The association between serological features of chronic Chlamydia pneumoniae infection and markers of systemic inflammation and nutrition in COPD patients

Introduction: Chlamydia pneumoniae is an obligatory human pathogen involved in lower and upper airway infections, including pneumonia, bronchitis. Asymptomatic C. pneumoniae carriage is also relatively common. The association of C. pneumoniae infections with the chronic obstructive pulmonary disease (COPD) course is unclear.

Objectives: The aim of the study was to investigate the association between chronic C. pneumoniae infection and clinical features of COPD, markers of inflammation and metabolic dysfunction.

Patients and methods: The study included 59 patients with stable COPD who had no, or had?≥2 acute exacerbations during last year. The level of IgA and IgG antibody against C. pneumoniae, IL-6, IL-8, resistin, insulin, adiponectin and acyl ghrelin was measured in serum by enzyme-linked immunosorbent assay (ELISA).

Results: No differences in clinical and functional data were observed between COPD patients without serological features of C. pneumoniae infection and chronic C. pneumoniae infection. The level of anti C. pneumoniae IgA significantly correlated with IL-8, IL-6, resistin concentration in group of frequent exacerbators. IgG level correlated negatively with acetyl ghrelin and body mass index (BMI) in patients without frequent exacerbations, in contrast to frequent COPD exacerbation group where significant correlations between IgG level and BMI was demonstrated. Serum IL-6 correlated positively with resistin and insulin and negatively with adiponectin in group of patients with serological features of chronic C. pneumoniae infection only.

Conclusions: Our study showed that chronic C. pneumoniae infection does not influence the clinical course of COPD in the both study groups. Chronic C. pneumoniae infections might be associated with a distinct COPD phenotype that affects metabolic dysfunction.     

Characterization of children with <Emphasis Type="Italic">Mycoplasma pneumoniae</Emphasis> infection detected by rapid polymerase chain reaction technique

We used a new polymerase chain reaction (PCR) system to identify the 16S rRNA gene of Mycoplasma pneumoniae and to diagnose lower respiratory tract infections caused by the microorganism. Nasopharyngeal swabs collected from 21 patients (22 episodes) tested positive for M. pneumoniae with the PCR. The age distribution of the patients was between 2 and 13 years. The diagnosis, including concomitant infection, was as follows: pneumonia (n = 11), acute bronchitis (n = 10), bronchial asthma (n = 4), and acute otitis media (n = 1). Six patients had bacterial superinfections. Positive findings for M. pneumoniae were noted together with exacerbation of asthma symptoms, suggesting that M. pneumoniae infection may play the role of an inducer. The PCR system constructed by us will contribute to revealing the clinical features of M. pneumoniae infection, and as a result, an appropriate chemotherapeutic agent can be chosen. We propose the usefulness of this PCR system to detect the microorganism in younger children.     

Bronchial hyperresponsiveness and bacterial respiratory infections.

Some studies suggest a potential role for bacterial respiratory tract infections in the development of bronchospasm and the progression of chronic obstructive pulmonary disease (COPD). Patients with bronchiectasis or cystic fibrosis have exaggerated airway reactivity; croup in children can also cause exaggerated upper and lower airway responsiveness. Bronchial obstruction after inhalation of Haemophilus influenzae and other bacteria has been reported. Between January 1989 and June 1990 we and two other centers studied 193 patients suffering from acute exacerbation of asthma. Fifty-two (27%) of these patients had bacteria in their sputum. Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Moraxella catarrhalis, and H influenzae were the most commonly isolated bacterial species. Antibiotics may be of value in the treatment of infective lung disease, not only by killing bacteria but also by preventing increases in bacterial histamine levels within the lung airways. Moreover, an antibiotic of proven efficacy can reduce airway reactivity in patients with bacterial exacerbations of COPD or bronchial asthma. In 12 patients with acute bacterial exacerbation of asthma and high airway reactivity to methacholine, a ten-day course of treatment with cefaclor and existing bronchodilators induced microbiologic cure and a slight but nonsignificant change in airway reactivity in nine patients. Antibiotic therapy has a minor but clear role in the control of acquired bronchial hyperreactivity during bacterial respiratory infections in asthmatic patients; however, because of airway inflammation, an antibiotic's efficacy is evident only when the inflammatory process subsides. Approaches designed to minimize airway reactivity may contribute to the prevention or reversal of respiratory failure during exacerbation of COPD and bronchial asthma.     

Doxycycline suppresses Chlamydia pneumoniae induced interferon-gamma responses in peripheral blood mononuclear cells in children with allergic asthma

Persistent respiratory infections caused by Chlamydia pneumoniae have been implicated in the pathogenesis of chronic diseases (e.g. asthma). Antibiotics are used to treat C. pneumoniae respiratory infections; however, the use of antibiotics as anti-inflammatory agents in treatment of asthma remains controversial. The current study investigated whether ciprofloxacin, azithromycin, or doxycycline can suppress C. pneumoniae-induced production of immunoglobulin (Ig) E or cytokines in peripheral blood mononuclear cells (PBMC) obtained from asthmatic children. Apart from blood, nasopharyngeal swab specimens were also collected to test for the presence of C. pneumoniae and/or M. pneumoniae (qPCR). PBMC (1.5 x 10⁶) from asthmatic pediatric patients (N = 18) were infected or mock infected for 1 h ± C. pneumoniae AR-39 at a multiplicity of infection (MOI) = 0.1, and cultured ± ciprofloxacin, azithromycin, or doxycycline (0.1 or 1.0 μg/mLmL) for either 48 h (cytokines) or 10 days (IgE). Interleukin (IL)-4, interferon (IFN)-γ and IgE levels in supernatants were measured (ELISA). When PBMC were infected with C. pneumoniae, IL-4 and IFNγ production increased (p = 0.06 and 0.03, respectively); IgE levels were low. The now-elevated levels of IL-4 didn't decrease significantly after addition of ciprofloxacin, azithromycin, or doxycycline. However, infected PBMC IFNγ formation decreased significantly when 0.1 μg/mL doxycycline was employed (p = 0.04); no dose of ciprofloxacin or azithromycin had any impact. This inhibitory outcome with doxycycline lends support to the use of tetracyclines as immune modulators and anti-inflammatory medications in treatment of C. pneumoniae-infected asthma patients.     

The role of respiratory infection in exacerbation of chronic obstructive pulmonary disease

Periods of acute deterioration known as exacerbations significantly lower the quality of life and health status of patients with chronic obstructive pulmonary disease (COPD), thus making treatment of these patients more expensive. Understanding of the pathogenesis of COPD exacerbations and their influence on the clinical course and prognosis of this disease has greatly improved during the last decades. Some aspects of the interrelation between the infectious pathogen and the host organism have been studied. According to modern data, respiratory infections present one of the main causes of exacerbations of the disease. The role of respiratory viruses, especially rhinoviruses and respiratory syncytial virus, which often precede secondary bacterial infections, have been found to be important in the etiology of COPD exacerbation. The main bacterial etio-pathogens of COPD exacerbations--the non-capsulated bacteria H. influenzae, S. pneumoniae, and M. catarrhalis, which in 25 to 50% of cases colonize the lower respiratory tract (LRT)--have been isolated. Colonization of the LRT of infectious agents (viruses and bacteria) results in chronization of the inflammatory process and progress of the disease. Besides, colonization correlates with the severity of the disease. A "vicious circle" theory has been put forward to explain the pathogenesis of COPD exacerbations. Etiological diagnostics of a COPD exacerbation will allow adequate choice of effective etiotropic therapy making it possible to eradicate the pathogen or lower microbial load in the respiratory tract, which will decrease the risk of recurrence and improve the prognosis of the disease.     

Effect of Prolonged Treatment with Azithromycin, Clarithromycin, or Levofloxacin on Chlamydia pneumoniae in a Continuous-Infection Model

Persistent infections with Chlamydia pneumoniae have been implicated in the development of chronic diseases, such as atherosclerosis and asthma. Although azithromycin, clarithromycin, and levofloxacin are frequently used for the treatment of respiratory C. pneumoniae infections, little is known about the dose and duration of therapy needed to treat a putative chronic C. pneumoniae infection. In this study, we investigated the effect of prolonged treatment with azithromycin, clarithromycin, or levofloxacin on the viability of C. pneumoniae and cytokine production in an in vitro model of continuous infection. We found that a 30-day treatment with azithromycin, clarithromycin, and levofloxacin at concentrations comparable to those achieved in the pulmonary epithelial lining fluid reduced but did not eliminate C. pneumoniae in continuously infected HEp-2 cells. All three antibiotics decreased levels of interleukin-6 (IL-6) and IL-8 in HEp-2 cells, but this effect appeared to be secondary to the antichlamydial activity, as the cytokine levels correlated with the concentrations of microorganisms. The levels of IL-1β, IL-4, IL-10, tumor necrosis factor alpha, and gamma interferon were too low to assess the effect of antibiotics. These data suggest that the dosage and duration of antibiotic therapy currently being used may not be sufficient to eradicate a putative chronic C. pneumoniae infection.     

Gram‐negative microbiota is related to acute exacerbation in children with asthma

BackgroundThe upper‐airway microbiota may be associated with the pathogenesis of asthma and useful for predicting acute exacerbation. However, the relationship between the lower‐airway microbiota and acute exacerbation in children with asthma is not well understood. We evaluated the characteristics of the airway microbiome using induced sputum from children with asthma exacerbation and compared the microbiota‐related differences of inflammatory cytokines with those in children with asthma.MethodsWe analysed the microbiome using induced sputum during acute exacerbation of asthma in children. We identified microbial candidates that were prominent in children with asthma exacerbation and compared them with those in children with stable asthma using various analytical methods. The microbial candidates were analysed to determine their association with inflammatory cytokines. We also developed a predictive functional profile using PICRUSt.ResultsA total of 95 children with allergic sensitisation including 22 with asthma exacerbation, 67 with stable asthma, and 6 controls were evaluated. We selected 26 microbial candidates whose abundances were significantly increased, decreased, or correlated during acute exacerbation in children with asthma. Among the microbial candidates, Campylobacter, Capnocytophaga, Haemophilus, and Porphyromonas were associated with inflammatory cytokines including macrophage inflammatory protein (MIP)‐1β, programmed death‐ligand 1, and granzyme B. Both Campylobacter and MIP‐1β levels were correlated with sputum eosinophils. Increased lipopolysaccharide biosynthesis and decreased glycan degradation were observed in children with asthma exacerbation.ConclusionGram‐negative microbes in the lower airway were related to acute exacerbation in children with asthma. These microbes and associated cytokines may play a role in exacerbating asthma in children.     

The effect of inhaled corticosteroids on Chlamydophila pneumoniae and Mycoplasma pneumoniae infection in children with bronchial asthma

The purpose of this study was to clarify whether inhaled corticosteroids (ICSs) increased the infectious load of Chlamydophila pneumoniae and/or Mycoplasma pneumoniae in the respiratory tracts of asthmatic children. We studied a total of 310 outpatients with chronic stable asthma. Real-time polymerase chain reaction (PCR)-positive results for C. pneumoniae were obtained in 21 of 310 (6.8%) throat samples and 21 of 293 (7.2%) nasopharyngeal samples. There was no significant difference in the rate of detection or in the quantity of detection for C. pneumoniae between the ICS group and the non-ICS group, nor were there differences among groups classified by Japanese pediatric guidelines (JPGL) severity criteria. Real-time PCR-positive results for M. pneumoniae were obtained in 60 of 310 (19.4%) throat samples and 49 of 293 (16.7%) nasopharyngeal samples. There was no significant difference in the rate of detection or the quantity of detection between the ICS group and the non-ICS group, nor were there differences among age groups. The results of this research do not support the hypothesis that ICSs influence the infectious load of C. pneumoniae and M. pneumoniae. ICSs did not increase C. pneumoniae or M. pneumoniae infection in the upper respiratory tract, in contrast to the effect of ICSs in causing oral candidiasis. Our data exclude the concern that there is an increase in C. pneumoniae and M. pneumoniae infections due to ICS use, the use of ICSs being the gold standard in the long-term anti-inflammatory treatment of persistent asthma in children and adults.     

Evidence for a causal relationship between respiratory syncytial virus infection and asthma

Respiratory syncytial virus (RSV) infects all children early in life, is the most common cause of infant lower respiratory tract infections, and causes disease exacerbations in children with asthma. Episodes of lower respiratory tract infection in early life are associated with asthma development. Whether RSV infection early in life directly causes asthma or simply identifies infants who are genetically predisposed to develop subsequent wheezing is debatable. Recent studies suggest that these two explanations are not mutually exclusive, and are likely both important in asthma development. An open-label study of RSV immunoprophylaxis administered to preterm infants reduced recurrent wheezing by 50%. Clinical trials of infant RSV prevention, delay or severity reduction on the outcome of childhood asthma would confirm the causal relationship between RSV infection and asthma, and offer a primary prevention strategy.     

Evidence for a causal relationship between respiratory syncytial virus infection and asthma

Respiratory syncytial virus (RSV) infects all children early in life, is the most common cause of infant lower respiratory tract infections, and causes disease exacerbations in children with asthma. Episodes of lower respiratory tract infection in early life are associated with asthma development. Whether RSV infection early in life directly causes asthma or simply identifies infants who are genetically predisposed to develop subsequent wheezing is debatable. Recent studies suggest that these two explanations are not mutually exclusive, and are likely both important in asthma development. An open-label study of RSV immunoprophylaxis administered to preterm infants reduced recurrent wheezing by 50%. Clinical trials of infant RSV prevention, delay or severity reduction on the outcome of childhood asthma would confirm the causal relationship between RSV infection and asthma, and offer a primary prevention strategy.     

Chlamydia pneumoniae and its role in chronic obstructive pulmonary disease

The diverging of T-helper (Th) cells into predominantly Thl and Th2 subsets on the basis of their cytokine profiles has decisively improved our understanding of the pathogenesis of many chronic infectious diseases. Recent data suggest that the presence of interferon-γ and the subsequent suppression of interleukin-4 production leads to a Thl-type reponse that is required for the resolution of infections caused by intracellular pathogens. The ability of the macrophages to respond aggressively during early antigen contact seems to be one crucial factor in the development of an appropriate Th-cell response. Several host-related factors can affect macrophage function and the polarization of T-cell responses, ie the shift from a Thl response to a Th2 one, and thus dramatically deteriorate the resolution of infections caused by intracellular agents such as Chlamydia pneumoniae. Chronic C. pneumoniae infection has been associated with several common chronic diseases, quite recently with chronic obstructive pulmonary disease. Chronic C. pneumoniae infection may amplify smoking-associated inflammation in the bronchi and may be a contributory factor in the development of irreversible pathological changes.     

Role of atypical bacterial infection of the lung in predisposition/protection of asthma

Asthma is a common inflammatory disease of the airways that results in airway narrowing and wheezing. Allergic asthma is characterised by a T-helper cell-type (Th) 2 response, immunoglobulin (Ig) E production, and eosinophilic influx into the airways. Recently, many clinical studies have implicated Mycoplasma pneumoniae and Chlamydia pneumoniae in the development and exacerbation of both chronic and acute asthma. It is widely accepted that M. pneumoniae and C. pneumoniae infections require Th1 immunity for clearance; therefore, according to the hygiene hypothesis, these infections should be protective against asthma. Here, we review the clinical evidence for the association and mechanisms of predisposition to and protection against asthma by these infections. We will examine the following question: Is it the absence of infection or the age of the individual on infection that confers susceptibility or resistance to asthma and does this vary between normal and predisposed individuals? We put forward a hypothesis of the effects of these infections on the development and prevention of asthma and how novel preventative and treatment strategies involving these microbes may be targeted against asthma.     

Airway mucins promote immunopathology in virus-exacerbated chronic obstructive pulmonary disease

The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus rich in mucin glycoproteins. Abnormal mucus accumulation is a cardinal feature of chronic respiratory diseases, but the relationship between mucus and pathogens during exacerbations is poorly understood. We identified elevations in airway mucin 5AC (MUC5AC) and MUC5B concentrations during spontaneous and experimentally induced chronic obstructive pulmonary disease (COPD) exacerbations. MUC5AC was more sensitive to changes in expression during exacerbation and was therefore more predictably associated with viral load, inflammation, symptom severity, decrements in lung function, and secondary bacterial infections. MUC5AC was functionally related to inflammation, as Muc5ac-deficient (Muc5ac^–/–) mice had attenuated RV-induced (RV-induced) airway inflammation, and exogenous MUC5AC glycoprotein administration augmented inflammatory responses and increased the release of extracellular adenosine triphosphate (ATP) in mice and human airway epithelial cell cultures. Hydrolysis of ATP suppressed MUC5AC augmentation of RV-induced inflammation in mice. Therapeutic suppression of mucin production using an EGFR antagonist ameliorated immunopathology in a mouse COPD exacerbation model. The coordinated virus induction of MUC5AC and MUC5B expression suggests that non-Th2 mechanisms trigger mucin hypersecretion during exacerbations. Our data identified a proinflammatory role for MUC5AC during viral infection and suggest that MUC5AC inhibition may ameliorate COPD exacerbations.     

Interleukin-11: stimulation in vivo and in vitro by respiratory viruses and induction of airways hyperresponsiveness.

To address the role of IL-11 in viral airways dysfunction, we determined whether infectious agents that exacerbate asthma stimulate stromal cell IL-11 production, determined whether IL-11 could be detected at sites of viral infection and evaluated the effects of IL-11 on airway physiology. Respiratory syncytial virus (RSV), parainfluenza virus type 3 (PIV3), and rhinovirus (RV) 14 were potent stimulators while cytomegalovirus and adenovirus only weakly stimulated and herpes simplex virus type 2 and bacteria did not stimulate IL-11 elaboration. IL-11 was not detected or barely detected in nasal aspirates from children without, but was detected in aspirates from children with viral upper respiratory tract infections. The levels of IL-11 were highest in patients with clinically detectable wheezing. IL-11 also caused nonspecific airways hyperresponsiveness in BALB/c mice. These studies demonstrate that three major causes of viral-induced asthma, RSV, RV, and PIV, in contrast to other viruses and bacteria, share the ability to induce stromal cell IL-11 production. They also demonstrate that IL-11 can be detected in vivo during viral respiratory infections, that the presence of IL-11 correlates with clinical bronchospasm and that IL-11 is a potent inducer of airways hyperresponsiveness. IL-11 may be an important mediator in viral airways disorders.     

Diagnosis of Legionella pneumophila,Mycoplasma pneumoniae,or Chlamydia pneumoniae lower respiratory infection using the polymerase chain reaction on a single throat swab specimen

Diagnosis of Mycoplasma pneumoniae and Chlamydia pneumoniae lower respiratory infections using DNA amplification by polymerase chain reaction (PCR) on throat swab specimens has been reported. In this study we determined the sensitivity of the detection of Legionella pneumophila in simulated throat swab specimens by PCR. Next, we compared the sensitivity and specificity of a single throat swab PCR with the current tests for diagnosis of Legionella spp., M. pneumoniae, and C. pneumoniae in patients with lower respiratory tract infections. Patients' work-up included: (a) throat swab speciment for Legionella spp., M. pneumoniae, and C. pneumoniae PCR; (b) throat swab specimen for C. pneumoniae, culture; (c) sputum specimen for L. pneumophila direct fluorescent antibody and culture; (d) urine specimen for L. pneumophila serogroup 1 antigen detection; and (e) serum specimen for L. pneumophila, M. pneumoniae, and C. pneumoniae acute and convalescent antibody titers. A total of 155 patients with lower respiratory infection were enrolled in this prospective study. Throat swab PCR was positive for Legionella spp. in five of the six patients with legionellosis, indicating the presence of this organism in the oropharynx of patients with Legionnaires disease. Mycoplasma pneumoniae PCR was positive in eight of the nine patients with mycoplasma infection. Chlamydia pneumoniae PCR was positive in the two patients with C. pneumoniae infection. None of the other 138 patients with negative PCR had other positive confirmatory tests for respiratory infection by these three organisms (100% specificity). PCR was able to detect 15 of the 17 infected (88.2%). Results of this investigation indicate that PCR on a single throat swab specimen is a rapid, sensitive, and specific test that may greatly simplify the diagnosis of lower respiratory infection caused by Legionella spp., Mycoplasma pneumoniae, or C. pneumoniae.     

Influenza vaccination for children with asthma

QUESTION Parents of children with asthma are encouraged by many health organizations to vaccinate their children against seasonal influenza viruses. Is the influenza vaccine efficient in preventing asthma exacerbation? Are current vaccinations safe to administer to children with asthma?ANSWER Infection with influenza viruses can cause substantial respiratory morbidity in children with underlying chronic disease such as asthma. Although vaccination against influenza does not reduce or shorten asthma exacerbations, the intramuscular trivalent vaccine is safe and has a beneficial effect on the quality of life of children with asthma.     

Understanding the mechanisms of viral induced asthma: new therapeutic directions

Asthma is a common and debilitating disease that has substantially increased in prevalence in Western Societies in the last 2 decades. Respiratory tract infections by respiratory syncytial virus (RSV) and rhinovirus (RV) are widely implicated as common causes of the induction and exacerbation of asthma. These infections in early life are associated with the induction of wheeze that may progress to the development of asthma. Infections may also promote airway inflammation and enhance T helper type 2 lymphocyte (Th2 cell) responses that result in exacerbations of established asthma. The mechanisms of how RSV and RV induce and exacerbate asthma are currently being elucidated by clinical studies, in vitro work with human cells and animal models of disease. This research has led to many potential therapeutic strategies and, although none are yet part of clinical practise, they show much promise for the prevention and treatment of viral disease and subsequent asthma.     

Inflammatory and bronchospastic factors in asthma exacerbations caused by upper respiratory tract infections

It is still uncertain how viral respiratory infections cause acute exacerbations of bronchial asthma, although several mechanisms have been proposed. We studied the relationship between the airway narrowing and the inflammatory and bronchospastic factors in peripheral venous blood and urine, in 30 patients with asthma at the exacerbations caused by upper respiratory tract infections (URTIs). Acute exacerbations caused decreases in peak expiratory flow rate (PEFR) in all 30 patients with asthma. Asthma exacerbations caused the rises in serum levels of interleukin-6, soluble intercellular adhesion molecule-1 and eosinophil cationic protein, concentrations of urinary leukotriene E4 and plasma histamine, compared with those in patients with asthma at a stable condition and those in 30 control subjects (p < 0.05). The values of PEFR at the exacerbations correlated with the levels of these factors. Treatment with oral glucocorticoids reversed the decreases in PEFR and the increases in these factors. At the onset of URTIs, rhinovirus and influenza type A virus were identified in 13 and 7 patients, respectively. Each of parainfluenza virus, adenovirus, and enterovirus was identified in one patient. These findings suggest that respiratory viral infections may cause acute asthma exacerbations via the production of mediators that induce inflammation and bronchospasm.