, were associated with annual means (SD) of 8097 (3084) and 2707 (196) underlying pneumonia and influenza deaths, 36 155 (11 055) and 11 321 (668) underlying respiratory and circulatory deaths, and 51 203 (15 081) and 17 358 (1086) all-cause deaths. For underlying respiratory and circulatory deaths, 90% of influenza- and 78% of RSV-associated deaths occurred among persons aged 65 years or older. Influenza was associated with more deaths than RSV in all age groups except for children younger than 1 year. On average, influenza was associated with 3 times as many deaths as RSV.
Mortality associated with both influenza and RSV circulation disproportionately affects elderly persons. Influenza deaths have increased substantially in the last 2 decades, in part because of aging of the population, underscoring the need for better prevention measures, including more effective vaccines and vaccination programs for elderly persons.
Humans are the only natural reservoir of measles virus (MV), one of the most contagious viruses known. MV infection and the
profound immunosuppression it causes are currently responsible for nearly one million deaths annually. Human signaling lymphocytic
activation molecule (hSLAM) was identified as a receptor for wild-type MV as well as for MV strains prepared as vaccines.
To better evaluate the role of hSLAM in MV pathogenesis and MV-induced immunosuppression, we created transgenic (tg) mice
that expressed the hSLAM molecule under the control of the lck proximal promoter. hSLAM was expressed on CD4+ and CD8+ T cells in the blood and spleen and also on CD4+, CD8+, CD4+ CD8+, and CD4− CD8− thymocytes. Wild-type MV, after limited passage on B95-8 marmoset B cells, and the Edmonston laboratory strain of MV infected
hSLAM-expressing cells. There was a direct correlation between the amount of hSLAM expressed on the cells' surface and the
degree of viral infection. Additionally, MV infection induced downregulation of receptor hSLAM and inhibited cell division
and proliferation of hSLAM+ but not hSLAM− T cells. Therefore, these tg mice provide the opportunity for analyzing and comparing MV-T cell interactions and MV pathogenesis
in cells expressing only the hSLAM MV receptor with those of tg mice whose T cells selectively express another MV receptor,
CD46.
The apparent worldwide resurgence of invasive Streptococcus pyogenes infection in the last two decades remains unexplained. At present, animal models in which toxic shock-like syndrome or necrotizing
fasciitis is induced after S. pyogenes infection are not well developed. We demonstrate here that infection with a nonlethal dose of influenza A virus 2 days before
intranasal infection with a nonlethal dose of S. pyogenes strains led to a death rate of more than 90% in mice, 10% of which showed necrotizing fasciitis. Infection of lung alveolar
epithelial cells by the influenza A virus resulted in viral hemagglutinin expression on the cell surface and promoted internalization
of S. pyogenes. However, treatment with monoclonal antibodies to hemagglutinin markedly decreased this internalization. Our results indicate
that prior infection with influenza A virus induces a lethal synergism, resulting in the induction of invasive S. pyogenes infection in mice.
Among infectious agents, measles virus (MV) remains a scourge responsible for 1 million deaths per year and is a leading cause of childhood deaths in developing countries. Although MV infection itself is not commonly lethal, MV-induced suppression of the immune system results in a greatly increased susceptibility to opportunistic bacterial infections that are largely responsible for the morbidity and mortality associated with this disease. Despite its clinical importance, the underlying mechanisms of MV-induced immunosuppression remain unresolved. To begin to understand the basis of increased susceptibility to bacterial infections during MV infection, we inoculated transgenic mice expressing the MV receptor, CD46, with MV and Listeria monocytogenes. We found that MV-infected mice were more susceptible to infection with Listeria and that this corresponded with significantly decreased numbers of macrophages and neutrophils in the spleen and substantial defects in IFN-gamma production by CD4(+) T cells. The reduction in CD11b(+) macrophages and IFN-gamma-producing T cells was due to reduced proliferative expansion and not to enhanced apoptosis or to altered distribution of these cells between spleen, blood, and the lymphatic system. These results document that MV infection can suppress both innate and adaptive immune responses and lead to increased susceptibility to bacterial infection.
Streptococcus pneumoniae is the chief cause of pneumonia in older adults, but it remains unclear whether use of the pneumococcal polysaccharide vaccine alters the overall risk of community-acquired pneumonia. In a large population of older adults, we assessed the effectiveness of the pneumococcal vaccine.
In this retrospective cohort study, 47,365 Group Health Cooperative members 65 years of age or older were assessed over a three-year period. The primary outcomes were hospitalization because of community-acquired pneumonia (validated by chart review), pneumonia in patients who were not hospitalized ("outpatient pneumonia," determined from administrative data sources), and pneumococcal bacteremia. The association between pneumococcal vaccination and the risk of each outcome was evaluated by means of multivariate Cox proportional-hazards models, with adjustment for age, sex, nursing-home residence or nonresidence, smoking status, medical conditions, and receipt or nonreceipt of influenza vaccine.
During the study period, 1428 cohort members were hospitalized with community-acquired pneumonia, 3061 were assigned a diagnosis of outpatient pneumonia, and 61 had pneumococcal bacteremia. Receipt of the pneumococcal vaccine was associated with a significant reduction in the risk of pneumococcal bacteremia (hazard ratio, 0.56; 95 percent confidence interval, 0.33 to 0.93) but a slightly increased risk of hospitalization for pneumonia (hazard ratio, 1.14; 95 percent confidence interval, 1.02 to 1.28). Pneumococcal vaccination did not alter the risk of outpatient pneumonia (hazard ratio, 1.04; 95 percent confidence interval, 0.96 to 1.13) or of any case of community-acquired pneumonia, whether or not it required hospitalization (hazard ratio, 1.07; 95 percent confidence interval, 0.99 to 1.14).
These findings support the effectiveness of the pneumococcal polysaccharide vaccine for the prevention of bacteremia, but they suggest that alternative strategies are needed to prevent nonbacteremic pneumonia, which is a more common manifestation of pneumococcal infection in elderly persons.
Context Previous studies have shown oseltamivir, a neuraminidase inhibitor,
to be effective in preventing influenza and treating experimental influenza.Objective To evaluate the efficacy and safety of oseltamivir in the treatment
of naturally acquired influenza infection.Design Randomized, placebo-controlled, double-blind study conducted January
through March 1998.Setting Sixty primary care and university health centers throughout the United
States.Participants A total of 629 healthy nonimmunized adults aged 18 to 65 years with
febrile respiratory illness of no more than 36 hours' duration with temperature
of 38°C or more plus at least 1 respiratory symptom and 1 constitutional
symptom.Interventions Individuals were randomized to 1 of 3 treatment groups with identical
appearing pills: oral oseltamivir phosphate, 75 mg twice daily (n = 211) or
150 mg (n = 209) twice daily, or placebo (n = 209).Main Outcome Measures Duration and severity of illness in individuals infected with influenza.Results Two individuals withdrew before receiving medication and were excluded
from further analyses. A total of 374 individuals (59.6%) were infected with
influenza. Their duration of illness was reduced by more than 30% with both
oseltamivir, 75 mg twice daily (median, 71.5 hours; P<.001),
and oseltamivir, 150 mg twice daily (median, 69.9 hours; P = .006), compared with placebo (median, 103.3 hours). Severity of
illness was reduced by 38% (median score, 597 score-hours; P<.001) with oseltamivir, 75 mg twice daily, and by 35% (median
score, 626 score-hours; P<.001) with oseltamivir,
150 mg twice daily, vs placebo (median score, 963 score-hours). Oseltamivir
treatment reduced the duration of fever and oseltamivir recipients returned
to usual activities 2 to 3 days earlier than placebo recipients (P≤.05). Secondary complications such as bronchitis and sinusitis
occurred in 15% of placebo recipients compared with 7% of combined oseltamivir
recipients (P = .03). Among all 629 subjects, oseltamivir
reduced illness duration (76.3 hours and 74.3 hours for 75 mg and 150 mg,
respectively, vs 97.0 hours for placebo; P = .004
for both comparisons) and illness severity (686 score-hours and 629 score-hours
for 75 mg and 150 mg, respectively, vs 887 score-hours for placebo; P<.001 for both comparisons). Nausea and vomiting occurred
more frequently in both oseltamivir groups (combined, 18.0% and 14.1%, respectively; P = .002) than in the placebo group (7.4% and 3.4%; P<.001).Conclusions Our data suggest that oral oseltamivir treatment reduces the duration
and severity of acute influenza in healthy adults and may decrease the incidence
of secondary complications.
In this issue of THE JOURNAL, the article by Thompson and colleagues1 estimates the burden of annual influenza mortality and provides much new and challenging information. The basic mortality question under consideration is what causes excess deaths during annual winter influenza "seasons"? Such mortality excesses can be estimated reasonably well from available data, but it is another problem entirely to determine what proportion is actually due to influenza. Traffic deaths, fire deaths, and other death categories can also increase during the same months.
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.
Context While hospitalization rates have declined overall, hospitalizations
for acute lower respiratory tract infections have increased steadily since
1980. Development of new approaches for prevention of acute respiratory tract
conditions requires studies of the etiologies of infections and quantification
of the risk of hospitalization for vulnerable patients.Objective To determine the frequency of specific virus infections associated with
acute respiratory tract conditions leading to hospitalization of chronically
ill patients.Design Analysis of viral etiology of patients hospitalized with acute respiratory
tract conditions between July 1991 and June 1995.Setting Four large clinics and related hospitals serving diverse populations
representative of Harris County, Texas.Patients A total of 1029 patients who were hospitalized for pneumonia, tracheobronchitis,
bronchiolitis, croup, exacerbations of asthma or chronic obstructive pulmonary
disease, and/or congestive heart failure.Main Outcome Measure Virus infection, defined by culture, antigen detection, and significant
rise in serum antibodies, by underlying condition; hospitalization rates by
low- vs middle-income status.Results Ninety-three percent of patients older than 5 years had a chronic underlying
condition; a chronic pulmonary condition was most common. Patients with chronic
pulmonary disease from low-income populations were hospitalized at a rate
of 398.6 per 10,000, almost 8 times higher than the rate for patients from
middle-income groups (52.2 per 10,000; P<.001).
Of the 403 patients (44.4% of adults and 32.3% of children) who submitted
convalescent serum specimens for antibody testing, respiratory tract virus
infections were detected in 181 (44.9%). Influenza, parainfluenza, and respiratory
syncytial virus (RSV) infections accounted for 75% of all virus infections.Conclusions Our study suggests that respiratory virus infections commonly trigger
serious acute respiratory conditions that result in hospitalization of patients
with chronic underlying conditions, highlighting the need for development
of effective vaccines for these viruses, especially for parainfluenza and
RSV.
Results: Vaccination rates were greater than 70% for each season. Among unvaccinated persons, hospitalization rates for pneumonia and influenza were twice as high in the influenza seasons as they were in the interim (noninfluenza) periods. Influenza vaccination was associated with fewer hospitalizations for pneumonia and influenza (adjusted risk ratio, 0.48 [95% CI, 0.28 to 0.82]) and with lower risk for death (adjusted odds ratio, 0.30 [CI, 0.21 to 0.43]) during the influenza seasons. It was also associated with fewer outpatient visits for pneumonia and influenza and for all respiratory conditions. Conclusions: For elderly persons with chronic lung disease, influenza is associated with significant adverse health effects and influenza vaccination is associated with substantial health benefits, including fewer outpatient visits, fewer hospitalizations, and fewer deaths. Health care providers should take advantage of all opportunities to immunize these high-risk patients.
Background: A lethal synergism exists between influenza virus and Streptococcus pneumoniae accounting for excess mortality during influenza epidemics. A small animal model of dual infection with these organisms would be useful for study of pathogenic mechanisms underlying this interaction. Methods: Groups of mice were infected with either mouse adapted influenza virus A/Puerto Rico/8/34 (H1N1), S. pneumoniae strain D39, both simultaneously, or pneumococcus following influenza virus. Weight loss, as a measure of morbidity, and mortality were followed. Blood cultures were collected 24 h after infection. Results: Mice infected simultaneously with both influenza virus and pneumococcus exhibited gradual weight loss and mortality commensurate with expectations for an additive process. In contrast, mice infected with pneumococcus 7 days following infection with influenza virus uniformly died in less than 24 h and were highly bacteremic. Discussion: A mouse model of sequential infection with influenza virus and S. pneumoniae has been developed. Mice infected with pneumococcus seven days after infection with influenza virus exhibit a synergistic lethality caused by overwhelming sepsis. This model will be useful for study of the mechanisms involved in pathogenic interactions between influenza virus and pneumococcus.
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.
Objective: To determine the incidence, cost, and outcome of severe sepsis in the United States.
Design: Observational cohort study.
Setting: All nonfederal hospitals (n = 847) in seven U.S. states.
Patients: All patients (n = 192,980) meeting criteria for severe sepsis based on the International Classification of Diseases, Ninth Revision, Clinical Modification.
Interventions: None.
Measurements and Main Results : We linked all 1995 state hospital discharge records (n = 6,621,559) from seven large states with population and hospital data from the U.S. Census, the Centers for Disease Control, the Health Care Financing Administration, and the American Hospital Association. We defined severe sepsis as documented infection and acute organ dysfunction using criteria based on the International Classification of Diseases, Ninth Revision, Clinical Modification. We validated these criteria against prospective clinical and physiologic criteria in a subset of five hospitals. We generated national age- and gender-adjusted estimates of incidence, cost, and outcome. We identified 192,980 cases, yielding national estimates of 751,000 cases (3.0 cases per 1,000 population and 2.26 cases per 100 hospital discharges), of whom 383,000 (51.1%) received intensive care and an additional 130,000 (17.3%) were ventilated in an intermediate care unit or cared for in a coronary care unit. Incidence increased >100-fold with age (0.2/1,000 in children to 26.2/1,000 in those >85 yrs old). Mortality was 28.6%, or 215,000 deaths nationally, and also increased with age, from 10% in children to 38.4% in those >85 yrs old. Women had lower age-specific incidence and mortality, but the difference in mortality was explained by differences in underlying disease and the site of infection. The average costs per case were $22,100, with annual total costs of $16.7 billion nationally. Costs were higher in infants, nonsurvivors, intensive care unit patients, surgical patients, and patients with more organ failure. The incidence was projected to increase by 1.5% per annum.
Conclusions: Severe sepsis is a common, expensive, and frequently fatal condition, with as many deaths annually as those from acute myocardial infarction. It is especially common in the elderly and is likely to increase substantially as the U.S. population ages.
A review of the epidemiology of invasive pneumococcal disease in Scotland was carried out using data from laboratory-based systems during the period 1988–99. This comprised 5456 (90·8%) isolates of Streptococcus
pneumoniae from blood, 467 (7·8%) from cerebrospinal fluid (CSF) and 84 (1·4%) from other sterile sites. The mean annual incidence of invasive disease was 9·8/105 population (9·0/105 for bacteraemia and 0·8/105 for meningitis). Invasive disease was highest in children <2 years of age and in the elderly [gt-or-equal, slanted]65 years (44·9/105 and 28·4/105 population in these age groups respectively). The highest incidence of pneumococcal meningitis, 11·8/105 persons occurred in children <2 years of age. Males had a higher incidence of pneumococcal bacteraemia and meningitis than females (male[ratio]female = 1·2[ratio]1 for bacteraemia (RR = 1·17, 95% CI 1·11, 1·24) and 1·5[ratio]1 for meningitis (RR = 1·41, 95% CI 1·18, 1·70)). Pneumococcal disease was highest in winter periods and coincided with influenza activity. The proportion of penicillin and erythromycin non-susceptible isolates increased from 4·2% in 1992 to 12·6% in 1999 and from 5·6% in 1994 to 16·3% in 1999 respectively. Our data confirm the substantial and increasing disease burden from pneumococcal disease and rise in prevalence of antibiotic non-susceptibility among pneumococci in Scotland. Continued surveillance of groups at increased risk for pneumococcal disease and the antibiotic susceptibility and serotype distribution of isolates are important to develop appropriate policies for the prevention of pneumococcal disease in Scotland.
To estimate winter viral-related morbidity and mortality in Tennessee nursing home residents during 4 consecutive years.
A retrospective cohort study.
Three hundred eighty-one Tennessee nursing homes.
Nursing home residents.
Viral surveillance data were used to define three seasons: influenza (influenza and respiratory syncytial virus (RSV) cocirculating), RSV (RSV alone circulating), and non winter-viral (neither virus circulating). Adjusted seasonal differences in rates of cardiopulmonary hospitalizations, antibiotic prescriptions, and deaths during these three seasons were calculated to estimate annual hospitalizations, courses of antibiotics, and deaths attributable to influenza and RSV from 1995 to 1999.
Nursing home residents had 81,885 person-years of follow-up. In the 63% of residents with comorbid conditions that increase influenza morbidity, influenza infection contributed to an estimated average of 28 hospitalizations, 147 courses of antibiotics, and 15 deaths per 1,000 persons annually. Similarly, RSV accounted for an annual average of 15 hospitalizations, 76 courses of antibiotics, and 17 deaths per 1,000 persons. Influenza and RSV accounted for 7% of cardiopulmonary hospitalizations and 9% of total deaths in high-risk residents during the 4 study years. Absolute morbidity and mortality were lower in residents without identified comorbid conditions but accounted for 15% of hospitalizations and 14% of deaths. These estimates depend on the assumption that morbidity and mortality from other respiratory viruses were distributed evenly between the three defined seasons.
Influenza and RSV substantially increased hospitalization rates, antibiotic use, and deaths in elderly nursing home residents each winter. These data should encourage persistent efforts toward disease prevention, and thoughtful study of vaccine development and delivery, diagnostic tools, and methods of prophylaxis and therapy.
Although bacterial superinfection in viral respiratory disease is a clinically well documented phenomenon, the pathogenic mechanisms are still poorly understood. Recent studies have revealed some of the mechanisms involved. Physical damage to respiratory cells as a result of viral infection may lead to opportunistic adherence of bacteria. Enhanced bacterial adherence by specific mechanisms has been documented for respiratory cells infected with influenza A virus, respiratory syncytial virus and adenovirus in both in vitro and in vivo models. To date, results of various experimental studies indicate that different mechanisms for increased bacterial adherence induced by viruses are operating for specific viral-bacterial combinations. In the present review, a number of key findings obtained during the past two decades is presented and discussed.
During two epidemics of influenza A infection in Stockholm 1969-72, 249 cases were selected for a study on the effect of bacterial superinfection. Bacterial involvement was demonstrated through cultures and serologic reactions. The occurrence of C-reactive protein in increased amount in serum was significantly more common in the group which had the strongest indication of bacterial infection. An increased duration of fever, and a higher incidence of pneumonia, leukocytosis and erythrocyte sedimentation rate over 50 mm/l h was also the rule in cases with bacterial involvement. During both epidemics the bacteria most often involved were pneumococci.
Several responses to bacterial endotoxin (lipopolysaccharide, LPS) LPS) have been examined in germfree (GF), Escherichia coli monoassociated (Mono), and conventional (Conv) mice, including immunogenicity, mitogenicity, and lethality. GF mice exhibited significant antibody responses to LPS at low concentrations and over a broad dose range. However, the development of this response was considerably different from Conv mice, i.e., Conv mice exhibited peak responses at 14 days after LPS administration, and titers decreased over the next 2 weeks. GF mice manifested moderate responses by 2 weeks and attained highest titers at 4 weeks, which were greater than those obtained with Conv mice. To assess the influence of a Gram-negative bacterial strain on the host's responsiveness of LPS, GF mice were monoassociated with E. coli K235 and compared to GF and Conv mice with regard to immunogenic, mitogenic, and toxic effects of endotoxin. When TNP-LPS immunogen was administered by either the i.p. or gastric route, the highest numbers of splenic anti-TNP PFC occurred in GF mice, whereas the Mono animals exhibited intermediate responsiveness. This pattern was also dose dependent since GF mice responded at TNP-LPS concentrations that were minimally immunogenic for Mono mice and nonimmunogenic for Conv mice. These differences were also reflected in anti-TNP responses in vitro. The splenic mitogenic responses to PHA, Con A, PWM, and LPS in these three groups were assessed, and no differences were noted with the various lectins. However, both GF and Mono mice yielded higher responses to LPS than was observed in Conv mice. Monoassociated mice were also intermediate in their sensitivity to LPS-induced lethality; GF mice were approximately 5-fold more resistant than Conv mice. The results of this study demonstrate that GF mice in contrast to Conv mice exhibit greater in vitro mitogenic and immunogenic responses and are more refractory to endotoxin.
Virus infections of the respiratory tract predispose it to bacterial superinfections. Epidemiological studies, clinical evidence of viral-bacterial co-infection and animal models of such interactions suggest a time course of events and several mechanisms by which viral potentiation may occur. It appears that structural and functional disruption of the respiratory mucosal epithelium is a major contributor to the synergistic effects of superinfection.
We examined the relation of invasive pneumococcal disease to season, atmospheric conditions, and the rate of respiratory virus isolation in a community-wide surveillance program in Houston. Among adults, the number of cases of pneumococcal bacteremia peaked in midwinter and declined strikingly in midsummer, indicating a high degree of inverse correlation with the ambient temperature. We detected significant correlations between the occurrence of pneumococcal disease and the isolation of respiratory syncytial virus (P < .001), influenza virus (P < .001), and all viruses except influenza virus (P < .001), as well as with air pollution, as measured by SO2 levels (P < .001). In contrast, the rate of invasive pneumococcal disease among infants and children was relatively more sustained from October through May, with a notable decrease in summer months; the incidence of pneumococcal disease was therefore less strongly correlated with cold weather and less closely associated with the isolation of respiratory syncitial virus or influenza virus. However, pneumococcal disease among infants and children was associated with isolation of these viruses after a 4-week lag period as well as with isolation of adenovirus and ragweed pollen counts. The finding, with regard to children, that correlations tended to be stronger for events that occurred 1 month previously than for those that occurred contemporaneously is consistent with the concept that viral or allergic events predispose to otitis media with effusion, which becomes suppurative and leads to pneumococcal bacteremia or meningitis. For adults, a more immediate predisposition to pneumococcal pneumonia and bacteremia because of viral infection or air pollution was suggested.
Superantigen hyperactivation of the immune system has variable, sometimes lethal consequences for the host. Here we show that concurrent influenza infection enhanced the effects of the bacterial superantigen staphylococcal enterotoxin B (SEB) in mice. The effect was T cell-dependent, and maximal synergism was observed when SEB was administered 7 days after the virus, a timepoint during infection associated with high viral titers, a vigorous cytotoxic T cell response, and extensive lung pathology. The influenza infection enhanced the SEB-induced cytokine response in terms of higher absolute levels of cytokine, sustained secretion, and localization to the respiratory tract. In particular, TNF and IFN-gamma were implicated in the mechanism of death because their neutralization protected the mice from death, and recombinant IFN-gamma and TNFalpha mimicked the lethal effect of SEB in influenza-infected mice. This lethal synergism between concurrent influenza infection and superantigen exposure points to the danger of secondary bacterial involvement in viral pneumonia, and suggests mechanisms that may contribute to sudden and unexpected death from influenza infection. In addition, these data demonstrate that the in vivo effects of superantigen exposure can be strongly influenced by the immune activation status of the host.
The safety and immunogenicity of purified fusion protein (PFP-2) respiratory syncytial virus (RSV) vaccine was evaluated in a randomized placebo-controlled, double-blind study of 64 healthy adults over age 60. Vaccination was well tolerated with no significant acute side-effects. Twenty-nine of 33 vaccinees (87%) showed a greater than or equal to fourfold rise in serum IgG to the F protein of RSV at 8 weeks post vaccination. Twenty of 33 vaccine recipients (61%) had a greater than or equal to fourfold rise in serum neutralizing titer to group A and/or group B RSV. Response to vaccination was inversely correlated with pre-immunization serum neutralizing titers. Active surveillance throughout the ensuring winter identified three RSV infections in the placebo group and none in the vaccine group. Thus, PFP-2 was found to be safe and immunogenic in healthy older adults.
To determine whether a systematic review of the literature could identify changes in the mortality of septic shock over time.
A review of all relevant papers from 1958 to August 1997, identified through a MEDLINE search and from the bibliographies of articles identified.
The search identified 131 studies (99 prospective and 32 retrospective) involving a total of 10,694 patients. The patients' mean age was 57 yrs with no change over time. The overall mortality rate in the 131 studies was 49.7%. There was an overall significant trend of decreased mortality over the period studied (r=.49, p < .05). The mortality rate in those patients with bacteremia as an entry criterion was greater than that rate in patients whose entry criterion was sepsis without definite bacteremia (52.1% vs. 49.1%; chi2=6.1 and p< .05). The site of infection altered noticeably over the years. Chest-related infections increased over time, with Gram-negative infections becoming proportionately less common. If all other organisms and mixed infections are included with the Gram-positives, the result is more dramatic, with these organisms being causative in just 10% of infections between 1958 and 1979 but in 31% of infections between 1980 and 1997.
The present review showed a slight reduction in mortality from septic shock over the years, although this result should be approached with caution. The heterogeneity of the articles and absence of a severity score for most of the studies limited our analysis. Furthermore, there was an increasing prevalence of Gram-positive causative organisms, and a change of the predominant origin of sepsis from the abdomen to the chest.
Influenza vaccine is underused in groups targeted for vaccination.
To define the effects of influenza and the benefits of influenza vaccination in elderly persons with chronic lung disease.
Retrospective, multiseason cohort study.
Large managed care organization.
All elderly members of a managed care organization who had a previous diagnosis of chronic lung disease.
Outcomes in vaccinated and unvaccinated persons for the 1993-1994, 1994-1995, and 1995-1996 influenza seasons were compared after adjustment for baseline demographic and health characteristics. All data were obtained from administrative databases.
Vaccination rates were greater than 70% for each season. Among unvaccinated persons, hospitalization rates for pneumonia and influenza were twice as high in the influenza seasons as they were in the interim (noninfluenza) periods. Influenza vaccination was associated with fewer hospitalizations for pneumonia and influenza (adjusted risk ratio, 0.48 [95% CI, 0.28 to 0.82]) and with lower risk for death (adjusted odds ratio, 0.30 [CI, 0.21 to 0.43]) during the influenza seasons. It was also associated with fewer outpatient visits for pneumonia and influenza and for all respiratory conditions.
For elderly persons with chronic lung disease, influenza is associated with significant adverse health effects and influenza vaccination is associated with substantial health benefits, including fewer outpatient visits, fewer hospitalizations, and fewer deaths. Health care providers should take advantage of all opportunities to immunize these high-risk patients.
While hospitalization rates have declined overall, hospitalizations for acute lower respiratory tract infections have increased steadily since 1980. Development of new approaches for prevention of acute respiratory tract conditions requires studies of the etiologies of infections and quantification of the risk of hospitalization for vulnerable patients.
To determine the frequency of specific virus infections associated with acute respiratory tract conditions leading to hospitalization of chronically ill patients.
Analysis of viral etiology of patients hospitalized with acute respiratory tract conditions between July 1991 and June 1995.
Four large clinics and related hospitals serving diverse populations representative of Harris County, Texas.
A total of 1029 patients who were hospitalized for pneumonia, tracheobronchitis, bronchiolitis, croup, exacerbations of asthma or chronic obstructive pulmonary disease, and/or congestive heart failure.
Virus infection, defined by culture, antigen detection, and significant rise in serum antibodies, by underlying condition; hospitalization rates by low- vs middle-income status.
Ninety-three percent of patients older than 5 years had a chronic underlying condition; a chronic pulmonary condition was most common. Patients with chronic pulmonary disease from low-income populations were hospitalized at a rate of 398.6 per 10000, almost 8 times higher than the rate for patients from middle-income groups (52.2 per 10000; P<.001). Of the 403 patients (44.4% of adults and 32.3% of children) who submitted convalescent serum specimens for antibody testing, respiratory tract virus infections were detected in 181 (44.9%). Influenza, parainfluenza, and respiratory syncytial virus (RSV) infections accounted for 75% of all virus infections.
Our study suggests that respiratory virus infections commonly trigger serious acute respiratory conditions that result in hospitalization of patients with chronic underlying conditions, highlighting the need for development of effective vaccines for these viruses, especially for parainfluenza and RSV.
A 1743 headline in The London Magazine cited
"news from Rome of a contagious distemper called the influenza."1
At that time, the pathogenic "influence" visited on the citizens of Italy
may have been thought to be occult or astral in origin. It is now well known,
however, that a family of RNA orthomyxoviruses causes the deadly respiratory
infections, which spread from person to person by the airborne route. In 1918-1919,
an influenza pandemic killed 21 million people worldwide and more than 500,000
in the United States.2 Currently, the Centers
for Disease Control and Prevention (CDC) estimates that 20,000 people die
in the United States each year from influenza, and 110,000 are hospitalized.3
Previous studies have shown oseltamivir, a neuraminidase inhibitor, to be effective in preventing influenza and treating experimental influenza.
To evaluate the efficacy and safety of oseltamivir in the treatment of naturally acquired influenza infection.
Randomized, placebo-controlled, double-blind study conducted January through March 1998.
Sixty primary care and university health centers throughout the United States.
A total of 629 healthy nonimmunized adults aged 18 to 65 years with febrile respiratory illness of no more than 36 hours' duration with temperature of 38 degrees C or more plus at least 1 respiratory symptom and 1 constitutional symptom.
Individuals were randomized to 1 of 3 treatment groups with identical appearing pills: oral oseltamivir phosphate, 75 mg twice daily (n = 211) or 150 mg (n = 209) twice daily, or placebo (n = 209).
Duration and severity of illness in individuals infected with influenza.
Two individuals withdrew before receiving medication and were excluded from further analyses. A total of 374 individuals (59.6%) were infected with influenza. Their duration of illness was reduced by more than 30% with both oseltamivir, 75 mg twice daily (median, 71.5 hours; P < .001), and oseltamivir, 150 mg twice daily (median, 69.9 hours; P = .006), compared with placebo (median, 103.3 hours). Severity of illness was reduced by 38% (median score, 597 score-hours; P < .001) with oseltamivir, 75 mg twice daily, and by 35% (median score, 626 score-hours; P < .001) with oseltamivir, 150 mg twice daily, vs placebo (median score, 963 score-hours). Oseltamivir treatment reduced the duration of fever and oseltamivir recipients returned to usual activities 2 to 3 days earlier than placebo recipients (P < or = .05). Secondary complications such as bronchitis and sinusitis occurred in 15% of placebo recipients compared with 7% of combined oseltamivir recipients (P = .03). Among all 629 subjects, oseltamivir reduced illness duration (76.3 hours and 74.3 hours for 75 mg and 150 mg, respectively, vs 97.0 hours for placebo; P = .004 for both comparisons) and illness severity (686 score-hours and 629 score-hours for 75 mg and 150 mg, respectively, vs 887 score-hours for placebo; P < .001 for both comparisons). Nausea and vomiting occurred more frequently in both oseltamivir groups (combined, 18.0% and 14.1%, respectively; P = .002) than in the placebo group (7.4% and 3.4%; P < .001).
Our data suggest that oral oseltamivir treatment reduces the duration and severity of acute influenza in healthy adults and may decrease the incidence of secondary complications.
Cytokines are soluble proteins that are produced and secreted as part of the immune response to a variety of tissue insults including infection, cancer, and autoimmunity. Most cytokines are secreted by cells of the immune system, but some (for example, type I interferons) are released from "nonimmunological" cells such as fibroblasts and epithelial cells. Cytokines have pleiotropic effects, acting on many somatic cell types to modulate the host's immune response. For the most part, cytokines exert their antimicrobial actions locally---they are secreted by cells in the area of infection, and their effects are restricted to neighboring cells. While many of their local effects benefit the host, cytokines are soluble molecules that may act systemically and are often responsible for many of the symptoms of infection (e.g., headache, fever, myalgia). In high concentrations they can be toxic, or even lethal. Human clinical trials involving the systemic injection of purified cytokines such as interleukins 2 and 12 and tumor necrosis factor alpha provide compelling evidence for the toxicity of these molecules. Likewise, studies of septic shock syndrome demonstrate how overproduction/aberrant production of inflammatory cytokines can lead to rapid mortality. The host may attempt to counter high cytokine levels by releasing soluble cytokine receptors (sCR) or by synthesizing high-affinity anti-cytokine antibodies (acAb), and these natural responses have spawned great interest as potential therapeutic approaches for alleviating cytokine-mediated disease. However, recent studies indicate that these in vivo interactions are much more complex than previously realized; administration of sCR or acAb may either inhibit or (paradoxically) enhance cytokine activity. An alternative therapeutic approach is to intervene at the source of cytokine production. T cells initiate cytokine production only upon antigen contact and terminate synthesis almost immediately after this contact is broken. Thus T cells secrete cytokines specifically at sites of infection and do not continuously produce these potentially toxic molecules while migrating through uninfected tissues or the bloodstream. By learning more about the molecular mechanisms involved with on/off regulation of cytokine production we may be able to develop novel therapeutic drugs to protect against cytokine-mediated immunopathology. This review discusses the regulation of cytokine function by sCR and acAb and compares this to the regulatory mechanisms that are associated with antigen-specific cytokine release by T cells.
We are grateful to Annette Lord for excellent secretarial support. This work was supported by National Institutes of Health grant AI-27028. This is manuscript number 12953-NP from the Scripps Research Institute.
Bacterial super-infections are the main cause of complication and mortality after influenza virus (IAV) infection. Since Bacillus thuringiensis (Bt) is considered non-pathogenic for humans and is widely sprayed in urban areas, the aim of this work was to evaluate the potential pathogenicity of a combined infection Bt-IAV in a mouse model of pneumonia. Bacteria used for super-infections were Bt serotype H34 isolated from human infection and the insecticidal strain 3a3b obtained from a commercial source. Virus strain was A/Scotland/20/74 (H3N2) adapted to BALB/c mice by serial lung passage. Combined infection with 4% of the viral lethal dose 50% (LD(50)) and 10(2) spores of Bt H34 killed 40% of the mice. Mortality rates increased up to 55% and 100% when combined infections were done with respectively 10(4) and 10(7) spores. The insecticidal strain Bt 3a3b was less pathogenic than Bt H34. A dose of 10(4) spores associated with 4% of IAV LD(50) killed 50% of the mice. This inoculum must be compared with the doses usually sprayed in agriculture: 10(11) spores m(-2). Total protection against super-infection was obtained when mice were treated with amantadine. Even if only a few cases of Bt human infection have been reported, these results suggest a possible risk for workers spraying Bt-based biopesticides during flu outbreaks.
In patients with Influenza, the risk of death from pneumonia is closely associated with age and chronic conditions. Mortality from influenza and pneumonia in Americans age > or = 65 has been increasing since 1980. Pneumonia following influenza is usually caused by a secondary bacterial infection. Pathogens most commonly implicated are Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae. Prompt empiric therapy effective against the suspected pathogen is indicated, whether the patient is being treated as an outpatient or requires inpatient observation or hospitalization for i.v. administration. Influenza vaccination of older patients living in the community has been shown to decrease hospitalizations for influenza and pneumonia by 52% and mortality by 70% in those with chronic lung disease. Protective rates are similar for residents of long-term care facilities.
To study the effect of early and continuous venovenous hemofiltration (CVVH) on the plasma concentrations of several humoral mediators of inflammation and subsequent organ dysfunction in septic patients.
Randomized, controlled trial.
Intensive care unit of a tertiary hospital.
Twenty-four patients with early septic shock or septic organ dysfunction.
Random allocation to receive 48 hrs of isovolemic CVVH at 2 L/hr of fluid exchange or no hemofiltration.
We measured the plasma concentrations of complement fractions C3a and C5a, interleukins 6, 8, and 10, and tumor necrosis factor alpha at baseline and 2, 24, 26, 48, and 72 hrs. A multiple organ dysfunction score (MODS) was calculated daily for each patient until death or discharge from the intensive care unit. The concentrations of most mediators decreased between baseline and 72 hrs. Some significant falls in concentration could be identified between specific time points, but CVVH was not associated with an overall reduction in any plasma cytokine concentrations. There was also no difference between the mean cumulative MODS for control survivors (43.3 +/- 19.7) and CVVH survivors (33.2 +/- 19.0; p = .30), and no difference between the average MODS calculated for all controls (4.1 +/- 1.9) and all CVVH subjects (3.3 +/- 1.7; p = .26). CVVH did not improve oxygenation, lower the platelet count, or reduce the duration of vasopressor support and mechanical ventilation.
Early use of CVVH at 2 L/hr did not reduce the circulating concentrations of several cytokines and anaphylatoxins associated with septic shock, or the organ dysfunction that followed severe sepsis. CVVH using current technology cannot be recommended as an adjunct to the treatment of septic shock unless severe acute renal failure is present.
A review of the epidemiology of invasive pneumococcal disease in Scotland was carried out using data from laboratory-based systems during the period 1988-99. This comprised 5456 (90.8%) isolates of Streptococcus pneumoniae from blood, 467 (7.8%) from cerebrospinal fluid (CSF) and 84 (1.4%) from other sterile sites. The mean annual incidence of invasive disease was 9.8/10(5) population (9.0/10(5) for bacteraemia and 0.8/10(5) for meningitis). Invasive disease was highest in children < 2 years of age and in the elderly > or = 65 years (44.9/10(5) and 28.4/10(5) population in these age groups respectively). The highest incidence of pneumococcal meningitis, 11.8/10(5) persons occurred in children < 2 years of age. Males had a higher incidence of pneumococcal bacteraemia and meningitis than females (male:female = 1.2:1 for bacteraemia (RR = 1.17, 95 % CI 1.11, 1.24) and 1.5:1 for meningitis (RR = 1.41, 95 % CI 1.18, 1.70)). Pneumococcal disease was highest in winter periods and coincided with influenza activity. The proportion of penicillin and erythromycin non-susceptible isolates increased from 4.2% in 1992 to 12.6% in 1999 and from 5.6% in 1994 to 16.3% in 1999 respectively. Our data confirm the substantial and increasing disease burden from pneumococcal disease and rise in prevalence of antibiotic non-susceptibility among pneumococci in Scotland. Continued surveillance of groups at increased risk for pneumococcal disease and the antibiotic susceptibility and serotype distribution of isolates are important to develop appropriate policies for the prevention of pneumococcal disease in Scotland.
A lethal synergism exists between influenza virus and pneumococcus, which likely accounts for excess mortality from secondary
bacterial pneumonia during influenza epidemics. Characterization of a mouse model of synergy revealed that influenza infection
preceding pneumococcal challenge primed for pneumonia and led to 100% mortality. This effect was specific for viral infection
preceding bacterial infection, because reversal of the order of administration led to protection from influenza and improved
survival. The hypothesis that influenza up-regulates the platelet-activating factor receptor (PAFr) and thereby potentiates
pneumococcal adherence and invasion in the lung was examined in the model. Groups of mice receiving CV-6209, a competitive
antagonist of PAFr, had survival rates similar to those of control mice, and lung and blood bacterial titers increased during
PAFr inhibition. These data suggest that PAFr-independent pathways are operative in the model, prompting further study of
receptor interactions during pneumonia and bacteremia. The model of lethal synergism will be a useful tool for exploring this
and other mechanisms underlying viral-bacterial interactions
Respiratory syncytial virus (RSV) is responsible for severe low respiratory tract infections in young infants and the elderly. To investigate whether BBG2Na, a recombinant subunit vaccine comprising aa 130-230 of the RSV G protein, induced protective Abs in subjects over 60 years during phase II clinical trial, pre- and postimmunization sera of individuals immunized with BBG2Na or placebo were transferred into SCID mice before RSV challenge. These sera dose-dependently reduced lung RSV titers. However at some points of serial dilutions, postimmunization sera of BBG2Na-immunized subjects only were significantly more efficient than the corresponding preimmunization sera, in agreement with the induction of an increased Ab response against multiple epitopes on RSV-A G protein. Thus, BBG2Na is immunogenic in the elderly and confers passive protection in mice after serum transfer. To our knowledge, this is the first description of protective Abs induced by a subunit vaccine in human.
R. J., LangleyE. L., TsalikJ. C. v., VelkinburghS. W., GlickmanB. J., RiceC., WangB., ChenL., CarinA., SuarezR. P., MohneyD. H., FreemanM., WangJ., YouJ., WulffJ. W., ThompsonM. A., MoseleyS., ReisingerB. T., EdmondsB., GrinnellD. R., NelsonD. L., DinwiddieN. A., MillerC. J., SaundersS. S., SodenA. J., RogersL., GazourianL. E., FredenburghA. F., MassaroR. M., BaronA. M. K., ChoiG. R., CoreyG. S., GinsburgC. B., CairnsR. M., OteroV. G., FowlerE. P., RiversC. W., WoodsS. F., Kingsmore. (2013) An Integrated Clinico-Metabolomic Model Improves Prediction of Death in Sepsis. Science Translational Medicine 5, 195ra95-195ra95
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To determine the safety and efficacy of filgrastim (r-metHuG-CSF) in combination with intravenous antibiotics to reduce the rate of mortality in patients with pneumonia and sepsis.
This study was multicenter, double-blind, and randomized.
Intensive care units PATIENTS Adult patients with bacterial pneumonia, either acquired or nosocomial, as confirmed by chest radiograph and positive culture or Gram-negative stain, and severe sepsis, defined as sepsis-induced hypotension or organ dysfunction.
Standard antibiotic therapy with or without filgrastim (300 microg/day) or placebo administered as a 30-min intravenous infusion. The study drug was started within 24 hrs of enrollment and was continued for 5 days or until the white blood cell count reached >75.0 x 10(9) cells/L.
The primary end point was the occurrence of mortality through day 29; secondary end points included occurrence of subsequent organ dysfunction, time to discharge from intensive care unit, number of days on mechanical ventilatory support, and time to death. Study-related observations were recorded through day 10 and included vital signs, onset of organ dysfunction, clinical laboratory variables, and adverse events. Filgrastim increased the white blood cell count to a median peak of 31.7 x 10(9) cells/L from a baseline of 12.3 x 10(9) cells/L. The two groups were well matched and did not differ significantly with regard to severe adverse events, time to death, occurrence of end-organ dysfunction, days of intensive care unit hospitalization, or days on mechanical ventilatory support. Mortality was low in both treatment groups; the mortality rate in patients with adult respiratory distress syndrome was similar between the two groups.
The addition of filgrastim to the antibiotic and supportive care treatment of patients with pneumonia complicated by severe sepsis appeared to be safe, but not efficacious in reducing mortality rates or complications from this infection.
Sepsis represents a substantial health care burden, and there is limited epidemiologic information about the demography of sepsis or about the temporal changes in its incidence and outcome. We investigated the epidemiology of sepsis in the United States, with specific examination of race and sex, causative organisms, the disposition of patients, and the incidence and outcome.
We analyzed the occurrence of sepsis from 1979 through 2000 using a nationally representative sample of all nonfederal acute care hospitals in the United States. Data on new cases were obtained from hospital discharge records coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification.
Review of discharge data on approximately 750 million hospitalizations in the United States over the 22-year period identified 10,319,418 cases of sepsis. Sepsis was more common among men than among women (mean annual relative risk, 1.28 [95 percent confidence interval, 1.24 to 1.32]) and among nonwhite persons than among white persons (mean annual relative risk, 1.90 [95 percent confidence interval, 1.81 to 2.00]). Between 1979 and 2000, there was an annualized increase in the incidence of sepsis of 8.7 percent, from about 164,000 cases (82.7 per 100,000 population) to nearly 660,000 cases (240.4 per 100,000 population). The rate of sepsis due to fungal organisms increased by 207 percent, with gram-positive bacteria becoming the predominant pathogens after 1987. The total in-hospital mortality rate fell from 27.8 percent during the period from 1979 through 1984 to 17.9 percent during the period from 1995 through 2000, yet the total number of deaths continued to increase. Mortality was highest among black men. Organ failure contributed cumulatively to mortality, with temporal improvements in survival among patients with fewer than three failing organs. The average length of the hospital stay decreased, and the rate of discharge to nonacute care medical facilities increased.
The incidence of sepsis and the number of sepsis-related deaths are increasing, although the overall mortality rate among patients with sepsis is declining. There are also disparities among races and between men and women in the incidence of sepsis. Gram-positive bacteria and fungal organisms are increasingly common causes of sepsis.