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Seroepidemiologic studies have provided information on the association of Chlamydia pneumoniae with the classical risk factors of coronary heart disease (CHD). C. pneumoniae infections are more common in smokers than in nonsmokers, suggesting that smoking predisposes to the development of chronic infection. Infections may also affect lipid metabolism. In persons with acute pneumonia caused by C. pneumoniae, high-density lipoprotein (HDL) values are lower and triglyceride values higher than seen in pneumonia caused by viruses and other bacteria. Furthermore, chronic C. pneumoniae infection is associated with elevated triglyceride and lowered HDL levels in healthy Finnish men. Recent studies also suggest that chronic C. pneumoniae infection considerably enhances the effect of the metabolic syndrome on the CHD risk. Thus, known CHD risk factors may be partly explained by their association with chronic C. pneumoniae infection. Further studies are needed to elucidate the pathogenetic mechanisms underlying these associations.
BACKGROUND: Childhood community-acquired pneumonia is a common illness, but there have been relatively few comprehensive studies of the viral and bacterial etiology in developed countries. The aim of the present investigation was to determine the etiology of community-acquired pneumonia in hospitalized children by several laboratory methods. METHODS: In a 3-year prospective study a nasopharyngeal aspirate for viral studies and acute and convalescent serum samples for viral and bacterial serology were taken from 254 children with symptoms of acute infection and infiltrates compatible with pneumonia in the chest radiograph. The role of 17 microbes was investigated. RESULTS: A potential causative agent was detected in 215 (85%) of the 254 patients. Sixty-two percent of the patients had viral infection, 53% had bacterial infection and 30% had evidence of concomitant viral-bacterial infection. Streptococcus pneumoniae (37%), respiratory syncytial virus (29%) and rhinovirus (24%) were the most common agents associated with community-acquired pneumonia. Only one patient had a positive blood culture (S. pneumoniae) of 125 cultured. A dual viral infection was detected in 35 patients, and a dual bacterial infection was detected in 19 patients. CONCLUSIONS: The possible causative agent of childhood community-acquired pneumonia can be detected in most cases. Further studies are warranted to determine what etiologic investigations would aid in the management of pneumonia. With effective immunization for S. pneumoniae and respiratory syncytial virus infections, more than one-half of the pneumonia cases in this study could have been prevented.
OBJECTIVE: Serum procalcitonin (PCT), C-reactive protein (CRP) and interleukin-6 (IL-6) concentrations were measured in 126 children hospitalized for community-acquired, radiologically confirmed pneumonia to assess whether these host response values could be used to distinguish bacterial from viral pneumonia. METHODS: The samples for PCT, CRP and IL-6 measurements were obtained on admission or the first day of hospitalization. The etiology of pneumonia was studied with an extensive panel of methods that detected 6 bacteria and 11 viruses. RESULTS: In all, 54% had evidence of bacterial pneumonia, and 32% had evidence of sole viral pneumonia. In 14% of the cases the etiology could not be determined. Children with bacterial pneumonia had significantly higher PCT (median 2.09 ng/ml vs. 0.56 ng/ml, P = 0.019) and CRP concentrations (96 mg/l vs. 54 mg/l, P = 0.008) than those with sole viral etiology. However, the values markedly overlapped. No significant difference in IL-6 concentrations was seen between the two patient groups. Using PCT > or = 2.0 ng/ml, CRP > or = 150 mg/l or IL-6 > or = 40 pg/ml, the specificity was > or =80% for bacterial pneumonia. The sensitivities with these cutoff values were 50% for PCT, 31% for CRP and 34% for IL-6. CONCLUSIONS: The results indicate that the measurement of serum PCT, CRP and IL-6 has little value in the differentiation of bacterial and viral pneumonia in children. However, in some patients with very high serum PCT, CRP or IL-6 values, bacterial pneumonia is probable.
The efficacy of pneumococcal vaccines in protecting against pneumococcal pneumonia can feasibly be measured only with a diagnostic technique that has a high specificity (0.98 to 1.00) and a sensitivity greatly exceeding that of blood cultures (>0.2 to 0.3). In this context immune-complex enzyme immunoassays (EIAs) offer a novel, convenient diagnostic method, and we have investigated three such assays with appropriate study populations in Kenya. Sera from 129 Kenyan adults with pneumococcal pneumonia and 97 ill controls from the same clinics, but without pneumococcal disease syndromes, were assayed with immune-complex EIAs for pneumolysin, C-polysaccharide, and mixed capsular polysaccharides (Pneumovax II). At an optical density (OD) threshold yielding a specificity of 0.95, the sensitivities (95% confidence intervals) of the assays were 0.22 (0.15 to 0.30), 0.26 (0.19 to 0.34), and 0.22 (0.15 to 0.29), respectively. For pneumolysin immune complexes, human immunodeficiency virus (HIV)-positive patients had a higher mean OD than HIV-negative patients (639 versus 321; P < 0.0001), but stratification by HIV infection status did not alter the performance of this test. Combining the results of all three EIAs did not enhance the diagnostic performances of the individual assays. In Kenyan adults the sensitivities of the immune-complex EIAs could exceed that of blood cultures only at levels of specificity that were insufficient for the performance of vaccine efficacy studies.
The characteristics of nine children with community acquired pneumonia with evidence of Streptococcus pneumoniae and Mycoplasma pneumoniae coinfection are described.
BACKGROUND AND OBJECTIVES: An equivalence study was conducted in which the efficacy and safety of a daily dose of 800 microgram of beclomethasone diproprionate administered via a multidose powder inhaler, Easyhaler, and via a metered-dose inhaler (MDI) with a large-volume spacer were compared in adult, newly diagnosed, steroid-naive asthmatic patients. Acceptability of the medications was also compared. METHODS: One hundred and forty-four patients were recruited into the double-blind, double-dummy, randomised, parallel-group multicentre study. The study treatment period was 8 weeks. It was preceded by a 2-week run-in period. Morning and evening peak expiratory flow (PEF), numbers of inhalations of a sympathomimetic and asthma symptoms were recorded daily. Spirometry and histamine challenge were performed, and health-related quality of life and morning serum cortisol levels measured during control visits. RESULTS: Criteria indicating treatment equivalence were met. The mean of the primary outcome variable, morning PEF, increased significantly, from 426 to 461 litres/min in the Easyhaler group and from 436 to 467 litres/min in the MDI+spacer group. Similar improvements between groups were also seen in relation to all secondary variables. Changes in serum cortisol levels were minor. In 6 out of 10 questions about device acceptability, the majority of patients rated Easyhaler as better than the MDI+spacer combination. CONCLUSION: It was concluded that the devices tested were equivalent in terms of efficacy and safety.
Xylitol possesses anti-bacterial effects on pneumococci in vitro. To study the effect in vivo, the nostrils of 80 rats were inoculated with pneumococci. Intervention groups (n = 20) received either a xylitol diet or xylitol nasal sprays. The control groups were on a normal diet or had saline sprays. After 3 days, a quantitative bacterial culture and a PCR were done from the mucosal suspension. Neither the mean colony-forming unit counts nor the PCR counts differed statistically significant between the xylitol and control groups. Thus, we found that xylitol had no significant effect on pneumococcal mucosal colonisation.
The effectiveness of simultaneously administered influenza and pneumococcal vaccines vs. influenza vaccine alone in preventing pneumonia, pneumococcal pneumonia and pneumococcal bacteraemia among the elderly was studied. The vaccines were offered to all persons aged 65 years or older (N=43,500) living in 35 administrative districts in Northern Finland. A total of 26,925 persons (62%) decided to participate. Allocation to the vaccination groups took place by year of birth (odd/even). The total follow-up of those vaccinated consisted of 38,037 person years. The incremental effectiveness of the pneumococcal vaccine was -20 (95% CI -50- + 10%) for pneumonia, -20 (95% CI -90- + 20%) for pneumococcal pneumonia and + 60% (95% CI -40- +90%) for pneumococcal bacteraemia. Thus the pneumococcal polysaccharide vaccine did not offer any additional protection from pneumonia among elderly people in Finland although it reduced the incidence of bacteraemia.
BACKGROUND: Seroepidemiologic studies have provided information on the interaction of Chlamydia pneumoniae with other known risk factors of coronary heart disease. C pneumoniae infection appears to be more common in smokers than in nonsmokers, suggesting that smoking predisposes to the development of chronic C pneumoniae infection. METHODS AND RESULTS: In identical twins, C pneumoniae-specific immunoglobulin A levels were found to be higher and cell-mediated immunity, measured as a lymphoproliferation response, lower in smoking twins than in their nonsmoking counterparts, suggesting that chronic C pneumoniae infections are common in smokers whose cell-mediated protective immunity appears to be lowered. Infections also may have an effect on lipid metabolism. Thus even in acute pneumonia caused by C pneumoniae, high-density lipoprotein (HDL) values are lower and triglyceride values higher than in pneumonia caused by viruses and other bacteria. Furthermore, chronic C pneumoniae infection has been associated with elevated triglyceride and lowered HDL levels in otherwise healthy Finnish men. We also have explored the combined effect of chronic C pneumoniae infection and markers of the metabolic syndrome (elevated body mass index, blood glucose and systolic blood pressure, and lowered HDL cholesterol) on the risk of cardiac events. The results suggest that chronic C pneumoniae infection enhances the effect of the metabolic syndrome on the risk of coronary heart disease. CONCLUSIONS: The known risk factors of coronary heart disease may be explained partly by their interaction with chronic C pneumoniae infection. Further studies are needed to elucidate the pathogenetic mechanisms underlying these interactions.
Helicobacter pylori causes a chronic gastric infection, which has been associated with coronary heart disease. To evaluate the mechanisms of this association, we studied whether the infection affects serum lipid levels as previously shown in acute infections. We analysed the serum samples of 880 males who participated in a reindeer herders' health survey in Northern Finland in 1989. H. pylori IgG and IgA antibodies were measured by enzyme-linked immunosorbent assay and triglyceride, total cholesterol and high-density lipoprotein cholesterol concentrations by routine enzymatic methods. A total of 52% of the subjects were positive for both H. pylori specific IgG and IgA and 31% were antibody-negative. The serum triglyceride and total cholesterol concentrations were significantly higher in the males with positive IgG and IgA antibody titres for H. pylori than in the males with no signs of infection (1.20 vs. 1.03 mmol/l, P < 0.001 and 6.59 vs. 6.11 mmol/l, P < 0.001, respectively). The associations remained statistically significant in non-smokers after the adjustment for age, body mass index (BMI) and social class. The finding supports the hypothesis that chronic infections may modify the serum lipid profile in a way that increases the risk of atherosclerosis.
BACKGROUND: Factors involved in the development of inflammation and asthma in nonatopic subjects have remained largely obscure, although there is some evidence to suggest that certain infections may play a role. OBJECTIVE: We investigated the association between serological evidence of Chlamydia pneumoniae infection and asthma in adults, and the possible modifying effect of the patients' atopic status on this association. METHODS: Four hundred and thirty consecutive patients who attended the hospital between 1992 and 1993 with symptoms suggestive of asthma, rhinitis or allergy were enrolled. Diagnostic procedures including lung function measurements and skin-prick tests were performed in all patients. The patients with established asthma (n = 332) were divided into those with recent asthma (n = 224, onset 1985 onward) and longstanding asthma (n = 108, onset before 1985). The controls (n = 98) comprised all subjects who did not meet the criteria of asthma. Serum immunoglobulin (Ig)G, IgA and IgM antibodies to C. pneumoniae were measured by the microimmunofluorescence test. RESULTS: In women, the prevalences of elevated IgG (a titre of >/= 128) and IgA (>/= 32) antibody levels and the age-adjusted geometric mean titres (GMT) of IgG and IgA antibodies were invariably highest among subjects with nonatopic longstanding asthma. Elevated IgG titres in women occurred in 11% of controls, in 28% of nonatopic recent onset asthmatics, and in 43% of asthmatics with nonatopic longstanding disease; for men the respective figures were 33, 50 and 64%. Logistic regression analysis controlling for age, sex and smoking showed that asthma was significantly associated with elevated IgG antibody levels to C. pneumoniae (odds ratio 3.3, 1.6-6.8 for longstanding asthma, 2.3, 1. 2-4.4 for recent asthma, and among women only 4.2, 1.6-10.9 for longstanding asthma, and 3.0, 1.3-7.2 for recent asthma). When the atopics and nonatopics were analysed separately, an even stronger relationship in the nonatopics was obtained for longstanding asthma (6.0,2.1-17.1). In contrast, the relationship between atopic asthma, either recent or longstanding, and elevated IgG titres was not significant, indicating that asthma per se does not predispose to C. pneumoniae infection. CONCLUSIONS: Asthma was significantly associated with elevated IgG antibody levels to C. pneumoniae, and this association was strongest for nonatopic longstanding asthma.
In searching for suitable methods for aetiological diagnosis of pneumococcal disease we determined capsular polysaccharide, C-polysaccharide and pneumolysin antibodies bound in immune complexes (IC) in Filipino children. Sera were obtained from 150 healthy infants (all under 12 months old) and from 350 paediatric patients (mean age 18 months) hospitalized with severe pneumonia. The findings in healthy children were not associated with age, sex or pneumococcal carrier status; 3-7% exceeded the cut-off limits for positivity in different antibody assays. By contrast, 97 (51%) of the 190 patients with a complete 3-sample series exceeded the cut-off limit for IC-bound pneumolysin-IgG in at least 1 of the serum samples studied. Positivity rates for IC-bound pneumolysin-IgG in the admission day, in-patient and convalescent sample of the 350 patients were 25%, 25% and 34%. Pneumolysin-IgM, capsular polysaccharide and C-polysaccharide antibodies in the IC were positive in only 4-6% of the patients' samples. IC-bound pneumolysin-IgG antibody assay seem to be a useful method for species-specific diagnosis of pneumococcal infections.
OBJECTIVES: To determine the etiology of community-acquired pneumonia in ambulatory children and to compare responses to treatment with azithromycin, amoxicillin-clavulanate or erythromycin estolate. METHODS: Ambulatory patients with pneumonia were identified at the Children's Medical Center of Dallas, TX. Children age 6 months to 16 years with radiographic and clinical evidence of pneumonia were enrolled and randomized to receive either azithromycin suspension for 5 days or a 10-day course of amoxicillin-clavulanate for those <5 years or erythromycin estolate suspension for those > or = 5 years. Blood culture was obtained in all patients and we obtained nasopharyngeal and pharyngeal swabs for culture and polymerase chain reaction (PCR) testing for Chlamydia pneumoniae and Mycoplasma pneumoniae and nasopharyngeal swabs for viral direct fluorescent antibody and culture. Acute and convalescent serum specimens were tested for antibodies to C. pneumoniae, M. pneumoniae and Streptococcus pneumoniae. Patients were evaluated 10 to 37 days later when repeat specimens for serology, PCR and culture were obtained. For comparative purposes healthy children attending the well-child clinic had nasopharyngeal and pharyngeal swabs obtained for PCR and culture for C. pneumoniae and M. pneumoniae. RESULTS: Between February, 1996, and December, 1997, we enrolled 174 patients, 168 of whom fulfilled protocol criteria for evaluation. There were 55% males and 63% were <5 years of age. All blood cultures were sterile and there was no correlation between the white blood cell and differential counts and etiology of pneumonia. Etiologic agents were identified in 73 (43%) of 168 patients. Infection was attributed to M. pneumoniae in 7% (12 of 168), C. pneumoniae in 6% (10 of 168), S. pneumoniae in 27% (35 of 129) and viruses in 20% (31 of 157). None of the swab specimens from 75 healthy control children was positive for C. pneumoniae or M. pneumoniae. Clinical response to therapy was similar for the three antibiotic regimens evaluated, including those with infection attributed to bacterial agents. CONCLUSION: Although a possible microbial etiology was identified in 43% of the evaluable patients, clinical findings and results of blood cultures, chest radiographs and white blood cell and differential counts did not distinguish patients with a defined etiology from those without a known cause for pneumonia. There were no differences in the clinical responses of patients to the antimicrobial regimens studied.
BACKGROUND: Aboriginal children in central Australia have attack rates for acute lower respiratory tract infection (ALRI) that are similar to those in developing countries. Although mortality rates are much lower than in developing countries, morbidity is high and ALRI is still the leading cause of hospitalization. However, there are no data on the etiology of ALRI in this population. METHODS: We prospectively studied 322 cases of ALRI in 280 Aboriginal children admitted to the hospital. Blood, urine and nasopharyngeal aspirate samples were examined for evidence of bacterial, viral and chlamydial infection. RESULTS: The combination of blood culture, viral studies and chlamydial serology provided at least 1 etiologic agent in 170 of 322 (52.5%) cases. Assays for pneumolysin immune complex and pneumolysin antibody increased etiologic diagnosis to 219 (68.0%). Blood cultures were positive in 6% but pneumolysin immune complex and pneumolysin antibody studies were positive in one-third of cases. Evidence of viral infection was present in 155 (48%) of cases compared with 12% in controls (P < 001). There were only 7 possible cases and 2 definite cases of Chlamydia trachomatis and 3 cases of Chlamydia pneumoniae. Coinfection was common in these children. CONCLUSION: These findings have implications for both standard treatment protocols and vaccine strategies. The high rate of coinfection may make it difficult to develop simple clinical predictors of bacterial infection. In the setting of a developed country with efficient patient evacuation services, management algorithms that focus on disease severity and need for hospital referral will be most useful to health staff in remote communities. Pneumococcal conjugate vaccines will be required to reduce the high attack rate of pneumococcal disease.
BACKGROUND: Moraxella catarrhalis is an important cause of bacterial otitis media, and a vaccine to prevent this disease would be highly desirable. Analysis of the dominant antigens on the surface of M. catarrhalis recognized by the human immune response to infection might aid in such a search. Such analysis would be most informative when studied in the eventual target age group for the vaccine; thus we have studied the immune response to M. catarrhalis in infants with otitis media. METHODS: Eighteen infants (mean age, 9.4 months) experiencing an episode of otitis media caused by M. catarrhalis were studied. Acute and convalescent antibody responses were studied by whole cell enzyme-linked immunosorbent assay (heterologous strain) and by immunoblotting of outer membrane proteins (OMPs). RESULTS: Specific IgG was detected in 17% of acute serum samples and in 61% of convalescent sera. A rise in specific IgG was detected in 10 of 12 (83%) children 8 months of age or older, compared with 1 of 6 (17%) in younger patients (P = 0.0128). Immunoblotting revealed antibody binding to several OMPs with some detectable cross-reactivity. Four dominant OMP targets were identified, corresponding to UspA, TbpB, CopB and a approximately 60-kDa protein. CONCLUSIONS: A combination of antigens might form the most suitable basis for a M. catarrhalis vaccine designed to prevent otitis media in this age group.
Whole blood, purified leukocyte fraction and serum were investigated as specimens for the detection of pneumococcal bacteremia by polymerase chain reaction (PCR) in mice. The PCR findings were compared to the blood culture results. Samples were taken from animals 3 and 12 h after intraperitoneal bacterial challenge. The pneumococcal culture was positive in 27% and 77% of blood samples at 3 and 12 h after challenge, respectively. All whole blood samples were positive by PCR at both time points. Of the buffy coat samples, two of the three pools were PCR-positive at 3 h and all pools at 12 h after bacterial challenge. In the serum sample group, only 40% of the sera were PCR-positive at 3 h, while at 12 h 90% of the samples were PCR-positive. According to these results, whole blood seems to be the best specimen for the detection of pneumococcal DNA by PCR in bacteremic mice.
Blood-based pneumolysin PCR was compared to blood culture and detection of pneumolysin immune complexes, as well as to detection of antibodies to pneumolysin and to C polysaccharide, in the diagnosis of pneumococcal infection in 75 febrile children. Invasive pneumococcal infection was suspected on clinical grounds in 67 of the febrile children, and viral infection was suspected on clinical grounds in 8 of the febrile children. In addition, 15 healthy persons were examined to test the specificity of the PCR assay. Plasma, serum, and leukocyte fractions were analyzed by PCR. The combination of all test results led to the diagnosis of pneumococcal infection in 25 patients. Pneumolysin PCR was positive in 44% of these children, an increase occurred in the pneumolysin antibodies in 39% and in the C polysaccharide antibodies in 30% of the patients; pneumolysin immune complexes were found in convalescent serum in 30%, pneumolysin immune complexes occurred in acute-phase serum samples in 16%, and a positive blood culture was found in 20% of the patients. None of the healthy controls had positive results by PCR. The results suggest that the diagnosis of Streptococcus pneumoniae infection from blood samples necessitates the use of several different assays. Pneumolysin PCR was the most sensitive assay, but its clinical value is reduced by the fact that three blood fractions are needed.