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1.
Antibiotics (Basel) ; 11(11)2022 Oct 30.
Article in English | MEDLINE | ID: mdl-36358172

ABSTRACT

The demographics and outcomes of ICU patients admitted for a COVID-19 infection have been characterized in extensive reports, but little is known about antimicrobial stewardship for these patients. We designed this retrospective, observational study to investigate our hypothesis that the COVID-19 pandemic has disrupted antimicrobial stewardship practices and likely affected the rate of antibiotic de-escalation (ADE), patient outcomes, infection recurrence, and multidrug-resistant bacteria acquisition. We reviewed the prescription of antibiotics in three ICUs during the pandemic from March 2020 to December 2021. All COVID-19 patients with suspected or proven bacterial superinfections who received antibiotic treatment were included. The primary outcome was the rate of ADE, and secondary outcomes included the rate of appropriate empirical treatment, mortality rates and a comparison with a control group of infected patients before the COVID-19 pandemic. We included 170 COVID-19 patients who received antibiotic treatment for a suspected or proven superinfection, of whom 141 received an empirical treatment. For the latter, antibiotic treatment was de-escalated in 47 (33.3%) patients, escalated in 5 (3.5%) patients, and continued in 89 (63.1%) patients. The empirical antibiotic treatment was appropriate for 87.2% of cases. ICU, hospital, and day 28 and day 90 mortality rates were not associated with the antibiotic treatment strategy. The ADE rate was 52.2% in the control group and 27.6% in the COVID-19 group (p < 0.001). Our data suggest that empirical antibiotic treatment was appropriate in most cases. The ADE rates were lower in the COVID-19 group than in the control group, suggesting that the stress associated with COVID-19 affected our practices.

2.
Antibiotics (Basel) ; 11(10)2022 Oct 20.
Article in English | MEDLINE | ID: mdl-36290104

ABSTRACT

BACKGROUND: In the period following the declaration of the COVID-19 pandemic, more evidence became available on the epidemiology of bacterial co-/superinfections (bCSs) in hospitalized COVID-19 patients. Various European therapeutic guidelines were published, including guidance on rational antibiotic use. METHODS: In this letter to the editor, we provide an overview of the largest meta-analyses or prospective studies reporting on bCS rates in COVID-19 patients and discuss why the reader should interpret the results of those reports with care. Moreover, we compare different national and international COVID-19 therapeutic guidelines from countries of the European Union. Specific attention is paid to guidance dedicated to rational antibiotic use. RESULTS: We found a significant heterogeneity in studies reporting on the epidemiology of bCSs in COVID-19 patients. Moreover, European national and international guidelines differ strongly from each other, especially with regard to the content and extent of antibiotic guidance in hospitalized COVID-19 patients. CONCLUSION: A standardized way of reporting on bCSs and uniform European guidelines on rational antibiotic use in COVID-19 patients are crucial for antimicrobial stewardship teams to halt unnecessary antibiotic use in the COVID-19 setting.

3.
Microbiol Spectr ; : e0230522, 2022 Oct 17.
Article in English | MEDLINE | ID: mdl-36250865

ABSTRACT

Clinicians in the emergency department (ED) face challenges in concurrently assessing patients with suspected COVID-19 infection, detecting bacterial coinfection, and determining illness severity since current practices require separate workflows. Here, we explore the accuracy of the IMX-BVN-3/IMX-SEV-3 29 mRNA host response classifiers in simultaneously detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and bacterial coinfections and predicting clinical severity of COVID-19. A total of 161 patients with PCR-confirmed COVID-19 (52.2% female; median age, 50.0 years; 51% hospitalized; 5.6% deaths) were enrolled at the Stanford Hospital ED. RNA was extracted (2.5 mL whole blood in PAXgene blood RNA), and 29 host mRNAs in response to the infection were quantified using Nanostring nCounter. The IMX-BVN-3 classifier identified SARS-CoV-2 infection in 151 patients with a sensitivity of 93.8%. Six of 10 patients undetected by the classifier had positive COVID tests more than 9 days prior to enrollment, and the remaining patients oscillated between positive and negative results in subsequent tests. The classifier also predicted that 6 (3.7%) patients had a bacterial coinfection. Clinical adjudication confirmed that 5/6 (83.3%) of the patients had bacterial infections, i.e., Clostridioides difficile colitis (n = 1), urinary tract infection (n = 1), and clinically diagnosed bacterial infections (n = 3), for a specificity of 99.4%. Two of 101 (2.8%) patients in the IMX-SEV-3 "Low" severity classification and 7/60 (11.7%) in the "Moderate" severity classification died within 30 days of enrollment. IMX-BVN-3/IMX-SEV-3 classifiers accurately identified patients with COVID-19 and bacterial coinfections and predicted patients' risk of death. A point-of-care version of these classifiers, under development, could improve ED patient management, including more accurate treatment decisions and optimized resource utilization. IMPORTANCE We assay the utility of the single-test IMX-BVN-3/IMX-SEV-3 classifiers that require just 2.5 mL of patient blood in concurrently detecting viral and bacterial infections as well as predicting the severity and 30-day outcome from the infection. A point-of-care device, in development, will circumvent the need for blood culturing and drastically reduce the time needed to detect an infection. This will negate the need for empirical use of broad-spectrum antibiotics and allow for antibiotic use stewardship. Additionally, accurate classification of the severity of infection and the prediction of 30-day severe outcomes will allow for appropriate allocation of hospital resources.

4.
Vet Res ; 53(1): 70, 2022 Sep 06.
Article in English | MEDLINE | ID: mdl-36068558

ABSTRACT

Bovine respiratory disease (BRD) is one of the most important diseases impacting the global cattle industry, resulting in significant economic loss. Commonly referred to as shipping fever, BRD is especially concerning for young calves during transport when they are most susceptible to developing disease. Despite years of extensive study, managing BRD remains challenging as its aetiology involves complex interactions between pathogens, environmental and host factors. While at the beginning of the twentieth century, scientists believed that BRD was only caused by bacterial infections ("bovine pasteurellosis"), we now know that viruses play a key role in BRD induction. Mixtures of pathogenic bacteria and viruses are frequently isolated from respiratory secretions of animals with respiratory illness. The increased diagnostic screening data has changed our understanding of pathogens contributing to BRD development. In this review, we aim to comprehensively examine experimental evidence from all existing studies performed to understand coinfections between respiratory pathogens in cattle. Despite the fact that pneumonia has not always been successfully reproduced by in vivo calf modelling, several studies attempted to investigate the clinical significance of interactions between different pathogens. The most studied model of pneumonia induction has been reproduced by a primary viral infection followed by a secondary bacterial superinfection, with strong evidence suggesting this could potentially be one of the most common scenarios during BRD onset. Different in vitro studies indicated that viral priming may increase bacterial adherence and colonization of the respiratory tract, suggesting a possible mechanism underpinning bronchopneumonia onset in cattle. In addition, a few in vivo studies on viral coinfections and bacterial coinfections demonstrated that a primary viral infection could also increase the pathogenicity of a secondary viral infection and, similarly, dual infections with two bacterial pathogens could increase the severity of BRD lesions. Therefore, different scenarios of pathogen dynamics could be hypothesized for BRD onset which are not limited to a primary viral infection followed by a secondary bacterial superinfection.


Subject(s)
Bovine Respiratory Disease Complex , Cattle Diseases , Coinfection , Pasteurella Infections , Respiratory Tract Diseases , Superinfection , Virus Diseases , Animals , Bacteria , Cattle , Cattle Diseases/microbiology , Coinfection/veterinary , Pasteurella Infections/veterinary , Respiratory System , Respiratory Tract Diseases/veterinary , Superinfection/veterinary , Virus Diseases/veterinary
5.
Biomolecules ; 12(5)2022 04 25.
Article in English | MEDLINE | ID: mdl-35625558

ABSTRACT

Neurological symptoms are increasingly recognized in SARS-CoV-2 infected individuals. However, the neuropathogenesis remains unclear and it is not possible to define a specific damage pattern due to brain virus infection. In the present study, 33 cases of brain autopsies performed during the first (February-April 2020) and the second/third (November 2020-April 2021) pandemic waves are described. In all the cases, SARS-CoV-2 RNA was searched. Pathological findings are described and compared with those presently published.


Subject(s)
COVID-19 , Adult , Autopsy , Brain , COVID-19/epidemiology , Humans , RNA, Viral , SARS-CoV-2
6.
Cell Biosci ; 12(1): 14, 2022 Feb 09.
Article in English | MEDLINE | ID: mdl-35139898

ABSTRACT

BACKGROUND: COVID-19 pneumonia has caused huge impact on the health of infected patients and associated with high morbidity and mortality. Shift in the lung microbial ecology upon such viral infection often worsens the disease and increases host susceptibility to superinfections. Bacterial superinfection contributes to the aggravation of COVID-19 and poses a great challenge to clinical treatments. An in-depth investigation on superinfecting bacteria in COVID-19 patients might facilitate understanding of lung microenvironment post virus infections and superinfection mechanism. RESULTS: We analyzed the adaptation of two pairs of P. aeruginosa strains with the same MLST type isolated from two critical COVID-19 patients by combining sequencing analysis and phenotypic assays. Both P. aeruginosa strains were found to turn on alginate biosynthesis and attenuate type VI secretion system (T6SS) during short-term colonization in the COVID-19 patients, which results in excessive biofilm formation and virulence reduction-two distinct markers for chronic infections. The macrophage cytotoxicity test and intracellular reactive oxygen species measurement confirmed that the adapted P. aeruginosa strains reduced their virulence towards host cells and are better to escape from host immune clearance than their ancestors. CONCLUSION: Our study suggests that SARS-CoV-2 infection can create a lung environment that allow rapid adaptive evolution of bacterial pathogens with genetic traits suitable for chronic infections.

7.
Front Cell Infect Microbiol ; 11: 683409, 2021.
Article in English | MEDLINE | ID: mdl-34458159

ABSTRACT

Objective: To investigate the presence of bacteria and fungi in bronchial aspirate (BA) samples from 43 mechanically ventilated patients with severe COVID-19 disease. Methods: Detection of SARS-CoV-2 was performed using Allplex 2019-nCoV assay kits. Isolation and characterisation of bacteria and fungi were carried out in BA specimens treated with 1X dithiothreitol 1% for 30 min at room temperature, using standard culture procedures. Results: Bacterial and/or fungal superinfection was detected in 25 out of 43 mechanically ventilated patients, generally after 7 days of hospitalisation in an intensive care unit (ICU). Microbial colonisation (colony forming units (CFU) <1000 colonies/ml) in BA samples was observed in 11 out of 43 patients, whereas only 7 patients did not show any signs of bacterial or fungal growth. Pseudomonas aeruginosa was identified in 17 patients. Interestingly, 11 out of these 17 isolates also showed carbapenem resistance. The molecular analysis demonstrated that resistance to carbapenems was primarily related to OprD mutation or deletion. Klebsiella pneumoniae was the second most isolated pathogen found in 13 samples, of which 8 were carbapenemase-producer strains. Conclusion: These data demonstrate the detection of bacterial superinfection and antimicrobial resistance in severe SARS-CoV-2-infected patients and suggest that bacteria may play an important role in COVID-19 evolution. A prospective study is needed to verify the incidence of bacterial and fungal infections and their influence on the health outcomes of COVID-19 patients.


Subject(s)
COVID-19 , Pharmaceutical Preparations , Superinfection , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Humans , Intensive Care Units , Microbial Sensitivity Tests , RNA, Viral , Respiration, Artificial , SARS-CoV-2 , Superinfection/drug therapy
8.
Cureus ; 13(8): e16818, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34522478

ABSTRACT

Primary herpes simplex virus 1 (HSV-1) infection in children (beyond the neonatal period) may be asymptomatic or manifest as herpetic gingivostomatitis accompanied by fever and other symptoms. However, severe, health- and life-threatening infection is observed in rare cases, especially in at-risk patients. Children with atopic dermatitis may develop extensive eczema herpeticum (eruptio varicelliformis Kaposi). Herpes simplex eye infection, herpes simplex encephalitis, and disseminated (generalized) herpes infection also pose danger. We present a boy with exacerbated infantile seborrhoeic dermatitis (ISD) and eczema herpeticum complicated by streptococcal sepsis. HSV transmission should be limited if possible by avoiding direct contact with those who recently developed lesions. Communication with parents and explaining how to properly care for the skin in a child with skin diseases that disturb its barrier function protecting against external factors is particularly important. Also, parents should be informed that "red flag" symptoms in a child should be an indication for a pediatric consultation. In the event of infection, the duration of symptoms can be reduced by promptly initiated acyclovir therapy.

9.
Cell Rep Med ; 2(4): 100229, 2021 04 20.
Article in English | MEDLINE | ID: mdl-33748789

ABSTRACT

The impact of secondary bacterial infections (superinfections) in coronavirus disease 2019 (COVID-19) is not well understood. In this prospective, monocentric cohort study, we aim to investigate the impact of superinfections in COVID-19 patients with acute respiratory distress syndrome. Patients are assessed for concomitant microbial infections by longitudinal analysis of tracheobronchial secretions, bronchoalveolar lavages, and blood cultures. In 45 critically ill patients, we identify 19 patients with superinfections (42.2%). Superinfections are detected on day 10 after intensive care admission. The proportion of participants alive and off invasive mechanical ventilation at study day 28 (ventilator-free days [VFDs] at 28 days) is substantially lower in patients with superinfection (subhazard ratio 0.37; 95% confidence interval [CI] 0.15-0.90; p = 0.028). Patients with pulmonary superinfections have a higher incidence of bacteremia, virus reactivations, yeast colonization, and required intensive care treatment for a longer time. Superinfections are frequent and associated with reduced VFDs at 28 days despite a high rate of empirical antibiotic therapy.


Subject(s)
COVID-19/pathology , Respiration, Artificial , Superinfection/diagnosis , Aged , Bronchoalveolar Lavage Fluid/microbiology , COVID-19/complications , COVID-19/virology , Cohort Studies , Critical Illness , Enterococcus faecalis/isolation & purification , Female , Humans , Incidence , Intensive Care Units , Length of Stay , Male , Middle Aged , Pseudomonas aeruginosa/isolation & purification , SARS-CoV-2/isolation & purification , Superinfection/complications , Superinfection/epidemiology , Time Factors
10.
Indian J Med Microbiol ; 39(1): 24-29, 2021 01.
Article in English | MEDLINE | ID: mdl-33610252

ABSTRACT

PURPOSE: Acute respiratory illness is the leading cause of hospitalization for young children. Current guidelines recommend against testing to identify specific viruses due to a lack of data on the benefit of such testing. This study was designed to characterize epidemiology, hospital course, and outcomes of the various common virus -related hospitalization in children. METHOD: Single-center retrospective chart review. All patients who had respiratory viral panel sent within 48 h of admission. Comparative demographic and outcome analysis. Statistical analysis using ANOVA and multivariable regression. RESULT: 1831 patients met the study criteria. Rhinovirus was the most common virus (55.9%). Coronavirus had the highest proportion of infants (61.2%), while influenza had the least (17.8%). Positive urine culture identified in 8.1% of patients, with blood and urine positivity at 2% each. Rhinovirus and parainfluenza were spread throughout the year, while Corona, RSV, and influenza were more predominant in winter months. Overall PICU admission rate 22.8% and was highest for RSV (28.0%) and lowest for adenovirus (13.5%). No difference in ICU length of stay among different virus. Intubation rate was 5.6% with a median duration of 5 days. Median hospital length of stay was 2 days and differ significantly with different virus (maximum four RSV and metapneumo virus). Mortality in the study population was 0.3%. CONCLUSION: The difference in the disease course of different viruses may justify the resources required to test for the respiratory viral panel. This study data can serve as a benchmark for comparison of disease course of COVID-19 compared to other viral infections.


Subject(s)
COVID-19/epidemiology , Hospitalization , SARS-CoV-2 , Aged , Aged, 80 and over , Biomarkers , COVID-19/diagnosis , COVID-19/therapy , COVID-19/virology , Child , Child, Preschool , Comorbidity , Disease Management , Female , Humans , Infant , Male , Middle Aged , Outcome Assessment, Health Care , Public Health Surveillance , SARS-CoV-2/classification , SARS-CoV-2/genetics , Symptom Assessment , Tomography, X-Ray Computed
11.
Ann Clin Microbiol Antimicrob ; 20(1): 69, 2021 Sep 25.
Article in English | MEDLINE | ID: mdl-34563202

ABSTRACT

BACKGROUND: Coronavirus SARS-CoV-2 causes COVID-19 illness which can progress to severe pneumonia. Empiric antibacterials are often employed though frequency of bacterial coinfection superinfection is debated and concerns raised about selection of bacterial antimicrobial resistance. We evaluated sputum bacterial and fungal growth from 165 intubated COVID-19 pneumonia patients. Objectives were to determine frequency of culture positivity, risk factors for and outcomes of positive cultures, and timing of antimicrobial resistance development. METHODS: Retrospective reviews were conducted of COVID-19 pneumonia patients requiring intubation admitted to a 1058-bed four community hospital system on the east coast United States, March 1 to May 1, 2020. Length of stay (LOS) was expressed as mean (standard deviation); 95% confidence interval (95% CI) was computed for overall mortality rate using the exact binomial method, and overall mortality was compared across each level of a potential risk factor using a Chi-Square Test of Independence. All tests were two-sided, and significance level was set to 0.05. RESULTS: Average patient age was 68.7 years and LOS 19.9 days. Eighty-three patients (50.3% of total) originated from home, 10 from group homes (6.1% of total), and 72 from nursing facilities (43.6% of total). Mortality was 62.4%, highest for nursing home residents (80.6%). Findings from 253 sputum cultures overall did not suggest acute bacterial or fungal infection in 73 (45%) of 165 individuals sampled within 24 h of intubation. Cultures ≥ 1 week following intubation did grow potential pathogens in 72 (64.9%) of 111 cases with 70.8% consistent with late pneumonia and 29.2% suggesting colonization. Twelve (10.8% of total) of these late post-intubation cultures revealed worsened antimicrobial resistance predominantly in Pseudomonas, Enterobacter, or Staphylococcus aureus. CONCLUSIONS: In severe COVID-19 pneumonia, a radiographic ground glass interstitial pattern and lack of purulent sputum prior to/around the time of intubation correlated with no culture growth or recovery of normal oral flora ± yeast. Discontinuation of empiric antibacterials should be considered in these patients aided by other clinical findings, history of prior antimicrobials, laboratory testing, and overall clinical course. Continuing longterm hospitalisation and antibiotics are associated with sputum cultures reflective of hospital-acquired microbes and increasing antimicrobial resistance. TRIAL REGISTRATION: Not applicable as this was a retrospective chart review study without interventional arm.


Subject(s)
Bacteria/drug effects , Bacterial Infections/complications , COVID-19/therapy , Cross Infection/complications , Fungi/drug effects , Mycoses/complications , Pneumonia/therapy , Sputum/microbiology , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents , Anti-Infective Agents/pharmacology , Bacteria/genetics , Bacteria/isolation & purification , Bacterial Infections/drug therapy , Bacterial Infections/microbiology , COVID-19/complications , COVID-19/mortality , COVID-19/virology , Cross Infection/drug therapy , Cross Infection/microbiology , Drug Resistance, Bacterial , Drug Resistance, Multiple, Fungal , Female , Fungi/genetics , Fungi/isolation & purification , Hospitalization , Humans , Intubation , Length of Stay , Male , Middle Aged , Mycoses/microbiology , Pneumonia/complications , Pneumonia/mortality , Pneumonia/virology , Retrospective Studies , SARS-CoV-2/physiology
12.
J Investig Med High Impact Case Rep ; 8: 2324709620926900, 2020.
Article in English | MEDLINE | ID: mdl-32462931

ABSTRACT

A 78-year-old male, originally from China, was brought to the hospital for weakness, urinary incontinence, confusion, and poor oral intake. He was started on empiric antibiotics, which were narrowed when blood cultures produced gram-negative bacteremia speciating to Klebsiella pneumoniae, sensitive to ceftriaxone. Computed tomography scan of the abdomen and pelvis demonstrated a large cystic region with air-fluid level in the left lobe of the liver. Suspecting this to be the source of the patient's bacteremia, the lesion was percutaneously drained and the fluid cultured, which also revealed ceftriaxone-sensitive Klebsiella pneumoniae. While a stool ova and parasite examination on the patient was negative, further workup was positive for Entamoeba histolytica antibody in the serum, detected via enzyme-linked immunosorbent assay and indicative of either current or past infection. This suggested possible prolonged subclinical infection with bacterial superinfection, especially given that Klebsiella pneumoniae is one of the most common organisms cultured from these abscesses. In patients with liver abscesses who immigrated from developing and/or endemic regions or have a relevant recent travel history, an underlying amoebic etiology of an abscess should be considered.


Subject(s)
Entamoeba histolytica/isolation & purification , Klebsiella Infections/complications , Klebsiella pneumoniae/isolation & purification , Liver Abscess, Amebic/complications , Superinfection/etiology , Aged , Anti-Bacterial Agents/therapeutic use , Antibodies, Protozoan/blood , Ceftriaxone/therapeutic use , China , Enzyme-Linked Immunosorbent Assay , Humans , Klebsiella Infections/diagnosis , Klebsiella Infections/drug therapy , Liver Abscess, Amebic/diagnosis , Liver Abscess, Amebic/drug therapy , Male , Superinfection/drug therapy
13.
Cell Rep ; 30(9): 2934-2947.e6, 2020 03 03.
Article in English | MEDLINE | ID: mdl-32130898

ABSTRACT

Secondary bacterial infections often complicate viral respiratory infections. We hypothesize that perturbation of the gut microbiota during influenza A virus (IAV) infection might favor respiratory bacterial superinfection. Sublethal infection with influenza transiently alters the composition and fermentative activity of the gut microbiota in mice. These changes are attributed in part to reduced food consumption. Fecal transfer experiments demonstrate that the IAV-conditioned microbiota compromises lung defenses against pneumococcal infection. In mechanistic terms, reduced production of the predominant short-chain fatty acid (SCFA) acetate affects the bactericidal activity of alveolar macrophages. Following treatment with acetate, mice colonized with the IAV-conditioned microbiota display reduced bacterial loads. In the context of influenza infection, acetate supplementation reduces, in a free fatty acid receptor 2 (FFAR2)-dependent manner, local and systemic bacterial loads. This translates into reduced lung pathology and improved survival rates of double-infected mice. Lastly, pharmacological activation of the SCFA receptor FFAR2 during influenza reduces bacterial superinfection.


Subject(s)
Dysbiosis/microbiology , Fatty Acids, Volatile/biosynthesis , Gastrointestinal Tract/microbiology , Influenza, Human/microbiology , Lung/microbiology , Pneumococcal Infections/complications , Superinfection/complications , Superinfection/microbiology , Acetates/pharmacology , Animals , Dysbiosis/complications , Dysbiosis/virology , Feeding Behavior , Gastrointestinal Microbiome/drug effects , Gastrointestinal Tract/drug effects , Humans , Macrophages, Alveolar/drug effects , Macrophages, Alveolar/microbiology , Macrophages, Alveolar/pathology , Mice, Inbred C57BL , Pneumococcal Infections/microbiology , Pneumococcal Infections/virology , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/metabolism , Respiratory Tract Infections/microbiology
14.
Vaccines (Basel) ; 7(3)2019 Sep 12.
Article in English | MEDLINE | ID: mdl-31547409

ABSTRACT

BACKGROUND: Influenza virus infection predisposes to secondary bacterial pneumonia. Currently licensed influenza vaccines aim at the induction of neutralizing antibodies and are less effective if the induction of neutralizing antibodies is low and/or the influenza virus changes its antigenic surface. We investigated the effect of suboptimal vaccination on the outcome of post-influenza bacterial superinfection. METHODS: We established a mouse vaccination model that allows control of disease severity after influenza virus infection despite inefficient induction of virus-neutralizing antibody titers by vaccination. We investigated the effect of vaccination on virus-induced host immune responses and on the outcome of superinfection with Staphylococcus aureus. RESULTS: Vaccination with trivalent inactivated virus vaccine (TIV) reduced morbidity after influenza A virus infection but did not prevent virus replication completely. Despite the poor induction of influenza-specific antibodies, TIV protected from mortality after bacterial superinfection. Vaccination limited loss of alveolar macrophages and reduced levels of infiltrating pulmonary monocytes after influenza virus infection. Interestingly, TIV vaccination resulted in enhanced levels of eosinophils after influenza virus infection and recruitment of neutrophils in both lungs and mediastinal lymph nodes after bacterial superinfection. CONCLUSION: These observations highlight the importance of disease modulation by influenza vaccination, even when suboptimal, and suggest that influenza vaccination is still beneficial to protect during bacterial superinfection in the absence of complete virus neutralization.

15.
Viral Immunol ; 32(3): 131-143, 2019 04.
Article in English | MEDLINE | ID: mdl-30822217

ABSTRACT

Influenza A viruses (IAVs) have multiple mechanisms for altering the host immune response to aid in virus survival and propagation. While both type I and II interferons (IFNs) have been associated with increased bacterial superinfection (BSI) susceptibility, we found that in some cases type I IFNs can be beneficial for BSI outcome. Specifically, we have shown that antagonism of the type I IFN response during infection by some IAVs can lead to the development of deadly BSI. The nonstructural protein 1 (NS1) from IAV is well known for manipulating host type I IFN responses, but the viral proteins mediating BSI severity remain unknown. In this study, we demonstrate that the PDZ-binding motif (PDZ-bm) of the NS1 C-terminal region from mouse-adapted A/Puerto Rico/8/34-H1N1 (PR8) IAV dictates BSI susceptibility through regulation of IFN-α/ß production. Deletion of the NS1 PDZ-bm from PR8 IAV (PR8-TRUNC) resulted in 100% survival and decreased bacterial burden in superinfected mice compared with 0% survival in mice superinfected after PR8 infection. This reduction in BSI susceptibility after infection with PR8-TRUNC was due to the presence of IFN-ß, as protection from BSI was lost in Ifn-ß-/- mice, resembling BSI during PR8 infection. PDZ-bm in PR8-infected mice inhibited the production of IFN-ß posttranscriptionally, and both delayed and reduced expression of the tunable interferon-stimulated genes. Finally, a similar lack of BSI susceptibility, due to the presence of IFN-ß on day 7 post-IAV infection, was also observed after infection of mice with A/TX98-H3N2 virus that naturally lacks a PDZ-bm in NS1, indicating that this mechanism of BSI regulation by NS1 PDZ-bm may not be restricted to PR8 IAV. These results demonstrate that the NS1 C-terminal PDZ-bm, like the one present in PR8 IAV, is involved in controlling susceptibility to BSI through the regulation of IFN-ß, providing new mechanisms for NS1-mediated manipulation of host immunity and BSI severity.


Subject(s)
Orthomyxoviridae Infections/veterinary , PDZ Domains/genetics , Superinfection/microbiology , Viral Nonstructural Proteins/genetics , Animals , Dogs , Gene Expression Regulation , HEK293 Cells , Host-Pathogen Interactions , Humans , Immunity, Innate , Influenza A Virus, H1N1 Subtype , Influenza A Virus, H3N2 Subtype , Influenza, Human/immunology , Interferon Type I/genetics , Interferon Type I/immunology , Interferon-beta/genetics , Interferon-beta/immunology , Madin Darby Canine Kidney Cells , Orthomyxoviridae Infections/virology , Virus Replication
16.
mBio ; 8(6)2017 11 14.
Article in English | MEDLINE | ID: mdl-29138299

ABSTRACT

Although viruses and viral capsids induce rapid immune responses, little is known about viral pathogen-associated molecular patterns (PAMPs) that are exhibited on their surface. Here, we demonstrate that the repeating protein subunit pattern common to most virus capsids is a molecular pattern that induces a Toll-like-receptor-2 (TLR2)-dependent antiviral immune response. This early antiviral immune response regulates the clearance of subsequent bacterial superinfections, which are a primary cause of morbidities associated with influenza virus infections. Utilizing this altered susceptibility to subsequent bacterial challenge as an outcome, we determined that multiple unrelated, empty, and replication-deficient capsids initiated early TLR2-dependent immune responses, similar to intact influenza virus or murine pneumovirus. These TLR2-mediated responses driven by the capsid were not dependent upon the capsid's shape, size, origin, or amino acid sequence. However, they were dependent upon the multisubunit arrangement of the capsid proteins, because unlike intact capsids, individual capsid subunits did not enhance bacterial clearance. Further, we demonstrated that even a linear microfilament protein built from repeating protein subunits (F-actin), but not its monomer (G-actin), induced similar kinetics of subsequent bacterial clearance as did virus capsid. However, although capsids and F-actin induced similar bacterial clearance, in macrophages they required distinct TLR2 heterodimers for this response (TLR2/6 or TLR2/1, respectively) and different phagocyte populations were involved in the execution of these responses in vivo Our results demonstrate that TLR2 responds to invading viral particles that are composed of repeating protein subunits, indicating that this common architecture of virus capsids is a previously unrecognized molecular pattern.IMPORTANCE Rapid and precise pathogen identification is critical for the initiation of pathogen-specific immune responses and pathogen clearance. Bacteria and fungi express common molecular patterns on their exteriors that are recognized by cell surface-expressed host pattern recognition receptors (PRRs) prior to infection. In contrast, viral molecular patterns are primarily nucleic acids, which are recognized after virus internalization. We found that an initial antiviral immune response is induced by the repeating subunit pattern of virus exteriors (capsids), and thus, induction of this response is independent of viral infection. This early response to viral capsids required the cell surface-expressed PRR TLR2 and allowed for improved clearance of subsequent bacterial infection that commonly complicates respiratory viral infections. Since the repeating protein subunit pattern is conserved across viral capsids, this suggests that it is not easy for a virus to change without altering fitness. Targeting this vulnerability could lead to development of a universal antiviral vaccine.


Subject(s)
Bacteria/immunology , Capsid Proteins/immunology , Capsid/immunology , Immunity, Innate , Pathogen-Associated Molecular Pattern Molecules , Toll-Like Receptor 2/metabolism , Viruses/immunology , Animals , Macrophages/immunology , Mice, Inbred C57BL , Mice, Knockout , Virus Diseases/immunology
17.
Support Care Cancer ; 24(9): 3943-50, 2016 09.
Article in English | MEDLINE | ID: mdl-27117557

ABSTRACT

PURPOSE: Epidermal growth factor receptor (EGFR) inhibitors are approved for use as targeted chemotherapeutic agents against multiple solid-organ malignancies. The most common side effect associated with EGFR inhibitor therapy is a papulopustular eruption, which can easily be confused with bacterial folliculitis. In this study, we examine the relative timing and location of the EGFR-induced papulopustular eruption compared to the associated bacterial superinfections. METHODS: In this retrospective chart review, patients enrolled in our institution's IRB-approved prospective registry of cutaneous reactions to chemotherapy were screened for inclusion. All patients who received an EGFR inhibitor and developed either a papulopustular eruption or bacterial superinfection at some point during treatment were included. RESULTS: Of the 157 patients who met inclusion criteria, 36 (23 %) developed bacterial superinfections at some point during EGFR therapy. Papulopustular eruptions developed in a highly predictable time course, with a mean time to onset of 1.5 weeks and mean duration of 9.4 weeks. Bacterial superinfections occurred at widely variable time points during therapy with a mean time to onset of 27.7 weeks. Papulopustular eruptions much more frequently affected the face (97 %), chest (75 %), and back (61 %), while bacterial superinfections occurred more commonly on the upper extremity (64 %), lower extremity (47 %), and abdomen (39 %). CONCLUSIONS: The EGFR inhibitor-induced papulopustular eruption has a stereotypical time course and occurs in a characteristic distribution affecting the central face, upper chest, and back. Bacterial superinfections more frequently affect the extremities, abdomen, and groin and may occur at any point during EGFR therapy.


Subject(s)
Bacterial Infections/pathology , ErbB Receptors/antagonists & inhibitors , Exanthema/chemically induced , Exanthema/microbiology , Folliculitis/chemically induced , Folliculitis/microbiology , Protein Kinase Inhibitors/adverse effects , Female , Humans , Male , Middle Aged , Retrospective Studies , Superinfection/microbiology , Superinfection/pathology
18.
J Infect Dis ; 213(12): 1876-85, 2016 06 15.
Article in English | MEDLINE | ID: mdl-26908732

ABSTRACT

BACKGROUND: Most preclinical studies assess vaccine effectiveness in single-pathogen infection models. This is unrealistic given that humans are continuously exposed to different commensals and pathogens in sequential and mixed infections. Accordingly, complications from secondary bacterial infection are a leading cause of influenza-associated morbidity and mortality. New vaccination strategies are needed to control infections on simultaneous fronts. METHODS: We compared different anti-influenza vaccines for their protective potential in a model of viral infection with bacterial superinfection. Mice were immunized with H1N1/A/California/7/2009 subunit vaccines, formulated with different adjuvants inducing either T-helper type 1 (Th1) (MF59 plus CpG)-, Th1/2 (MF59)-, or Th17 (LTK63)-prone immune responses and were sequentially challenged with mouse-adapted influenza virus H1N1/A/Puerto Rico/8/1934 and Staphylococcus aureus USA300, a clonotype emerging as a leading contributor in postinfluenza pneumonia in humans. RESULTS: Unadjuvanted vaccine controlled single viral infection, yet mice had considerable morbidity from viral disease and bacterial superinfection. In contrast, all adjuvanted vaccines efficiently protected mice in both conditions. Interestingly, the Th1-inducing formulation was superior to Th1/2 or Th17 inducers. CONCLUSIONS: Our studies should help us better understand how differential immunity to influenza skews immune responses toward coinfecting bacteria and discover novel modes to prevent bacterial superinfections in the lungs of persons with influenza.


Subject(s)
Influenza A Virus, H1N1 Subtype/immunology , Influenza Vaccines/immunology , Influenza, Human/prevention & control , Staphylococcal Infections/prevention & control , Staphylococcus aureus/immunology , Superinfection/prevention & control , Adjuvants, Immunologic/administration & dosage , Animals , Bacterial Toxins/administration & dosage , Enterotoxins/administration & dosage , Escherichia coli Proteins/administration & dosage , Female , Humans , Immunization , Influenza Vaccines/administration & dosage , Influenza, Human/complications , Influenza, Human/microbiology , Mice , Mice, Inbred BALB C , Oligodeoxyribonucleotides/administration & dosage , Polysorbates/administration & dosage , Specific Pathogen-Free Organisms , Squalene/administration & dosage , Staphylococcal Infections/complications , Staphylococcal Infections/microbiology , Superinfection/microbiology
19.
Journal of the Korean Pediatric Society ; : 918-920, 2003.
Article in Korean | WPRIM (Western Pacific) | ID: wpr-112015

ABSTRACT

Herpes simplex virus infection of the hand in children occurs after auto-inoculation from herpetic gingivostomatitis or herpes labialis. Herpetic whitlow should be suspected based on clinical signs. Diagnosis can be made by PCR or virus culture. Many misdiagnosed cases suggests that this disease is not sufficiently known. Surgical interventions may be harmful and should be avoided. We report a case of herpetic whitlow with bacterial superinfection in a three-year-old girl.


Subject(s)
Child , Diagnosis , Female , Hand , Herpes Labialis , Humans , Polymerase Chain Reaction , Simplexvirus , Stomatitis, Herpetic , Superinfection
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