Clinical features of pneumonia associated with influenza virus infection

The history of influenza pandemics was reviewed and clinical manifestations of pneumonia associated with influenza virus infections are described. Several types of pneumonia associated with the influenza virus infection have been reported: 1) influenza complicated by secondary bacterial pneumonia, 2) primary influenza virus pneumonia, 3) combined influenza virus and bacterial pneumonia. Secondary bacterial pneumonia often produces a syndrome that is clinically distinguishable from that of primary viral pneumonia. In primary influenza virus pneumonia, chest roentgenography revealed bilateral infiltrations but no consolidation. Histologically, diffuse alveolar damage and hemorrhagic bronchiolitis were frequently observed in primary influenza virus pneumonia, in which case the prognosis was the worst. Although rare, the possibility of bronchiolitis obliterans organizing pneumonia associated with influenza virus infection should be recognized. H. influenzae, S. pneumoniae, or S. aureus were frequently associated with influenza viral infection, and treatment against these bacteria should be considered.     

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.     

Complicated secondary pneumonia after swine-origin influenza A virus infection in an immunocompetent patient

The pandemic of the swine-origin influenza A virus (S-OIV) in 2009 demonstrated severe viral pneumonia followed by acute respiratory distress syndrome (ARDS). Although ARDS would be caused by the influenza virus pneumonia itself, it has remained unclear whether other respiratory viral or bacterial infections coexist with S-OIV pneumonia. We report an immunocompetent patient with methicillin-resistant Staphylococcus aureus (MRSA) and Herpes simplex virus (HSV) pneumonia secondary to S-OIV infection. A 57-year-old man previously without major medical illness was admitted to our hospital with severe pneumonia accompanied by ARDS due to S-OIV. In his clinical course, anti-influenza treatment was not effective. Sputum culture revealed the presence of MRSA, and HSV was isolated in broncho-alveoler lavage (BAL) fluid. Administration of an antiviral agent (acyclovir), an antibacterial agent (linezolid), and a corticosteroid (methylprednisolone) successfully improved the pneumonia and ARDS. HSV pneumonia can scarcely be seen in healthy people. However recently it has been recognized as a ventilator-associated pneumonia. Although coexistence of Streptococcus pneumoniae and MRSA was reported in S-OIV pneumonia, secondary viral infection has not been reported. The present report is the first patient with HSV pneumonia secondary to S-OIV infection. We propose that a possibility of hidden HSV pneumonia should be taken into consideration in patients with prolonged severe pneumonia due to influenza infection.     

SULFONAMIDE CHEMOTHERAPY OF COMBINED INFECTION WITH INFLUENZA VIRUS AND BACTERIA

1. Sulfonamide chemotherapy controls the bacterial component of combined infection with influenza virus and pneumococci in rats. 2. Reinstillation of fluid (broth, physiological salt solution) into the respiratory passages of mice several days after sublethal viral infection converts the viral infection into a lethal one. 3. Sulfonamide chemotherapy controls the bacterial component of combined bacterial and viral infection of mice, produced by intrabronchial inoculation of mixtures of bacteria and sublethal or lethal doses of virus. 4. Bacterial pneumonia may be superimposed upon sublethal viral infection in mice by inhalation of fine droplets of bacterial suspension several days after inoculation of virus. Normal mice inhaling fine droplets of bacterial suspension fail to develop obvious disease. 5. Sulfonamide chemotheiapy controls bacterial pneumonia superimposed on sublethal viral infection by inhalation of fine droplets of bacterial culture. 6. The secondary bacterial penumonia does not convert the sublethal viral infection into a lethal one. 7. If another pandemic of influenza occurs, it is probable that sulfonamide chemotherapy will be valuable in the treatment of secondary bacterial pneumonia and will be effective in lowering the case fatality rate if the viral component of the infection is not severe enough by itself to cause death.     

PULMONARY EDEMA IN INFLUENZAL PNEUMONIA OF THE MOUSE AND THE RELATION OF FLUID IN THE LUNG TO THE INCEPTION OF PNEUMOCOCCAL PNEUMONIA

Pulmonary edema is a component of the fully developed influenza viral lesion in the mouse. Mice with experimental pulmonary fluid have an increased susceptibility to inhaled pneumococci and under these circumstances the organisms grow in the lung and produce the lesion of bacterial pneumonia. The presence of pulmonary edema in the lesion due to the influenza virus in the lung of the mouse appears to account adequately for the previous observation that inhaled pneumococci grow in the influenza viral lesion. Mice dying of pneumococcal septicemia after inhaling fine droplets containing this organism do not have pneumonia. The delay in migration of polymorphonuclear leucocytes into the lung after injection of pneumococci suspended in serum is an important factor in susceptibility to infection since it allows ample time for pneumococci to grow in the pulmonary fluid. The slow phagocytic action of pulmonary macrophages likewise permits growth of pneumococci. Conditions in human beings that are known to be complicated by pulmonary edema are also known to be associated with increased susceptibility to secondary bacterial pneumonia.     

白细胞不增高的社区获得性肺炎病原分析及临床特征

目的：分析外周血白细胞正常或降低的社区获得性肺炎(CAP)病因及临床特点。方法：采用标准的培养技术及血清学方法检测89例白细胞不高的CAP患者呼吸道及血液标本的常见病原体，并分析其临床资料。结果：89例中军团菌属最多，占28．1％(25／89)，病毒占18．0％(16／89)，其中主要为流感病毒A(6例)、流感病毒B(7例)，肺炎支原体占18．0％(16／89)，细菌占4．3％(3／89)，肺炎衣原体最少(1／89)，有38．2％(34／89)的患者不能明确病原体，多种病原体混合感染占25．8％。病毒性肺炎、军团菌肺炎及肺炎支原体肺炎的临床症状、体征、外周血白细胞、胸部影像均无特异性，其鉴别须靠病原微生物检查。结论:外周血白细胞正常或降低的CAP病因主要为非典型病原体和病毒，对这类CAP的经验治疗应以大环内酯类抗生素或抗病毒药物为主。     

Pathogenesis of Staphylococcus aureus necrotizing pneumonia: the role of PVL and an influenza coinfection

Only recently necrotizing pneumonia was defined as a specific disease entity that is caused by a Panton-Valentine leukocidin (PVL)-producing Staphylococcus aureus strain and is frequently preceded by an influenza infection. Necrotizing pneumonia is characterized by a sudden onset and rapid worsening of symptoms, leukopenia, airway hemorrhages, severe respiratory failure and a high mortality rate. Despite clear epidemiological data, the function of PVL in necrotizing pneumonia has been controversially discussed due to conflicting results from different disease models. Furthermore, there are many proposed mechanisms how a viral infection could facilitate and interact with a bacterial superinfection. In this review, we summarize current data from 43 clinical cases and results from various infection models on necrotizing pneumonia. We discuss the contribution of S. aureus PVL and a preceding influenza infection and present a concept of the pathogenesis of necrotizing pneumonia.     

A distinct influenza infection signature in the blood transcriptome of patients who presented with severe community acquired pneumonia

ABSTRACT: INTRODUCTION: Diagnosis of severe influenza pneumonia remains challenging because there is a lack of correlation between the presence of influenza virus and clinical status. We conducted gene expression profiling in the whole blood of critically ill patients to identify a gene signature that would allow clinicians to distinguish influenza infection from other causes of severe respiratory failure, such as bacterial pneumonia, and non-infective systemic inflammatory response syndrome. METHODS: Whole blood samples were collected from critically ill individuals and assayed on Illumina HT-12 gene expression beadarrays. Differentially expressed genes were determined by linear mixed model analysis and over-represented biological pathways determined using GeneGo MetaCore. RESULTS: The gene expression profile of H1N1 influenza A pneumonia was distinctly different from bacterial pneumonia and systemic inflammatory response syndrome. The influenza gene expression profile is characterized by up-regulation of genes from cell cycle regulation, apoptosis and DNA-damage response pathways. In contrast, no distinctive gene-expression signature was found in patients with bacterial pneumonia or systemic inflammatory response syndrome. The gene expression profile of influenza infection persisted through 5 days of follow-up. Furthermore, in patients with primary H1N1 influenza A infection who subsequently developed bacterial co-infection, the influenza gene-expression signature remained unaltered, despite the presence of a super-imposed bacterial infection. CONCLUSIONS: The whole blood expression profiling data indicates that the host response to influenza pneumonia is distinctly different from that caused by bacterial pathogens. This information may speed up identification of the cause of infection in patients presenting with severe respiratory failure, allowing appropriate patient care to be undertaken more rapidly.     

Etiology and clinical study of community-acquired pneumonia in 157 hospitalized children

We tried to verify whether the currently employed diagnosis and treatment of community-acquired pneumonia in children were appropriate. For this purpose, we created tentative criteria for the classification of pediatric community-acquired pneumonia. We classified the community-acquired pneumonia into ten categories: (1) bacterial, (2) concomitant viral-bacterial, (3) viral, (4) mycoplasmal, (5) concomitant mycoplasmal-bacterial, (6) concomitant mycoplasmal-viral, (7) chlamydial, (8) concomitant chlamydial-bacterial, (9) concomitant chlamydial-viral, and (10) unknown. Children aged 1 month to 13 years with radiographic and clinical evidence of pneumonia were enrolled. Between October 2001 and September 2002, we enrolled 165 patients. The etiologic agents were determined in 126 of the 157 (80.3%) patients who were finally diagnosed with pneumonia. Two blood cultures were positive for Haemophilus influenzae type b and Streptococcus pneumoniae. A viral infection alone was found in 28 of the 157 patients (17.8%), a bacterial (without mycoplasmal) alone infection in 42 (26.8%), a concomitant viral-bacterial infection in 28 (17.8%), and a mycoplasmal infection in 27 (17.2%) patients. RS virus was identified in 28 patients (17.8%), influenza A in 12 (7.6%), parainfluenza 3 in 8 (5.1%), adenovirus in 8 (5.1%), and influenza B and measles virus in 1 patient each. Streptococcus pneumoniae was the most common cause of bacterial pneumonia. We chose the initial treatment according to clinical and laboratory findings on admission (i.e., patients' age, clinical course, chest X-ray, and laboratory findings). In 68 of the 71 patients with bacterial (without mycoplasmal) pneumonia, an appropriate antibacterial-agent was prescribed. In 25 of the 27 patients with mycoplasmal pneumonia, clindamycin and minocycline were prescribed.     

Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection

The World Health Organization estimates that lower respiratory tract infections (excluding tuberculosis) account for approximately 35% of all deaths caused by infectious diseases. In many cases, the cause of death may be caused by multiple pathogens, e.g., the life-threatening bacterial pneumonia observed in patients infected with influenza virus. The ability to evolve more efficient immunity on each successive encounter with antigen is the hallmark of the adaptive immune response. However, in the absence of cross-reactive T and B cell epitopes, one lung infection can modify immunity and pathology to the next for extended periods of time. We now report for the first time that this phenomenon is mediated by a sustained desensitization of lung sentinel cells to Toll-like receptor (TLR) ligands; this is an effect that lasts for several months after resolution of influenza or respiratory syncytial virus infection and is associated with reduced chemokine production and NF-kappaB activation in alveolar macrophages. Although such desensitization may be beneficial in alleviating overall immunopathology, the reduced neutrophil recruitment correlates with heightened bacterial load during secondary respiratory infection. Our data therefore suggests that post-viral desensitization to TLR signals may be one possible contributor to the common secondary bacterial pneumonia associated with pandemic and seasonal influenza infection.     

C-reactive protein as predictor of bacterial infection among patients with an influenza-like illness

Objective

During the influenza season patients are labeled as having an influenza-like illness (ILI) which may be either a viral or bacterial infection. We hypothesize that C-reactive protein (CRP) levels among patients with ILI diagnosed with a bacterial infection will be higher than patients diagnosed with an influenza or another viral infection.

Methods

We enrolled a convenience sample of adults with ILI presenting to an urban academic emergency department from October to March during the 2008 to 2011 influenza seasons. Subjects had nasal aspirates for viral testing, and serum CRP. Bacterial infection was determined by positive blood cultures, radiographic evidence of pneumonia, or a discharge diagnosis of bacterial infection. Receiver operating characteristic curve, analysis of variance, and Student t test were used to analyze results.

Results

Over 3 influenza seasons there were 131 total patients analyzed (48 influenza infection, 42 other viral infection and 41 bacterial infection). CRP values were 25.65 mg/L (95% CI, 18.88-32.41) for influenza, 18.73 mg/L (95% CI, 12.97-24.49) for viral and 135.96 mg/L (95% CI, 99.38-172.54) for bacterial. There was a significant difference between the bacterial group, and both the influenza and other viral infection groups (P < .001). The receiver operating characteristic curve for CRP as a determinant of bacterial infection had an area under the curve of 0.978, whereby a CRP value of <20 had a sensitivity of 100% and >80 had a specificity of 100%.

Conclusion

C-reactive protein is both a sensitive and specific marker for bacterial infection in patients presenting with ILI during the influenza season.     

Pneumopathies communautaires d'origine virale en réanimation chez l'adulte immunocompétent

There is little data available in the literature on the incidence, etiology and the consequences of community-acquired severe viral pneumonia in the non-immunodeficient adult. In most studies, the viral etiology has not been investigated. The results of studies carried out over the last ten years show a frequency of between 1 and 13.6%. Diagnosis is frequently based on serological testing, but full testing is only carried out in under 50% of cases. In France, respiratory viruses are mainly influenza virus (40–50%), followed by respiratory syncytial virus (RSV: 14%), parainfluenza virus (20–30%), and adenovirus (12–14%). Viruses responsible for pulmonary infection introduced via the hematogenic pathway (varicella-zoster, Epstein-Barr, measles, enterovirus, etc.) are less common, but easier to diagnose. Epidemiological studies should include a thorough investigation of the viral etiology, with for the majority of viruses, viral antigen detection by IF or Elisa, or viral isolation and culture. Serological testing is useful for certain viruses (measles, Epstein-Barr, Hantavirus). Molecular biological techniques are in the process of being assessed. Routinely, the lack of efficient therapeutic agents to treat cases of severe viral pneumonia limits the interest of an etiological approach. RSV infection can be easily and inexpensively diagnosed by viral antigen detection, or viral isolation and culture, but the diagnosis for influenza must be made early after the onset of symptoms, otherwise serological diagnosis may be made a posterior. The aim of such research is to introduce suitable anti-influenza prophylaxis for at-risk subjects, and hygienic measures to limit RSV cross-transmission.     

Surveillance of viral respiratory tract infections over a one year period in mainly hospitalized Austrian infants and children by a rapid enzyme-linked immunosorbent assay diagnosis

In order to obtain more information on viral respiratory tract infections in Austrian infants and children, nasopharyngeal secretions from 1432 infants and children, collected from October 1984 to October 1985, were screened for the presence of respiratory syncytial virus (RSV), adenoviruses, parainfluenza virus type 1, 2, and 3, and influenza viruses type A and B, by enzyme-linked immunosorbent assay (ELISA). The results obtained were analyzed with respect to incidence, seasonal distribution and clinical syndromes associated with the different viral pathogens investigated and also with the practicability of ELISA diagnostics over long distances. A viral etiology of acute respiratory tract infection was confirmed in 372 (26%) infants. RSV was detected in 286 (20%) of the nasal secretions and was thus the most frequently encountered agent. RSV infections occurred mainly in the winter months and were often associated with bronchitis, bronchiolitis, and pneumonia. Only sporadic infections were found with one of the other viruses investigated.     

儿童禽流感肺炎与细菌性肺炎的胸部放射征象分析

[目的]探讨儿童H3N1型禽流感病毒性肺炎与细菌性肺炎的胸部放射表现特点。[方法]回顾性分析2例经世界卫生组织确认为H3N1型禽流感病毒感染患者胸部放射表现,并与65例儿童细菌性肺炎进行对比。[结果]本组2例H3N1型禽流感病毒性肺炎患者初期表现为单发片絮状渗出病变,密度高,边缘模糊,短期内病灶变化快;进展期由下至上扩展到多个肺叶、肺段,进展迅速;恢复期病变由弥漫性多发病变逐转变为局限病变;磨玻璃样密度病变影存在于各期。细菌性肺炎多无此特点,细菌性肺炎初期多为单发片状渗出病变,进展期病变局限于肺段、肺叶,恢复期多从近肺门侧开始吸收,病灶吸收较禽流感病毒性肺炎快,且吸收完全。[结论]儿童H3N1型禽流感病毒性肺炎的胸部放射表现具有一定特征性,放射动态观察则是与儿童细菌性肺炎鉴别诊断的重要手段。     

Cytokine markers as predictors of type of respiratory infection in patients during the influenza season

Objective

The objective of this study is to characterize the cytokine response among patients presenting with an influenza-like illness who are infected with the influenza virus, a bacterial pneumonia, or another viral infection. We hypothesize that there are differences in proinflammatory and anti-inflammatory cytokines in relation to cytokines associated with the humoral response during viral and bacterial respiratory infections.

Methods

We enrolled adults who presented to an urban academic emergency department during the 2008 to 2011 influenza seasons with symptoms of fever and a cough. Subjects had nasal aspirates tested by viral culture, and peripheral blood drawn to quantify cytokine concentrations. Cytokine concentrations were compared between groups using the Wilcoxon rank sum test, and receiver operating characteristic curves were calculated.

Results

A total of 80 patients were enrolled: 40 with influenza infection, 14 patients with a bacterial pneumonia as determined by infiltrate on chest x-ray, and 26 patients negative for influenza infection and infiltrate. There were differences between the bacterial pneumonia group, and all other viral infections grouped together with regard to interleukin (IL) 4 (2.66 vs 16.77 pg/mL, P < .001), IL-5 (20.57 vs 57.57 pg/mL, P = .006), IL-6 (403.06 vs 52.69 pg/mL, P < .001), granulocyte macrophage colony-stimulating factor (18.26 vs 66.80 pg/mL, P < .001), and interferon γ (0.0 vs 830.36 pg/mL, P < .001). Interleukin 10 concentrations were elevated in patients with influenza (88.69 pg/mL) compared with all other groups combined (39.19 pg/mL; P = .003).

Conclusion

Cytokines IL-4, IL-5, IL-6, granulocyte macrophage colony-stimulating factor, and interferon γ may serve as distinct markers of bacterial infection in patients with an influenza-like illness, whereas IL-10 is uniquely elevated in influenza patients.     

Viral pneumonias. A diagnostic and therapeutic challenge

Viral pneumonias are both a diagnostic and a therapeutic challenge for primary care physicians. The illness should be suspected when an upper respiratory tract infection progresses to include dyspnea and cyanosis. Rapid diagnostic tests are now available to detect most of the viruses that cause pneumonias. Fortunately, viral pneumonias usually resolve without specific antiviral therapy; however, ribavirin is indicated for respiratory syncytial virus pneumonia in children and ganciclovir sodium (Cytovene) for cytomegalovirus pneumonia in immunocompromised patients. Acyclovir (Zovirax) is indicated for pneumonias due to herpes simplex virus and varicella-zoster virus infections. A high index of suspicion for bacterial superinfections is essential to reduce the risk of death from this complication.     

Immunotherapy with a combination of intravenous immune globulin and p4 peptide rescues mice from postinfluenza pneumococcal pneumonia

Alternate therapies are needed for treatment of secondary bacterial pneumonia following influenza. The immunomodulatory peptide P4 has shown promise in mouse models of primary pneumococcal infection. Mice infected with influenza virus and then challenged with Streptococcus pneumoniae were treated with a combination of P4 peptide and intravenous immune globulin. Survival was improved from 20% to 80% in treated mice relative to controls. Clinical cure correlated with increased clearance of bacteria and decreased lung consolidation. Greater trafficking of professional phagocytic cells to the site of pneumococcal infection coupled with enhanced opsonophagocytosis as manifest by decreased surface display of Fcγ receptors (FcγR) on neutrophils and macrophages were associated with P4 peptide treatment. This suggests that the mechanism of action for improved clearance of bacteria engendered by P4 is through improved uptake by phagocytes mediated by IgG Fc-Fcγ receptor interactions following antibody-mediated opsonophagocytosis of bacteria. Antibody-based therapies, when coupled with immune modulators, such as P4 peptide, may be an effective tool together with antibiotics in our armamentarium against severe pneumonia.     

Potentiation of infectivity and pathogenesis of influenza virus by host and bacterial proteases

Infectivity and pathogenicity of influenza viruses are based on the interplay between the viral glycoprotein hemagglutinin (HA) and host proteases. HA receives its full biological activities by proteolytic cleavage of a precursor molecule at a definite cleavage site. Proteases selected by the Clara cells in the bronchial epithelia and many kind of bacteria, are virus activate proteases responsible for the cleavage activation and pathogenicity of influenza viruses. Although influenza in normal individuals is usually confined to the upper respiratory tract, the infection often develops into fatal pneumonia in aged patients, where bacterial infections often occur. Synergistic effects of bacterial infections on the pathogenesis of influenza viruses are described in regard to the cleavage activation of HA.     

The novel parainfluenza virus hemagglutinin-neuraminidase inhibitor BCX 2798 prevents lethal synergism between a paramyxovirus and Streptococcus pneumoniae

An association exists between respiratory viruses and bacterial infections. Prevention or treatment of the preceding viral infection is a logical goal for reducing this important cause of morbidity and mortality. The ability of the novel, selective parainfluenza virus hemagglutinin-neuraminidase inhibitor BCX 2798 to prevent the synergism between a paramyxovirus and Streptococcus pneumoniae was examined in this study. A model of secondary bacterial pneumonia after infection with a recombinant Sendai virus whose hemagglutinin-neuraminidase gene was replaced with that of human parainfluenza virus type 1 [rSV(hHN)] was established in mice. Challenge of mice with a sublethal dose of S. pneumoniae 7 days after a sublethal infection with rSV(hHN) (synergistic group) caused 100% mortality. Bacterial infection preceding viral infection had no effect on survival. The mean bacterial titers in the synergistic group were significantly higher than in mice infected with bacteria only. The virus titers were similar in mice infected with rSV(hHN) alone and in dually infected mice. Intranasal administration of BCX 2798 at 10 mg/kg per day to the synergistic group of mice starting 4 h before virus infection protected 80% of animals from death. This effect was accompanied by a significant reduction in lung viral and bacterial titers. Treatment of mice 24 h after the rSV(hHN) infection showed no protection against synergistic lethality. Together, our results indicate that parainfluenza viruses can prime for secondary bacterial infections. Prophylaxis of parainfluenza virus infections with antivirals might be an effective strategy for prevention of secondary bacterial complications in humans.