Obstructive endo-bronchial pseudotumour due to herpes simplex type 2 infection in an HIV-infected man.

We report a 31-year-old man with an obstructive bronchial lesion due to herpes simplex type 2 infection, who responded promptly to endoscopic resection and oral treatment with acyclovir. Exophytic lesions of the respiratory tract are rare, potentially life-threatening, but readily treated complication of herpes simplex virus infection in HIV-infected individuals.

Syk: a novel target for treatment of inflammation in lung disease.

Spleen Tyrosine Kinase (Syk) is widely expressed in the immune system and functions in the transmission of inflammatory signals via ITAM-bearing cell surface receptors. The broad expression pattern and importance of Syk in regulating innate immunity and the inflammatory response have led to significant interest from the pharmaceutical industry to developing anti-Syk therapeutics for the treatment of inflammatory disorders such as allergic rhinitis and rheumatoid arthritis. While the function and regulation of Syk has been well-described in leukocytes, where its primary role is an early transducer of signaling following immunoreceptor engagement, Syk has recently been described in non-immune cells, such as the airway epithelium, that also play an important role in mediating the inflammatory response. This manuscript will focus on the expression and function of Syk in the context of inflammatory lung diseases, and review recent data that have demonstrated novel roles for Syk in airway epithelial cells, particularly its role in mediating the human rhinovirus (HRV) induced inflammatory response and viral cell entry. In addition, data describing the efficacy of novel Syk inhibitors in the management of inflammatory diseases in animal models and early clinical trials are also reviewed.

Human metapneumovirus infection induces long-term pulmonary inflammation associated with airway obstruction and hyperresponsiveness in mice.

BACKGROUND: Human metapneumovirus (hMPV) is a newly described paramyxovirus that is associated with bronchiolitis, pneumonia, and asthma exacerbation. The objective of the present work was to study the duration of pulmonary inflammation and the functional consequences of infection with hMPV by use of a BALB/c mouse model. METHODS: BALB/c mice were inoculated with 1 x 10(8) TCID(50) of hMPV type A (C-85473), and viral persistence in lungs was assessed by reverse-transcription polymerase chain reaction for 154 days after infection. Pulmonary inflammation was characterized in histopathological experiments by use of a validated scoring system, and periodic acid-Schiff (PAS) staining of lung sections was used to document increased mucus production, also until day 154. Finally, respiratory functions were analyzed by taking plethysmographic measurements until day 70. RESULTS: Persistence of viral RNA and significant pulmonary inflammation were noted until day 154, whereas the findings for PAS staining suggested that mucus production was increased only until day 12. Maximal breathing difficulties occurred on day 5, and airway obstruction and hyperresponsiveness were still significant until at least day 70. CONCLUSION: Acute hMPV infection in BALB/c mice is associated with long-term pulmonary inflammation that leads to significant obstructive disease of the airways. This animal model will be of a great benefit in the evaluation of novel therapeutic and prophylactic modalities.

Infectious etiologies in acute exacerbation of COPD.

Acute exacerbation (AE) is a frequent episode during the prolonged chronic course of chronic obstructive pulmonary disease (COPD), which entails significant morbidity and mortality. The purpose of this study was to determine the frequency distribution of infectious etiologies in these episodes. Two hundred forty hospitalizations for AECOPD were included in a prospective, purely serologically based study. Paired sera were obtained for each of the hospitalizations and were tested using immunofluorescence or EIA methods to identify 13 different pathogens. Only significant changes in antibody titers were considered diagnostic. The mean age ( +/- SD) of the patients was 66.8 +/- 9.0 years and 179 (84%) were males. In 175 (72.9%) hospitalizations at least one infectious etiology was identified. In 117 (48.8%) hospitalizations at least one of 7 viral etiologies was identified. In 72 (30.0%) hospitalizations at least one of the following atypical bacteria was identified: Legionella spp. in 40 (16.7%), Mycoplasma pneumoniae in 34 (14.2%), and Coxiella burnetii in a single hospitalization. In 58 (24.2%) hospitalizations at least one classic bacterial etiology was found: Streptococcus pneumoniae in 48 (20.0%), Hemophilus influenzae in 10 (4.2%) and Moraxella catarrhalis in 9 (3.8%). More than one etiology was found in 72 (30.0%) hospitalizations. There were no significant differences in the etiologic distribution when the patients were classified by severity of airway obstruction or the clinical type of the exacerbation. We conclude that in most cases of hospitalization due to AECOPD the infectious etiology is viral or atypical bacteria and is classic bacteria in only a minority of cases. More than one etiologic cause can be identified in a third of the cases. The frequency distribution of the etiologies is not associated with the severity of airway obstruction or the clinical type of the exacerbation. The results of our study suggest that atypical bacteria should be covered in antibiotic regimens recommended for AECOPD. This issue should be addressed in future studies.

Comparison of different methods of total RNA extraction for viral detection in sputum.

Examination of sputum specimens can be used for monitoring airway inflammation by means of immunological and molecular techniques. RNA extraction is essential for measurement of cytokine gene expression and for detection of many viral pathogens in sputum. In this study, three RNA extraction methods used commonly (acid guanidinium thiocyanate-phenol-chloroform extraction, Trizol and RNeasy Mini kit) were compared on the sputum of 14 patients who had chronic obstructive pulmonary disease. The effect of dithiothreitol pre-treatment on sputum RNA extraction was also investigated. The yield and purity of total RNA were determined by spectrophotometry. Reverse transcription-polymerase chain reaction (RT-PCR) results of the house keeping gene (glyceraldehyde-3-phosphate dehydrogenase) and RNA sequences specific to common respiratory viruses were compared. The results showed that (1) total RNA extracted with Trizol had highest yield and purity among the three RNA extraction methods; (2) there was no significant difference among the three RNA extraction methods on the house keeping gene and viral detection by RT-PCR; (3) dithiothreitol pre-treatment did not improve either the purity of total RNA, or RT-PCR signal. Moreover, dithiothreitol treatment reduced significantly the yield of total RNA. The results of the study indicate that the Trizol method appears to be superior for total RNA extraction from sputum, and dithiothreitol pre-treatment does not increase the efficiency of RNA extraction and RNA detection in sputum specimens.

Reduced interferon-gamma secretion by natural killer cells from rats susceptible to postviral chronic airway dysfunction.

After parainfluenza type 1 (Sendai) virus infection as weanlings, Brown Norway (BN), unlike Fischer 344 (F344), rats develop an asthma-like phenotype. Reduced postinfection interferon (IFN)-gamma levels in bronchoalveolar lavage fluid from BN weanlings and the prevention of chronic airway sequelae in BN rats by IFN-gamma treatment led to the hypothesis that cells from BN weanlings have a reduced ability to secrete IFN-gamma. After stimulation with Sendai virus or interleukin (IL)-12, splenocytes from uninfected BN weanlings secreted significantly less IFN-gamma than did splenocytes from F344 weanlings (P < 0.005), as determined by enzyme-linked immunosorbent assay. Because levels of potential IFN-gamma-secreting cells in the spleen differed between the strains, natural killer (NK) cells, an important IFN-gamma source during early antiviral responses, were purified from spleens of uninfected weanlings. When stimulated with IL-12, BN NK cells secreted significantly less IFN-gamma than did F344 NK cells (P < 0.001). Incubation of NK cells from either strain with IL-12 and IL-18 resulted in synergistic increases in IFN-gamma production, but BN cells still secreted significantly less IFN-gamma than did F344 cells (P < 0.05). Similarly, after incubation with either IFN-alpha or IFN-alpha plus IL-18, BN NK cells secreted significantly less IFN-gamma than did F344 NK cells (P < 0.05). Therefore, reduced IFN-gamma secretion by NK cells in BN weanlings may play a role in the development of postviral chronic airway dysfunction.

Chronic bronchitis: the role of viruses.

Mucus is produced by the epithelial cells in the glands, gland ducts, and the cells lining the airway lumen in the lower airways. The chronic cough and sputum production that defines chronic bronchitis is associated with an inflammatory reaction involving this mucus-secreting apparatus. Respiratory viral infections target the epithelial cells of the lung producing desquamation, microvascular dilatation, edema, and an inflammatory cell infiltrate. These changes predispose the lower airways to bacterial infection by interfering with mucociliary clearance and reducing bacterial killing by macrophages. The exact role of those infections in the pathogenesis of chronic bronchitis has not been clearly determined but they probably play a critical role in inducing bacterial colonization and initiating acute exacerbations of COPD. This article reviews the classification of the viral agents responsible for respiratory tract infection and the nature of the changes they produce in the normal airways and in the airways of patients with chronic bronchitis during acute infections.

Bactericidal activity of a monocytic cell line (THP-1) against common respiratory tract bacterial pathogens is depressed after infection with respiratory syncytial virus.

Non-typable Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis and respiratory syncytial virus (RSV) are commonly isolated from patients during the course of chronic obstructive pulmonary disease (COPD). Earlier studies found that virus infection enhanced binding of bacterial respiratory pathogens to epithelial cells in vitro. The objective of the present study was to assess the effect of RSV infection of a human monocytic cell line on bactericidal activity and cytokine production in response to these bacterial respiratory pathogens. The effect of RSV infection on binding, uptake and intracellular killing of bacteria by a human monocytic leukaemia cell line, THP-1, was assessed. Cell culture supernates were examined with a mouse fibroblast cell assay for tumour necrosis factor-alpha (TNF-alpha) bioactivity. Expression of CD14, CD11a, CD18, CD15 and CD29 on uninfected and RSV-infected THP-1 cells was assessed by flow cytometry in relation to differences in bacterial binding. RSV infection of THP-1 cells significantly decreased their ability to bind and kill bacteria. Compared with uninfected cells, fewer bacteria bound to RSV-infected THP-1 cells and the surface antigens that have been reported to bind bacteria were expressed at lower levels on RSV-infected cells. RSV-infected cells incubated with bacteria exhibited less TNF-alpha bioactivity than uninfected cell incubated with bacteria. The results elucidate some of the mechanisms involved in the increased susceptibility of virus-infected patients to secondary bacterial infection. Reduced bacterial killing by virus-infected monocytes might contribute to reduced clearance of bacteria from the respiratory tract and damage elicited by the bacteria or cytokine response in COPD patients.

Significance of respiratory syncytial virus (RSV) infection in the 1st year of life.

BACKGROUND: In this study we investigated the frequency, symptoms and predisposing factors of respiratory syncytial virus (RSV) infection during the 1st year of life in infants with obstructive airway disease in comparison with infants without airway disease. PATIENTS: We enrolled 216 infants in their 1st year of life, who were hospitalized because of obstructive airway disease. As an age- and sex-balanced control group, we examined 133 infants hospitalized for other reasons than airway disease. METHOD: A deep pharyngeal swab was taken from all infants and immediately examined for the presence of RSV antigen by using an enzyme immunoassay (Directigen). Patient data were surveyed by a questionnaire. RESULTS: The frequency of RSV infections among infants with obstructive airway disease (34.3%; n = 74) differed significantly from the control group (15%; n = 20; p < 0.01). The frequency of RSV-infected infants with obstructive airway disease decreased with age ranging from 39.1% in trimenon I to 29.0% in trimenon IV. This trend was not observed in the control group. With respect to clinical symptoms and risk factors, there were no differences between RSV-infected versus noninfected infants. CONCLUSION: RSV is an important agent causing lower obstructive airway disease (34.3% of all patients). There are no specific symptoms that can be used for diagnosing RSV infection. In order to prevent other patients on the ward from contracting nosocomial RSV infection and in the light of therapeutic options, one should test newly admitted patients presenting with symptoms of an obstructive airway disease for RSV antigen. On a ward with high-risk patients, we would recommend the use of an RSV test for all new patients.

Acute exacerbations in chronic obstructive pulmonary disease (COPD)--microbial patterns and risk factors.

Around 25% of patients with stable chronic obstructive pulmonary disease (COPD) show some evidence of tracheobronchial colonization. It is, however, probable that the vast majority of patients become colonized at some time during the course of the disease. A variety of factors including current smoking and viral infections predispose to bacterial colonization and subsequently acute exacerbations. In fact, infectious aetiologies account for around 50-75% of acute COPD exacerbations. Bacterial pathogens are present in around 50% of patients, Haemophilus influenzae and Streptococcus pneumoniae being the most frequently encountered pathogens. Pseudomonas aeruginosa and probably also Gram-negative enteric bacilli are more frequently found in patients with more severe airflow limitation. Viral infections are present in around 10-20%, with Influenzavirus representing the most frequent viral pathogen. Only recently, evidence for infection by Chlamydia pneumoniae has been found in 5-20% of patients. Predictors of distinct aetiologies have only infrequently been studied so far. Thus, it currently remains difficult to make adequate predictions on clinical grounds in the individual patient. Nevertheless, we would advocate to tentatively stratify the initial antimicrobial treatment according to the severity of the acute exacerbation episode and the presence of individual risk factors. The validation of such an approach may result in significant progress in our understanding of the role of infection and infectious agents in different subgroups of patients with acute exacerbations.

[Immunoglobulin E, viral antibodies and obstructive lung disease in adults. The relation between antibody level in serum, lung function and non-specific bronchial reactivity]. / Immunglobulin E, virusantistoffer og obstruktiv lungesykdom hos voksne. Forholdet mellom antistoffnivå i serum, lungefunksjon og uspesifikk bronkial reaktivitet.

We have measured immunoglobulin E levels and respiratory virus antibodies and examined their possible role as risk factors for obstructive lung disease in adults. We observed that increased total serum IgE levels were associated with reduced lung function in subjects with obstructive lung disease, but not in asymptomatic subjects. Subjects sensitised to indoor allergens (house dust mites, cats and mould) had reduced lung function and increased, non-specific, bronchial responsiveness compared with individuals who were not sensitised to indoor allergens. Similar relationships were not observed for subjects sensitised to outdoor allergens (birch and timothy). The presence of respiratory virus antibodies was vaguely associated with reduced lung function, but was not related to increased, non-specific, bronchial responsiveness. In adults in this community sensitisation to indoor allergens is a strong predictor of reduced lung function and increased, non-specific, bronchial responsiveness, which are again closely associated with obstructive lung disease.

Detection of human T lymphotropic virus type I proviral DNA in patients with diffuse panbronchiolitis.

In Japan a number of reported cases of diffuse panbronchiolitis (DPB) have been associated with human T lymphotropic virus type I (HTLV-I) infection. In this study the hypothesis that HTLV-I proviral DNA may be prevalent in DPB was examined using polymerase chain reaction (PCR) for the region of env or the two-step PCR for the pX region of this virus. The presence of HTLV-I proviral DNA was studied in the peripheral blood mononuclear cells (PBMC) obtained from 10 patients with DPB. The presence of proviral DNA in PBMC in 12 patients with chronic obstructive pulmonary disease (COPD), eight patients with idiopathic interstitial pneumonia (IIP), four patients disease were also studied as relevant controls. The lung tissue obtained from 11 patients with DPB, 12 patients with diffuse aspiration bronchiolitis (DAB) at autopsy, and the surgical lung samples obtained from 12 patients with bronchogenic cancer were also studied. Peripheral blood mononuclear cells obtained from one DPB patient and one bronchogenic carcinoma patient were positive for the HTLV-I pX region. The presence of the pX region was also found in the lung tissue of three DPB patients (27.3%) and one DAB patient (8.3%). None of other subjects were positive for HTLV-I proviral DNA, In conclusion, HTLV-I is not the causative virus in the pathogenesis of COPD, IIP, bronchiectasis and bronchogenic carcinoma. There is a likelihood that HTLV-I infection is associated with some cases of DPB; however this association needs further verification.

Epidemiology of respiratory viruses in persons with and without asthma and COPD.

The occurrence of respiratory viruses in persons with asthma and COPD must be viewed against the behavior of the viruses in persons without these conditions. There are multiple agents involved, and reinfections with the same virus are frequent. Infections and illnesses generally decrease in frequency with increasing age. Thus, it can be expected that infections among children, with or without asthma, will be more frequent than among adults in general. Evaluation of studies of viral activity in persons with asthma and COPD should differentiate between increased susceptibility and production of exacerbations. The latter may simply indicate the potential for greater severity, but not a higher frequency, of infections. Whatever viruses are circulating at a particular time can produce exacerbations; the studies are most conclusive for asthma in children, probably because infections in general are more common in this age group. Data also suggest increased susceptibility, although results are less clear than for exacerbations. Therefore, persons with chronic respiratory diseases should be considered a risk group for current and developmental vaccines and antiviral medications.

Mechanisms of airway narrowing and hyperresponsiveness in viral respiratory tract infections.

Viral respiratory tract infections are associated with an acute increase in airway responsiveness in normal subjects and patients with asthma. Airway responsiveness is also increased at least transiently in animals during acute viral infections. In this article, we discuss possible mechanisms whereby viral infections can increase airway responsiveness, emphasizing the effects of viral-induced airway epithelial damage during acute lytic infection and the mechanical consequences of airway inflammation and edema, both internal and external to the smooth muscle layer. We also describe possible mechanisms by which acute lytic viral infections could induce chronic sequelae in atopic individuals and contribute to the development of persistence of asthma. Finally, results of recent studies from our laboratory that document adenoviral genome in lungs of patients with chronic obstructive pulmonary disease (COPD) and long-term persistence of respiratory syncytial viral genome and protein in an animal model are discussed in terms of the possible role of latent and persistent viral infections in the pathogenesis of asthma and COPD.