Post-influenza Pneumonia Research Articles

Post-vaccination immunity and pneumonia incidence in medical workers in response to various flu vaccination regimens between the 1st and 2nd peaks of COVID-19 morbidity

Background.In the absence of a vaccine against SARS-CoV-2, seasonal influenza vaccination during the pandemic contributed to lowered COVID-19 susceptibility and severity. The study was aimed to assess the state of post-influenza vaccination immunity, pneumonia frequency and severity in medical workers after using various flu vaccination regimens, between the 1st and 2nd peaks of COVID-19 epidemic rise.Materials and methods.Comparatively analyzed data on the levels of antibodies against influenza virus strains and pneumonia incidence in 487 medical workers was carried out: 1st group — unvaccinated in 2020–2021 (n = 281), 2nd group — vaccinated against influenza (Sovigripp), (n = 98), 3rd group — received combined vaccination against influenza and pneumococcus (Prevenar 13), (n = 108).Results.6 months after vaccination, the highest rates of influenza virus were detected in the A(H3N2), the level of seroprotection (≥ 1:40) ranged from 49.0% in unvaccinated (1st group) to 53.4–53.2% in those who received combined vaccination (group III), as well as influenza alone (2nd group), p 0.05; for strain A(H1N1) the level of seroprotection in 1st group is 24.5%, lower (p 0.04) than in 2nd group — 32.7%, but does not differ from the levels of 40.4% in group III; for strain B the level of seroprotection is the lowest ranging from 19.4% in the group of unvaccinated subjects up to 22.4% in 2nd group and 23.4% in 3rd group. The pneumonia incidence in 1st group (3.9%), 2nd group (3.1%), 3rd group (4.6%) did not differ, however, among all vaccinated subjects severity of pneumonia clinical course was mild, whereas in unvaccinated employees, except for mild course (45.4%, 5 out of 11 people) pneumonia in 36.4% (4 out of 11 people) cases was assessed as moderate and in 18.2% (2 out of 11 people) cases — severe with fatal outcomes.Conclusion.The study showed that 6 months after seasonal influenza immunization between the 1st and 2nd peaks of COVID-19 epidemic rise, the immunogenicity of the vaccine meets the CPMP criterion for the A(H3N2) strain. In vaccinated patients, the proportion of pneumonia with COVID-19 clinical picture was mild in 100% of cases, and in unvaccinated patients in 36.4% of cases — of moderate severity and in 18.2% — severe with fatal outcome.

The influenza-injured lung microenvironment promotes MRSA virulence, contributing to severe secondary bacterial pneumonia.

Influenza infection is substantially worsened by the onset of secondary pneumonia caused by bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). The bidirectional interaction between the influenza-injured lung microenvironment and MRSA is poorly understood. By conditioning MRSA exvivo in bronchoalveolar lavage fluid collected from mice at various time points of influenza infection, we found that the influenza-injured lung microenvironment dynamically induces MRSA to increase cytotoxin expression while decreasing metabolic pathways. LukAB, a SaeRS two-component system-dependent cytotoxin, is particularly important to the severity of post-influenza MRSA pneumonia. LukAB's activity is likely shaped by the post-influenza lung microenvironment, as LukAB binds to (and is activated by) heparan sulfate (HS) oligosaccharide sequences shed from the epithelial glycocalyx after influenza. Our findings indicate that post-influenza MRSA pneumonia is shaped by bidirectional host-pathogen interactions: host injury triggers changes in bacterial expression of toxins, the activity of which may be shaped by host-derived HS fragments.

REPEAT PRESENTATION OF A FEBRILE RESPIRATORY ILLNESS SECONDARY TO HYPERSENSITIVITY PNEUMONITIS

SESSION TITLE: Medical Student/Resident Occupational and Environmental Lung Disease SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Dyspnea is one of the most common reasons for presentation to the hospital. Antigen mediated lung diseases are an important cause of dyspnea however due to the wide variation in clinical presentation, the large number of possible antigens, and a lack of diagnostic tests identification can be difficult.1 Thus, a high index of suspicion must be maintained to prevent missed or delayed diagnosis. CASE PRESENTATION: A 44-year-old nonsmoker with an insignificant past medical history originally presented to an outpatient urgent care with an acute onset of fever, dyspnea, productive cough, and myalgias. He was empirically treated for bacterial pneumonia with an oral antibiotic. After initial improvement, his symptoms progressed and he ultimately presented to the emergency room with fever and worsening dyspnea. He was admitted with acute hypoxic respiratory failure and sepsis secondary to presumed post-influenza pneumonia (standard chest radiograph showed left lower lobe infiltrate). He was fluid resuscitated and received broad spectrum antibiotics. With antibiotics his fever dissipated although he continued to remain hypoxic and was discharged on hospital day seven on three liters of oxygen via nasal cannula. At hospital follow up one week later he continued to endorse dry cough and severe dyspnea (being only able to ambulate household distances with oxygen prior to having to rest). Exam was significant for crackles in the bilateral lung bases along with hypoxia (oxygen saturation dropped to 83% with removal of his nasal cannula during rest). Further history revealed the patient owned seven parakeets which were kept in the same room that the patient slept. He also endorsed unintentional 12-pound weight loss over the past 3 months. CT imaging was pursued which showed diffuse ill-defined centrilobular micronodularity and ground glass opacities throughout both lungs. Based upon this new information serum hypersensitivity pneumonitis screen was performed and ultimately returned negative for the presence of six antigens (only bird antigen on the screen was pigeon serum). Based upon the patient meeting five out of six clinical criteria for a validated clinical predication rule a diagnosis of hypersensitivity pneumonitis was established (92% Likelihood).2 He was advised to avoid further exposure to his birds and outpatient pulmonology consultation was arranged. After a short course of prednisone and avoiding further exposure the patient's symptoms resolved. DISCUSSION: Hypersensitivity pneumonitis is an important disease to keep on the differential for a patient presenting with dyspnea. CONCLUSIONS: Early diagnosis is of the upmost importance as with avoiding further exposure early lung disease can be potentially completely reversed. This case also illustrates the importance of taking a complete history and how routine use of validated clinical predication rules can help you make a diagnosis. Reference #1: 1. Riario Sforza, G.G., Marinou, A. Hypersensitivity pneumonitis: a complex lung disease. Clin Mol Allergy. 2017; 15, 6. Reference #2: 2. Lacasse Y, Selman M, Costabel U, Dalphin JC, Ando M, Morell F, Erkinjuntti-Pekkanen R, Muller N, Colby TV, Schuyler M, Cormier Y. Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med. 2003;168(8):952. DISCLOSURES: No relevant relationships by Catherine Cheney, source=Web Response No relevant relationships by Chris Morris, source=Web Response

Survival during influenza-associated bacterial superinfection improves following viral- and bacterial-specific monoclonal antibody treatment.

Postinfluenza bacterial superinfections cause increased morbidity and mortality compared with singular infection with influenza during both pandemics and seasonal epidemics. Vaccines and current treatments provide limited benefit, a rationale to conduct studies utilizing alternative therapies. FY1 and an optimized version, MEDI8852, anti-influenza HA mAbs, have been shown to neutralize influenza virus during singular influenza infection. MEDI4893*, an anti-Staphylococcus aureus α-toxin mAb, has been shown to improve survival when administered prophylactically prior to S. aureus pneumonia. Our objective was to determine if mAbs can improve survival during postinfluenza bacterial pneumonia. We administered FY1 in a murine model of postinfluenza methicillin-resistant S. aureus (MRSA) pneumonia and observed improved survival rates when given early during the course of influenza infection. Our findings indicate decreased lung injury and increased uptake and binding of bacteria by macrophages in the mice that received FY1 earlier in the course of influenza infection, corresponding to decreased bacterial burden. We also observed improved survival when mice were treated with a combination of FY1 and MEDI4893* late during the course of postinfluenza MRSA pneumonia. In conclusion, both FY1 and MEDI4893* prolong survival when used in a murine model of postinfluenza MRSA pneumonia, suggesting pathogen-specific mAbs as a possible therapeutic in the context of bacterial superinfection.

Microorganisms associated with respiratory syncytial virus pneumonia in the adult population.

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.

Effect of triazavirine on the outcome of a lethal influenza infection and secondary bacterial pneumonia following influenza in mice

ABSTRACT Pneumonia often occurs as secondary infection post influenza disease and accounts for a large proportion of the morbidity and mortality associated with seasonal and pandemic influenza outbreaks. The antiviral drug triazavirine is licensed in Russia for the treatment and prophylaxis of acute respiratory infections, including influenza A and B viruses. In the present study, we investigated the efficacy of triazavirine in a mouse model of secondary Staphylococcus aureus pneumonia following A/California/04/2009 (H1N1)pdm09 influenza virus infection. We also performed a study of the efficacy of triazavirine against the A/California/04/2009 (H1N1)pdm09 lethal influenza infection in mice. In this model, triazavirine at the dose of 25 mg/kg/day significantly enhanced the survival of animals (60% compared to 20%) and the mean survival time to death, prevented weight loss, and reduced viral titer in the lungs of mice infected with influenza virus. At doses of 50 and 100 mg/kg/day, triazavirine was highly effective in the treatment of the secondary bacterial pneumonia following influenza infection in mice. At these doses, triazavirine protected 67-75% of animals against death, increased the mean survival time to death by twofold, and reduced the virus titer by 2.2-3.0 log10TCID50/ml compared to the mice in the control group. These findings suggest the possible benefit of triazavirine treatment in reducing post influenza pneumonia incidence in humans.

Histone Deacetylase Inhibition Protects Mice Against Lethal Postinfluenza Pneumococcal Infection.

Secondary bacterial pneumonia following influenza virus infection is associated with high mortality, but the mechanism is largely unknown. Epigenetic gene regulation appears to play key roles in innate and adaptive immunity. We hypothesized that histone acetylation, a major epigenetic mechanism associated with transcriptionally active chromatin, might contribute to the poor outcome of postinfluenza pneumonia. Prospective experimental study. University research laboratory. C57BL/6 male mice. Mice were infected intranasally with 1.0 × 10 colony-forming units of Streptococcus pneumoniae, 7 days after intranasal inoculation with five plaque-forming units of influenza virus A/H1N1/PR8/34. The mice were intraperitoneally injected with the histone deacetylase inhibitor trichostatin A (1 mg/kg) or vehicle once a day from 1 hour after pneumococcal infection throughout the course of the experiment. The primary outcome was survival rate. Trichostatin A significantly suppressed histone deacetylase activity and significantly improved the survival rate of mice (56.3%) after postinfluenza pneumococcal infection when compared with vehicle-treated mice (20.0%), which was associated with a significant decrease in the total cell count of the bronchoalveolar lavage fluid. The interleukin-1β level in the serum and the number of natural killer cells in the lungs were significantly lower in the trichostatin A-treated group. The histone deacetylase inhibitor trichostatin A protects mice against postinfluenza pneumonia possibly through multiple factors, including decreasing local cell recruitment into the lungs and suppressing systemic inflammation.

Inflammatory monocytes enhance disease progression during post-influenza MRSA pneumonia

Abstract Morbidity associated with influenza pandemics of the last century has been significantly associated with secondary bacterial infections. It is generally believed that the enhanced susceptibility to secondary bacterial infection is due to influenza-suppressed innate immunity. Interestingly, preceding influenza infection does not inhibit inflammatory cell recruitment during secondary bacterial infection. In fact, due to the recruitment of inflammatory monocytes, there are increased numbers of phagocytes in influenza and bacterial coinfected airways. The protective role of monocytes during influenza infection alone is well recognized; however, it is not clear how this phagocyte population contributes to post-influenza bacterial pneumonia. Using CC-Chemokine Receptor 2 deficient (CCR2−/−) mice defective in airway monocyte recruitment, we are currently investigating the role of inflammatory monocytes during influenza and methicillin-resistant Staphylococcus aureus (MRSA) coinfection. Specifically, C57BL/6 mice were infected intranasally with a sublethal dose of PR8 and subsequently MRSA on day seven post-influenza infection. Despite their delay in viral clearance, coinfected CCR2−/− mice exhibited significantly reduced bacterial burdens and importantly, improved survival rates compared with WT mice. Moreover, pro-inflammatory cytokine response in coinfected CCR2−/− mice was significantly decreased, suggesting an attenuation in lung inflammation. In summary, we found that by inhibiting bacterial clearance and perpetuating lung inflammation, inflammatory monocytes exacerbate adverse disease outcome during post-influenza MRSA pneumonia.

Type I IFNs are master regulators of susceptibility to post-influenza MRSA pneumonia (IRM11P.632)

Abstract Bacterial superinfections are common and often life-threatening complications of influenza infection. Others reported that increased susceptibility to superinfection occurs 7 days after influenza infection, and we demonstrated that it was due to decreased IL-13 and concomitant increase in IL13Ra2, which allowed for increased IFN-g, while early IL-13 production at day 3 provided protection from MRSA superinfection. However, mechanisms regulating IL-13 and IFN-g during influenza disease are unknown. We hypothesized that type I IFNs, induced by many respiratory infections, including those with influenza and MRSA are master regulators of susceptibility to superinfection. We determined that similar to the increase in IL-13, levels of IFN-b peaked at days 2-3 after influenza infection and were replaced by IFN-a by day 7, when mice are known to be susceptible to superinfection. At day 3 after influenza infection Ifnar-/- mice were more susceptible to MRSA superinfection, did not produce IL-13, but had increased IL13Ra2 and IFN-g compared to wild-type mice, and administration of rIL-13 to the Ifnar-/- mice partially restored protection from MRSA superinfection. Using bone marrow chimeric mice and Itgax-Cre mice we determined that early protection to superinfection required type I IFN signaling from the CD11c+ cell. These results support a role for type I IFNs in the early protective response to post-influenza superinfection and a role for their regulation of IL-13 and IFN-g.

IVA induced IFNs facilitate development of secondary pneumococcal pneumonia in human lung tissue

Introduction: Preceding influenza virus A (IVA) infections can predispose the lung to secondary bacterial pathogens like Streptococcus pneumoniae (S.p.) by modulation of the anti-bacterial defence, which is associated with higher morbidity and mortality. However, mechanisms underlying the inflammatory potentiating effect of IVA for S.p. infections in human lung tissue are still unclear. Besides morphological changes of the alveolar epithelium, resulting in improved access to receptors, the influence of IVA regarding changes of inflammatory immunity seems to be an important factor contributing to the severeness of post influenza pneumonia.

Female resistance to pneumonia identifies lung macrophage nitric oxide synthase-3 as a therapeutic target.

To identify new approaches to enhance innate immunity to bacterial pneumonia, we investigated the natural experiment of gender differences in resistance to infections. Female and estrogen-treated male mice show greater resistance to pneumococcal pneumonia, seen as greater bacterial clearance, diminished lung inflammation, and better survival. In vitro, lung macrophages from female mice and humans show better killing of ingested bacteria. Inhibitors and genetically altered mice identify a critical role for estrogen-mediated activation of lung macrophage nitric oxide synthase-3 (NOS3). Epidemiologic data show decreased hospitalization for pneumonia in women receiving estrogen or statins (known to activate NOS3). Pharmacologic targeting of NOS3 with statins or another small-molecule compound (AVE3085) enhanced macrophage bacterial killing, improved bacterial clearance, and increased host survival in both primary and secondary (post-influenza) pneumonia. The data identify a novel mechanism for host defense via NOS3 and suggest a potential therapeutic strategy to reduce secondary bacterial pneumonia after influenza.

The use of inducers of apoptosis in treatment of experimental influenza infection and prevention of chronic Postinfluenza lung lesions

Influenza is a respiratory infection that is widespread throughout the world. Its complications are diverse and in many cases include excessive proliferation of cells in the respiratory tract as a factor of the pathogenesis of influenza. The present work studies the effectiveness of using the apoptosis inducer 6-[3-(1-adamantide)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN) for prevention of chronic lung lesions at the stage of postinfluenza pneumonia. Mice were infected with influenza virus A/mallard/Pennsylvania/10218/84(H5N2); level of virus reproduction in the lungs, specific lethality to animals, and the morphological structure of foci of postinfluenza pneumonia were then studied at the 15th day post infection. AHPN was shown to decrease the virus’ infectious activity in lung tissue by 1.2–1.5 lgEID50/0.2 mL, depending on the dose used, compared with the control group and to lead to a slight decrease of lethality of animals (the protection index being 12.5–37.5%). Use of AHPN restricted both proliferative and infiltrative components of chronic foci of postinfluenza pneumonia. It exhibited the most pronounced effect on morphology of the lung tissue when used on the fourth to seventh day after infection, i.e., in the period of the greatest activation of processes of the tissue inflammatory infiltration and regeneration of bronchiolar epithelium. Thus, use of apoptosis inducers can prevent development of postinfluenza complications with proliferative component.

Regulation of IFN-γ by IL-13 dictates the susceptibility to secondary post-influenza MRSA pneumonia (INM3P.439)

Abstract Post-IAV superinfections are the primary cause of deaths during IAV pandemics. The superinfection in mice 7 days after IAV infection results in exacerbated bacterial pneumonia mediated by type I and II IFNs. However, the sequelae of cytokine responses early in IAV infection, that eventually determines the later susceptibility is not understood. Here we examined whether the susceptibility to superinfection with MRSA varies during IAV infection. In the first 3 days of IAV infection mice had increased resistance to MRSA superinfection, which required IFNAR and IL-13 signaling to inhibit IFN-γ. IFN-γ-mediated high susceptibility to MRSA pneumonia 7 days after IAV infection was associated with increased IL-13Rα2 production, and was reversible by treatment with mrIL-13 or anti-IL-13Rα2. Thus, early in IAV infection IFNAR signaling maintained IL-13, which increased resistance to MRSA. Then, as IAV infection progressed, the capacity for IL-13 signaling was inhibited, in part by increased IL-13Rα2, resulting in increased IFN-γ levels and susceptibility to MRSA superinfection. Thus, IAV induces a sequence of cytokine responses where early IFNAR-dependent IL-13 signaling suppresses IFN-γ production resulting in enhanced resistance to MRSA challenge. Understanding these cytokine sequelae is critical to development of immunotherapies for IAV-MRSA coinfection since perturbations in the sequence of these events at the wrong time could increase susceptibility to MRSA and/or IAV.

Protecting Against Post-influenza Bacterial Pneumonia by Increasing Phagocyte Recruitment and ROS Production

Seasonal and especially pandemic influenza predispose patients to secondary bacterial pneumonias, which are a major cause of deaths and morbidity. Staphylococcus aureus is a particularly common and deadly form of post-influenza pneumonia, and increasing staphylococcal drug resistance makes the development of new therapies urgent. We explored an innate immune-mediated model of the lung to define novel mechanisms by which the host can be protected against secondary staphylococcal pneumonia after sub-lethal influenza infection. We found that stimulating the innate immunity in the lung by overexpression of GM-CSF will result in resistance to S. aureus pneumonia after sublethal influenza infection. Resistance was mediated by alveolar macrophages and neutrophils, and was associated with increased production of reactive oxygen species (ROS) by alveolar macrophages. Resistance was abrogated by treatment with agents that scavenged ROS. We conclude that stimulating innate immunity in the lung markedly reduces susceptibility to post-influenza staphylococcal pneumonia and that this may represent a novel immunomodulatory strategy for prevention and treatment of secondary bacterial pneumonia after influenza.

Effect of Linezolid on Clinical Severity and Pulmonary Cytokines in a Murine Model of Influenza A and Staphylococcus aureus Coinfection

Excessive inflammation contributes to the severity of post influenza pneumonia caused by methicillin resistant S.aureus (MRSA). Linezolid, vancomycin, and clindamycin are antibiotics used for MRSA infections. Linezolid has immunomodulatory properties. We report on the effects of the three antibiotics on microbial clearance, pulmonary cytokines and clinical course in a murine model of influenza and MRSA coinfection.MethodsB6 mice were infected with influenza A virus and 3 days later with MRSA, both intranasally. Treatment with placebo, linezolid, vancomycin or clindamycin started immediately after MRSA infection and continued for 72 hours. Bacterial and viral titers as well as cytokine concentrations in the lungs were assessed 4 and 24 hours after MRSA coinfection. Mice were weighted daily for 13 days.ResultsCoinfected mice had increased pulmonary IL-1β, TNF-α and mKC at 4 and 24 hours, IL-6, IL-10 and IL-12 at 4 hours and IFN-γ at 24 hours after MRSA coinfection (all P<0.05). Compared to placebo, coinfected mice treated with linezolid, vancomycin or clindamycin had decreased pulmonary IL-6 and mKC at 4 hours and IFN-γ at 24 hours after MRSA coinfection (all P<0.05). IL-1β, TNF-α and IL-12 were similar in antibiotic-treated and placebo groups. All antibiotics similarly reduced MRSA without effect on influenza titers. Linezolid-treated mice had less weight loss on days 4–6 after influenza infection compared to placebo (all P<0.05). On all other days weight change was similar among all groups.ConclusionsThis is the first report comparing the effects of antibiotics on cytokines and clinical outcome in a murine model of influenza and MRSA coinfection. Compared to placebo, antibiotic treatment reduced maximum concentration of IL-6, mKC and IFN-γ in the lungs without any difference among antibiotics. During treatment, only linezolid delayed weight loss compared to placebo.

Influenza‐associated bacterial pathogens in patients with 2009 influenza A (H1N1) infection: impact of community‐associated methicillin‐resistant Staphylococcus aureus in Queensland, Australia

Secondary bacterial pneumonia due to community onset methicillin-resistant Staphylococcus aureus (MRSA) has become a highly publicised cause of influenza-associated death. There is a risk that case reports of fatal outcomes with post-influenza MRSA pneumonia may unduly influence antibiotic prescribing. The aim of this study was to demonstrate the incidence of community-onset MRSA pneumonia in 2009 H1N1 influenza patients. The microbiology records of patients positive for influenza A (H1N1) in 2009 were reviewed for positive blood or respiratory tract cultures and urinary pneumococcal antigen results within a Queensland database. Patients with such positive results within 48 h of hospital admission and a positive H1N1 influenza result in the prior 6 weeks were included. In 2009, 4491 laboratory-confirmed pandemic influenza A (H1N1) infections were detected. Fifty patients (1.1% of the H1N1 cohort) who were hospitalised with H1N1 and who had a bacterial respiratory tract pathogen were identified. Streptococcus pneumoniae (16 patients; 32%), Staphylococcus aureus (13 patients; 26%) and Haemophilus influenzae (9 patients; 18%) were the most commonly cultured organisms. Of the cohort of 4491 patients, MRSA was detected in only two patients, both of whom were admitted to intensive care units and survived after prolonged admissions. Influenza-associated community-onset MRSA pneumonia was infrequently identified in the 2009 H1N1 season in Queensland, despite community-onset MRSA skin and soft tissue infections being very common. Although post-influenza MRSA pneumonia is of great concern, its influence on empiric-prescribing guidelines should take into account its incidence relative to other secondary bacterial pathogens.

Bench-to-bedside review: Bacterial pneumonia with influenza - pathogenesis and clinical implications

Seasonal and pandemic influenza are frequently complicated by bacterial infections, causing additional hospitalization and mortality. Secondary bacterial respiratory infection can be subdivided into combined viral/bacterial pneumonia and post-influenza pneumonia, which differ in their pathogenesis. During combined viral/bacterial infection, the virus, the bacterium and the host interact with each other. Post-influenza pneumonia may, at least in part, be due to resolution of inflammation caused by the primary viral infection. These mechanisms restore tissue homeostasis but greatly impair the host response against unrelated bacterial pathogens. In this review we summarize the underlying mechanisms leading to combined viral/bacterial infection or post-influenza pneumonia and highlight important considerations for effective treatment of bacterial pneumonia during and shortly after influenza.

Treatment of Post-Influenza Pneumonia in Health Care Workers

Treatment of Post-Influenza Pneumonia in Health Care Workers

A Reduced Capacity To Generate Activated Protein C and the Role of PAI-1 Deficiency on Coagulation Activation and Fibrin Formation during Murine Influenza Pneumonia.

Background: Recent studies have shown that influenza activates coagulation in vitro. We aimed to study influenza and post-influenza pneumonia induced hemostatic changes in vitro and to study the role a reduced capacity to generate activated protein C (APC) and PAI-1 deficiency on the prothrombotic state.Methods: C57BL/6 mice were inoculated with influenza or PBS (control). After 14 days these mice received S. pneumoniae. PAI-1−/− , TM pro/pro and control mice were inoculated with influenza. Controls for the influenza-infected PAI-1−/− and TM pro/pro mice were C57BL/6 mice and wild-type littermates, respectively. TATc, PAI-1, D-dimer levels, fibrin deposition and pro-inflammatory cytokines were studied on day 0, 2, 4, 8, 14, 15 and 16.Results: Influenza-infected C57BL/6 mice showed a dose dependent increase in TATc, PAI-1 and fibrin deposition compared to non-infected controls. Median TATc levels increased from 5.3 at baseline to 12.8 ng/ml at day 4 and PAI-1 levels increased from 4.0 to 16.0 IU/ml (both p<0.05). TATc and PAI-1 levels remained unchanged in non infected controls. Mice recovered from influenza infection were highly susceptible to pneumococcal pneumonia as reflected by a 3-fold increase in cytokines compared to non-influenza infected controls. In addition, an increase in TATc and PAI-1 levels was seen (both p<0.05). Furthermore, influenza-infected TM pro/pro mice showed higher TATc levels (16.2 vs. 12.0 ng/ml, p<0.05) and higher D-dimer levels (2.6 vs. 2.0 μg/l, p<0.05) compared to infected controls 4 days after infection. In influenza-infected PAI-1−/− mice TATc levels were similar as in infected controls, but D-dimer levels were increased (4.0 vs. 2.2 μg/l, p< 0.05).Conclusion: This study demonstrates that influenza and post-influenza pneumonia exert a prothrombotic state in vivo. Mice with a reduced capacity to generate APC show increased thrombin generation. PAI-1 deficiency does not effect coagulation activation but results in a hyperfibrinolytic state.

Involvement of the platelet-activating factor receptor in host defense againstStreptococcus pneumoniaeduring postinfluenza pneumonia

Although influenza infection alone may lead to pneumonia, secondary bacterial infections are a much more common cause of pneumonia. Streptococcus pneumoniae is the most frequently isolated causative pathogen during postinfluenza pneumonia. Considering that S. pneumoniae utilizes the platelet-activating factor receptor (PAFR) to invade the respiratory epithelium and that the PAFR is upregulated during viral infection, we here used PAFR gene-deficient (PAFR-/-) mice to determine the role of this receptor during postinfluenza pneumococcal pneumonia. Viral clearance was similar in wild-type and PAFR-/- mice, and influenza virus was completely removed from the lungs at the time mice were inoculated with S. pneumoniae (day 14 after influenza infection). PAFR-/- mice displayed a significantly reduced bacterial outgrowth in their lungs, a diminished dissemination of the infection, and a prolonged survival. Pulmonary levels of IL-10 and KC were significantly lower in PAFR-/- mice, whereas IL-6 and TNF-alpha were only trendwise lower. These data indicate that the pneumococcus uses the PAFR leading to severe pneumonia in a host previously exposed to influenza A.