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Despite advances in HIV treatment, bacterial pneumonia continues to cause considerable morbidity and mortality in patients with HIV infection. Studies of biomarker associations with bacterial pneumonia risk in treated HIV-infected patients do not currently exist. We performed a nested, matched, case-control study among participants randomized to continuous combination antiretroviral therapy (cART) in the Strategies for Management of Antiretroviral Therapy trial. Patients who developed bacterial pneumonia (cases) and patients without bacterial pneumonia (controls) were matched 1∶1 on clinical center, smoking status, age, and baseline cART use. Baseline levels of Club Cell Secretory Protein 16 (CC16), Surfactant Protein D (SP-D), C-reactive protein (hsCRP), interleukin-6 (IL-6), and d-dimer were compared between cases and controls. Cases (n = 72) and controls (n = 72) were 25.7% female, 51.4% black, 65.3% current smokers, 9.7% diabetic, 36.1% co-infected with Hepatitis B/C, and 75.0% were on cART at baseline. Median (IQR) age was 45 (41, 51) years with CD4+ count of 553 (436, 690) cells/mm(3). Baseline CC16 and SP-D were similar between cases and controls, but hsCRP was significantly higher in cases than controls (2.94 µg/mL in cases vs. 1.93 µg/mL in controls; p = 0.02). IL-6 and d-dimer levels were also higher in cases compared to controls, though differences were not statistically significant (p-value 0.06 and 0.10, respectively). In patients with cART-treated HIV infection, higher levels of systemic inflammatory markers were associated with increased bacterial pneumonia risk, while two pulmonary-specific inflammatory biomarkers, CC16 and SP-D, were not associated with bacterial pneumonia risk.

Key Points Mortality from influenza viruses is strongly linked to secondary bacterial invaders. In the most extreme example, more than 95% of the 50 million or more deaths during the 1918 pandemic were complicated by bacterial pneumonia. Influenza viruses differ in their propensity to support bacterial superinfection, depending on the expression of particular virulence factors. Nascent pandemic strains that emerge from the avian reservoir naturally possess many such traits; often these are lost over time as the viruses reach an equilibrium with their hosts. Similarly, different strains of bacteria express different virulence factors that enable them to take advantage of virus-mediated alterations to lung physiology and immunity. The regional distribution of these strains probably influences the severity of influenza epidemics and pandemics. Disruption of lung physiology by respiratory viruses breaches natural barriers to infection and promotes bacterial co-infection. Receptors that can be used by bacteria for adherence and infection are uncovered and upregulated. Viruses and bacteria express factors that subvert, inhibit or eliminate host immune responses. Paradoxically, the resulting pathogen overgrowth might lead to augmented inflammatory responses and immune-mediated host damage. Although they are typically secondary invaders during influenza infections, bacteria express virulence factors that promote viral pathogenesis. This results in increased viral load and decreased clearance. There are many key unanswered questions in the field of co-infections. A better understanding of the complex relationships between virus, host and bacteria will aid us in combating common manifestations, such as community-acquired pneumonia, and help us to prepare for the inevitable next severe influenza pandemic. Mortality from influenza viruses is strongly linked to secondary bacterial invaders. Here, Jonathan A. McCullers reviews viral and bacterial virulence factors that contribute to the pathogenesis of co-infections by disrupting physical barriers, dysregulating immune responses and delaying a return to homeostasis. Concern that a highly pathogenic virus might cause the next influenza pandemic has spurred recent research into influenza and its complications. Bacterial superinfection in the lungs of people suffering from influenza is a key element that promotes severe disease and mortality. This co-pathogenesis is characterized by complex interactions between co-infecting pathogens and the host, leading to the disruption of physical barriers, dysregulation of immune responses and delays in a return to homeostasis. The net effect of this cascade can be the outgrowth of the pathogens, immune-mediated pathology and increased morbidity. In this Review, advances in our understanding of the underlying mechanisms are discussed, and the key questions that will drive the field forwards are articulated.

Background. The frequent lack of a microbiological diagnosis in community-acquired pneumonia (CAP) impairs pathogen-directed antimicrobial therapy. This study assessed the use of comprehensive multibacterial, multiviral molecular testing, including quantification, in adults hospitalized with CAP. Methods. Clinical and laboratory data were collected for 323 adults with radiologically-confirmed CAP admitted to 2 UK tertiary care hospitals. Sputum (96%) or endotracheal aspirate (4%) specimens were cultured as per routine practice and also tested with fast multiplex real-time polymerase-chain reaction (PCR) assays for 26 respiratory bacteria and viruses. Bacterial loads were also calculated for 8 bacterial pathogens. Appropriate pathogen-directed therapy was retrospectively assessed using national guidelines adapted for local antimicrobial susceptibility patterns. Results. Comprehensive molecular testing of single lower respiratory tract (LRT) soecunebs achieved pathogen detection in 87% of CAP patients compared with 39% with culture-based methods. Haemophilus influenzae and Streptococcus pneumoniae were the main agents detected, along with a wide variety of typical and atypical pathogens. Viruses were present in 30% of cases; 82% of these were codetections with bacteria. Most (85%) patients had received antimicrobials in the 72 hours before admission. Of these, 78% had a bacterial pathogen detected by PCR but only 32% were culture-positive (P < .0001). Molecular testing had the potential to enable de-escalation in number and/or spectrum of antimicrobials in 77% of patients. Conclusions. Comprehensive molecular testing significantly improves pathogen detection in CAP, particularly in antimicrobial-exposed patients, and requires only a single LRT specimen. It also has the potential to enable early de-escalation from broad-spectrum empirical antimicrobials to pathogen-directed therapy.

The COVID-19 epidemic has a catastrophic impact on global well-being and public health. More than 27 million confirmed cases have been reported worldwide until now. Due to the growing number of confirmed cases, and challenges to the variations of the COVID-19, timely and accurate classification of healthy and infected patients is essential to control and treat COVID-19. We aim to develop a deep learning-based system for the persuasive classification and reliable detection of COVID-19 using chest radiography. Firstly, we evaluate the performance of various state-of-the-art convolutional neural networks (CNNs) proposed over recent years for medical image classification. Secondly, we develop and train CNN from scratch. In both cases, we use a public X-Ray dataset for training and validation purposes. For transfer learning, we obtain 100% accuracy for binary classification (i.e., Normal/COVID-19) and 87.50% accuracy for tertiary classification (Normal/COVID-19/Pneumonia). With the CNN trained from scratch, we achieve 93.75% accuracy for tertiary classification. In the case of transfer learning, the classification accuracy drops with the increased number of classes. The results are demonstrated by comprehensive receiver operating characteristics (ROC) and confusion metric analysis with 10-fold cross-validation.

Background Despite recent advances in microbiological techniques, the etiology of community-acquired pneumonia (CAP) is still not well described. We applied polymerase chain reaction (PCR) and conventional methods to describe etiology of CAP in hospitalized adults and evaluated their respective diagnostic yields. Methods 267 CAP patients were enrolled consecutively over our 3-year prospective study. Conventional methods (i.e., bacterial cultures, urinary antigen assays, serology) were combined with nasopharyngeal (NP) and oropharyngeal (OP) swab samples analyzed by real-time quantitative PCR (qPCR) for Streptococcus pneumoniae, and by real-time PCR for Mycoplasma pneumoniae, Chlamydophila pneumoniae, Bordetella pertussis and 12 types of respiratory viruses. Results Etiology was established in 167 (63%) patients with 69 (26%) patients having ≥1 copathogen. There were 75 (28%) pure bacterial and 41 (15%) pure viral infections, and 51 (19%) viral–bacterial coinfections, resulting in 126 (47%) patients with bacterial and 92 (34%) patients with viral etiology. S. pneumoniae (30%), influenza (15%) and rhinovirus (12%) were most commonly identified, typically with ≥1 copathogen. During winter and spring, viruses were detected more frequently (45%, P =.01) and usually in combination with bacteria (39%). PCR improved diagnostic yield by 8% in 64 cases with complete sampling (and by 15% in all patients); 5% for detection of bacteria; 19% for viruses ( P =.04); and 16% for detection of ≥1 copathogen. Etiology was established in 79% of 43 antibiotic-naive patients with complete sampling. S. pneumoniae qPCR positive rate was significantly higher for OP swab compared to NP swab ( P <.001). Positive rates for serology were significantly higher than for real-time PCR in detecting B. pertussis ( P =.001) and influenza viruses ( P <.001). Conclusions Etiology could be established in 4 out of 5 CAP patients with the aid of PCR, particularly in diagnosing viral infections. S. pneumoniae and viruses were most frequently identified, usually with copathogens. Viral–bacterial coinfections were more common than pure infections during winter and spring; a finding we consider important in the proper management of CAP. When swabbing for qPCR detection of S. pneumoniae in adult CAP, OP appeared superior to NP, but this finding needs further confirmation. Trial registration ClinicalTrials.gov Identifier: NCT01563315 .

Respiratory syncytial virus (RSV) has been recognized as responsible for severe respiratory illness in adults, especially in the elderly. While pneumonia is commonly observed during RSV infection, the burden and epidemiology of bacterial superinfection is poorly understood. The aim of this study was to identify microorganisms associated with RSV-positive pneumonia in adults. A retrospective study was conducted during three consecutive winters (October to April 2013–2016) in the University Hospital of Lyon, France. During RSV circulation periods, a systematic RSV screening was performed by reverse-transcription PCR on all respiratory samples collected from adults. Records of RSV-positive patients were subsequently analyzed to identify radiologically confirmed pneumonia cases. Bacteria were identified by standard bacteriology cultures or urinary antigen screening and classified as potentially causative of pneumonia if quantification was above the specific threshold as defined by the European Manual of Clinical Microbiology. Overall, 14,792 adult respiratory samples were screened for RSV detection by PCR. In total, 292 had a positive RSV detection (2.0%) among which 89 presented with pneumonia including 27 bacterial superinfections (9.3%) with Streptococcus pneumonia, Haemophilus influenza, Staphylococcus aureus, Pseudomonas aeruginosa, and Moraxella catarrhalis. Most patients were elderly (55.6%) and patients with comorbidities (77.8%). A more severe outcome was observed for RSV-bacteria-associated pneumonia compared with RSV pneumonia: length of stay was significantly longer (16 days vs 10 days) and ICU hospitalization more frequent (66.7% vs 21.0%) (p < 0.05). In conclusion, we did not observe major differences in the epidemiology of bacterial superinfections in RSV-positive pneumonia compared to reports on post-influenza pneumonia.

Secondary bacterial pneumonia following an influenza A virus (IAV) infection is a major cause of morbidity and mortality. Although it is generally accepted that preceding IAV infection leads to increased susceptibility to secondary bacterial infection, details regarding the pathogenic mechanism during the early stage of superinfection remain elusive. Influenza A virus (IAV) infection predisposes the host to secondary bacterial pneumonia, known as a major cause of morbidity and mortality during influenza virus epidemics. Analysis of interactions between IAV-infected human epithelial cells and Streptococcus pneumoniae revealed that infected cells ectopically exhibited the endoplasmic reticulum chaperone glycoprotein 96 (GP96) on the surface. Importantly, efficient pneumococcal adherence to epithelial cells was imparted by interactions with extracellular GP96 and integrin α V , with the surface expression mediated by GP96 chaperone activity. Furthermore, abrogation of adherence was gained by chemical inhibition or genetic knockout of GP96 as well as addition of RGD peptide, an inhibitor of integrin-ligand interactions. Direct binding of extracellular GP96 and pneumococci was shown to be mediated by pneumococcal oligopeptide permease components. Additionally, IAV infection induced activation of calpains and Snail1, which are responsible for degradation and transcriptional repression of junctional proteins in the host, respectively, indicating increased bacterial translocation across the epithelial barrier. Notably, treatment of IAV-infected mice with the GP96 inhibitor enhanced pneumococcal clearance from lung tissues and ameliorated lung pathology. Taken together, the present findings indicate a viral-bacterial synergy in relation to disease progression and suggest a paradigm for developing novel therapeutic strategies tailored to inhibit pneumococcal colonization in an IAV-infected respiratory tract. IMPORTANCE Secondary bacterial pneumonia following an influenza A virus (IAV) infection is a major cause of morbidity and mortality. Although it is generally accepted that preceding IAV infection leads to increased susceptibility to secondary bacterial infection, details regarding the pathogenic mechanism during the early stage of superinfection remain elusive. Here, we focused on the interaction of IAV-infected cells and Streptococcus pneumoniae , which revealed that human epithelial cells infected with IAV exhibit a cell surface display of GP96, an endoplasmic reticulum chaperon. Notably, extracellular GP96 was shown to impart efficient adherence for secondary infection by S. pneumoniae , and GP96 inhibition ameliorated lung pathology of superinfected mice, indicating it to be a useful target for development of therapeutic strategies for patients with superinfection.

Severe viral pneumonia is associated with a high mortality rate. However, due to the vulnerability of critically ill patients, invasive diagnostic methods should be performed with caution in the intensive care unit (ICU). It would be helpful if the prevalence, risk factors, and clinical impact of virus detection are elucidated. We evaluated patients with severe pneumonia between January 1st 2008 and December 31st 2015. Reverse transcription-polymerase chain reaction (RT-PCR) analysis was performed for 8 respiratory viruses when viral pathogen could not be excluded as the origin of severe pneumonia. The baseline characteristics, laboratory results, microbiological findings, and clinical outcomes of the patients were analyzed. Of the 2,347 patients admitted to the medical ICU, 515 underwent RT-PCR for respiratory viruses, 69 of whom had positive results. The detection rate was higher during the winter, with a community onset, in patients with history of recent chemotherapy, and low platelet count. Additional bronchoscopic sampling along with upper respiratory specimen increased the yield of viral detection. Respiratory syncytial virus was the most common pathogen detected, while influenza A was the most common virus with bacterial coinfection. Respiratory virus detection led to changes in clinical management in one-third of the patients. The detection of viral pathogens in patients with severe pneumonia is not rare, and can be more common in certain group of patients. Invasive sampling for RT-PCR can be helpful, and such detection can lead to positive changes in clinical management.

: Pneumonia is a major complication of influenza that contributes to mortality. Clinical characteristics and factors of influenza virus contributing to the severity and mortality of pneumonia have not been fully elucidated. : The objective was to clarify clinical characteristics and factors contributing to the severity and mortality of influenza-associated pneumonia ( ). : We retrospectively analyzed patients with . : From December 1999 to March 2016, 210 patients with a median age of 69 (range, 17 to 92) years with based on positive rapid antigen tests, increased antibody titers of paired sera, or positive results of reverse transcription polymerase chain reaction were admitted to our institution. A multivariate analysis found that advanced age (≥ 65 years), pneumonia subtypes (unclassified), diabetes mellitus, and acute kidney injury complicated with were independent factors associated with disease severity, whereas pneumonia subtypes (mixed viral and bacterial pneumonia and unclassified), healthcare-associated pneumonia, acute kidney injury complicated with , and severity on admission (severe) were independent factors associated with non-survival. : The clinical characteristics of are varied, and the contribution of several factors to the severity and mortality of suggest their importance in either preventing or managing after it develops.

The risk of influenza A virus (IAV) is more likely caused by secondary bacterial infections. During the past decades, a great amount of studies have been conducted on increased morbidity from secondary bacterial infections following influenza and provide an increasing number of explanations for the mechanisms underlying the infections. In this paper, we first review the recent research progress that IAV infection increased susceptibility to bacterial infection. We then propose an assumption that autophagy and apoptosis manipulation are beneficial to antagonize post-IAV bacterial infection and discuss the clinical significance.